ESR

Type 1 diabetes complications

Dehydration hyperglycemic and hypoglycemic coma diabetic ketoacidosis

What are the effects of castration on the male genital system if performed (i) before puberty (ii) in the adult?

(i) Failure to develop secondary sex characteristics (eg beard, pubic hair, low voice, etc); failure to develop accessory glands. (ii) Atrophy of accessory glands.

What tissues form the erectile tissue of the penis? Which nerves innervate it?

"Spongework" consisting of a network of endothelial lined vascular sinuses (irregular blood channels) surrounded by connective tissue and strands of smooth muscle. Sensory and autonomic innervation.

list the symptoms of hypercalcaemia

"Stones, Bones, Groans, Thrones and Psychiatric Overtones" • Stones (renal or biliary) Since these calcium-phosphate complexes may move down the ureter, hypercalcaemia is also associated with blood in the urine (haematuria) and recurrent renal tract infections (pyelonephritis). • Bones (bone pain) • Groans (abdominal pain, nausea and vomiting) • Thrones (polyuria) • Psychiatric overtones (depression, anxiety, cognitive dysfunction, insomnia, coma) • The neuromuscular symptoms of hypercalcemia are caused by calcium blocking sodium channels which inhibits depolarization of nerve and muscle fibers • Hypercalcemia decreases heart rate but increases contractility which can show up as a short QT interval on ECG • Increase gastrin production may raise acidity and lead to peptic ulcers

recognise a section through the ovary (cat)

(Cats have several Graafian follicles that rupture) Very low power view of longitudinal section of mature ovary (cat); non-pregnant (toluidine blue stain?). The human ovary is considerably larger, measuring about 1 x 2 x 3 cm. At low magnification, many follicles can be seen at various stages of development. The 'services' for the ovary are carried in through the hilum to the broad ligament which is not shown in this image. Large numbers of primordial (arrested at the first meiosis division) and primary follicles are located in the cortex, close to the outer epithelium. At least 30 secondary follicles at various stages of development are visible, some of which include the oocyte in the plane of section; the largest, most mature follicles lie near the surface of the ovary as they approach ovulation. There are no corpora albicantes in this ovary (although there are a few atretic follicles): this finding, plus the numerous cortical oocytes gives an indication of the age of the animal. What would you suggest?

Adrenomedullary Hypofunction

(Rare) Failure to synthesise and/or secrete catecholamines results in hypotension and hypoglycaemia After adrenalectomy / destruction of medulla, no need to replace epinephrine - corticosteroid replacement sufficient

Thiazide diuretics and diabetes

(Thiazide diuretics eg. Bendroflumethiazide are commonly used in hypertension as they can cause vasodilatation through an unknown mechanism) Thiazide diuretics like metolazone are used in heart failure to block the Na-Cl cotransporter on the distal tubule to increase NaCl excretion, water goes with it. Thiazide diuretics induce hypokalaemia, which opens the ATP sensitive K+ channel in the beta cells as K+ effluxes. Insulin is not release

Name the four main components of the male reproductive system and their functions. Name the epithelium lining each.

(a) Testes - gonads: produce sperm; testosterone; two testes containing numerous highly coiled seminiferous tubules lined with stratified germinal epithelium. (b) Genital tract: modification of testicular secretions; storage; expulsion. Ducts connecting testes to urethra; for each testis - efferent ducts, the ductus epidydimis, and the ductus (vas) deferens; function - modification, collection, storage and conduction of spermatozoa; pseudostratified columnar epithelium with long microvilli (stereocilia). (c) Accessory (exocrine glands) glands: fluid components of semen; paired seminal vesicles and a single prostate gland; function - secretion of nutritive seminal fluid; simple columnar/cuboidal secretory epithelium (or pseudostratified) in seminal vesicles and prostate; also, bulbo-urethral glands - mucous secretion, lubrication. (d) Penis: ejaculation of semen into female genital tract; pseudostratified columnar epithelium.

Which hormones secreted by the pituitary influence (i) interstitial cells; (ii) the process of spermatogenesis?

(i) LH stimulates interstitial cells to produce testosterone. (ii) FSH controls secretion of androgen binding protein by Sertoli cells, allowing concentration of testosterone within the seminiferous tubules and sperm maturation.

Uterine tubes

(oviducts, Fallopian tubes) - conduct ova towards uterus, fertilisation occurs along tube simple cuboidal / columnar epithelium of ciliated cells and secretory cells

ACTH hypersecretion

- From pituitary corticotrophs = Cushing's disease - Ectopic - From small cell lung tumours outside normal negative feedback loop.

Anovulation: Hypothalamus level

- Hypogonadotropic hypogonadism - Idiopathic - Stress/Exercise/Anorexia - Kallman's syndrome (no neuronal migration or production of GnRH)

GWAS studies identify 'obesity genes'

- MC4R Melanocortin receptor 4; mutations in ~5% of obese population - FTO Fat mass and obesity-associated protein; 16% of Europeans show 'risk' variant

Anovulation: Ovary level

- PCOS - Gonadal dysgenesis/agenesis - 45,X (Turner) - Mosaics - 47,XXX - 46,XX (Perault syndrome) - 46,XY (Swyer's syndrome) - Resistant ovary syndrome - Premature ovarian failure - Idiopathic - Secondary to treatment like chemotherapy

Anovulation: Anterior pituitary level

- Pituitary tumour - Prolactin (50%) - ACTH - TSH secreting - Nonfunctioning - Sheehan's syndrome - Hypothyroidism

Main conclusions:

- Utilising neurotransmitters or their receptors as target for weight-loss drugs is difficult because of side effects - The amount of weight-loss achieved due to pharmaceutical intervention is usually small - The placebo effect is significant - Currently gastric bypass is the most effective procedure to achieve sustained, substantial weight-loss - However, maintained calorie-restricted diet achieves the same - Targeting circulating factors involved in appetite control might mimic some of the effects of bariatric surgery - GLP-1 mimetics are currently the most effective option - Development of non-peptide (oral) GLP-1R agonists would be useful - The field is rapidly evolving with combination treatments However, all interventions must be combined with sustained life-style changes (increased exercise + calorie balanced diet) to achieve and maintain a healthy weight (and life)

Progestogen uses

- antagonist used in contraception (± oestrogen) - Menopausal Hormone Therapy (+ oestrogen)

AgRP (Agouti-related peptide):

- co-localises with NPY and is an antagonist of the melanocortin system Disruption of AgRP synthesis reduces body weight and increases metabolism but does not affect food intake.

Oestrogen uses

- contraception (+ progestogen) - Menopausal Hormone Therapy (± progestogen)

GnRH Antagonists- ganirelix

- ovulation induction + gonadotropins, for ART) - prostate cancer

Combined Hormonal Contraceptive Adverse Effects

- small ↑risk of cervical cancer - small ↑risk of breast cancer (but people who have never used = past users) (↓ risk of ovarian, endometrial and colorectal cancer) - small ↑ risk of venous thromboembolic disease - small ↑ risk of stroke and myocardial infarction

Vitamin D effect on Ca2+ concentration

1,25-dihydroxycholecalciferol increases absorption of calcium from the intestine. It also promotes bone breakdown by osteoclasts. Calcitriol also suppresses the synthesis and secretion of PTH and limits parathyroid cell growth.

Type 1 diabetes treatment with insulin

1-3 insulin injections/day of the same insulin Multiple daily injections (4-5) with different insulins Continuous subcutaneous insulin infusion ('pump') (Peptide hormones orally would just be digested)

Epidermal Growth Factor Receptor (MAPK pathway)

1. Binding of EGF to each EGFR monomer induces a structural change that allows the monomers to dimerize. Proximity of the cytosolic domains allows cross-phosphorylation. 2. Tyrosine-phosphates act as docking sites for Grb-2, which is attached to Sos. Sos is a guanine nucleotide exchange factor (GEF) it only catalyses when it has been recruited to the membrane via Grb-2. 3.Sos catalyses the exchange of GDP for GTP on membrane-bound Ras, activating it. Ras is a small G-protein. Unlike the heterotrimeric G-proteins, Ras is monomeric. Ras also has a slower GTPase activity (0.02 per min vs ~3 per min) than heterotrimeric G-proteins. The GTPase activity can be increased ~10^5-fold by GAPs (GTPase activating proteins). 4.GTP:Ras binds and activates Raf, a membrane-bound protein kinase. 5.A series of protein kinases such as MAPK are phosphorylated and activated, resulting in the phosphorylation of several transcription factors, altering their activity.

Describe the PI-3 kinase pathway as stimulated by insulin

1. Binding of insulin to the dimeric receptor forces the PTK domains together, followed by cross-phosphorylation. This fully activates the kinase activity, and is followed by more cross-phosphorylation. 2. These phosphorylated tyrosine residues act as docking sites for IRS-1 (insulin receptor substrate 1), which gets phosphorylated. Insulin receptor substrate-1 is phosphorylated on several tyrosine residues. It is already associated with the membrane due to its PH domain, which can bind PIP2. Once phosphorylated, it can dissociate from the insulin receptor.. 3. Phosphorylated IRS-1 can bind PI-3K (phosphoinositide-3 kinase), which, now located at the membrane, phosphorylates PIP2 at position 3, forming PIP3 (phosphatidylinositol-3,4,5 trisphosphate). 5. PIP3 allows both PDK1 (phosphoinositide-dependent kinase-1) and PKB (protein kinase B) to associate with the membrane via their PH (pleckstrin homology) domains. 6. Phosphorylated PKB dissociates from the membrane and phosphorylates its target proteins.

Human uterus, menstrual Ai: stratum compactum

1. Blood vessel 2. Lymphocyte (nucleated cell in a blood vessel) 3. Lumen of the uterine glands 4. 5. Lumen of the uterus

Human testis, adult: high power, iron haematoxylin and eosin

1. Nucleus of smooth muscle in the musculofibrous capsule 2. Cytoplasm of musculofibrous capsule cells 4. Type B spermatogonia 4. Collagen or reticular fibres in ECM 5. Spermatid 6. Sertoli cell 7. Spermatozoa 8. Primary spermatocyte 9. Type A spermatogonia 10. Leydig cells

Combined Hormonal Contraceptive mechanisms of action

1. Oestrogen: reduced FSH release - follicle fails to develop and mature - no endogenous Oestrogen surge 2. Progestogen: - Inhibition of LH surge => no ovulation - cervical mucus unfavourable for fertilization 3. Oestrogen + Progestogen: - abnormal endometrial development => conditions unfavourable for implantation

Seminal vesicles Aii

1. Smooth muscle wall of an artery or arteriolar 2. Smooth muscle 3. Arteriole? 4. Nucleus of a Schwann cell from a nerve bundle 5. Capillary 6. Lymphocyte (uncleared blood cell) 7. Nucleus of an endothelial cell

Human vaginal cervix A

1. Stratified squamous epithelium continuous with the vagina 2. Simply columnar epithelium 3. Epithelium of a cervical mucous gland (behind the stratified squamous epithelium) 4. Endothelial cells of an arteriole

Immunoassays: Special qualities

1. Very sensitive • can detect picomolar concentrations (10^-12 M) • due to the high affinities of antibodies for antigens • need only small quantities of serum e.g. 10μL 2. Highly hormonally specific • can distinguish between T3 and T4 and between different steroids • due to the high specificity of antigen recognition 3. Very precise • simple steps with micropipettes and responses measured with instruments capable of highly reproducible signal measurements e.g. radioactivity counters, spectrophotometers 4. High sample throughputs simple steps with specially designed equipment e.g. microtitre plates for ELISAs, with 96 Optical Densities being read in 20 seconds. 5. CHEAP • inexpensive reagents used at high dilutions • very profitable to run for e.g. a private pathology service 6. Highly developed Quality Control Systems in e.g. the UK • Nationwide basis (NEQAS) • monthly checks on all immunoassay labs • T4 measured across the UK with as little as 10% variance across the country.

Progestogen only: Mechanisms of action

1. cervical mucus unfavourable for fertilization low volume high viscocity 2. endometrium unsuitable for implantation, no endometrial proliferative phase 3. in some preparations: inhibition of LH surge => no ovulation needs to have high enough progesterone Must be taken every day, no hormone free period like the combined pill Adverse: irregular bleeding reversible bone resorption?

Progestogen actions

1. feedback action Lower frequency of GnRH pulses, lower FSH & LH release 2. cyclical effects on uterus. Progesterone opposes the oestrogen driven proliferation of the endometrium - endometrial secretory phase for fertilisation - implantation-favouring cervical secretion (↓volume, ↑viscosity) 3. in pregnancy: development of uterus and breast suppression of contractility in uterus

Oestrogen actions

1. female development 2. feedback action Lower LH & FSH release (low [oestrogen]), increase LH (&FSH) release (high [oestrogen]) 3. cyclical effects on uterus - endometrial proliferative phase (including ↑expression of Progesterone R) - fertilization-favouring cervical secretion (↑volume, ↓viscosity) 5. metabolic - anabolic - retention of salt and water 6. cardiovascular - maintain normal vascular function - ↑ coagulability of blood - ↑HDL and ↓LDL & cholesterol 7. reduce bone resorption

Management Of Patients With Growth Disorders

1.Clinical observation •Patient history: rule out multiple non-endocrine causes eg respiratory/ cardiac/ renal problems •Appearance: proportionate growth? •Anthropometric measurements: growth velocity/ bone age/ pubertal stages etc Measure serum GH: by immunoassay Need 0.5 ml blood Send to Chemical Pathology for immunoassay

Boys and girls - pubic hair stages:

1.Prepubertal (can see velus hair similar to abdominal wall) 2.Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia 3.Darker, coarser and more curled hair, spreading sparsely over junction of pubes 4.Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs 5.Adult in type and quantity.

define the main roles for 11 HSD in the liver

11b-HSD in the Liver, lung, fat, gonad, pituitary is mostly Type 1 11bHSD Type 1 can re-activate glucocorticoids for actions at the MR Overexpression, especially in fat, can lead to symptoms similar to "Metabolic syndrome" and apparent glucocorticoid excess

Cortisone

11βHSD in the liver In aldosterone target cells (kidney, colon & parotid gland) and in placenta, 11βHSD oxidation of cortisol to cortisone. Basis for anti-inflammatory action of oral cortisone and methylprednisone (vs. lack of action of 11-keto- steroids when bypass the liver).

Oestrogens are synthesized from Androgens

17,20 lyase is upregulated by LH in the theca. This is important for producing androgens Aromatase in the granulosa is invovled in the final step of oestrogen synthesis from androgens

Prader-Willi Syndrome

2.4 Prader-Willi syndrome is a genetic disorder caused by an abnormality of chromosome 15. Common clinical characteristics include hypogonadism, short stature, hypotonia, dysmorphic features, hypoventilation, changes in body composition, obesity and obesity‑related diseases, and behavioural problems. Prader-Willi syndrome occurs in between 1 in 15,000 and 1 in 25,000 live births. Men with Prader-Willi syndrome have a final adult height of about 154 cm; women have a final adult height of 145-159 cm.

outline the structure of insulin

21 amino-acid α-chain and 30 amino-acid β-chain joined by two disulphide bonds. subtle differences elicit immune responses in a proportion of patients; the most appropriate mammalian source of insulin for clinical use is porcine insulin since this differs in only a single amino-acid residue (position 30 of the β-chain) between human and porcine insulin.

What treatments does someone with 21 hydroxylase deficient CAH require?

21 hydroxylase converts progesterone into deoxycorticosterone DOC which would converts into corticosterone then aldosterone in the zona glomerulosa. It also converts 17-alpha-hydroxyprogesterone into 11-deoxycortisol which converts into cortisol The pathway gets pushed into the one that produces DHEA. They would require an aldosterone and cortisol replacement and androgen suppression in females.

Pulsatile secretion pattern of GH

24 hr profile, taking blood samples every 20 mins major peaks during sleep stages 3/4 delayed sleep/ delayed rise in GH cannot interpret a single random sample 24 hr profile inconvenient for patient and lab

Multiple Endocrine Neoplasia Type 2

2A- extracellular domain of RET Parathyroid hyperplasia Medullary thyroid carcinoma Pheo-chromo-cytoma (tumour of the adrenal glands) 2B- intracellular domain of RET, the tyrosine kinase bit Mucosal neuromas Mariano I'd body habits Medullary thyroid carcinoma Pheo-chromo-cytoma

Posterior aspect of the thyroid gland

4 parathyroid glands attached to posterior surface Sense Ca Secrete PTH

The thyroid nodule

4-7% prevalence Benign (90%) Multinodular goitre, Follicular adenomas, Hurthle-cell adenomas, Hashimoto's thyroiditis, Cysts (colloid, blood) Malignant (10%) Papillary carcinoma, Follicular carcinoma, Medullary carcinoma (of the C-cells), Anaplastic carcinoma, Primary lymphoma, Metastatic (breast, renal)

Case 3: A 55 year old lady presents with a 3 month history of a growing lump in the neck. The GP has sent for an ultrasound scan which shows a nodule in the thyroid. Her thyroid function tests are within normal limits.

5. What is the most likely cause for the nodule in the thyroid? 6. What other things could it be? 7. What test should you arrange? 8. What treatments are available for thyroid cancer?

Alternative Fates of Testosterone

5alpha-DHT for male external genitalia, binds to androgen receptor

Na+ movement regardless of aldosterone

65% Na+ reabsorbed in proximal tubules; 25% reclaimed in nephron loops Na+ never secreted into filtrate Water in filtrate follows Na+ if ADH is present Increased Na+ in urine leads to increased water loss

list the body's calcium pools

99% of our calcium is in bone as hydroxyapatite, Ca10(PO4)6(OH)2 in chronic illnesses, hydroxyapatite can be accessed and much more Ca can be lost from bone The other 1% is non-skeletal calcium found predominantly in cells with only 0.1% in the extracellular fluid (ECF)- readily exchangeable

T3/T4 transport in blood

99.9% bound to 3 different transport proteins, otherwise the kidneys would filter them out as they are less than 10kDa The most important binding protein is Thyroxine Binding Globulin (TBG) a glycoprotein that binds both T3 and T4 The other binding proteins are transthyreitin and albumin

Height v Age

< 2 years: supine length >2 years: • Standing height • Use a stadiometer • Careful positioning • Reproducible (1% CV) • Repeat regularly

Urine free cortisol

A 24 hour urine free cortisol level reflects cortisol secretion throughout a day. The majority of Cushing's have elevated levels of urine free cortisol, but mild Cushing's syndrome can have normal levels. Thus, a normal 24 hour urine free cortisol does not exclude the diagnosis of Cushing's syndrome. Other conditions can increase urine free cortisol including depression, chronic alcoholism, and eating disorders. Thus not as reliable and often skipped.

Immunology of Graves' disease

A genetic predisposition HLA DR17, DQ2, ? Environmental trigger T cell infiltration B and plasma cells Cytokine production Anti TSH-R Abs produced by the B cells

What is diabetes?

A metabolic disorder of multiple aetiologies characterised by chronic hyperglycaemia and disturbances in carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both.

Clinical problems arising directly from obesity include:

Coronary heart disease Type 2 diabetes Osteoarthritis Certain forms of cancer Sexual impotence

Polly had been married for 4 years and has been trying for a family for the majority of that time. She was not taking any contraceptive precautions. She presents saying she has not had a menstrual bleed for four months. What is your first course of action?

A pregnancy test.

Calibration or Standard Curve

A series of tubes are set up with known hormone concentrations The unknown sample can then be compared to the standard curve in which you know the radioactivity so can work out the amount of hormone in the sample

Sibutramine

A serotonin / noradrenaline reuptake inhibitor. Effects relies on the noradrenergic activation of J33-adrenoceptors on adipose tissue non-shivering thermogenesis Weight loss reversed on cessation of drug treatment. Side effects are related to sympathetic activation and increased serotonergic transmission- increase in mean arterial blood pressure

Low-dose dexamethasone suppression test results in Ectopic ACTH syndrome

A tumour in the lungs, thyroid, pancreas or thymus gland can, in rare instances produce ACTH High cortisol and high ACTH as the cortisol cannot exert negative feedback control on the ACTH

Human vaginal cervix Ai

A- transition between stratified squamous and simple columnar epithelium 1. Cervical stroma 2. Vein 3. Squames of the stratified squamous epithelium 4. Simple columnar epithelium 5. Lymphatic 6. basal cells Possibly inappropriate crosstalk between the two types of epithelium as their growth is regulated by different factors can cause the stratified squamous epithelium to undergo neoplasia. This occurs in addition to cofactors such as carcinogens and HPV.

Further PHC / endopeptidase action:

ACTH alpha, beta, gamma MSH b-Endorphins

Adrenocorticotrophin Hormone (ACTH)

ACTH can be acted upon by endopeptidases to generate α-melanocyte stimulating hormone (α-MSH). In adrenocortical cells, ACTH acts via a 7 transmembrane domain receptor to increase intracellular cAMP concentrations.

ACTH structure

ACTH is a 39 amino-acid peptide produced by post-translational processing of pro-opiomelanocortin (POMC). Other POMC products include alpha-melanocyte stimulating hormone (MSH) and beta-endorphin.

Skin colour changes and HPA pathology

ACTH is cleaved from POMC that also yields β-endorphin and α-MSH which is secreted from the intermediate lobe of the pituitary and regulates the production of melanin. Over expression of these POMC cleavage products can cause skin colour changes associated with pathology of the HPA

Skin colour changes and HPA pathology

ACTH is cleaved from POMC, a molecule that also yields α-MSH which is secreted from the intermediate lobe of the pituitary and regulates the production of melanin. Over expression of these POMC cleavage products can cause skin colour changes associated with pathology of the HPA.

Differential Diagnostic Testing:

ACTH testing CT of the adrenal glands MRI of the pituitary gland Inferior petrosal sinus sampling

Differential Diagnostic Testing

ACTH testing after the low dose dexamethosone suppression test- distinguishes between all of them. In Cushing's disease there is normal or elevated ACTH, low ACTH in Cushing's Syndrome, high ACTH in Ectopic ACTH syndrome CT of the adrenal glands to see if there is one or multiple tumours on it MRI scan of the pituitary and Inferior Petrosal Sinus sampling to distinguish between Cushing's disease and Ectopic ACTH syndrome

Diabetes insipidus treatment

AVP analogues such as desmopressin can be used to treat cranial DI no point replacing hormone if the receptor doesn't work. May need K+ replacement in nephrogenic DI

Vasopressin

AVPR2 is expressed in the kidney tubule, predominantly in the membrane of cells of the distal convoluted tubule and collecting ducts Activation of it by Vasopressin triggers fusion of aquaporin-2-with the apical plasma membrane of the collecting duct principal cells, increasing water reabsorption.

Conn's syndrome signs and tests

Abdominal CT scan that shows adrenal mass ECG shows heart rhythm abnormalities due to low potassium levels Elevated plasma and urinary aldosterone level Low plasma renin activity

list the major clinical conditions associated with growth disorders

Achondroplasia Acromegaly Gigantism Malabsorption syndrome Hypothyroidism Larson dwarfism Turner's syndrome

Changes in K+ with acidosis and alkalosis

Acidosis causes decreased K(+) secretion and increased reabsorption in the collecting duct. Alkalosis has the opposite effects, often leading to hypokalemia. • ECF K+ levels rise with acidosis • ECF K+ levels fall with alkalosis

Acromegaly and diabetes

Acromegaly is caused by raised GH post-puberty, 25% have a pituitary tumour. Diabetes is one complication, as Growth hormone stimulates the liver to release insulin-like growth factor (IGF-1). IGF-1 stimulates glycogenesis in skeletal muscle and decreases glucose uptake. It increases lipolysis in adipose tissue to shift the energy source from glucose In the liver glycogenolysis and gluconeogenesis are stimulated. This increases glucose concentration to cause the same symptoms as in diabetes- polyuria, polydipsia, neuropathies, retinopathies etc

Trends in menarche

Across the world girls have been reaching puberty at earlier and earlier ages Lifestyle and genetic predisposition interact Eating more, exercising less, increased body fat Adipose tissue is a significant source of oestrogen Increasing body fat tends to speed-up puberty in girls

Thiazolenediones glitazones

Act primarily on skeletal muscle and adipose tissue to increase insulin-stimulated glucose uptake Agonists for PPARgamma (peroxisome proliferator-activated receptor) Upregulates target genes such as IRS1, IRS2, PI3K, GLUT4 taken once or twice daily with or without food Rosiglitazone (Avandia), withdrawn from the market in Europe due to an increased risk of cardiovascular events. Pioglitazone (Actos), withdrawn in France and Germany due to raised risk of bladder cancer. Troglitazone (Rezulin), withdrawn from the market due to an increased incidence of drug-induced hepatitis.

Vasopressin analogues

Actions of AVP can also be either mimicked or blocked by structural analogues Lysine-vasopressin (porcine) = low potency V2 receptor agonist Desmopressin (synthetic) = highly selective V2 receptor agonist

Why aren't adrenal androgens relevant in a healthy male?

Actions of DHEA swamped by testosterone - DHEA = 2% of total plasma androgen - DHEA is very "weak" (D5, 17-ketosteroid)

Cellular actions of T4/T3

Actions of T4/T3 require changes in gene expression - takes time to elicit a final physiological response

Aldosterone analogues

Actions of aldosterone can be either mimicked or blocked by structural analogues of aldosterone (e.g. 9 fludrocortisone = pure MR agonist; spironoloactone = MR antagonist.

Activation of aldosterone

Activation of angiotensin receptors in the zona glomerulosa of the adrenal cortex stimulates aldosterone release from these glands The most potent stimulus of aldosterone synthesis is increased plasma K+ concentration which depolarizes the zona glomerulosa cells, thereby opening membrane Ca2+ channels. The increased cell Ca2+ is a potent stimulator of aldosterone production. ACTH does have some small stimulatory effect on aldosterone production but it is not an important regulator of this production. A fall in plasma volume and blood pressure when Na2+ drops also enhances aldosterone secretion

Stress and the Adrenal Gland

Acute stress - Catecholamines Chronic stress - Glucocorticoids Elevation of plasma [ glucose ]: • Altered carbohydrate metabolism • Increased fat mobilisation • Increased protein catabolism • Decreased sensitivity to insulin

How can a defect in ACTH drive to the adrenal cortex be differentiated from Addison's disease?

Addison's disease - ALL adrenal steroids suppressed ACTH defect - only ACTH-dependent steroids are decreased. Therefore: - [ aldosterone ] unaltered by ACTH defect - [ aldosterone ] decreased in Addison's disease- polyuria; polydipsia; Na+ intake

Vitiligo

Addison's disease is an autoimmune destruction of the adrenal cortex Vitiligo can be seen in individuals with Addison's disease- it may be that the autoantibodies destroy the melanocytes and the cortical cells.

Addison's disease

Addison's disease is the autoimmune destruction of the adrenal cortex resulting in reduced cortisol and aldosterone potential causes include tuberculosis Addison's disease can also develop from taking steroid medications for a long time, then sudden withdrawal - iatrogenic.

Hyposecretion of Anterior Pituitary Hormones

Adenohypophyseal cells are sensitive to irradiation - progressive loss of cell function with somatotrophs being most sensitive. The hyposecretion of individual anterior pituitary hormones is rare

Uterine factor

Adenomyosis- endometrial tissue migrates into the myometrium Uterine septum- during development the uterus septum isn't resorbed

Adinopectin and liver insulin sensitivity

Adinopectin decreases the expression of PEPCK and G6Pase in liver decreasing hyperglycaemia Through AdipoR2 it decreases liver gluconeogenesis.

Anti-inflammatory proteins in obesity

Adinopectin inhibits activation of macrophages and inhibits TNF-a secretion by monocytes and macrophages stimulating them to produce anti-inflammatory cytokines such as IL-10 Both IL-10 and adiponectin are produced less as obesity increases

Adiponectin

Adinopectin is another adipokine only secreted by mature adipocytes. Its expression depends on PPARGamma It is normally found at very high levels in the plasma but these are lower in obesity Large adipocytes secrete TNF alpha which inhibit adinopectin

Adipocytes size

Adipocytes can increase diameter 20x but adipogenesis can also increase the number of adipocytes available Hyperplasia (an increase in cell number) is a relatively healthy way to increase TAG storing capacity, hypertrophy (an increase in cell size) is associated with several problems

Adipose tissue development

Adipocytes develop from stem cells into preadipocytes, and then into mature adipocytes, under the influence of the transcription factor PPARγ Mature adipocytes are sensitive to insulin, expressing insulin receptors for lipid transport and synthesis They also secrete adipokines such as leptin, chemerin, adiponectin etc.

Adiponectin and atherosclerosis

Adiponectin inhibits TNF-alpha signalling, decreasing the expression of adhesion molecules like VCAM-1 and E-selection on endothelial cells. This inhibition also stops the formation of foam cells.

Hypertension and the RAS system

Adipose tissue expresses most of the components of the RAAS system, with mature adipocytes producing more angiotensin. More angiotensin is produced in obesity in visceral adipocytes Adipose tissue also responds to angiotensin II with decreased hyperplasia, decreased sensitivity to insulin, and increased inflammation.

Distribution of adipose tissue

Adipose tissue includes adipocytes, vascular tissue and immune cells The largest depot in most individuals is the subcutaneous adipose tissue Adipokine secretion in various depots

Adipose tissue and inflammation

Adipose tissue produces IL-6, IL-8, IL-1beta, TNF alpha, chemokines etc. these proteins stimulate immune responses, recruiting immune cells and stimulating the maturation of tissue cells These proteins also inhibit preadipocyte maturation Severity of chronic inflammation correlates well with the size of visceral adipocytes

Leptin, angiogenesis and cancer

Adipose tissue produces chemo lines such as CCL2 and leptin Invasive cancer cells may express chemokine receptors, inflamed Leptin is a promoter of angiogenesis which plays an important role in wound healing where it is released by subcutaneous fat Leptin is a chemoattractant for monocytes and macrophages and increases their production of TNF-alpha, which can be angiotensin at low levels VEGF is produced by the macrophages that infiltrate chronically inflamed adipose tissue. It acts synergistically with leptin to promote angiogenesis in tumours IL-6 also increases expression of VEGF

Obesity and tumours

Adipose tissue produces growth factors that stimulate angiogenesis the development of blood vessels that supply the tumour- neovascularization Plasma levels of adipokines do not always show an association with cancer risk because the mechanism may be paracrine i.e. tumours have locally increased levels of the adipokine produced by surrounding adipose tissue

Adipokines

Adipose tissue releases a large number of adipokines. It is believed that many of the conditions associated with obesity are mediated by the changes in adipokine secretion that occur as obesity progresses Adipokines may act at the autocrine and paracrine levels with both central and peripheral effects

Adrenal anatomy

Adrenal glands are small, triangular glands (4-6g in adult) superior to kidneys. They consist of • Medulla - catecholamine synthesis and secretion • Cortex (up to 90% of gland) - site of corticosteroid synthesis Medulla comprised of columnar, chromaffin cells (cords around vascular spaces).

Adrenarche

Adrenarche is the span of 8-15 years where Dehydroepiandrosterone DHEA and DHEAS rise Hormonal changes underlies puberty Its significance for puberty is unclear Occurs up to 2 years before menarche

T2DM care strategy

Advice: exercise, healthy eating diet, not smoking accelerated CV risk, regular testing & education BP: aim < 140/80mmHg Cholesterol: Statin treatment Drugs: Consider aspirin or ACEI Eyes: Check yearly retinopathy Feet: Check yearly infections, ulcers, gangrene Glycaemia: General target for HbA1c 48-58 mmol/mol Customised targets e.g. for elderly

Gigantism surgery

After surgery: •In some cases impaired endocrine function can recover, if the normal but compressed pituitary tissue has been preserved •For others, difficulties in growth, development and sexual maturation may persist. Careful replacement therapy needed for a normal life

Risk factors for type 2 diabetes

Age Genetic predisposition high fat/sugar diet Obesity Physical inactivity Prenatal factors Foetal malnutrition

Insulin Therapy

Aim to mimic physiological background and post- prandial peaks of insulin without hypoglycaemia 2/3 in morning and 1/3 in evening 2/3 as intermediate acting Subcutaneous during normal therapy IV for diabetic ketoacidosis, around the time of surgery

Actions of Aldosterone

Aldosterone promotes Na+ reabsorption and K+ secretion in the distal part of the kidney, the rectum, and the ducts of the salivary and sweat glands.

Structural and functional domains of steroid hormone receptors (Transcription factor)

All hormone receptors consist of a single peptide chain. At the C terminus is the specific binding domain for the ligand. This site is hydrophobic. Within this region or in close proximity is the activation function domain AF2 responsible for hormone dependent transcriptional activation and the dimerisation domain. The ligand binding domain also binds coactivator and corepressor proteins. Hinge region: Thought to be a flexible domain that connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution. A DNA-binding domain: contains two zinc fingers that binds to specific sequences of DNA, the hormone response elements (HRE). the N- terminal domain is hypervariable in length and composition. Contains the activation 1 (AF-1) whose action is independent of the presence of ligand. The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 in the E-domain to produce a more robust upregulation of gene expression.

Functions of phosphorus

All nucleotides contain a phosphate group which is an essential component. Normally, the major urinary buffer pair is HPO42-/H2PO4-. This pairing also contributes to cell and ECF buffering though there are more important buffers in cells and ECF. Cell membranes consists of a phospholipid bilayer with the hydrophobic tails in apposition and the hydrophilic heads in contact with the fluid in the cell interior and on the outside of the cell. Thus the phosphate contributes to membrane stability. • the cell energy 'currency' is largely ATP, a triphosphate. Phosphorylation of proteins result in enzyme activation and is a major component of cellular signaling. Phosphorus has a major structural role in bone where it reacts with calcium to give the mineral, calcium hydroxyapatite (Ca10(PO4)6(OH)2).

Synthesis of Adrenal Cortical Hormones

All of the steroid hormones are synthesized from cholesterol. The gland itself can make some cholesterol but the bulk of the cholesterol used is taken up from the pool of cholesterol synthesized in the liver and carried in the plasma bound to VLD lipoproteins.

Enzyme action for steroid hormone synthesis

All steroid hormones are synthesised from the C27 substrate, structure of cholesterol. So the removal of 6 carbons from this sterol which is catalysed by the enzyme cytochrome P450 cholesterol-side chain cleavage (P450CSCC) is the rate-determining step in steroidogenesis. Once pregnenolone is formed it passes out of the mitochondrion and into the ER where it is acted upon by a series of steroidogenic enzymes. Each of the 3 zones of the adrenal cortex synthesises a different steroid product, due to the differential expression of key steroidogenic enzymes in each adrenocortical zone.

Achondroplasia treatment

Alleviate symptoms •Phase 1 started 2012 C-Natiuretic peptide •Phase 2 2016

Potential mediators/mechanisms of bypass surgery

Altered bile acid/FGF-19 signalling, microbiome, gut hormones, neural signalling, GI nutrient-sensing Reprogramming of intestinal glucose. Reduced hepatic and pancreatic triglycerides. Reduced glucotoxicity. Weight loss

The types of enzymes in steroidogenesis

Although several different enzymes participate in the synthesis of steroid hormones, each enzyme belongs to one of the following 2 families: Hydroxysteroid dehydrogenases (HSDs) Cytochrome P450 enzymes

Vasopressin and CTH

Although the major release of vasopressin is from the posterior pituitary, it is also synthesized the paraventricular nucleus. Vasopressin is then released into the median eminence to the anterior pituitary where it augments the effects of CRH so that there is greater ACTH release.

ACTH and vasopressin

Although the major release of vasopressin is from the posterior pituitary, some is also synthesized by cells in the paraventricular nucleus which release into the median eminence to the anterior pituitary. Though not, itself, a significant stimulator of ACTH secretion, it augments the effects of CRH so that there is greater ACTH release.

Amines

Amines are derived from the amino acid tyrosine and are secreted from the thyroid and the adrenal medulla. As well as the adrenergic amine hormones or catecholamines (epinephrine and norepinephrine), other hormones whose structures derive from the amino acid tyrosine include the thyroid hormones. These hormones do not form a single homogeneous group.

Glucagon-amino acid feedback loop

Amino acids provoke glucagon secretion Glucagon increase oxidation of amino acids; carbon converted to energy, nitrogen to urea which gets converted back to amino acids

Differential Diagnostic Testing: MRI Pituitary

An MRI scan of the pituitary is used to distinguish between pituitary tumours and non-pituitary ACTH- secreting tumours. The majority have a pituitary lesion (often very small), a MRI of the pituitary gland with gadolinium enhancement is the initial approach. When a pituitary tumour is identified referral is for surgical removal. However ~10% of the population have incidental pituitary tumours on MRI. Thus ~10-15% of patients with the ectopic ACTH syndrome may also have an abnormal pituitary gland MRI.

With all the symptoms: a long history of complaints about periods, some increased body hair growth (hirsutism) on her face and arms, a constant battle to keep her weight down and a BMI of 30, the consultant also ordered an OGGT (oral glucose tolerance test) What is this and why is it relevant?

An OGTT is where the patient is asked to take a glucose drink and their blood glucose level is measured before and at intervals after the sugary drink is taken. stage of impaired glucose regulation fasting plasma glucose < 7.0 mmol/L 75g OGTT 2-hour value > 7.8 but < 11.1 Polycystic ovarian syndrome (PCOS) is generally characterised by an excess production of androgens (male hormones - usually testosterone), anovulation (the egg is not released by the ovary) and amenorrhoea, and by a varying degree of insulin resistance. Hormone imbalances also affect the menstrual cycle in PCOS, causing infertility problems. Most women with this condition do not have regular monthly periods. Often they have chronic anovulation and amenorrhoea, but they may also experience irregular periods and uterine bleeding.

Hypertension and Inflammation

An increase in Reactive oxygen species seen in inflammation is also a vasoconstrictor, which further depletes NO. The stimulation of angiotensinogen production (not just by adipocytes).

Androgens

Androgens like DHT and testosterone stimulate the maturation of sperm in men and support the development of male secondary sexual characteristics e.g. pubic, axilliary and facial hair growth

T3 and T4 and other hormones

Antagonises insulin • Adrenaline - ↑lipolysis, glycogenolysis, ↑HR Decreases the secretion of GHRH Decreases the secretion and release of TSH

How do we measure growth?

Anthropometric Measurements Six examples: Yield clinically useful age related patterns 1. Height V Age 2. RATE OF GROWTH v AGE 3. Bone Age / Bone Maturation 4. Pubertal Stages 5. Height V Chronological Age (Population) 6. SD Score

Treatment for hyperthyroidism

Antithyroid drugs PTU, methimazole and carbimazole inhibit thyroperoxidase. These can be used for toxic MNG/adenoma and Graves' disease although there may be remission with the latter Rash/urticaria/arthralgia (up to 10%) Agranulocytosis (0.2%)

Apparent Mineralocorticoid Excess (AME)

Apparent mineralocorticoid excess is an autosomal recessive disorder caused by mutations in the HSD11B2 gene, which encodes the kidney isozyme of 11β-hydroxysteroid dehydrogenase type 2. This enzyme is expressed in aldosterone-selective epithelial tissues such as the kidney, colon, salivary and sweat glands. In these tissues, HSD11B2 oxidizes the glucocorticoid cortisol to the inactive metabolite cortisone, thus preventing illicit activation of the mineralocorticoid receptor. So you get high levels of cortisol inducing aldosterone-like actions

Apparent mineralocorticoid excess

Apparent mineralocorticoid excess is the failure of the enzyme to protect the MR in distal nephron (and colon) Clinical presentation of hyperaldosteronism but low plasma [aldosterone] with suppression of the renin-angiotensin system Enzyme fails to perform guardian role if mutated or inhibited.

Islet Amyloid PolyPeptide (IAPP or amylin)

Appears to suppress insulin secretion

Human uterus, promenstrual, TS: very low power, H&E

Approximately 6th day of menstrual cycle, early proliferative phase The structure of wall of uterus is layered: A. Endometrium (E, mucosa) Composed of three strata: Stratum compactum (SC) the only layer which gets built up in the first part of the menstrual cycle and is discarded at the end of the cycle. Stratum spongiosum (SS) Stratum basalis (SB), containing huge blood vessels B. Myometrium (M, thick muscle) The myometrium contains densely interlaced bundles of smooth muscle, numerous large blood vessels in region adjoining serosa. C. Peritoneum (P, serosa)

Stimulation of GH

Arginine Thyroid hormones Gonadal hormones

Aromatase inhibitors

Aromatase Inhibitors (Anastrozole) where aromatase is involved in oestrogen synthesis is also used to treat breast cancer

Glucose Flux - Fasting State

As blood [ glucose ] lowers, insulin secretion lowers Many cells become unable to take up glucose and switch to alternative fuels for energy eg. FA Neurones need constant supply of glucose Glycogen reserve breakdown is stimulated by the absence of insulin and the presence of glucagon

Osmotic pressure

As water moves from compartment A to compartment B, the hydrostatic pressure increases in compartment B. Eventually this pressure increases the water activity to equal that of compartment A. This pressure is the osmotic pressure of the system. That is, the hydrostatic pressure that would need to be applied to stop osmosis. At equilibrium, compartment B would still have the higher solute concentration

Gastric-intestinal stimulation of insulin

As well increased glucose concentration, free amino-acids and increased glucagon concentration a number of gastro-intestinal hormones gastrin, secretin, cholecystokinin and glucose-dependent insulinotrophic peptide

Development of Sexual Phenotype

At fertilisation • Spermatozoan with either an X or a Y chromosome determines sex by fusing with an X-bearing ovum At ~4 weeks of development • Proliferation of cells in the urogenital ridge creates the bipotential gonad At ~7 weeks of gestation (sex determination) • 46,XY gonad becomes a testis • 46,XX gonad remains as an ovary

Non-enzymatic glycation

At high concentrations of glucose almost all proteins are susceptible to glycation where there is the reversible formation of Schiff's bases between their lysine residues. Further chemical reactions with excess glucose irreversibly give an Amadori product. This happens to a limited extent even in healthy individuals but in the presence of excess glucose, this process is enhanced so that a variety of proteins become glycated e.g. haemoglobin Proteins with shorter half lives may also be glycated e.g. albumin and low-density lipoproteins. This process is reversible, but ultimately further irreversible processes occur including the formation of a 3-deoxyglucosone and the so-called advanced end-products of glycation (AGEP). AGEs appear to give rise to the severe modification of these proteins often with internal cross-linking within the protein and external cross-linking with other proteins. this leads to impairment of the normal turnover of these proteins and this may contribute to the pathology of diabetes. Fortunately more can now be done for the patients using laser surgery to seal off the leaking blood vessels. However, similar problems in the kidney give rise to increased mortality among diabetics. Here This can lead to the glycation of enzymes and structural proteins, irreversibly if AGEPs are formed. Underlies many long term effects of diabetes

Oestrogen

At high concentrations, oestrogen creates a positive feedback on both the hypothalamus and the pituitary. The LH surge initiates ovulation and triggers a decline of oestrogen produced by the follicle. LH also transforms the ruptured follicle into the corpus luteum.

Glucose and hormone levels

At normal resting plasma concentrations, there is relatively little secretion of either insulin or glucagon. Increasing blood glucose concentration results in increasing insulin concentration and inhibition of glucagon release. When glucose falls below normal, glucagon is secreted, and insulin secretion suppressed. The two hormones therefore work together to stabilize blood glucose.

How do ionised calcium levels regulate vitamin D activity?

At serum calcium concentrations less than 2.2 mmol/L, the activity of renal 1alpha-hydroxylase is maximal whereas the activity of 24-hydroxylase is minimal. At serum concentrations of calcium between 2.2 and 2.6 mmol/L, the renal 1alpha-hydroxylase activity is inversely proportional to the calcium concentration while the 24-hydroxylase activity increases in direct proportion to the calcium concentration. This reciprocal relationship ensures that at low calcium concentrations, the generation of calcitriol is maximised, and at high calcium concentrations, the generation of this hypercalcaemic hormone is minimised.

What changes would you expect after menopause?

Atrophy, no oocytes, absence of follicles, numerous corpora albicantia, scarred and pitted surface, growth of fibrous tissue, etc

Causes of hypothyroidism

Autoimmune primary hypothyroidism- much more common in women Can be iatrogenic from surgery, radioactive iodine or anti-thyroid drugs Thyroiditis e.g. Hashimoto's Iodine deficiency Congenital- Thyroid dyshormogenesis (can't make hormone) or athyreosis (no thyroid) Secondary hypothyroidism: pituitary disease or surgery

Body Mass Index (BMI)

BMI = Mass in kg divided by height in metres squares <18.5: underweight 18.5-25 is normal 25-30 is overweight >30 is obese

BMI

BMI is a height to weight ratio calculated by weight (kg) divided by height2 (m). BMI is just one assessment of a person's body fat stores, though it's considered to be the most precise measure of body fat stores. BMI is not an accurate reflection of total body fat for athletes or people with edema

Energy expenditure

Basal Metabolic Rate (BMR) is 23.5 kCal/kg; females 22.5 kCal/kg 1760 kCal/day for 75 kg male Typical expenditure for office worker ~2000 kCal/day (This can double with hard manual labour)

Inhibition of aldosterone- 'negative feedback'

Because of the regulation of plasma osmolarity, when we retain extracellular Na+ we don't increase its concentration as we are retaining water with it to preserve plasma osmolarity. Therefore, when Na+ is retained, plasma volume and blood pressure increase, and this inhibits aldosterone secretion.

Control of hydrophilic and hydrophobic hormones

Because of this distinction between hydrophilic hormone synthesis and release, the plasma concentration of a peptide/protein hormone or catecholamine can be controlled at both the level of hormone synthesis and at the level of secretion. In contrast, since hydrophobic hormones can pass freely across the plasma membrane of the cells that constitute the endocrine glands, their rate of secretion is directly proportional to the rate of their synthesis.

Vitamin D effect on cells

Being fat-soluble, 1,25-hydroxycholecalciferol diffuses into cells where it binds to a vitamin D receptor that functions as a transcription factor modulating gene expression- it triggers the transcription and production of new proteins. The 1,25-dihydroxycholecalciferol is metabolized to 1,24,25-trihydroxycholecalciferol, an inactive compound that is excreted largely through the biliary system.

Vitamin D movement in the body

Being lipid soluble, these prohormones are carried in blood bound to vitamin D-binding protein VDBP. In the liver, vitamin D3 is hydroxylated to 25-hydroxycholecalciferol by 25-hydroxylase. This is the most abundant of the circulating vitamin D metabolites. In the kidneys, the 25-hydroxycholecalciferol is hydroxylated again to give either the active metabolite 1,25-dihydroxycholecalciferol or the inactive metabolite 24,25-dihydroxycholecalciferol that is excreted.

Benign FNA (fine needle aspiration)

Benign features "THY2" • presence of abundant colloid, overgrown follicle

Beta blockers and diabetes

Beta-blockers can mask the signs of hypoglycaemia- one symptom is rapid heart beat and beta blockers slow heart beat nonselective propranolol, β1-selective atenolol and metoprolol significantly decrease insulin sensitivity in patients with hypertension. Carvedilol, a third generation beta blocker increases insulin sensitivity

Brown adipose tissue

Brown adipose tissue produces heat through non-shivering thermogenesis Upon stimulation by the beta 3 adrenergic receptor, lipolysis and fatty acid oxidation are activated The proton gradient generated by the electron transport chain is then 'wasted' via UCP1

Insulin signalling: the PI3-kinase pathway

Binding of insulin to the dimeric receptor forces the PTK domains together, followed by cross-phosphorylation of the receptors. These phosphorylated tyrosine residues act as docking sites for IRS-1 (insulin receptor substrate 1), which gets phosphorylated. Other proteins can dock at the active receptor or at IRS-1 including GLUT4 for its translocation Insulin receptor substrate-1 is phosphorylated on several tyrosine residues. It is already associated with the membrane due to its PH domain, which can bind PIP2. Once phosphorylated, it can dissociate from the insulin receptor 3. Phosphorylated IRS-1 can bind PI-3K (phosphoinositide-3 kinase), which, now located at the membrane, phosphorylates PIP2 at position 3, forming PIP3 (phosphatidylinositol-3,4,5 trisphosphate). PIP3 allows both PDK1 (phosphoinositide-dependent kinase-1) and PKB (protein kinase B) to associate with the membrane via their PH (pleckstrin homology) domains. Phosphorylated PKB dissociates from the membrane and phosphorylates its target proteins.

Hyperthyroidism

Blood tests: Thyroid Stimulating Hormone is low, Thyroxine is high What's the underlying cause? • Graves' disease (autoimmune) • Thyroid adenoma • Thyroid inflammation Treat by reducing the production of T3 and T4

Hyperglycemia symptoms

Blurred vision Excessive thirst Polyuria

PTH actions

Bone Kidney GI tract

Ca2+ is critical for

Bone mineralisation: has a major structural role as the mineral, calcium hydroxyapatite (Ca10(PO4)6(OH)2), in bone. It also strengthens the enamel layer in teeth Blood clotting: It binds to proteins, thus altering their tertiary structure and their activity- some of the clotting factors are activated by Ca2+ binding. Muscle contraction, Cardiac action potential, nerve function Enzyme action Exocytosis of hormones and neurotransmitters: calcium is required for secretory vesicles to fuse with the plasma membrane of secretory cells and neurones Intracellular signalling: cellular responses to hydrophilic hormones/growth factors that act via calcium-dependent protein kinases (e.g. protein kinase C)

describe the nature of target cell receptors for GH

Both GH and prolactin activate PRL receptors Only GH activates somatogenic receptors cell surface receptors linked to tyrosine kinase initiate intracellular phosphorylation cascades ectodomain / transmembrane domain / cytoplasmic domain

Hashimoto's thyroiditis v Graves' disease

Both autoimmune

Glycogen Synthase (GS) & Glycogen Phosphorylase (GP)

Both enzymes can be converted between active and less active forms using a system of protein kinases PKA phosphorylates and activates Phosphorylase Kinase, which activates GP PKA phoshorylates and inactivates GS, which prevents cycling of glucose-1-P Glycogen breakdown

Plasma phosphate

Bound to protein (10%). Complexed with sodium, calcium, and magnesium (35%). Inorganic phosphate (55%).

Boys: Tanner Stages

Boys - development of external genitalia Stage 1: Prepubertal Stage 2: Enlargement of scrotum and testes; scrotum skin reddens and changes in texture Stage 3: Enlargement of penis (length at first); further growth of testes Stage 4: Increased size of penis with growth in breadth and development of glans; testes and scrotum larger, scrotum skin darker Stage 5: Adult genitalia

Growth rate differences between boys and girls

Boys begin growth spurt about 2 years later than girls They are taller at take-off and reach the peak height velocity later. There is a greater height gain between take-off and the cessation of growth in boys • 10cm difference in adult height between men/women due to the height difference at take-off

Hormonal cancer treatment

Breast cancer • Tamoxifen (SERM) • Anastrozole Prostate cancer- supress testosterone production as testosterone proliferates it • GnRH agonist (cont. dosing ± anti-Androgen) • GnRH antagonist

Over a 2-3 year period of time, oestrogens stimulate:

Breast growth Widening of the pelvis Increased adipose tissue Growth of the uterus Height / body growth Growth and vascularity of the endometrium and uterine lining

Ovary during pregnancy

CA- corpus albicans, lumps of scar tissue that remain after the corpus luteum of menstruation begins to involute and degenerate. Human ovary (pregnant, corpus luteum): very low power, H&E Note the single corpus luteum of pregnancy that occupied about two thirds of the volume of the ovary Secondary follicles (S) are relatively small and collapsed Note the prominent theca of the secondary follicles, a feature of pregnancy The very palely stained blobs are corpora albicantes (CA) Of what is a corpus albicans made? Strands of theca lutein (TL) cells (fairly small cells) may be seen penetrating from the periphery into the main mass of follicular lutein cells (large and vacuolated). Androgens are produced here and are converted in the granulosa cells by aromatase to oestrogen. The granulosa cells also produce progesterone. Underneath are the granulosa lutein cells The central cavity of the corpus luteum (persisting from the ovulated secondary follicle) contains a fuzz of protein precipitate and loose connective tissue, formed by invading thecal connective tissue cells The hilum (H) and broad ligament (L) are present in this image where the major blood vessels come in. Note the large blood vessels: these are branches of the ovarian and uterine arteries (which branch off the aorta) Ovarian stroma is full of small blood vessels, especially capillaries surrounding follicles There will also be veins and lymph vessels here

list the symptoms and signs of hypocalcaemia

CATs go numb" - convulsions, arrhythmias, tetany, and numbness in the hands and feet and around the mouth. Muscle cramps and carpopedal spasm Trousseau's sign (B) Myopathy (numbness) and paraesthesia (pins and needles) due to the importance of calcium in the control of the neuromuscular system Mood swings and depression Tetany and neuromuscular excitability. Can in extreme cases lead to epilepsy Chvostek's sign (A) Convulsions Cardiac arrhythmias (long QT interval on ECG) Cataract

Other factors affecting puberty

CNS lesions - advanced or delayed puberty Endocrine markers of body development such as leptin are implicated in the onset of puberty, but are unlikely to be causally involved as its trigger

Hypothalamic parvicellular hormone cellular pathways

CRH and GHRH stimulate protein synthesis and secretion via generation of cAMP GnRH and TRH act via the PLC/IP3/Ca2+ pathway.

Corticotrophin Releasing Hormone (CRH)

CRH is secreted in the median eminence which reaches the ACTH basophilic cells in the anterior pituitary through the portal circulation. Here CRH binds to G protein-coupled receptors, that acting through adenylyl cyclase, stimulate the cyclic AMP-dependent protein kinase A (PKA) signal transduction pathway.

ACTH release

CRH reaches the ACTH-secreting basophilic cells in the anterior pituitary through the portal circulation. Here it binds to G protein-coupled receptors, that acting through adenylyl cyclase, stimulate the cyclic AMP-dependent protein kinase A (PKA) signal transduction pathway.

Transcellular absorption of calcium

Ca2+ enters the epithelial cells from the intestinal lumen through TRP (transient receptor potential) Ca2+-channels down its electrochemical gradient. As the it enters the cells, it is immediately bound to calbindin, a vitamin D-dependent Ca2+-binding protein. It remains bound until it is extruded across the basolateral membrane by a Ca2+-ATPase.

Prolactinoma treatment

Cabergoline is a long-acting dopamine agonist, which can be used to reduced prolactin actions and prolactin secretion by causing tumour shrinkage. If the hormones profile for prolactin were not significantly elevated then the most likely diagnosis would have been a large non-functional pituitary tumour and transphenoidal surgery would have been the best option. Treatment with long-acting somatostatin analogues can also be used to see if tumour shrinkage can be achieved.

Cabergoline

Cabergoline is a medication mainly used for the treatment of prolactin secreting pituitary tumors, but it has been shown to normalize cortisol levels in 20-40% of patients with CD. Unfortunately, the effects of cabergoline tend to wear off over time and cortisol levels rise despite continued treatment.

Calcitonin

Calcitonin is secreted by the parafollicular or C cells of the thyroid They are embryologically distinct from thyroid cells - derived from the neural crest they are Amine Precursor Uptake and Decarboxylating (APUD) cells The Calcitonin gene codes for 136 amino acids and these are spliced into the 32 amino acid peptide calcitonin

Vitamin D and PTH

Calcitriol suppresses the synthesis and secretion of PTH and limits parathyroid cell growth. Low levels of calcitriol downregulate Vitamin D receptors in the parathyroid glands leading to stimulation of PTH gene expression, increasing PTH secretion. It may facilitate parathyroid cell proliferation.

Dietary calcium

Calcium in dairy products and eggs is well absorbed. But calcium in vegetables is often complexed to organic acids, such as oxalates and citrates. Also, calcium binds to long-chain fatty acids. Complexing and binding hinder calcium absorption.

Polyglandular Autoimmune Syndrome Type 2

Can be triggered by Immunotherapy with anti-PD- 1 and anti-CTLA4 mAbs Thyroid disease (Graves' or Hashimoto) Type 1 DM against pancreatic beta cells Addison's disease Pernicious anaemia- against parietal cells that produce intrinsic factor Vitiligo- against melanocytes Hypoparathyroidism- against parathyroid glands Hypogonadismagainst steroid-producing cells in testicles or ovaries

Insulin Stimulates Hepatic Glycogen Storage

Can't just have glucose as cell will die via osmosis. Insulin activates hexokinase in the liver which phosphorylates glucose trapping it in the cell Insulin also activates enzymes directly involved in glycogen synthesis including phosphofructokinase and glycogen synthase and inhibits the activity of glucose-6-phosphatase

Carbimazole

Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from iodinating and coupling the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine) Delayed onset • Rash • GI upset • Agranulocytosis • relapse is 50%

Hydrophilic Hormones

Catecholamines are also hydrophilic hormones because they possess numerous polar hydroxyl groups. Prostaglandins, while lipid derivatives, are rendered hydrophilic by the presence of a carboxylic acid group - a remnant of their origin from arachidonic acid. Because of their hydrophilicity peptide /protein hormones and catecholamines are unable to pass through the hydrophobic core of the plasma membrane. Hence, in order to influence the activity of intracellular enzymes, the binding of hydrophilic hormones to their cell surface receptors must initiate a transmembrane signalling pathway that typically involves second messengers and protein kinase/phophatase enzymes. Hydrophilic hormones includes the Protein and Peptide hormones including: Insulin (pancreas), thyroid stimulating hormone, growth hormone and prolactin (anterior pituitary), oxytocin and vasopressin (poster pituitary), and calcitonin (thyroid). Plus hydrophilic amines including dopamine (CNS) and epinephrine (adrenal medulla).

Adrenoreceptors

Catecholamines are hydrophilic and interact with plasma membrane receptors • Adrenoceptors are divided into two classes: • alpha-adrenoceptors usually coupled to PI-PLC/Ca2+ • alpha-receptors, when activated, generally produce excitatory responses of smooth muscle • beta-adrenoceptors usually coupled to AC-cAMP-PKA

The adrenal gland synthesises and secretes two distinct classes of hormones:

Catecholamines e.g. adrenaline whose amines are hydrophilic Corticosteroids, glucocorticoid, mineralocorticoids and adrenal androgens in which steroids are hydrophobic

Familial Partial Lipodystrophy 3 (MIM 604367)

Caused by mutations of the PPARGamma gene- Dominant negative or haploinsufficiency Progressive, gradual loss of subcutaneous adipose tissue from extremities, normally beginning in puberty. There is also increased deposition of TAG in muscles and liver Hypertriglyceridemia, low HDL, severe insulin-resistance leading to diabetes as well as other metabolic irregularities

Other causes of high aldosterone

Causes: Primary - low renin, high aldosterone • Conn's syndrome Primary - low renin, low aldosterone • DOC producing tumour/CAH (DOC is converted to aldosterone) • Cushing's syndrome • Apparent mineralocorticoid excess Secondary - high renin, high aldosterone • Chronic haemorrhage/decrease in blood volume stimulates RAAS system to stimulate aldosterone. • Heart failure leading to decreased GFR

Posterior lobe of the pituitary gland

Cell bodies of magnocellular neurones in the paraventricular (PVN) and supraoptic nucleus (SON) of the hypothalamus synthesise the hormones and project into the posterior pituitary lobe along the supraoptic-hypothalamic tract where the hormones are stored in the axon terminals. When the hypothalamic neurons fire, their action potentials arriving at the axon terminals cause the hormones to be secreted into the inferior hypophyseal circulation.

Cervix & vagina

Cervix - neck of uterus; birth canal - simple epithelium; abrupt transition to stratified squamous epithelium of vagina is frequent site of malignant transformation Vagina - site of introduction of spermatozoa; birth canal - stratified squamous epithelium

Describe events for each of the three stages of parturition.

Cervix Dilation - Cervix dilates to 10 cm, amniotic membranes rupture. Expulsion - lasts from complete dilation of cervix to birth of baby. Uterine contractions assist in expulsion out the vagina. Placental Stage - delivery of the placenta or afterbirth and the uterus contracts to prevent excessive bleeding.

Neuropathy

Changes in small blood vessels due to glycation can contribute to neuropathy. Possibly accumulation of polyols. Also disturbances occur in inositol metabolism and phosphatidylinositol which are important to signal transduction and nerve transmission. Diabetic retinopathy Exude proteins which accumulate underneath the retina Retinal infarcts (soft exudate). Lack of oxygen triggers a response in cell, hypoxia response, leads to growth of VEGF (vascular endothelial growth factor) which grow new blood vessels New blood vessels which are not very good and haemorrhage (the red blobs). Can bleed into the vitreous humour (vitreous haemorrhage) cannot see into the eye.

Diabetic foot pathologies

Charcot joints Edema Fallen arches Infections Ischaemia Neuropathy Ulcers loss of sensation in his lower limbs, and a pressure location due to his Charcot joints. He has quite dry skin and loss of soft tissue.

Case Study: At birth baby G is found to have ambiguous genitalia. There is no penis, but an enlarged clitoris is evident. If you carried out chromosomal analysis what would you expect the result to be if you suspected Congenital Adrenal Hyperplasia?

Chromosomal analysis reveals baby G has as an XX genotype. XY individuals would show a penis and no clitoris and not be affected by the insignificant changes in androgens associated with CAH. The internal organs are female including ovaries, fallopian tubes, uterus and upper vagina. The fallopian tubes, uterus and upper vagina develop because without testes, there is no anti-mullerian hormone to supress differentiation of the mullerian ducts into the female genital tract.

Nicotine

Chronic administration reduces food intake

Cushing's syndrome causes

Chronic stress Ectopic ACTH secretion like from a tumour in the lungs, thyroid, pancreas or thymus gland, which can, in rare instances, produce hormones Functional ZF (zona fasciculata) tumour Long-term use of corticosteroid hormones such as cortisone or prednisone

Stress and the hormonal axes

Chronic stress over-rides negative feedback on CRH and ACTH and the hypothalamo-pituitary-adrenal axis becomes hyperactive: Loss of GnRH and GHRH- repressed following withdrawal of hypothalamic releasing hormones.

Increased ACTH Drive

Chronic stress- increased CRH Glucocorticoid resistance - loss of negative feedback as the receptors are not working CRH-independent secretion of ACTH from pituitary (corticotroph) tumour Ectopic ACTH secretion e.g. small cell lung tumour Defect in cortisol synthesis e.g. CAH or Addison's disease

Cholesterol synthesis

Chylomicron remnants transport cholesterol to the liver where they are stored, broken down by Bile Acids and released as VLDL into the circulation. HDL transfers cholesteryl esters to VLDL in exchange for phospholipids and triglycerides turning it into IDL then LDL as they lose more triglyceride- their cholesterol content becomes greater LDL is taken into a cell via the LDL receptor through endocytosis, where the contents can be converted into steroid hormones HDL collects cholesterol particles as they travel through blood vessels and deposits them in the liver where they are broken down by bile acids. From here, they can go to steroidogenic organs such as the ovaries and testes for the formation of steroid hormones

Seminal vesicles Ai

Circular muscle layers Fibrous connective tissue with blood vessels and nerve bundles

Relationship between cortisol and aldosterone

Circulating levels of the glucocorticoid cortisol are some 100 to 1000x higher than the circulating levels of aldosterone. The affinity of the two steroids for the aldosterone receptor are very similar. So why doesn't cortisol overwhelm the effects of aldosterone? This is prevented by the presence of the enzyme 11-β-hydroxysteroid dehydrogenase 2 in all tissues that respond to aldosterone. This enzyme rapidly oxidises cortisol to cortisone that does not bind to the aldosterone receptor which is now free to respond appropriately to the cell levels of aldosterone.

Abnormalities in secretion pattern of GH

Classic idiopathic GH deficiency • absent or only feeble peaks GH excess • Continuous secretion of high GH • Absent pulsatility

describe and sketch the structure of thyroid follicles

Colloid has thyroglobulin Microvilli present on the epithelial cells

Urinalysis normal values

Color- Varies from colorless to dark amber. Specific gravity- Ranges from 1.003-1.030 pH- Ranges from 4.6-8.0, average is 6.0 Glucose, nitrates, ketones, proteins Not normally present. Erythrocytes Not normally present. Hemoglobin Not normally present. Bilirubin Not normally present, though traces of urobilinogen may be. Leukocytes Not normally present.

Seminal vesicle C

Columnar epithelium Fibromuscular tissue underneath the folds of the epithelium

Ketoacidosis symptoms

Coma Increased rate of breathing- The low pH stimulates the respiratory centre Presence of ketones in the urine Smell of acetone on the breath

Causes of vasopressin hyper secretion

Common disorder of fluid and electrolyte balance • Syndrome of inappropriate ADH secretion (SIADH) Intra-cranial trauma/infection • Pneumonia • Malignant disease (small lung cell cancer, other carcinoma) • Selected narcotics/analgesics (nicotine, surgery) • Prolonged strenuous exercise (marathon, hot weather training)

Pituitary dysfunction

Communication between hypothalamus and pituitary can be disrupted by several mechanisms: cranial trauma pressure on pituitary stalk, usually secondary to a pituitary tumour occlusion of hypophyseal portal circulation and/or supra-optic hypothalamic tract inflammation / infection congenital defects of midline structures (septo-optic dysplasia = panhypopituitarism with blindness) Kallman's syndrome (absence of GnRH neurones from hypothalamus)

Secondary hyperparathyroidism

Compensation for long-standing hypocalcaemia- poor calcium intake / absorption Response to low calcitriol in chronic renal failure Sub-periosteal bone reabsorption, may lead to cyst formation and bone pain Renal calculi- calcium phosphate stones

Achondroplasia complications

Complications: ear infections (Eustachian tube blockages), sleep apnea (central or obstructive), hydrocephalus and spinal compression.

Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia is a group of autosomal recessive disorders with loss-of-function mutations and decreased expression of adrenal steroidogenic enzymes. Most common is 21-hydroxylase deficiency This results in little or no synthesis of cortisol and aldosterone. Cortisol usually negatively feeds back on ACTH. The elevated ACTH causes the hyperplasia

Congenital hypothyroidism

Congenital hypothyroidism can be caused by iodine deficiency which is the most common cause, dyshormonogenesis (defect in thyroid synthesis) or non-goitrous congenital hypothyroidism Check for jaundice untreated leads to cretinism - severe neurological impairment Check for jaundice

Conn's Syndrome

Conn's syndrome is a primary hyperaldosteronism due to adrenal hyperplasia or a tumour. Causes high blood pressure

Ovary ApB

Cortex of the ovary The largest follicle in this image is a primary follicle Primordial follicles on the outside, surrounded by flattened cells The primary oocyte (O) has enlarged The granulosa cells have multiplied mitotically and formed a zona granulosa (ZG) The ovarian stromal cells have begun to organise themselves around the follicle, forming the theca folliculi (TF) The space between the oocyte and the zona granulosa in this image is an artefact

Inhibition of GH

Cortisol Glucose Free fatty acids

Cortisol and Gluconeogenesis

Cortisol activates the glucocorticoid receptor inside cells to increase the expression of key gluconeogenic enzymes: Glucose-6-phosphatase which converts glucose-6-P into glucose Fructose-1,6-bisphosphatase which converts fructose-1,6-P2 into fructose 1-P PEPCK, PEP carboxykinase which converts Oxaloacetate(OAA) into Phosphoenol pyruvate PEP

Metabolic Actions of Cortisol

Cortisol increases the expression of those gluconeogenic enzymes required to bypass the irreversible steps in the glycocolytic pathway- it increases hepatic gluconeogenesis the availability of amino-acids as gluconeogenic substrates- protein catabolism, prominent during starving Cortisol increases the catabolism of triglycerides lipolysis, increasing the availability of glycerol for gluconeogenesis. the use of alternative respiratory substrates to spare glucose oxidation- stimulates the β-oxidation of fatty acids in selected tissues (it is not possible for NEFAs to serve as a gluconeogenic substrate) Inhibits IMGD via GLUT4

Juvenile Cushing's Syndrome

Cortisol inhibits Growth Hormone- don't achieve full growth potential proportionate limbs truncal obesity symptoms of cortisol excess GH low

Loss of glucocorticoids in the neonate

Cortisol initiates production of fetal lung pulmonary surfactant helping the baby to breathe after birth.

Metabolic Co-operation

Cortisol is not the only hyperglycaemic hormone: Catecholamines and Glucagon use the cAMP CREB pathway Cortisol exerts PERMISSIVE genomic actions- Activated GR (bound to GREs) synergise with activated CREB (bound to CREs) in genes encoding relevant metabolic enzymes. Takes time, long term metabolic effects.

Gluconeogenic Substrates

Cortisol must increase substrate provision: Increased expression of hormone sensitive lipase for increased generation of glycerol from TAG (NEFA cannot be used for gluconeogenesis) Increased expression of endopeptidases for increased hydrolysis of proteins to liberate 6 gluconeogenic amino-acids

Circadian Cortisol Rhythm

Cortisol peak in the morning peaks at around 08:00h shortly after waking and reaches a nadir at around 21:00h.

Why does glucocorticoid resistance result in hyperpigmentation?

Cortisol would usually feedback negatively on CRH and ACTH

Cranial diabetes insipidus

Cranial diabetes insipidus is the impaired secretion of ADH from the posterior pituitary It often occurs after surgery or following a head trauma There is still some plasma AVP because AVP is co-secreted with CRH parvocellular neurons

Insulin analogues

Created to alter pharmacokinetics- human insulin clumped together inhibit hexamerisation so more rapid acting Aspart is rapid acting Delgudec has a fatty acid chain so it can bind albumin meaning it is slow acting and longer lasting form insoluble depots under skin → ultra slow acting

Cushing's disease v Cushing's syndrome

Cushing's disease is a pituitary defect producing ACTH Cushing's syndrome is increased cortisol action NOT due to a pituitary tumour

Cushing's disease and diabetes

Cushing's disease is a pituitary defect producing ACTH. ACTH stimulates the adrenal cortex to produce cortisol Untreated Cushing's disease leads to high levels of cortisol During stress and with low blood glucose, cortisol inhibits β cell insulin secretion and stimulates α cell glucagon secretion. It also increases fat metabolism by up-regulating expression of the HSL enzyme to spare glucose. Glucagon decreases fatty acid synthesis, stimulates glycogenolysis and gluconeogenesis and inhibits glycolysis in the liver.

Cushing's disease

Cushing's disease is caused by hypersecretion of ACTH from adrenocorticotrophic anterior pituitary tumours (insensitive to cortisol negative feedback). (In addition to the altered distribution of body fat in Cushingoid patients, patients with ACTH secreting pituitary tumours tend to be hyperpigmented, classically with acanthosis nigricans).

Low-dose dexamethasone suppression test results in Cushing's Syndrome

Cushing's syndrome is caused by either excessive cortisol-like medication or a tumor that either produces or results in the production of excessive cortisol by the adrenal glands The cortisol is not suppressed so there is elevated cortisol. High negative feedback on ACTH so low or undetectable ACTH

Cystic fibrosis

Cystic fibrosis is an autosomal recessive disease caused by mutations in both alleles for the cystic fibrosis transmembrane conductance regulator- CFTR protein CFTR is involved in the production of sweat, digestive fluids, and mucus. When the CFTR is not functional, secretions which are usually thin instead become thick. Cystic fibrosis affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections preventing the pancreas from working properly to digest food.

GH and the JAK2/STAT5 pathway

Cytokine receptors all have a tyrosine kinase called JAK bound to their cytosolic domains Upon GH binding, its receptor dimerises and the cytoplasmic tyrosine kinase JAK2 is recruited. JAK2 binds to the juxtamembrane region of the intracellular domains of the receptor known as box 1. Binding of the GH realigns the subunits by rotation and closer apposition, resulting in the catalytic domains of the JAK2 kinases being close enough to phosphorylate each other. This lowers the Km of the kinase for its substrate, activating it.

Describe the JAK/STAT pathway initiated by erythropoietin

Cytokine receptors all have a tyrosine kinase called JAK bound to their cytosolic domains; the EpoR has a JAK2 kinase. Epo simultaneously binds two EpoRs, bringing the JAK kinases close enough for each to phosphorylate the activation lip of the other. This lowers the Km of the kinase for its substrate, activating it. The JAK kinases phosphorylate the receptors allowing STAT5 (a member of the Signal Transduction and Activation of Transcription (STAT) family) to bind via their SH2 domains to the EpoR and also get phosphorylated. The phosphorylated STAT5s dissociate from the receptor, dimerise, exposing a nuclear localisation sequence. The STAT5 dimer enters the nucleus and its DNA-binding domain binds to specific DNA regulatory sequences to control the expression of target genes.

Cytokine Receptors

Cytokines are a family of small (~160 aas) signalling molecules, with a characteristic arrangement of four alpha helices, controlling the growth and differentiation of a number of cells. Cytokine receptors do not have an intrinsic enzyme activity, rather they recruit an enzyme. The receptors all have a tyrosine kinase called JAK bound to their cytosolic domains, which phosphorylate transcription members of the Signal Transduction and Activation of Transcription (STAT) family. Although cytokine receptors can activate other pathways, e.g. the MAPK pathway, the JAK/STAT pathway is normally only activated by cytokines.

Chromaffin cell product release

Cytoplasm of chromaffin cells rich in secretory granules - released in response to acetylcholine (Ach). Granules also contain met- and leu-enkephalins (opiates) synthesised within medulla. Release can be stimulated: • directly (histamine, serotonin (5HT) and ACh-mimetics (e.g. carbachol and nicotine)) • indirectly via vasomotor centre of the medulla oblongata.

d-Amphetamine

D-amphetamine is a competitive inhibitor of noradrenaline uptake which reduces food intake through the activation of a1-adrenoceptors and J3-adrenoceptors in the hypothalamus. It has little / no effects on serotonin uptake. In high (toxic?) doses, it causes impulse- independent release of noradrenaline and dopamine. Dopamine transmission in the limbic (reward) system causes behavioural arousal and dependence.

DHEA into oestrogen

DHEA can also be metabolised in peripheral tissues - particularly adipose tissue to oestrogens. This is particularly important in post-menopausal women when the peripheral synthesis of oestradiol from adrenal DHEA exceeds the output of oestradiol from the ovaries. Hence, androgens produced in the adrenal cortex can support the growth of oestrogen-dependent tumours e.g. breast and uterine tumours and carcinomas in post-menopausal women.

DHEA

DHEA is a weak steroid that has only low affinity for the androgen receptor. Since the adrenal gland contains a steroid sulphotransferase enzyme, DHEA tends to leave the adrenal cortex as dehydroepiandrosterone sulphate (DHEAS). In potential target cells, the sulphate is removed by a steroid sulphatase enzyme.

Autonomic neuropathy

Damage to nerves supplying the skin, sweat glands, heart and blood vessels, sexual organs and viscera involved in autonomic regulation.

Peripheral neuropathy

Damage to sensory nerves arising from the hands and feet.

Hypo-aldosteronism

Decreased Na+ reabsorption in the distal part of the kidney tubules, decreased K+ and H+ secretion. Lower blood pressure Hyperkalemia Metabolic acidosis.

explain the mechanisms underlying the metabolic consequences of insulin deficiency

Decreased glucose uptake into muscle Decreased glycogen synthesis Increased glycogenolysis Decreased glycolysis Increased gluconeogenesis Increased lipolysis Increased ketosis Decreased lipogenesis

SIADH symptoms

Decreased level of consciousness Cognitive impairment: short-term memory loss, disorientation and confusion. Focal or generalised seizures Brain stem herniation (severe acute hyponatraemia) resulting in coma and respiratory arrest. Hypervolaemia: pulmonary oedema, peripheral oedema, raised jugular venous pressure and ascites.

Salt-wasting Congenital Adrenal Hyperplasia symptoms

Dehydration Poor feeding Diarrhea Vomiting Heart rhythm problems (arrhythmias) Low blood pressure Very low blood sodium levels Low blood glucose Too much acid in the blood, called metabolic acidosis (pronounced met-uh-BOL-ik as-i-DOH-sis) Weight loss Shock, a condition where not enough blood gets to the brain and other organs. Shock in infants with salt-wasting is called adrenal crisis. Signs include confusion, irritability, rapid heart rate, and/or coma.

LEVOTHYROXINE (synthetic T4)

Delayed onset of action Monitor clinical status and TSH Aim to achieve a normal TSH Danger of overdose: angina and heart failure.

Growth hormone exception

Despite being water soluble, growth hormone (GH) is bound to a protein in the plasma. Growth hormone-binding protein has the same amino acid sequence as the extracellular component of the GH receptor.

Low-dose dexamethasone suppression

Dexamethosone is a cortisol like hormone so would usually exert the same negative feedback effect. Currently, the most widely used test- administration of a small dose of dexamethasone (1 mg) at 11:00 p.m. followed by a measurement of serum cortisol early the following morning.

Mitochondrial diabetes

Diabetes and deafness (DAD) or maternally inherited diabetes and deafness (MIDD) or mitochondrial diabetes is a subtype of diabetes which is caused from a point mutation at position 3243 in human mitochondrial DNA, which consists of a circular genome. This affects the gene encoding tRNALeu.[1][2] Because mitochondrial DNA is contributed to the embryo by the oocyte and not by spermatozoa, this disease is inherited from maternal family members only.[1] As indicated by the name, MIDD is characterized by diabetes and sensorineural hearing loss.[1] This begins with a reduction in the perception of frequencies above approximately 5 kHz which progressively declines, over the years, to severe hearing loss at all frequencies.[1] The diabetes that accompanies the hearing loss can be similar to Type 1 diabetes or Type 2 diabetes; however, Type 1-like diabetes is the more common form of the two. MIDD has also been associated with a number of other issues including kidney dysfunction, gastrointestinal problems, and cardiomyopathy The A3243G mutation in mitochondrial DNA can be present in any tissue, however, it is more commonly present in tissues with lower replication rates such as muscle.[3] The presence of this mutation can lead to decreased oxygen consumption as a result of reduced function of the respiratory chain and a decrease in oxidative phosphorylation.[8] In some people, this reduction in function of the respiratory chain is suggested to be caused by unbalanced amounts of proteins that are encoded by mitochondrial DNA, due to the presence of the A3243G mutation.[3] However, in other people, the same amount of mitochondrial proteins are generated, but their stability is compromised due to the improper incorporation of amino acids at the UUR codons of the mitochondrial mRNAs. This is a result of the mutated tRNALeu(UUR) with its decreased function in protein synthesis.[8] A decrease in function of the respiratory chain as a result of a mitochondrial DNA mutation could result in a decrease of ATP production. This decrease in ATP could have detrimental effects on other processes in the body. One such process is insulin secretion by pancreatic Beta-cells.[3] In pancreatic Beta-cells, precise levels of ATP/ADP regulate the opening and closing of the KATP channel, which controls the secretion of insulin. When mutations in the mitochondria disrupt the ATP/ADP ratio, this channel cannot function properly and this can result in a person being deficient in insulin.[3] Since the age of onset is later in a person's life, it has been suggested that age plays a role in contributing, along with the reduced ATP/ADP ratio, to the slow deterioration of the function of B-cells. Hearing loss, as caused by the 3243 mitochondrial DNA mutation, is seen in the form of progressive cochlear dysfunction. Although the mechanism by which the mutation in the tRNALeu(UUR) causes this dysfunction of the cochlea is still under investigation, it has been hypothesized that it involves the ion pumps required for sound transduction.[9] As the mutation in the tRNALeu(UUR) leads to unbalanced amounts or unstable respiratory chain enzymes, respiration and oxidative phosphorylation are reduced, leading to lower levels of ATP.[3][8] Naturally, the most metabolically active organs in a person will be affected by this ATP deficiency. Included in these metabolically active organs is the cochlear stria vascularis.[1] The stria vascularis and the hair cells, both essential to sound transduction, make use of ion pumps to regulate the concentration of ions including K+, Na+, and Ca2+ using ATP. Without sufficient levels of ATP, these concentration gradients are not maintained and this can lead to cell death in both the stria vascularis and the hair cells, causing hearing loss Initially, the person is treated by dietary changes and hypoglycaemic agents. This does not last long before the person has to be started on insulin (within 2 years of diagnosis).

Diabetes insipidus

Diabetes insipidus is the result of too little ADH producing copious amounts of urine There are two types, cranial and nephrogenic

Diabetes and gangrene

Diabetes mellitus is a risk factor for peripheral vascular disease, thus for dry gangrene, but also a risk factor for wet gangrene, particularly in patients with poorly controlled blood sugar levels, as elevated serum glucose creates a favorable environment for bacterial infection

The pancreas and diabetes

Diabetes mellitus is one complication of chronic pancreatitis Cystic fibrosis-related diabetes- the thick secretions in cystic fibrosis can damage the beta cells in the pancreas with subsequent scarring Excessive thirst, urination, unexplained weight loss, hyperglycaemia Treatment: insulin, oral hypoglycaemias

Oral anti-diabetic agents

Dietary control of type II diabetes is preferable to drug treatment If diet fails, type II diabetics can be given oral anti-diabetic agents Three classes of anti-diabetic drugs: 1. Sulphonylureas: tolbutamine, glibenclamide 2. Biguanides: metformin 3. Thiazolenediones: piaglitazone

Diet, obesity and leptin

Dietary fat and fructose which do not stimulate insulin production do not increase leptin secretion, this may be one reason why such diets are associated with obesity

Chronic decreased glucocorticoid production can arise from:

Diseases affecting the adrenal gland that limit cortisol production. Diseases affecting the anterior pituitary that decrease its production of ACTH Diseases affecting the hypothalamus that decrease its production of CRH.

Which cells of the testis are especially sensitive to X-rays and anti-mitotic drugs?

Dividing cells of the germinal epithelium high dosages would cause atrophy of germinal cells; Sertoli cell population spared; infertility.

Anaplastic (unrecognisably thyroid cells) carcinoma

Do not contain NIS so cannot treat with radioactive iodine • Older patients 60y+ • Present as rapidly enlarging nodule plus compressive sx • Treatments • Thyroidectomy +/- tracheostomy • Ext beam radiotherapy • Chemotherapy: no good results • Very poor prognosis

Prolactin secretion inhibition

Dopamine released from the arcuate nucleus of the hypothalamus is released into the median eminence and normally inhibits prolactin secretion.

Suppression Test

Drink a glucose solution: sample every 20 mins for 4 hrs/ measure GH • Suppression due to rise in glucose No suppression seen with GH excess conditions eg. pituitary tumour of somatotrophs • Late rise due to the fall in glucose in response to a natural rise in endogenous insulin ie. a mini-ITT naturally induced at the end of the supression test

Drug treatment of thyroid disease

Drug class : thioureylenes Examples: Methimazole, propylthiouracil both inhibit iodination of tyrosine residues. Propylthiouracil also inhibits the peripheral conversion of T4 to T3 (the active hormone). Used for diffuse toxic goitre, nodular goitres are removed surgically. The drugs are orally active HOWEVER, because of large T4 reserve, the onset of the clinical effect is slow. Propylthiouracil has faster onset of clinical effect than methimazole because it also inhibits the conversion of T4 to T3 Unwanted effect: inhibition of granulocyte formation in the bone marrow.

BNF treatment summaries for obesity

Drug treatment should never be used as the sole element of treatment and should be used as part of an overall weight management plan. An anti-obesity drug should be considered only for those with a BMI of≥ 30 kg/m2, in whom diet, exercise and behaviour changes fail to achieve a realistic reduction in weight. In the presence of associated risk factors, it may be appropriate to prescribe an anti-obesity drug to individuals with a BMI of ≥ 28 kg/m2. A vitamin and mineral supplement may also be considered if there is concern about inadequate micronutrient intake, particularly for vulnerable groups such as in the elderly and younger patients.

Epididymis

Ductus epididymis: TS through head of anatomical epididymis: Rete testis and efferent ducts Proximal end, not much smooth muscle. Connective tissue running between the coils It is sufficient to be aware of their general structure The tubules sectioned here are ductus epididymis (tubules with regular epithelium and prominent microvilli); tubules with irregular epithelium are efferent ducts At the edge is a portion of the thick testicular capsule, the tunica albuginea. Note the regular tall columnar epithelium with apical microvilli; tubules surrounded by circular/spiral smooth muscle fibres merging into the connective tissue stroma Characteristically the ductus epididymis contains sperm within the lumen

Familial Partial Lipodystrophy 3 (MIM 604367): haploinsufficiency

Due to the non-functional allele there is only 50% expression of a functional gene product, so that the normal effects of PPARγ on gene expression are greatly reduced

Cellular Actions of Oxytocin: Establishment of maternal behaviour:

During parturition, there is an increase in concentration of oxytocin in csf, and oxytocin acting within the brain plays a major role in establishing maternal behaviour.

Gestational Diabetes Mellitus

During pregnancy Macrosomia (babies too big), resp distress, early delivery Resolves after delivery but may recur Risk factors: Obesity, family history T2DM, prev GDM ↑future risk of T2DM, hypertension Insulin, metformin Rx

Lactation

During pregnancy the breast develops the capacity to produce and release milk. This is under the control of the steroid hormones, placental lactogen and prolactin. The decrease in progesterone just prior to birth results in an increased sensitivity of the milk secreting alveolar cells to prolactin. Prolactin stimulates milk secretion by acting on receptors on alveolar cells. Suckling induces prolactin secretion via a neuroendocrine reflex. This reflex leads to a decrease in inhibitory dopamine (prolactin inhibitory factor) and an increase in the prolactin release. The milk is removed from the breast by the stimulation of the milk ejection reflex. In addition to stimulating prolactin secretion, thereby ensuring the availability of milk for a subsequent feed, suckling stimulates a second pathway that stimulates the release of oxytocin. Oxytocin acts on myoepithelial cells that surround alveoli cells thereby stimulating milk ejection.

Puberty

During puberty there is the gonadarche and adrenarche resulting in sexually dimorphic growth differences and econdary sexual characteristics Adrenarche is the adrenal androgen driven growth of pubic and axillary hair Secular trend towards an earlier age of onset of puberty

Human testis, adult: high power, iron haematoxylin and eosin

During spermiogenesis the cytoplasm of the spermatid is reduced and phagocytosed by the Sertoli cells as the nucleus condenses and the acrosome forms Synchronous development is enabled by hundreds of spermatids being connected to one another by very fine cytoplasmic processes that persist as the spermatozoa form and which break only when the spermatozoa are released into the lumen A- germinal epithelium containing the Sertoli cells, primary spermatocytes, spermatogonia

Oestrogen, FSH and LH

During the first part of the menstrual cycle, oestrogen provides negative feedback to the FSH-producing cells in the anterior pituitary, so FSH levels remain low. It also inhibits LH release. Shortly before ovulation, however, higher oestrogen levels stimulate LH release and this is what causes ovulation.

Describe the MAPK signal transduction pathway, and how dysregulation of this pathway relates to cancer.

EGFR is overexpressed in some epithelial cancers. In this case, a small amount of receptor can dimerize in the absence of ligand. Proximity of the cytosolic domains allows cross-phosphorylation. Since the tyrosine kinase activity is already present, this is enough to initiate signal transduction where the tyrosine-phosphates act as docking sites for Grb-2, which is attached to Sos, Sos catalyses the exchange of GDP for GTP on membrane-bound Ras, activating it., GTP:Ras binds and activates Raf, a membrane-bound protein kinase, RAF phosphorylates a series of protein kinases such as MAPK. This results in the phosphorylation of several transcription factors, altering their activity. an inappropriate 'grow and divide' signal is sent to the cell. A therapeutic antibody (cetuximab) targets the extracellular domain of the receptor, sterically blocking the ability of the receptor to dimerise. This has been successfully used in colorectal cancers.

Immunoassay: ELISA

ELISA works by exactly the same principle, but uses as its label linked to the second antibody, an enzyme, which generates colour when a suitable substrate is added. This is therefore an Enzyme Linked Immunosorbent Assay Much safer than radiolabelling

molecular mechanisms of nuclear ERs

ERs are in the nucleus and dimerise in response to their agonist. They recognise estrogen receptive elements (ERE) on DNA. Co-activators are recruited.

Innervation of the chromaffin cells

Each chromaffin cell is innervated by a cholinergic, pre-ganglionic sympathetic neurone. Derive from splanchnic nerves (exit CNS between T8 and T11). Some chromaffin cells form paraganglia - collections of chromaffin cells scattered in retroperitoneal and retropleural sites. Normal function unknown, but can (rarely) give rise to phaeochromacytomas.

Symptoms of Addison's disease

Early-stage symptoms are depression or flu-like • fatigue • muscle weakness • low mood • loss of appetite and unintentional weight loss • increased thirst Over time • dizziness • fainting • cramps • exhaustion • darkened skin, or darkened lips or gums

Glycaemic control and eating disorders

Eating disorders can be more common in teenagers with chronic illnesses, such as diabetes. The increased focus on eating and the weight gain associated with good glycemic control increase their susceptibility to eating disorders such as anorexia and bulimia. ​

Ectopic lipid deposition

Ectopic lipid deposition is the deposition of lipid in skeletal muscle and in the liver due to the inability of subcutaneous adipocytes to handle the load of fat storage. This may lead to an increase in other compounds, such as ceramide, that alter signalling pathways. Substances that inhibit adipogenesis e.g. TNF-alpha, angiotensin are implicated in this process.

The metabolic effects of nsulin

Elevated blood glucose stimulates the release of insulin which binds to cell receptors. It increases GLUT4 expression in the plasma membrane to increase glucose uptake especially in the liver, muscle and adipose tissue Increased glycogen synthesis in the liver and skeletal muscle in partiicular (If glucose is in excess triglycerides are formed from glucose in adipose tissue (lipogenesis)) Decrease in glycogenlysis in the liver Decreased use of other energy substrates in favor of glucose. Liver: increased glycogenesis. Decreased glycogenolysis and gluconeogenesis. Skeletal muscle: increased glycogenesis and glucose uptake Adipose: increased lipogenesis and glucose uptake

Late-Night Salivary Cortisol

Elevated cortisol in Cushing's syndrome between 23:00-00:00 is the earliest detectable abnormality. Cortisol is usually very low at this time, but in Cushing's syndrome, the value is elevated. many things may cause a false positive result, thus additional testing is always needed.

Tests for prolactinoma

Endocrine blood tests would be performed. Prolactin levels of 6,000mU/L would usually indicate raised prolactin due to stalk compression caused by a large non- functional tumour. large macroprolactionmas >1cm in diameter usually have >10,000 mU/L prolactin levels. Additional measures of other pituitary hormones can show pan-hypopituitarism due to compression of the remaining pituitary tissue due to the tumour. In this case cortisol, thyroxine, TSH, LH, FSH were all reduced. Identification of possible pituitary tumours can be carried out by MRI, or CT.

Types of Hormones

Endocrine: Act on cells far from the site of release. Are secreted into the blood. Only target cells express the receptor, e.g., insulin and adrenaline. Paracrine: Act on nearby cells only. They diffuse in the interstitial fluid and are rapidly inactivated by local enzymes, e.g., histamine. Juxtacrine: The hormone is either bound to the membrane (this requires physical contact between cells) or the hormone is secreted into the extracellular matrix. Autocrine: Act on the cell that released the hormone, e.g., T-cells and interleukin-2.

11 beta-HSD Inhibition

Endogenous mammalian compounds • Bile pigments (e.g. deoxycholate) • Sterols (e.g. cholesterol, lanosterol) • Steroids (e.g. progesterone) Iatrogenic • Carbenoxolone (GA ester) • Furosemide Other • Glycyrrhetinic acid (e.g. in liquorice, herbal remedies)

Uterus during menstruation

Endometrium and portion of myometrium, during menstruation (2nd day) Note the "weeping" of glandular and stromal debris, mixed with blood, into the uterine lumen

Control of [Catecholamine]

Epinephrine and norepinephrine concentrations dependent on: -synthesis and secretion -uptake and metabolism Uptake is more important than metabolism. Epinephrine and norepinephrine concentrations are controlled by post-ganglionic endocytosis.

What are the principal histological components of the mammary gland and what changes occur in each of these during pregnancy?

Epithelia - ducts Connective tissue - intra-, interlobular, interlobar; plus BV, nerves and lymphatics, fat Epithelium - proliferation of ducts; secretory units formed; secretory alveoli Connective tissue - progressive reduction in amount; blood vessels increase in number

Erythropoietin

Erythropoietin is a cytokine released by the kidney in response to low oxygen. It stimulates the transcription of genes in erythroid progenitors that prevent them from undergoing apoptosis, and stimulate them to differentiate into erythrocytes (RBCs). The use of supplemental erythropoietin to increase the level of erythrocytes in the blood is banned in international athletic competitions. The use of supplemental erythropoietin is also dangerous, as the surplus erythrocytes can clot small blood vessels. Several athletes have died of stroke during exercise due to erythropoietin doping.

Glycation and artherosclerosis

Examples of circulating proteins that may be modified by glucose to the first stage, are the complexes that carry cholesterol around in the blood and are known as low-density lipoproteins. These may become cross-linked to proteins in the extracellular matrix of the arterial wall and are then recognised by receptors known by the abbreviation RAGE on macrophages, a cell type that internalises the total protein complex, leading to pathological changes in the artery wall know as atherosclerosis.

HbA1c

Excess glucose increases glycation of Hb • We use HbA1c as a easily accessible measure of glycaemia • HbA1c reflects average glycaemia over past 90 days or so (dependent on red blood cell life)

Hypervitaminosis D symptoms

Excessive amounts of vitamin D in the body can cause hypercalcaemia Long-term complications include kidney stones, kidney damage, kidney failure, excess bone loss, calcification (hardening) of the arteries and soft tissues. Hypercalcaemia can also cause abnormal heart rhythms

Why must patients be "weaned off"of glucocorticoids?

Exogenous glucocorticoids e.g. dexamethasone, prednisolone, etc. suppress CRH / ACTH Adrenal cortex atrophies Risk of iatrogenic Addison's syndrome

Overexpression of agouti

Expression of agouti in the hypothalamus chronically antagonises Mc4r on particular neurons disrupting its function. These neurons normally act to inhibit feeding behaviour

Gametes Numbers

External fertilization requires large numbers of oocytes and spermatozoa. Mammals, fertilize internally reducing the numbers of eggs shed, in humans only one or two at a time, reducing the energy resources invested in egg production In fact, considerable egg wastage still occurs in mammals A woman acquires all her eggs when she is herself a fetus, with numbers peaking at around 7 million at 6 months of fetal life Thereafter, most eggs die in the ovary during fetal, neonatal and pubertal life.

The ovarian cycle follicular phase

FSH causes many primordial follicles to develop into primary follicles. These continue to develop into secondary follicles. The follicular cells surrounding the primary oocyte divide and secrete oestrogen. Usually one of the secondary follicles becomes dominant and develops into a mature Graafian follicle. The secretion of LH and FSH from the anterior pituitary also reach peak levels and the LH surge causes a rapid growth in the mature or Graafian follicle. The primary oocyte continues its meiotic process and arrests at metaphase II as a secondary ooctye. The graafian follicle subsequently ruptures, releasing the secondary oocyte into the pelvic cavity. The Graafian follicle collapses and develops into the corpus luteum.

FSH. And LH action in males

FSH stimulates spermatogenesis LH stimulates the testicular interstitial cells to produce testosterone. There is very little oestrogen production. The released FSH and LH feed back to the hypothalamus to inhibit further release. The elevated testosterone levels also inhibit further FSH, LH, and GnRH release.

FSH and LH

FSH travels in the bloodstream from the anterior pituitary to the ovaries. At the ovaries FSH promotes follicular growth. The increased follicular growth promotes oestrogen production. The small increases in oestrogen levels inhibit the release of FSH and LH into the blood, but promote their accumulation in the anterior pituitary.

Family I receptors

Family I, non-steroid receptors i.e., RAR, VDR, and TR, bind preferentially to response elements composed of two half-sites arranged as tandem repeats These receptors form heterodimers with the retinoid X receptor RXR, even in the absence of ligand, and exert a repressive silencing effect on basal promoter activity that is reversed upon ligand binding

Family II receptors

Family II receptors comprise 'orphan nuclear receptors' (oNRs) because they lack known physiological ligands, except RXR

Family III receptors

Family III NRs are the classic steroid hormone receptors: glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR), and oestrogen receptor (ER) Although most steroid receptors are located in the nucleus, ~ 5% of steroid receptors localizes to the plasma membrane, including classic steroid receptors (ERs, PR, and AR).

Obesity treatment strategies

Food intake is determined by a combination of homeostatic and hedonic factors - Targeting of peripheral factors, that signal energy balance - Targeting of central nervous pathways • Can nutrient absorption be prevented? Consume non-nutritious food- Interfere with gut epithelium Increase energy expenditure?- Interfere with mitochondrial function Gastric bypass surgery reduces the capacity to eat?

Consequences of Gastric bypass surgery for GLP-1

Fasting GLP-1 levels after these procedures are not altered, including compared with obese patients who experienced similar weight loss achieved by a low-calorie diet (1,300-1,800 kcal/day) or by gastric band Enhanced postprandial GLP-1 responses are observed • The GLP-1 response is greater after RYGBP than after SG (approximately fivefold and threefold enhancement of preoperative response, respectively) • The enhanced GLP-1 response was not observed in obese patients who were calorically restricted • There is usually a progressive increase in GLP-1 response during the first postoperative year • The enhanced GLP-1 responses persist in the long term • Changes in GLP-1 secretion are in stark contrast to the relatively unaltered secretion of its incretin counterpart GIP

Insulin resistance

Fat in ectopic sites- liver, heart, pancreas Activation of the immune system causing inflammation- possibly reacting to fat at the ectopic sites, oral bacteria Increase in pro-inflammatory cytokines like TNF and IL-6. This flows to the liver and changes insulin sensitivity leading to insulin resistance. Insufficient insulin secretion

Growth hormone effects in adipose tissue

Fatty acids and glycerol are liberated from triglycerides (lipolysis), and are released into the blood. This allows tissues to shift from glucose to other energy sources

Diabetic foot care

Feet should be checked for tiny cuts and scratches before going to bed each night Shoes checked before putting them on. Proper footwear is critical to avoid pressure sores.

Female development

Female development is driven by adrenal steroids The average age for girls to start puberty is 11, while for boys the average age is 12.

Gametes

Fertility requires quality gametes: • 40% of sub-fertility is caused by a male factor- low testosterone, low sperm movement towards the egg • 20% is related to poor egg quality • 30% of all miscarriages are a result of chromosomal errors in the egg

Fertilization

Fertilization is a multistep process of zona and plasmalemma penetration by a single sperm. Sperm penetration is developed by the acrosome reaction and the binding to key proteins (ZP3) in the zona pellulida.

Foetal insulin

Fetal insulin stimulates growth more than glucose control However, in a diabetic mother, increased glucose transfer to the fetus stimulates excessive insulin secretion, causing increased growth (macrosomia), difficult delivery (e.g. shoulder dystocia) and risk of neonatal hypoglycaemia

Macular edema

Fluid leaks into the part of the eye where sharp, straight-ahead vision occurs, causing swelling and blurred vision.

SIADH treatment

Fluid restriction Hypertonic saline Urea Demeclocyline is an antibiotic, inhibits cAMP downsteam of the V2R Vasopressin 2 receptor antagonists- vaptans

Glucose storage

Following phosphorylation by either hexokinase or glucokinase, the glucose-6-phosphate is either incorporated into glycogen as in muscle and liver or into triglyceridges as in adipose tissue

Placental hormones

Following the 4th month the rising levels of placental estrogen and progesterone are sufficient to maintain the pregnancy. Relaxin human chorionic somatomammotropin (hCS) placental produced corticotropic releasing hormone

Malabsorption syndrome

For example Coeliac disease causes proportional growth failure GH normal • e.g. gluten-sensitive enteropathy • Prompt response to gluten-free diet

Pregnancy

For healthy pregnancy to proceed to term, changes need to occur to prevent immune mediated rejection of the semi-allogenic fetus. At the same time, the immune system must maintain, or enhance, protection of mother and fetus from external pathogens. In pregnancy hCG is critical as it rescues the corpus luteum from involution, and this maintains progesterone secretion by the ovarian granulosa cells. hCG's usefulness as a diagnostic marker of pregnancy stems from the fact that it is one of the earliest secreted products of the conceptus. The placental production of hCG peaks between 8-10 weeks of gestation, and remains at a lower level for the remainder of pregnancy. hCG is support of the corpus luteum, taking over for LH on ~8th day after ovulation, 1 day after implantation, when b-hCG is first detected in maternal blood. Implantation occurs 5-6 days after ovulation and hCG must appear by 4 days after ovulation to rescue corpus luteum. Hence, blastocyst need to implant within a narrow window of opportunity.

Nuclear transfer of the cytoplasm receptors

For receptors that are localised in the cytoplasm like the Glucocorticoid receptor, hormone binding induces a conformational change that results in dissociation of the chaperone complex, allowing it to translocate to the nucleus by means of its NLS.

Immunoassay: Competitive binding assay for smaller hormones

For smaller hormones eg T3 / T4 and all steroids, must use another design which does not rely upon the formation of a "sandwich" In each tube a constant amount of antibody and radiolabelled hormone is added. Then to each one a variable amount of that same hormone is added. The unlabelled standard T4 competes more effectively with the constant amount of radiolabelled T4, meaning there is less radioactivity. The control tube has radiolabelled hormone and antibody. Both are used to form the calibration curve. So for a patient sample, we measure the radioactivity and read off the calibration curve to find the amount of hormone

KATP channels are found in a variety of tissues

Found in heart muscle In the pancreatic beta cells for glucose dependent insulin release Vascular smooth muscle tone In central and peripheral neurons as glucose sensors in the brain Muscle fatigue Protective during ischemia Ischemic preconditioning

Proliferative retinopathy

Fragile, abnormal blood vessels develop and leak blood into the center of the eye, blurring vision.

Prolactinoma

Functional pituitary tumours - rare PRL hypersecretion (Prolactinoma) - Most common functional pituitary tumours can be shrunk (to operative size) by administration of a dopamine agonist - e.g. bromocriptine. Prolactinomas cause galactorrhea and suppression of the HPG axis.

GH and prolactin structure

GH and prolactin share similar structures; approx. 190 aa peptides with internal disulphide bonds at equivalent positions. GH and prolactin work through structurally homologous receptors and are capable of stimulating each other's receptors to limited degree.

Hypersecretion of Selected Anterior Pituitary Hormones - 1

GH hypersecretion - Gigantism (infancy)/ Acromegaly (adulthood) TSH hypersecretion (Very rare) - High [TSH] usually reflects hypothyroidism

Growth Of Long Bones

GH increases growth plate thickness is the response used for the classical in vivo bioassay for

GHRH action

GHRH (10aa) and Somatostatin (14aa) are small hypothalamic peptides Both act on G-protein coupled receptors on somatotrophs GHRH activates adenylate cyclase Somatostatin acts via via an inhibitory G protein to inhibit adenylyl cyclase

Incretin insulin stimulation mechanism

GIP and GLP-1 bind to their GCPRs which increase Adenylate cyclase and cAMP and protein kinase A Protein kinase A closes the K+ channels, depolarises, open VDCC, Ca2+ entry causes insulin release.

Incretins and insulin

GIP release from duodenal cells is stimulated by lumen hyperosmolarity and contributes to the early stimulation of insulin secretion in response to the hyperglycemia that results from intestinal digestion and absorption of carbohydrate.

Incretin mimetics / GLP-1 analogues

GLP-1 receptor agonists exenatide (Byetta), twice-daily injection or one weekly injection Liraglutide-liraglutide (Victoza), once-daily injection Improve glycemic control, Low risk of hypoglycemia, Cause sustained weight loss -Expensive -Nausea a common side effect

Human prostate Bbi

Ganglion in the connective tissue 1. Nucleus of a fibroblast in a connective tissue sheath 2. Nucleus of a Schwann cell 3. Myelinated cell? 4. Capillary 5. Nucleolus of a neurone in the ganglion 6. 7. Cytoplasm of a neurone 8. Nucleus of a satellite cell 9. Capillary 10. Something in the nerve bundle

People with diabetes sometimes experience gastroparesis. Describe what this is, and what other symptoms is can lead to.

Gastroparesis means food stays in your stomach longer than normal. This can lead to bloating, stomach pains, diarrhea and/or constipation. to avoid getting bloated eat lots of smaller meals throughout the day.. Eating most of your food at the start of the day is also recommended, as going to bed on a full stomach can often result in bloating.

Physiological actions of T3 and T4

Generalised: act on target cells in multiple tissues T3 is more bioactive than T4 • Increase basal metabolism • Promote growth and development with GH • positively chronotropic and inotropic • regulates alertness development of fetal brain

Dyshormonogenesis

Genetic defects in • NIS • Thyroglobulin • Pendrin • Thyroperoxidase • Iodothyrosine deiodinase • Dual oxidase 2 • Hypothyroidism plus goitre

Hashimoto thyroiditis

Genetic links to HLA DR5, CTLA4 Initially hyperthyroid with a brief release of stored thyroid hormones Cytotoxic lymphocytes cause apoptosis of thyroid cells Autoimmune +ve anti-TPO Abs cause necrosis and apoptosis The thyroid is infiltrated by nodules of lymphoid cells on microscopy May be a part of PGAIS type 2

Gestational diabetes mellitus

Gestational diabetes is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy. Risk factors include being overweight, previously having gestational diabetes, a family history of type 2 diabetes, and having polycystic ovarian syndrome It increases the risk of pre-eclampsia, depression, and of needing a Caesarean section. Babies born to mothers with poorly treated gestational diabetes are at increased risk of macrosomia, of having hypoglycemia after birth, and of jaundice. Long term, children are at higher risk of being overweight and of developing type 2 diabetes.

Gestational diabetes

Gestational diabetes is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy.[2] Gestational diabetes generally results in few symptoms;[2] however, it increases the risk of pre-eclampsia, depression, and of needing a Caesarean section.[2] Babies born to mothers with poorly treated gestational diabetes are at increased risk of macrosomia, of having hypoglycemia after birth, and of jaundice.[2] If untreated, diabetes can also result in stillbirth.[2] Long term, children are at higher risk of being overweight and of developing type 2 diabetes.[2] Gestational diabetes can occur during pregnancy because of insulin resistance or reduced production of insulin.[2] Risk factors include being overweight, previously having gestational diabetes, a family history of type 2 diabetes, and having polycystic ovarian syndrome.[2] Diagnosis is by blood tests.[2] For those at normal risk, screening is recommended between 24 and 28 weeks' gestation.[2][3] For those at high risk, testing may occur at the first prenatal visit.[2] Maintenance of healthy weight and exercising before pregnancy assist in prevention.[2] Gestational diabetes is treated with a diabetic diet, exercise, medication (such as metformin), and sometimes insulin injections.[2] Most women manage blood sugar with diet and exercise.[3] Blood sugar testing among those who are affected is often recommended four times a day.[3] Breastfeeding is recommended as soon as possible after birth.[2] The precise mechanisms underlying gestational diabetes remain unknown. The hallmark of GDM is increased insulin resistance. Pregnancy hormones and other factors are thought to interfere with the action of insulin as it binds to the insulin receptor. The interference probably occurs at the level of the cell signaling pathway beyond the insulin receptor.[21] Since insulin promotes the entry of glucose into most cells, insulin resistance prevents glucose from entering the cells properly. As a result, glucose remains in the bloodstream, where glucose levels rise. More insulin is needed to overcome this resistance; about 1.5-2.5 times more insulin is produced than in a normal pregnancy.[21]

Gigantism

Gigantism is high prepubertal GH due to a benign tumour of the somatotrophs Autonomous, unregulated, non-pulsatile GH secretion Excessive early growth and height attainment surpasses growth potential: Prolonged pre-pubertal linear growth period prior to an exaggerated growth spurt

Girls: Tanner Stages

Girls - breast development • Stage 1: Prepubertal • Stage 2: Breast bud stage with elevation of breast and papilla; enlargement of areola • Stage 3: Further enlargement of breast and areola; no separation of their contour • Stage 4: Areola and papilla form a secondary mound above level of breast • Stage 5: Mature stage: projection of papilla only, related to recession of areola

Glomerular abnormality/pyelonephritis

Glomerular abnormality due to changes in basement membranes by glycation. Proteins like albumin leak through AGEs appear to give rise to the severe modification of these proteins often with internal cross-linking within the protein and external cross-linking with other proteins. this leads to impairment of the normal turnover of these proteins There is distortion of the structure of the collagen leading to the formation of nodular structures that enhance the permeability of the blood vessels. glomerular basement membrane also becomes nodular (Kimmelstiel-Wilson nodules) with loss of function as a permeability barrier allowing albumin to appear in the urine (microalbuminuria). Renal disease is an important cause of death in diabetes and the presence of albumin in the urine is a useful aid for prognosis.

Glucagon and glycogen

Glucagon increases the net catabolism of glycogen by: increasing the phosphorylation of glycogen synthetase Glucagon activates adenylyl cyclase which increases cAMP activates PKA which activates phosphorylase kinase. By phosphorylation, it activates glycogen phosphorylase Glucagon also inhibits phosphoprotein phosphatase preventing the dephosphorylation of glycogen phosphorylase.

Glucagon

Glucagon is synthesized in pancreatic α cells. Preproglucagon is encoded on chromosome 2. Within the rough ER of the pancreatic α cells, preproglucagon is processed prohormone convertases 1 and 2 to form a 29 amino-acid peptide hormone, glucagon. Glucagon is a single polypeptide chain. It is stored as granules in cytoplasmic vesicles until release is stimulated. Although (in contrast to insulin), zinc is not an absolute requirement for the synthesis or secretion of glucagon, metal complexes with glucagon increase the half-life of this peptide hormone. an increase in the plasma glucose concentration suppresses glucagon release whereas a fall in plasma glucose increases the synthesis and secretion of glucagon in pancreatic α-cells.

Control of fat metabolism by glucagon

Glucagon tends to inactivate the enzyme acetyl-CoA carboxylase, decreasing the synthesis of fatty acids to stimulate fat catabolism. This will spare glucose metabolism / promote gluconeogenesis from glycerol Glucagon also activates PKA which phosphorylates and hence activates HSL

Glucocorticoids

Glucocorticoids like cortisol increase plasma glucose concentration

Contraception

Health need: • given choice, most women prefer limiting pregnancies • 121 million unintended pregnancies/year • 73.3 million abortions/year, 45% of which unsafe • 5 -13% of all pregnancy-related deaths are due to unsafe abortions

Insulin secretion mechanism

Glucose diffuses through GLUT2 into the beta cell Glucose kinase puts a phosphate from ATP onto the glucose to make glucose-6-phosphate (this traps it inside the cell) G-6-P generates ATP through the Krebs cycle High ATP:ADP ratio closes the ATP-sensitive K+ channel so K+ stays in This leads to depolarisation which opens L-type Ca2+ channels This increases Ca2+ entry which cause the secretory granules to fuse with the membrane releasing insulin and C-peptide (sometimes used as a proxy marker)

Glucose Disposal

Glucose disposal = the rate of uptake into peripheral tissue Insulin mediated Skeletal muscle + adipose tissue Non-insulin mediated CNS + other tissues The liver can take up glucose or release glucose

Blood glucose

Glucose is essential for cell metabolism, so BGL are usually maintained between 4-7 mmol/L (72-126 mg/dL) for optimum cell function. Blood glucose provides accurate information about how the body is controlling glucose metabolism. Blood glucose is indicated in a range of conditions: Diabetes Seizures Enteral and parenteral feeding Liver disease or pancreatitis Head injury or unconsciousness Stroke Alcohol or drug intoxication Sepsis

Lens opacity

Glycation of crystallin - the clear protein of the lens. Accumulation of polyols and osmotic disturbance

Growth hormone effects in skeletal muscle

Glycogenesis is stimulated. Decreased glucose uptake

Growth hormone effects in the liver

Glycogenolysis and gluconeogenesis are stimulated Cell liver glucose concentration rises Glucose is secreted into the blood, raising plasma glucose concentration.

FSH and LH release in males

GnRH reaches the FSH and LH-secreting basophilic cells in the anterior pituitary and binds to G protein-coupled receptors in the phosphoinositide system, elevating cell Ca2+ concentration that triggers the exocytotic release of FSH and LH. In males, there is pulsatile release of GnRH at a constant frequency. This results in pulsatile release of FSH and LH.

FSH and LH release in females

GnRH reaches the FSH-secreting and LH-secreting basophilic cells in the anterior pituitary and binds to G protein-coupled receptors in the phosphoinositide system, elevating cell Ca2+ concentration that triggers the exocytotic release of FSH and LH.

Male Hypothalamo- Pituitary Gonadal Axis

GnRH released from the hypothalamus act on the gonadotrophins cells in the anterior pituitary to release FSH and LH LH stimulates the Leydig cells to secrete testosterone. Testosterone negatively feeds back on the gonadotrophins A Y chromosome the testes determining gene, internal genitalia male Rare where XX, translocation of the gene.

Hormonal control of male reproductive functions

GnRH stimulates the gondotrophic cells of the anterior pituitary to increase the secretion of Leutinizing hormone (LH) and Follicle stimulating hormone (FSH). LH binds to the receptors of the Interstitial Cells of Leydig between the seminiferous tubules and stimulates the secretion of testosterone. FSH and testosterone cause the Sertoli cells to produce Androgen-binding protein (ABP). This protein binds to testosterone and helps maintain high testosterone levels near the spermatogenic cells.

explain the endocrine control of bone metabolism

Gonadal steroids maintain skeletal mass- oestrogen deficiency is linked to post-menopausal osteoporosis. Insulin, GH and thyroid hormones promote skeletal growth and maturation. Calcitonin acts to inhibit osteoclasts Glucocorticoid excess results in decreased bone density. PTH stimulates osteoclasts to increase their RANKL expression, promoting their recruitment and differentiation. they release Ca2+ from bone. Vitamin D promotes bone breakdown by osteoclasts

Gonadarche

Gonadarche is where there is increased GnRH, gonadotrophins and gonadal steroids during pubertal activation. Pulsatile GnRH secretion is the key and primary event underlying gonadal activation. 1st changes- increased night gonadotrophin secretion There is a critical body weight / body fat needed that is permissive for puberty- when athletes lose weight e.g. the gonadal axis is turned off. This attainment is being achieved at progressively earlier ages during the last century

Causes of hyperthyroidism

Graves' disease Multinodular goitre or Toxic adenoma Thyroiditis: subacute, Hashimoto, De Quervain Ectopic TSH: hCG in early pregnancy, recombinant TSH Drugs: Amiodarone, Exogenous iodine (Jod- Basedow), Thyroxine Ectopic thyroid tissue: metastases from thyroid carcinoma, struma ovarii Pituitary disease: TSHoma

Graves' disease

Graves' disease is an autoimmune disease where autoantibody against TSH receptor binds and activates the receptor TSH-R Abs are not subject to negative feedback, as is TSH therefore thyroid stimulation persists resulting in thyrotoxicosis

GRB-2 in the MAPK pathway

Grb-2 attached to Sos binds to the tyrosine-phosphates, which was phosphorylated by the binding of EGF to each EGFR monomer induces a structural change that allows the monomers to dimerize where the proximity of the cytosolic domains allowed cross-phosphorylation. The Sos catalyses the exchange of GDP for GTP on membrane-bound Ras, activating this kinase. A series of protein kinases are phosphorylated and activated, resulting in the phosphorylation of several transcription factors, altering their activity.

Growth deficiency in children

Growth hormone deficiency in children Growth hormone use following cranial irradiation Small for gestational age (SGA) •Growth delay in children with chronic renal failure •Turner Syndrome •Prader-Willi Syndrome In Adult: •Growth hormone deficiency continued into adulthood

Metabolic effects of growth hormone

Growth hormone is an important metabolic hormone, which stimulates net protein anabolism, lipolysis, and linear bone growth.

Growth hormone

Growth hormone is ecreted from somatotrophs in the anterior pituitary from preformed granules

GH Replacement?

Growth hormone receptor-deficient people Laron Syndrome do not get two of the major diseases of aging, cancer and diabetes • A 22-year study followed 100 Laron's along with 1,600 relatives of "normal stature." • Only one non-lethal case of cancer was diagnosed. As far as the 1,600 relatives go, 5% developed diabetes in the same time period while 17% were diagnosed with cancer • Therefore GH activity in adults who are beyond their growing years may be harmful!

Growth hormone release inhibition

Growth hormone release is inhibited by somatostatin and also by glucocorticoids.

Growth hormone release stimulation

Growth hormone release is stimulated by ghrelin which is involved in the control of food intake and by androgens and oestrogen where its release in adolescence is linked to sexual maturation.

Growth hormone secretion

Growth hormone secretion is also pulsatile. It stimulates the liver to release insulin-like growth factor (IGF-1). Growth hormone and IGF-1 inhibit further growth hormone secretion acting both on the anterior pituitary and the hypothalamic arcuate nucleus.

Effects of Growth Hormone

Growth hormone stimulates of cartilage growth and new bone formation. increased liver secretion of insulin-like growth factors (IGF-1 and -2) Although it is water soluble, some 50% is carried in the plasma bound to a protein identical in structure to the extracellular portion of the hormone's peripheral receptor. There is a diurnal pattern to its secretion with peaks during sleep.

Growth delay in chronic renal failure

Growth impairment is a common problem in children with chronic kidney disease (CKD) and is associated with significant morbidity and mortality [1,2]. Several factors may contribute, including inadequate nutrition, metabolic acidosis, renal osteodystrophy, and insensitivity to the action of growth hormone (GH) [ CKD-mineral and bone disorder (CKD-MBD), metabolic acidosis, anaemia, loss of electrolytes and water and disturbances of the somatotropic and gonadotropic hormone axes also contribute to growth failure. CKD is a state of growth hormone (GH) insensitivity that is characterized by deficiency of functional insulin-like growth factor 1 (IGF1) due to reduced GH receptor expression in target organs such as the liver and disturbed GH receptor signalling via the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) pathway due to inflammation-induced suppressor of cytokine signalling (SOCS) expression and increased IGF binding capacity due to excess of IGF binding proteins (IGFBPs). Finally, reduced release of hypothalamic gonadotropin-releasing hormone (GnRH), due to uraemia-related inhibitory factors such as angiotensin II (ANGII) and steroid treatment, might result in decreased circulating levels of bioactive luteinizing hormone (LH), hypogonadism and reduced pubertal growth spurt.

Gα subunits

Gαs activates adenylyl cyclase, increases [cAMP] Gαi inhibits adenylyl cyclase, decreases [cAMP] Gαq activates phospholipase C, increases [DAG], [IP3] and [Ca++] Etc. There are also multiple Gβ and Gγ isoforms. The Gβγ complexes may alter specificity of receptor-G-protein binding, co-operate in transduction, or shut pathways down.

Hepatocyte growth factor

HGF is produced in adipose tissue, and elevated in the plasma in obesity. Disrupts adherens junctions, promoting cell dispersal. Hepatocyte growth factor also has angiogenic properties in tumours

Hormone Response Elements

HRE DNA sequences to bind to a specific hormone receptor complex and regulate transcription They are commonly a pair of inverted repeats separated by three nucleotides as receptors binds as a dimers A gene may have many different response elements, allowing complex control to be exerted over the level and rate of transcription

Hormone-sensitive lipase

HSL catalyses the rate-determining step in fat metabolism- TAG to DAG plus NEFA

High risk of developing foot infections

Has had diabetes for more than 10 years History of smoking Older than 40 years Reduced peripheral pulses

What is HbA1C?

HbA1c is the percentage of non-enzymatic glycosylation of Hb, the attachment of a glucose group Haemoglobin remains glycated for the lifetime of the red blood cell, which is around three months meaning HbA1C gives a measure of how good glycemic (blood glucose) control has been over the previous three months. Ideally the HbA1c should be below 7%.

Long term complications of diabetes

Heart and vascular disease Atherosclerosis Coronary Artery Disease Peripheral vascular disease Blindness (Retinopathy) Stroke Kidney failure Renal artery disease Nephropathy Amputations Diabetic foot Neuropathy peripheral and autonomic Erectile dysfunction

Epididymis A

Here a few tubules are cut in true cross section. Note regularity of the columnar epithelium apical specialisation of epithelial cells with microvilli. 2. How many types of cell are present in the epithelium? Note also the smooth muscle of the tubule and the surrounding connective tissue containing fibroblasts, collagen fibres and small blood vessels. As you get closer to the vas deferens, the amount of smooth muscle increases to 3 layers. Nuclei of spermatozoa in the lumen.

Inhibition of Glucagon Secretion

High Glucose GLP-1

Pseudohypoparathyroidism

High PTH but there is renal resistance to it Normal GH proportionate limbs not achieving full growth potential round face short 4th metacarpal

blood flow in the thyroid gland itself

High blood flow- twice that of the kidney for delivery of I- and TSH and export of T3 and T4 A net of capillaries surround each thyroid follicle This is responsible for the audible "bruit" of an overactive thyroid gland like in Grave's disease

Phaeochromocytomas

High blood pressure- don't respond to anti-hypertensive medication pounding headaches heart palpitations flushing of the face nausea • Phaeochromocytomas are derived from adrenal medulla catecholamine-producing chromaffin cells, whereas extra- adrenal paragangliomas arise from chromaffin cells outside the adrenal (ie. a phaeochromocytoma is an intra- adrenal paraganglioma).

Diabetes signs

High blood sugar level fasting plasma glucose > 7mM, random glucose levels > 11mM Excessive urination, glucosuria, thirst Muscle wasting, Weight loss, Extreme fatigue

Diet-induced obesity

High fat diet- mice fed on this diet exhibit increased weight gain, modest hyperglycaemia, insulin resistance etc used as a model of impaired glucose tolerance and early Type II diabetes Cafeteria diet - Standard chow +assortment of human snack items (highly palatable, energy dense) ad libitum. This diet encourages hedonic feeding. CAF-fed consumed ~30% more calories/day (HFD decreased gram intake, to normalise caloric intake), and gained the most weight. They also had worse hyperglycaemia, highest levels of plasma FFA, higher levels of infiltrating macrophages and 'crown-like structures' and dramatically altered pancreatic islets. This may be a better model of metabolic syndrome than the HFD diet.

Glucose and glucagon

High glucose, high ATP:ADP ratio, closure of K+ channel inactivation of Na+ channel, less depolarisation, closure of P/Q-type Ca2+ channel less Ca2+ less release of glucagon

Primary hyperparathyroidism

High levels of PTH PTH stimulates conversion to active Vitamin D increase Ca2+ and phosphate absorption in the intestines It stimulates osteoclasts which release Ca2+ from bone. PTH blocks the reabsorption of phosphate at the proximal tubule and increases reabsorption of calcium from the distal tubule hypercalcaemia accompanied by phosphaturia

Adrenal Tumours

High risk surgery with excess catecholamines under anaesthesia First need to block alpha-adrenoceptors, must be non-competitive so there's no wash out Control blood pressure, could use calcium channel blocker Beta-blocker

Human prostate A- normal glands

Highly vascularised fibromuscular connective tissue separates the glandular elements It can be difficult to differentiate the smooth muscle cells from the fibrous connective tissue

Monitoring glycaemic control

Home BG monitors provide rapid spot reading using capillary blood HbA1C provides a long-term measurement Fructosamine which measures glycated albumin is an alternative measurement if there is haemoglobinopathy- Medium-term

Gα GPCRs

Hormone-bound receptor causes the exchange of GDP for GTP, activating the Gα subunit. The (dissociated) Gα subunit then interacts with an enzyme, until it hydrolyses the GTP to GDP, becoming inactive again (takes seconds to minutes)

Hydrophilic hormone action

Hormones act by altering intracellular proteins; because hydrophilic hormones can't cross the plasma membrane, they act by binding to receptors on the outer plasma membrane surface of the target cell. The binding of the hormone to the receptor causes an increase in the concentration of 'second messenger' in the cell, which alters the activity of other proteins.

Classes of Hormone

Hormones are grouped into three broad classes based on their biochemical structure: Peptides & proteins Amines Steroids

Anterior lobe of the pituitary gland

Hormones of the anterior lobe are synthesised by the parvicellular neurones in the hypothalamus (GHRH, GHIH TRH, CRH, GnRH, PIH) and terminate in the median eminence. From here they diffuse into the primary capillary plexus and go through the hypophyseal portal veins to the anterior lobe. Here the hormones stimulate or inhibit the anterior lobe cells to secrete hormones that diffuse into the secondary capillary plexus. This leaves to enter the systemic venous system

Specific hormonal gene regulation

Hormones regulate the function of their target cells via receptor mediated pathways. Water soluble hormones interact with their receptors at the cell surface and have their effect through second messengers Hydrophobic hormones that are lipid soluble and therefore can pass through the cell membrane interact with intracellular receptors cytosolic or nuclear.

Until recently Orlistat was the only anti-obesity drug not withdrawn from the market due to side effects

However, compliance can be low because of unpleasant gastric effects Higher specificity (targeting specific receptor subtypes only) • Combination drugs (two independent targets combined - higher potency for weight loss; or at lower doses less side-effects)

Recombinant human insulin

However, the majority of insulin now in clinical use is recombinant human insulin; The two cDNA sequences encoding the α- and β-chains of insulin are translated in E.coli, isolated, purified and chemically combined with the 3 disulphide bonds at the appropriate molecular positions.

Oviduct

Human fallopian tube (ampulla): very low power, haematoxylin and OG erythrosin The main features are obvious at this low power of magnification: extensively folded mucosa smooth muscle layer numerous blood vessels in adventitia

Hydrophilic Hormones

Hydrophilic hormones are proteins (e.g. insulin), peptides, or amino acid derivatives (e.g. adrenaline) that can dissolve in the plasma without needing transport by binding proteins, although there are exceptions about half of the catecholamines are loosely bound to plasma albumin

list the clinical consequences of MR hyper-stimulation by cortisol

Hyper- stimulation of MR by cortisol results in: • anti-natriuresis • alkalosis • increased fluid resorption • hypervolemic hypertension • kaliuresis leading to hypokalemia • hypokalemia (potentially fatal) • Muscle weakness (including cardiac), fatigue Why isn't the anti-natriuresis accompanied by hypernatremia?

Hypercalcaemia and Cancer

Hypercalcaemia is a common feature of malignant disease When malignant cells metastasise to bone, they secrete "osteoclast-activating factors" such as prostaglandins and interleukins In addition, a common feature of cancerous cells including those that have not metastasised is the synthesis of parathyroid hormone related peptide (PTHRP): a hypercalcaemic hormone with a structure similar to that of PTH.

clinical symptoms associated with increased production and/or action of adrenal corticosteroids

Hyperglycaemia (increased hepatic gluconeogenesis, increased protein catabolism and increased glycogenolysis in the liver and muscle) • Insulin resistance (diabetes mellitus NIDDM in extreme) • Redistribution of body fat (increase lipolysis in limbs via hormone sensitive lipase; increased central lipogenesis - moon face (+hirsutism due to the gonadal hormones from POMC?), buffalo hump (fat distribution between the scapulas) and abdominal adiposity (can see abdominal striae, stretch marks exaggerated due to weakened collagen) • Increased bruising due to weakened vessel walls • Immune suppression (involution of lymphatic tissue and thymus) - Anti-inflammatory action (PLA2) - Lymphatic / thymus involution - Antagonise cytokine action • Increased stomach acid (link to gastric ulcer) • Osteoporosis • Hyperandrogenism (male-pattern baldness, acne and hirsutism - gonadal dysfunction + cliteromegaly = female pseudohermaphroditism; precocious puberty in extreme) • Hypokalemia (possible neuropathy) • Anti-natriuresis • Alkalosis • Hypervolemic hypertension (headaches, blurred vision & stroke)

Effects of increased aldosterone

Hypernatraemia High blood pressure Oedema, ascites Hypokalaemia

Adrenomedullary Hyperfunction

Hypersecretion of epinephrine results in: hypertension and hyperglycaemia (+ insulin resistance) Usually due to phaeochromocytoma Phaeochromocytoma may be associated with medullary carcinoma of the thyroid: • Multiple Endocrine Neoplasia (MEN)2

Hypertension and obesity

Hypertension is risk factor for cardiovascular disease and closely correlated with increased BMI It is even more closely correlated with measures of abdominal adiposity. Weight loss can decrease hypertension

What effects will hyper- or hypo-ventilation have on serum calcium levels?

Hyperventilation causes alkalosis causing more calcium to associate with protein. This results in a decrease in the concentration of free Ca 2+ ions (hypocalcaemia). Hypoventilation causes a resultant acidosis meaning less proteins and ions associate with calcium

A fall in calcium levels

Hypocalcaemia stimulates release of PTH directly by inactivation of the calcium sensing receptors (CaR) on parathyroid cells. The plasma PTH concentration increases within minutes of a fall in serum calcium levels. 1α-hydroxylase increases active vitamin D - 1,25 dihydroxyvitamin D (calcitriol) in the kidney. Prolonged hypocalcaemia for weeks or months promotes the development of parathyroid gland hyperplasia- characteristic of hyperparathyroidism.

List the clinical symptoms associated with decreased production and/or action of adrenal corticosteroids

Hypoglycaemia (tiredness and weakness) Vomiting Hyper-pigmentation (skin creases and mouth) due to overproduction of POMC to compensate Failure of adrenarche due to low levels of androgens not seen as much in healthy men due to testosterone (sparse growth of axillary and pubic hair in girls) Hyponatremia / natriuresis • Hyperkalemia / anti-kaliuresis • Acidosis • polyuria leading to polydypsia • Hypovolemic hypotension.

Unwanted effects of insulin

Hypoglycaemia: manage with scrutiny of regimen, diet exercise, alcohol Antibody formation- most common with animal insulin Allergic reactions Lipdystrophy: vary injection site Somogyi rebound hyperglycaemia Weight gain: trophic effect of insulin difficult to manage

Unwanted effects of sulphonylureas

Hypoglycaemia: more likely with longer acting drugs, and with reduced renal clearance, and if there is displacement of protein binding Increased appetite with weight gain so used in non-obese type II

Hypoglycemia symptoms

Hypoglycemia symptoms result from increased secretion of hormones that can raise blood glucose epinephrine and glucagon and decreased energy available in the brain. Anxiety Confusion Incoordination Increased heart rate Pallor Sweating

describe the possible causes of hypocalcaemia

Hypoparathyroidism Hypomagnesaemia- The secretion of the PTH protein requires magnesium Renal failure- calcitriol deficiency Pseudohypoparathyroidism Respiratory and/or metabolic alkalosis can decrease ionic Ca2+ concentration because as the pH rises, more calcium associates with proteins like albumin

Plasma hormone levels in different conditions that result in decreased hormone production:

Hypothalamic damage: ↓ CRH, ↓ ACTH, ↓ cortisol. Anterior pituitary damage: ↑ CRH, ↓ ACTH, ↓ cortisol. Adrenal gland damage: ↑ CRH, ↑ ACTH, ↓ cortisol.

Radioiodine side effects

Hypothyroidism eventually in 70-80% Worsening of thyroid eye disease Pregnancy- Advised not to get pregnant for 6/12 after

Diabetic ketoacidosis complications

Hypovolaemic shock Hypokalaemia Gastroparesis Coma

Measuring IGF-1

IGF-1 levels are also measured by immunoassay. not as widely used as GH measurements. Confined to specialist centres IGF Binding Proteins - measured in specialist centres for difficult cases - research rather than routine

IGF1 action

IGF1 binding dimerises its receptor forces the PTK domains together, followed by cross-phosphorylation. These phosphorylated tyrosine residues act as docking sites for IRS-1 (insulin receptor substrate 1), which gets phosphorylated. Phosphorylated IRS-1 can bind PI-3K (phosphoinositide-3 kinase), which, now located at the membrane, phosphorylates PIP2 at position 3, forming PIP3 (phosphatidylinositol-3,4,5 trisphosphate). PIP3 allows both PDK1 (phosphoinositide-dependent kinase-1) and PKB (protein kinase B) to associate with the membrane via their PH (pleckstrin homology) domains. Phosphorylated PKB dissociates from the membrane and phosphorylates its target proteins. IRS-1 is a docking protein, as it can bind many proteins other than PI-3K, including Grb-2 (thereby activating the MAPK pathway) as Grb-2 attached to Sos binds to the tyrosine-phosphates. The Sos catalyses the exchange of GDP for GTP on membrane-bound Ras, activating it., GTP:Ras binds and activates Raf, a membrane-bound protein kinase, A series of protein kinases are phosphorylated and activated, resulting in the phosphorylation of several transcription factors, altering their activity.

Ketoacidosis treatment

IV fluid to replace the fluids lost through excessive urination insulin to lower the blood glucose and inhibit the ketogenesis. insulin also causes K+ to enter cells so some K+ is added to the replacement fluid and plasma [K+] needs to be monitored carefully. correction of blood pH with bicarbonate.

Hypoparathyroidism

Iatrogenic- accidental removal of parathyroid glands during thyroid surgery Idiopathic- no known cause for failure of parathyroid hormone secretion. Low circulating PTH, hypocalcaemia and hyperphosphataemia

describe conditions under which cortisol is able to access the MR

If 11bHSD is fully active, why might cortisol gain inappropriate access to MR? [ Cortisol ] high (e.g. Cushing's disease, glucocorticoid resistance) Exceed capacity of enzyme

How do we keep our water input and output equal?

If our bodies can't maintain a balance between fluid consumption and loss, there can be serious consequences. For example, drinking too much water causes excess fluid to enter our cells causing their swelling. we do not need to consume the exact amount of water lost as water is produced as a by-product of metabolism.

AVP and osmolality

If plasma osmolality is below 280mOsm/kg (equivalent to 280mmol/L) then basal [ AVP ] is 0.4 - 1.4 pmol/L independent of plasma osmolality. If plasma osmolality rises above 280mOsm/kg then plasma [AVP] (pmol/L) rises to 0.38 pmol/l x ( X - 280 ) where X = plasma osmolality [in mOsm/kg] AVP secretion will rise by >35% if plasma osmolality increases by 5mOsm/kg (i.e.2%) 4% plasma osmolality - 3.5X [ AVP ] •

Progesterone and pregnancy

If pregnancy occurs, the corpus luteum continues to produce progesterone and the secretion of GnRH continues to be suppressed. In the fourth month, the placenta takes over progesterone production.

How is diabetes mellitus diagnosed? WHO criteria

If symptoms present Fasting plasma glucose ≥7 mmol/L Random plasma glucose ≥11.1 mmol/L 2 hour OGTT ≥11.1 mmol/L If no symptoms Two of the above DM may now be diagnosed on basis of HbA1c ≥6.5% (48 mmol/mol)

Contrast ovarian events if fertilization occurs with when it does not.

If the secondary oocyte is not fertilized it degenerates. The corpus luteum also degenerates and the cycle begins again with new follicular development triggered by GnRH and FSH. If fertilization occurs, the secondary oocyte completes meiosis giving rise to an ovum which will undergo a successive series of cell divisions and eventually implant in the uterus. The corpus luteum will be supported by hormones from the placenta and will not degenerate until the end of pregnancy.

explain how GH is measured: immunoassay

Immunoassay ELISA (Enzyme Linked Immunosorbant Assay) large-scale routine use very precise and sensitive does not measure biological potency directly

Immunoassays: sandwich assays

Immunoassays use a specific antibody developed for the hormone The negative control tube has just the hormone One tube with less hormone, other tube with more To quantify, add a second antibody, which is radiolabelled- the first antibody must be added before the radiolabelled one, as the radiolabelled one could bind to anything The two antibodies forms a sandwich with the hormone Count radioactivity from the triple complex Can only be used for hormones with M.Wt. > 1000 as 2 antibodies cannot simultaneously bind to smaller hormones

Diabetes and atherosclerosis

Impaired Endothelial function: ↓NO production Modification of lipoproteins LDL particles oxidised/glycated Macrophages have receptors for AGE Take up modified LDL to form 'foam cells' Proliferation of smooth muscle cells Macrophage activation Chemokine release

Prediabetes

Impaired glucose tolerance and impaired fasting glucose. These are also associated with increased cardiovascular risk. Early treatment may reduce progression to diabetes Healthy eating advice / weight management / exercise effective in slowing progression. Meteor fin is useful but less effective. Impaired glucose tolerance: fasting plasma glucose < 7.0 mmol/L 75g OGTT 2-hour value > 7.8 but < 11.1 Impaired fasting Glycaemia: fasting plasma glucose > 6.1 mmol/L but < 7.0 OGTT needed to exclude diabetes.

Nephrogenic diabetes insipidus

Impaired renal response to ADH, defects in the action of AVP at V2 receptors

Endocrine Causes of Hypocortisolaemia

Impaired steroidogenesis in Addison's disease, CAH Decreased ACTH drive: • Decreased hypothalamic CRH drive • Decreased pituitary ACTH output • ACTH resistance

Effects of bypass surgery on glucose homeostasis

Improved beta cell function/functional beta cell mass Improved insulin sensitivity Reduced hepatic glucose production Increased glucose utilisation and effectiveness

Feedback loop of oxytocin

Impulses are sent to the neurosecretory cells of the hypothalamus and oxytocin is released into the capillaries of the pituitary gland. The blood carries the hormone to the uterine tissue. Oxytocin targets the myometrium and causes the smooth muscle to contract forcefully. This pushes the fetus further into the cervix and stretches it even more. This sends additional impulses to the hypothalamus and a positive feedback loop is created. This continues until the fetus is expelled from the uterus and the cervix is no longer stretched.

Low-dose dexamethasone suppression test results in Cushing's disease

In Cushing's disease there is a pituitary defect causing high ACTH It is subject to some negative feedback so high doses of dexamthesone would suppress the cortisol, normal to elevated ACTH

Histological Changes In Type 1 diabetes

In Type 1 diabetes autoimmune reaction against beta cells leads to infiltration of the pancreatic islet by T- cells which eventually destroys the gland.

Histological changes in Type 2 diabetes

In Type 2 diabetes the pancreatic islet is not usually affected. In some patients with long standing diabetes, there are amyloid deposits fibres of islet amyloid polypeptide. The beta cells degenerate leaving behind the amyloid deposits

Adrenarche

In a healthy girl, puberty can be divided into several stages, including adrenarche, pubarche and menarche. Adrenarche is the female pattern of androgen-dependent hair growth The output of androgens from the ovaries is very limited in a healthy girl so adrenarche relies on the DHEAS. After desulphation, DHEAs can undergo conversion in peripheral tissues e.g. adipose and skin to the more potent androgens, androstenedione, testosterone and 5α-dihydrotestosterone.

Insulin resistance effects

Long term insulin resistance can lead to pancreatic beta-cell failure and type 2 diabetes It is also correlated with lipid deposition in skeletal muscle and liver ectopic lipid deposition in obesity

Skeletal muscle contraction

In a relaxed muscle, calcium is brought into the sarcoplasmic reticulum and bound to calsequestrin. A Ca-ATPase pump lowers the calcium concentration in the cytoplasm. A nerve impulse releases calcium into the cytoskeleton At rest, the myosin is physically separated from actin by the troponin complex. Ca2+ binds to TnC rearranging the complex. Myosin can now bind tightly to actin forming cross bridges. When ATP binds, it closes the ATP cleft in the S1 head and opens the actin binding one. This weakens the S1 head binding to actin so myosin dissociates from it. ATPase in the myosin head converts ATP into ADP and Pi. This causes the ATP cleft to close. The energy released during ATP hydrolysis changes the angle of the myosin head into a "cocked" position. If the actin binding sites are uncovered, a cross-bridge will form; that is, the myosin head spans the distance between the actin and myosin molecules. Pi is then released, allowing myosin to expend the stored energy as a conformational change. The myosin head moves toward the M line, pulling the actin along with it. As the actin is pulled, the filaments move approximately 10 nm toward the M line. This movement is called the power stroke, as it is the step at which force is produced. As the actin is pulled toward the M line, the sarcomere shortens and the muscle contracts. at the end of the power stroke, the myosin head is in a low-energy position. ADP is released. The whole cycle can then start again.

Glucose concentrations

In acute stress, adrenaline increases plasma glucose concentration as part of the "fight or flight" response. To control plasma glucose concentrations, catecholamines and glucocorticoids must affect protein, carbohydrate and fat metabolism.

DHEA and cortisol synthesis

In adrenocortical cells, ACTH acts via a 7 transmembrane domain receptor to increase intracellular cAMP concentrations. The second messenger increases the uptake of cholesterol substrate in the form of plasma lipoproteins, the expression of the StAR protein and the expression and activity of key steroidogenic enzymes The synthesis of both DHEA and cortisol is completely upon ACTH.

explain the role for 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) in protection of the MR

In aldosterone target cells and placenta cells cortisol is oxidised by Type 2 11bHSD to cortisone. Type 2 is especially active in the kidney collecting ducts, colon, salivary glands and placenta, so then aldosterone can bind to its receptor Type 1 converts it back to cortisol.

DHEAs in adolescent boys

In an adolescent boy, the output of DHEAS from the zona reticularis of the adrenal cortex is relatively unimportant since the testis produces androstenedione and testosterone which are more potent. They support the development of secondary sexual characteristics e.g. the growth of pubic, axillary and facial hair at puberty.

Somatostatin, glucagon and glucose

In delta cells, the closure of the ATP-sensitive K+ channel with high glucose depolarises VDCC, increasing Ca2+ entry to release somatostatin Somatostatin acts on alpha cells to inhibit glucagon secretion Therefore somatostatin inhibits glucagon secretion under high glucose

The variable pulsatile release of FSH and LH in females

In females, there is pulsatile release of GnRH at frequencies that differ through the menstrual cycle. Low- amplitude, high frequency pulses, seen early in the menstrual cycle, favour FSH release. High-amplitude, low-frequency pulses seen later in the menstrual cycle favour LH release.

Hydrophobic Hormones

In general, hydrophobic hormones are non-polar molecules, often comprising cyclic carbon structures which may be derivatives of: cholesterol (as for the steroid hormones) tyrosine (as in the case of the thyroid hormones) or derivatives of the fat-soluble vitamins, A & D. Hydrophobic hormones can diffuse across the plasma membrane to interact directly with intracellular receptors. In the unbound state, these receptors can be located either in the cytoplasm or in the nucleus (dependent on the precise identity of the receptor). In either event, ligand-activated receptors must translocate into the nucleus and dimerise in order to bind to DNA and exert their actions as ligand-dependent transcription factors, either increasing or decreasing the rate of transcription of target genes. The activated genes are transcribed, translated and then the protein output subsequently change cellular activity and alters cell behaviour. These processes are therefore not instantaneous but do produce robust sustained effects over minutes, hours or days. Hydrophobic hormones includes the Steroids and some Amines. Steroids include oestrogen and testosterone (ovary and testis) and aldosterone and cortisol (adrenal cortex). Hydrophobic amines include thyroxine (thyroid).

Glycogen in skeletal muscle contraction

In less than 1 second, 5nM Ca2+ partially activates phosphorylase kinase in striated muscle. This initiates glycogenolysis exactly as work begins giving muscle partial access to this large fuel store. Glycogen is the main initial fuel for all unrehearsed work.

Differential Diagnostic Testing: CT of the adrenal glands

In patients with low ACTH levels, the problem is usually in the adrenal gland. CT scanning of the adrenals identifies whether there is a solitary or multiple cortisol- producing adrenal tumours resulting in cortisol excess.

Cushing's disease treatments

In patients with pituitary disease, there are two additional medications that can be used. • Cabergoline • Pasireotide

Human mammary gland Ai

In resting mammary glands the secretory alveoli are virtually absent, but the system of ducts is present The intralobular duct epithelium is usually a single layer of cuboidal cells with basal nuclei The ducts are surrounded by myoepithelial cells (M) which are only lightly stained (and which make the outside of the ducts look fuzzy) Note the abundant capillaries (Cap) in the intralobular connective tissue

Secondary hyperaldosteronism

In secondary hyperaldosteronism, the excess aldosterone is caused by something outside the adrenal gland that mimics the primary condition. It is related to disorders such as: Cirrhosis of the liver, Heart failure, or over-activity of the renin-angiotensin system i.e. a renin producing tumor.

Family III receptor activation

In the absence of ligand, these NRs are in non-functional complexes with heat-shock proteins thus transcriptionally inactive Upon ligand activation, the nuclear receptors bind DNA as homodimers to response elements, configured as palindromes composed of two nucleotide sequences separated by 3bp's.

Epinephrine and cortisol

In the acute stress reaction, epinephrine inhibits β cell insulin secretion and stimulating α cell glucagon secretion. These effects, together with its other metabolic effects, raise blood glucose concentration. Cortisol has similar actions.

Development of the pancreas

In the developing foetus, the pancreas arises from dorsal and ventral outgrowths of the foregut. These outgrowths form a branching duct system with exocrine acini forming at the termini of these ducts.

Somatostatin

In the endoplasmic reticulum of the pancreatic delta cells, the signal peptide is removed from preprosomatostatin to give prosomatostatin. Processing of prosomatostatin can result in two somatostatins; SS-14 and SS-28. In the pancreas, only SS-14 is produced, while the intestine produces mainly SS-28. The synthesised somatostatin is stored as granules in cytoplasmic vesicles until release is stimulated. Within the islets, this SS-14 exerts a paracrine suppression of both insulin and glucagon secretion.

Fetal adrenal cortex

In the fetal adrenal cortex there is early cortisol biosynthesis, followed by the production of large amounts of DHEA/DHEAS. A series of enzymatic reactions gives rise to different oestrogens: oestradiol, oestrone and oestriol, the latter detected from the end of the first trimester onwards in maternal urine.

Growth Regulation Throughout Life

In the foetus IGF-2 controls growth During infancy: nutrition rather than GH/IGF-1 is the most important during year 1 y Postnatal growth rapid (15cm/y), declines by 3 to a plateau (6cm/y) At puberty GH/IGF-1 rise - get growth spurt then oestrogens close the growth plates at the end of puberty in boys and girls After puberty GH steadily declines throughout adult life resulting in the "somatopause", central adiposity and decreased muscle mass

24-hydroxylation: 25-hydroxycholecalciferol to the inactive metabolite 24,25-dihydroxycholecalciferol

In the kidneys, 24-hydroxlyase acts on 25-hydroxyvitamin D to form 24, 25- dihydroxyvitamin D which is excreted. Calcitriol induces 24-hydroxylase increasing plasma [PO42-] increases the inactivation of 25-hydroxy-vitamin D by 24-hydroxylase. The 24-hydroxy-metabolites may play a role in bone development, but no clear function is apparent in adulthood.

Vitamin D metabolism in the kidneys

In the kidneys, the 25-hydroxycholecalciferol is hydroxylated again to give either: the active metabolite 1,25-dihydroxycholecalciferol via 1α- hydroxylase activity at position C1 or 24-hydroxylation at position C24 catalysed by 24-hydroxylase to give the inactive metabolite 24,25-dihydroxycholecalciferol that is excreted

1α- hydroxylation in the kidneys: 25-hydroxycholecalciferol to the active metabolite 1,25-dihydroxycholecalciferol

In the kidneys, the 25-hydroxycholecalciferol is hydroxylated again to give the active metabolite 1,25-dihydroxycholecalciferol via 1α- hydroxylase This process is stimulated by PTH majorly so that the mobilization of bone calcium reservoirs is accompanied by increased intestinal absorption of dietary calcium growth hormone, cortisol, oestrogen and prolactin increase 1-alpha-hydroxylase

Oxytocin and lactation

In the months following birth, the auditory input from a crying infant will also trigger secretion of oxytocin, which then stimulates contraction of the lobulo-alveolar ducts of the breast, causing ejection of milk from the nipple.

Bilateral adrenolectomy?

In the past, the identification of a pituitary adenoma was more difficult, and therefore patients underwent removal of the adrenal glands Because the pituitary tumour was not removed, the tumour enlarged and excessive production of ACTH continued. The excess ACTH stimulates pigment production in the skin. Nelson' syndrome develops within 1-4years of surgery in about 15-25% of patients.

GHRH and somatostatin control

In the presence of GHRH and somatostatin the anterior pituitary synthesises and stores GH in secretory granules ready for the next pulse of growth hormone secretion. Higher brain centres allow inputs such as stress to override normal physiological regulation of growth and can reduce growth potential.

Insulin synthesis and processing

In the rough ER of the pancreatic beta cells, preoproinsulin is cleaved at the N-terminus to pro insulin Proinsulin passes into the Golgi apparatus where it is packaged into vesicles that contain pro-hormone convertase The enzyme hydrolyses the proinsulin to liberate the connecting C-peptide, leaving the insulin joined by 2 disulphide bonds As proinsulin molecules are processed, the insulin molecules form hexamers associated with zinc atoms. On stimulation, the membranes of the β-granule fuse with the plasma membrane of the β-cell to secrete insulin- this is both Ca2+- and energy-dependent).

Control of vasopressin secretion

Increase in plasma osmolality also increases neural stimulation of thirst. Increase in angiotensin II increases firing of a sub-fornical organ.

Biguanides

Increase uptake of glucose by tissues. Unlike the sulphonylureas, these drugs do not require functional islets of Langerhans Orally active Suppress appetite, Reduce plasma LDL, Excreted via the kidney

Metabolic effects of insulin in cells

Increased GLUT4 expression in the plasma membrane to increase glucose transport into cells especially in the liver, muscle and adipose tissue Glucose storage by cells initially as glycogen particularly in the liver and skeletal muscle. If glucose is in excess triglycerides are formed from glucose in adipose tissue (lipogenesis) Decrease in glycogenlysis in the liver Decreased use of other energy substrates in favor of glucose.

Metabolic effects of insulin in skeletal muscle

Increased GLUT4 expression in the plasma membrane to increase glucose uptake Glucose storage by cells initially as glycogen Decreased use of other energy substrates in favor of glucose.

Metabolic effects of insulin in adipose tissue

Increased GLUT4 expression in the plasma membrane to increase glucose uptake If glucose is in excess triglycerides are formed from glucose in adipose tissue lipogenesis

Hyper-aldosteronism

Increased Na+ reabsorption in the distal part of the kidney tubules and increased K+ and H+ secretion. Higher blood pressure Hypokalemia The increased H+ secretion results in increased plasma HCO3- concentration and a metabolic alkalosis.

effects from increased glucocorticoid secretion or chronic administration.

Increased glucocorticoids results in hyperglycemia, and there is weight gain resulting from stimulation of appetite by the hormones. Difficulty sleeping reflects effects on the hypothalamus and may be related to decreased melatonin secretion. Other CNS effects include impaired memory. The loss of bone mineral results from reduced intestinal Ca2+ absorption that leads to negative calcium balance with loss of Ca2+ from bone in an attempt to maintain normal plasma Ca2+ levels. This loss of bone mineral result in reduced bone density (osteoporosis) with weaker bones that are liable to fracture. The mobilization of amino acids leads to loss of muscle mass with muscle weakness. The breakdown of tendons results from glucocorticoids inhibiting collagen synthesis, as does the skin fragility and easy bruising. Immunodeficiency also develops.

Retinopathy

Increased glycation of basement membrane protein of capillaries of the eye Formation of exudates due to overproduction of these glycoproteins and increased permeability and weakness. Bleeding into vitreous humour occurs - blindness. Crystallin in lens glycated causing cataracts

Summary of long term problems of Diabetes

Increased incidence of cardiovascular disease • Peripheral vascular disease • Renal disease (microangiopathy) • Retinal disease (microangiopathy) • Lens opacity (cataracts) • Neuropathy (impaired nerve conductance) • Autonomic (bladder, stomach, blood vessels, erections) • Sensory • Motor • Skin infections (gangrene, thrush and other yeasts) • Osteoarthritis

ACTH action

Increased uptake of cholesterol substrate in the form of plasma lipoproteins expression of the StAR protein expression and activity of key steroidogenic enzymes

Outline possible causes of adrenal dysfunction and iatrogenic adrenal symptoms

Increased/decreased endocrine drive to the adrenal cortex- may reflect hormone production from a functional endocrine tumour, not necessarily within the normal endocrine axis; e.g. small cell lung tumours Increased/decreased activity of one or more enzymes required foradrenal steroidogenesis Destruction of one or more zones of the adrenal cortex e.g. by an autoimmune disease Defects in steroid receptor function (specificity, ligand binding and/or transcriptional activity) exogenously administered corticosteroids will result in same clinical presentation as those caused by increased endogenous corticosteroids (e.g. iatrogenic Cushing's syndrome).

Actions of thyroid hormone

Increases cardiac output, heart rate, ventilation rate, basal metabolic rate, sympathetic activity •Potentiates brain development •Increases metabolism of proteins and carbohydrates

Repression of 1-alpha-hydroxylation in the kidneys

Increasing ionized Ca2+ decreases 1,25-dihydroxycholecalciferol production Calcitrol represses 1α- hydroxylase increasing plasma [PO42-] also decreases the activity of 1alpha-hydroxylase.

Other drugs used in the treatment of type II DM

Incretin mimetics / GLP-1 analogues DPP-4 inhibitors (gliptins)

describe the indirect physiological actions of GH

Indirect actions via IGF1 growth promotion clonal expansion of chondrocytes growth of bones / soft tissue / viscera

The complex aetiology of Type 2 diabetes

Individual patients have a complex mix of genetic predisposition to obesity Epigenetic predisposition ('fetal programming') in the womb like with gestational diabetes, starvation during pregnancy Differing abilities to compensate: ß-cell proliferation, adipose tissue inflammatory response, tendency to become insulin resistant Different environmental exposures: Diet, activity, Intercurrent illness, Exposure to drugs e.g. steroids Differing access to healthcare

Background of obesity

Individuals are regarded as obese when their body mass index weight in kg / height in metres2 exceeds 30, although waist circumference is now thought to be a better indicator of visceral fat. The maintenance of stable body weight requires fine control of food intake. Body weight increases when energy intake (food) exceeds energy expenditure.

Measure height and weight, calculate a BMI, and document these findings accurately.

Infants should be weighed without any clothing, and children should be weighed in their underwear. To measure the weight of a person who cannot stand erect you should use a chair or bed scales.

Cancer and inflammation

Inflammation has also been linked to cancer risk and tumour phenotype, promoting agression, survival and metastasis.

Oxidative stress

Inflammation is the reaction to oxidative stress to clear everything

CLASSES OF ANTIOBESITY AGENTS:

Inhibitors of energy intake Inhibitors of fat absorption Enhancers of energy expenditure Stimulators of fat mobilizati

GH deficiency

Initially GH replacement was in the form of cadaveric pituitary GH as GH from other species does not stimulate growth in humans The development of Creutzfeldt-Jakob disease (a degenerative brain disorder) in those who were treated with hGH produced in this way, led to the discontinuation of all products derived from the human pituitary gland This has led to development of artificial (recombinant) hGH (rhGH) to treat children with growth disorders since 1985.

Thyroid scintigram

Inject 99mTc-labelled pertechnate which is taken up by NIS (sodium-iodide symporter) into the follicular cells and can under a gamma camera Graves' disease will have smooth uptake, outlines the thyroid gland all across it Someone with multinodular goitre, some bits of the thyroid take up more than others- iodide not ring driven by TSH

Provocative Tests

Inject insulin: sample every 20 mins for 4hrs and measure GH • Known as an ITT Insulin Tolerance Test • CAUTION: risk of dangerous hypoglycaemia • GH rise due to fall in glucose, not rise in insulin per se • Alternative stimulators eg. Ghrelin/GHRH/bovril/exercise/ clonidine*

Phosphate in cells

Inorganic phosphate (Pi) makes up 16% of the total. It is largely there as HPO42-, given a cell pH ~ 7.2. Phosphocreatine, an energy store for the muscle contributes 70% of the total. This would not be true for other cell-types that do not store energy in this form. High energy triphosphates (ATP, GTP) and their diphosphates (ADP, GDP) make up 8% of the total. Hexose phosphate (Glucose-6P) makes up 6% of the total.

Acromegaly

Insidious in onset Pituitary tumours in 25% at post mortem - usually stain for prolactin high GH post puberty- no increased height or increase in linear growth possible because of oestrogen closure of growth plate

Insulin and the synthesis of fatty acids

Insulin activates phosphoprotein phosphatase to increase the dephosphorylation of acetly-CoA carboxylase which generates malonyl CoA. It also inhibits cAMP-independent kinase to prevent phosphorylation of it Insulin also inhibits the activity of hormone-sensitive lipase

Insulin, glucagon and somatostatin

Insulin from the β cells inhibits glucagon secretion. It may do this directly or indirectly, by stimulating release of somatostatin. Glucagon from the α cells stimulates both insulin and glucagon secretion. Somatostatin from the δ cells inhibits both glucagon and insulin secretion. It also inhibits continuing secretion of its own somatostatin. The major determinants of insulin and glucagon release are blood glucose levels.

Insulin

Insulin has actions that resemble leptin and stimulates its release. It gains entry to the brain through specific transporters. It is thought to reduce NPY synthesis and to regulate POMC (pro-opiomelanocortin)-releasing neurones by stimulating POMC synthesis. Under some circumstances, insulin can also increase food intake.

After a protein rich meal

Insulin increases which increases glycogen synthesis and glucose uptake Glucagon also increases leading to glycogenolysis and amino acid oxidation. Amino acid oxidation causes gluconeogenesis which along with glycogenolysis increases glucose output There is an overall neutral glucose effect

Insulin and glycogen synthetase

Insulin inhibits cAMP-independent kinase and activates phosphoprotein phosphatase to prevent the phosphorylation and hence inactivation of glycogen synthetase

Insulin and hyperkaleamia

Insulin is also released in response to hyperkalemia to protect excitable muscle cells from serious cardiac arrhythmias and skeletal muscle paralysis.

Control of fat metabolism by insulin

Insulin is an anabolic hormone which increases the net synthesis of triglyceride/triacylglycerol TAG: stored in adipose tissue It promotes the synthesis of fatty acids in the liver It also inhibits the breakdown of fat in adipose tissue

Insulin breakdown

Insulin is removed from the circulation by renal glomerular filtration. Insulin is taken from the glomerular filtrate into the renal proximal tubular cells where it is broken down into its constituent amino acids.

Hormones controlling blood sugar

Insulin lowers blood sugar. Glucagon, adrenaline, glucorticosteroids and growth hormone raise blood sugar.

Diabetic ketoacidosis

Insulin normally blocks ketogenesis by inhibiting the transport of free fatty acid derivatives into the mitochondrial matrix. Unopposed glucagon stimulates mitochondrial conversion of free fatty acids into ketones The ketoacids produced create metabolic acidosis which is metabolised into acetone Decreased insulin causes hyperglycaemia as GLUT4 expression and glucose uptake and storage are reduced. This causes osmotic diuresis.

Insulin Resistance

Insulin resistance is an inadequate response to normal levels of insulin which can be caused by the down-regulation of receptors, proteins downstream in the signalling pathway or inflammatory signalling pathways inhibiting the serine phosphorylation of IRS for example.

Adipose tissue during the fed state

Insulin stimulates the uptake of glucose which is used in the synthesis of triacylglycerol The TAG is stored in large droplets for later use

Human testis, adult: medium power, iron haematoxylin and eosin

Interstitial cells, or Leydig cells (IC), are endocrine cells that are found dispersed in the loose connective tissue between seminiferous tubules, in irregular clumps of variable size These cells secrete testosterone and are typically endocrine in appearance, with large cytoplasm, round pale nucleus and prominent nucleolus Largely under the influence of luteinising hormone secreted from the pituitary gland. In males, luteinising hormone may be called interstitial cell stimulating hormone, although this practice is deprecated

Breast - pregnancy

Intralobular connective tissue lighter, giving room for growth of the glands In pregnant breast, there are now clearly defined lobules consisting of a mixture of massed ducts with variable numbers of secretory alveoli, the proportion depending on how far pregnancy had advanced Note that the changes are patchy, some lobules showing many dilated irregular-shaped secretory units while others consist solely of ducts The eosinophilic secretion in the ducts is colostrum How have the amounts of intralobular and interlobular connective tissue changed, compared to resting breast? Much less intralobular tissue as the glands have proliferated. In the human, milk production begins 2-3 days after giving birth at which time the secretory units (and thus the lobules) distend further, reducing the connective tissue component to a minimum.

Iodide (I-)

Iodide is taken up from the blood by thyroid epithelial cells via the sodium-iodide symporter It is transported into the lumen of the follicle along with thyroglobulin via pendrin

What is the optimum HbA1C?

It is not true that the lower you go the better things are 'Normal' HbA1c of <6.5% (<48 mmol/mol) • is difficult to achieve without causing hypos • may be associated with ↑mortality We aim for 6.5-7.5% (48-59 mmol/mol) Quality of life is paramount

Endometrium

Looking for a polyp (benign endometrial tissue), fibroids, scar tissue • Progesterone challenge • Hysteroscopy

Type 1 diabetes mellitus- insulin dependent

Juvenile onset. Autoimmune destruction of β cells of islets of Langerhans in pancreas. Daily injection of insulin is essential Prone to ketoacidosis

Regulation of Potassium Balance

K+ interferes with the activity of excitable cells so needs to be controlled Aldosterone, stimulates K+ secretion (and Na+ reabsorption) by principal cells Adrenal cortical cells are directly sensitive to the K+ content of ECF where increased K+ causes the release of aldosterone which causes K+ secretion • Abnormal aldosterone levels severely influence K+ levels

Ketoconazole

Ketoconazole is an antifungal that blocks the production of cortisol However its effectiveness is limited by side effects including liver damage.

Fetal Growth and Development

Key hormones/axis include: • Thyroidaxis • Insulin • GH-IGFaxes • Cortisol • Steroids GH and especially IGF's are important for fetal growth

GLP-1

L cells in the bowel, particularly the small intestine secrete GLP-1 in response to food They stimulate the B cells, causing the rise in insulin before glucose even comes into the blood GLP-1 binds to its GCPR increasing Adenylate cyclase and cAMP and protein kinase A Protein kinase A closes the K+ channels, depolarises, open VDCC, Ca2+ entry causes insulin release DPP-4 inactivates GLP-1

Incretins

L cells secrete GLP-1 K cells secrete GIP. DPP-4 inactivate them and they are excreted in the kidneys Both cells live in the lining of the bowel, particularly the small intestine sensing the nutrients coming in. They stimulate the B cells, causing the rise in insulin before glucose even comes in.

The control of spermatogenesis

LH stimulates the Interstitial Cells of Leydig to secrete testosterone. FSH and testosterone cause the Sertoli cells to produce Androgen-binding protein (ABP)which helps maintain high testosterone levels near the spermatogenic cells. Testosterone stimulates the final stages of spermatogenesis and is converted to dihydrotestosterone (DHT) which may function to promote sperm cell formation. Sertoli cells release inhibin when the level of spermatogenesis needed for the male reproductive system has been attained. Inhibin acts as a negative feedback control on the anterior pituitary to regulate FSH secretion.

Case 1: TYPE ONE A fourteen year old girl was admitted to hospital in coma. Her mother stated that she had been in good health and became ill two weeks prior to admission. She had developed a sore throat and moderate fever and then she lost her appetite and did not feel well. A few days before admission, she complained of being thirsty and needed to get up several times in the night to urinate. On the day of admission the girl began to vomit, became drowsy and difficult to arouse. On examination she was dehydrated, her skin was cold and she was breathing heavily: her breath had a sweet odour. Her blood pressure was 90/60 and her pulse rate rapid (115/min).

Laboratory tests revealed the following (normal range in brackets): Glucose 33mM (3.6-6.1mM) -hydroxybutyrate 12mM (less than 0.25mM) Acetoacetate 2.5mM (less than 0.2mM) Bicarbonate 6mM (24-28mM) Urea 12mM (2.8-8.8mM) Blood pH 7.05 (7.35-7.45) Potassium 5.8mM (3.4-5.1mM) Creatinine 160jtM (60-132jtM) Insulin levels were very low In the urine, both glucose and ketone bodies were found in abundance. Treatment Insulin and fluids to correct ketoacidosis. Management of K+ is essential because this can cause death if not regulated. Bicarbonate is given if acidosis is very severe. Coma or reduced consciousness is caused by the low pH, cation disturbance and high blood osmolality due to glucose. This is rapidly rectified by treatment.

The effects of the lack of insulin

Lack of insulin results in the reduction in the transport and utilisation of glucose, leading to hyperglycaemia. Insulin usually inhibits glucagon, and so higher concentrations of glucagon lead to glycogenolysis in the liver Insulin also normally promotes the uptake of amino acids into cells and their assimilation into proteins and opposes the breakdown of stored fat (triacylglycerols) to glycerol and fatty acids in adipose tissue. the increased availability of glycerol from lipolysis and the release of amino acids enhances gluconeogenesis the presence of the fatty acids suppresses further the utilisation of glucose in muscle.

Lactating mammary gland (feline): very low power, H and OG erythrosin

Lactating breast The lobules are a densely packed mass of dilated, irregular, thin-walled secretory units (alveoli) there is no distinction between secretory alveoli and intralobular ducts The lobules are poorly demarcated from one another by thin strands of collagenous connective tissue (the interlobular septa) intralobular connective tissue cannot be seen The secretory units and interlobular ducts contain the secreted milk, seen as an eosinophilic protein coagulum with a foamy vacuolated appearance where the fat droplets have been dissolved out during preparation Note the characteristic tendency for the fatty component of the secretion to separate out and polarise within the alveoli

Retinopathy is a common complication of diabetes. Blood vessel damage from a diabetic retinopathy can cause vision loss in two ways.

Macular edema Proliferative retinopathy

Calcitonin

Made by the C-cells, measured when we have C-cell tumours Calcitonin is a peptide hormone that antagonises PTH, lowering Ca Probably not significant in human Ca metabolism

Unwanted effects of biguanides

Lactic acidosis with high doses and in people with kidney disease- Lactate uptake by the liver is diminished with metformin use because lactate is a substrate for hepatic gluconeogenesis, a process that metformin inhibits. I Reduced vitamin B12 adsorption- The B12-intrinsic factor complex uptake by ileal cell membrane receptors is known to be calcium-dependent, and metformin affects calcium-dependent membrane action the resulting B12 deficiency can be reversed by administering calcium

Large adipocytes

Large adipocytes secrete substances that are pro-inflammatory and cause insulin resistance.

Hexose Transporters- GLUT4

Large integral membrane proteins • 12 membrane-spanning regions • CytoplasmicC-terminaltail • CytoplasmicN-terminaltail • Glycosylated on one of the extracellular loops

Cushing's Syndrome Diagnosis

Late-night salivary cortisol should be low, raised in the syndrome Urine free cortisol Low-dose dexamethasone suppression testing

Leptin resistance in obesity

Leptin crosses the blood-brain barrier via a receptor. This is a saturable transport mechanism. In obesity, there is leptin resistance in the hypothalamus possibly due this saturation. There is also hypothalamic insulin resistance. Also has a proinflammatory effect. The levels of leptin found in the CSF of obese individuals is relatively low compared to the high plasma levels, central administration does have some effect on weight loss.

Macrophage Infiltration in obesity

Leptin increases macrophage infiltration of adipose tissue as seen in obesity. The macrophages are typically clustered around individual adipocytes, forming 'crown-like structures' (CLS) found around dead adipocytes that appear to have undergone necrosis Adipocyte death is increased with the size of the adipocytes Infiltrating macrophages may then secrete large amounts of proinflammatory cytokines - infiltration has been shown to occur before hyperinsulinemia.

Leptin and feeding

Leptin is a protein secreted primarily by mature adipocytes Leptin increases with feeding and insulin and decreases with fasting. It acts in the hypothalamus to decrease appetite and increase energy expenditure Obese individuals have high leptin levels but they do not regulate their body fat- leptin resistance

Leptin

Leptin is primarily secreted by the adipocytes so that circulating levels reflect the amount of body fat. It acts in the hypothalamus to depress appetite, and also affects insulin signalling where the absence of leptin causes insulin resistance

Leptin and puberty

Leptin is produced by adipocytes and provides a measure of fat mass It acts on the hypothalamus to reduce appetite and increase thermogenesis. Leptin is the product of the obese gene, mutations in which increase food intake and lower body temperature, leading to obesity. Leptin deficient mice are infertile, a feature reversed by treatment with leptin.

Leptin

Leptin is produced by adipose tissue. Increasing fat stores increases leptin production. It acts in the 'satiety centre' of the hypothalamus, the ventromedial hypothalamus to reduce fat deposition by decreasing food intake and increasing energy expenditure. Therefore a decline in fat stores reduces leptin production, thus increasing appetite and decreasing energy expenditure. Activation of sympathetic outflow contributes to this increase in energy expenditure.

Leptin resistance

Leptin levels are higher in obese than lean humans and so many cases of obesity are thought to reflect a form of leptin resistance. There is also evidence that leptin influences synaptic number and the activity, suggesting a role in hypothalamic plasticity. May even be important in early neuronal development.

Hormonal Activation of Puberty by leptin?

Leptin levels rise during puberty, and patients with mutations in the leptin gene or receptor fail to enter puberty. This failure can be overcome by treatment with leptin However, leptin is unable to initiate puberty precociously Thus, leptin may provide some form of permissive or background presence that is essential for a triggering the GnRH signal to operate, such as kisspeptin 1, the expression of which is down-regulated under conditions of negative energy balance.

list and explain the physiological actions of T3.

Leptin stimulates TRH and TSH Control of body temperature Stimulates fatty acid and bile acid synthesis Stimulates muscle regeneration and repair Beta cell maturation

Hypertension and leptin

Leptin stimulates the sympathetic nervous system to increase energy expenditure, increasing blood pressure. This is not affected by leptin resistance. Leptin induces the secretion and expression of the receptor of endothelia-1, a vasoconstrictor in endothelial cells and smooth muscle cells Leptin also promotes smooth muscle cell proliferation and the production of pro-inflammatory cytokines like TNF-alpha and IL-6

Leptin and insulin resistance

Leptin usually improves insulin resistance via AMPK, so the leptin resistance seen in obesity, where there is saturation of the transporter through increased leptin expression by adipose tissue leads to insulin resistance.

Pro-inflammatory proteins and obesity

Leptin, IL-6, angiotensin and TNF alpha are increased in obesity IL-6 is produced by adipose tissue, where levels predict the onset of Type 2 diabetes. It inhibits adiponectin expression and causes the liver to make inflammatory proteins like CRP. Leptin is a chemoattractant, responsible for the infiltration of macrophages into adipose tissue in obesity. Some aspects of inflammation are dependent on the renin-angiotensin system which is overactive in adipose tissue of obese people

Central control - Brain structures

Lesion of the ventromedial hypothalamus causes hyperphagia and obesity - satiety center? Lesion of the lateral hypothalamus reduces food intake and bodyweight - feeding center? Injection of glucose antimetabolites into the 4th ventricle induces feeding - brainstem involved in control of food intake?

Increasing levels of adinopectin

Levels are increased by dieting, exercise and synthetic ligands to PPARy such as thiazolidinediones Increasing adiponectin levels increases insulin sensitivity. Adiponectin is also anti-inflammatory, inhibits TNF-a secretion by monocytes and macrophages. Higher adiponectin levels have also been assoc. with a decreased risk for cardiovascular problem

General treatment of hypothyroidism

Levothyroxine (T4) half-life 1 week Liothyronine (T3) half-life 3-6 h Thyroid extract cow, pigs T3 > T4, not suitable Treat and titrate to normal TSH

Adrenal Crisis

Life-threatening complications of adrenal insufficiency seen in Addison's disease and Congenital Adrenal Hyperplasia Most commonly an infection, gastroenteritis- reduced absorption of orally induced glucocorticoids

Treatment of type 2 diabetes

Lifestyle management Weight loss Bariatric surgery Very low calorie diets Treat decreased insulin sensitivity with Metformin, a biguanide Oral hypoglycaemic agents: Sulphonylureas, metformin, Gliptins, thiazolidinediones, gliflozins GLP-1 analogues Insulin therapy

Types of Hormone Receptors

Ligand-gated ion channels, e.g. Acetylcholine receptor The signal is transduced to the cell via the change in membrane potential, etc., when the ion channel is opened. Receptor enzymes, e.g. Insulin receptor Enzymatic activity of receptor is activated by hormone-binding. Enzyme-recruiting receptors, e.g. Cytokine receptors Hormone-binding induces the recruitment and activation of protein kinases. G-protein coupled receptors, e.g. Adrenaline receptors Hormone-binding activates GTP-binding proteins.

Lipodystrophies

Lipodystrophies are disorders involving loss of adipose tissue through lipoatrophy or selective loss from particular regions. They illustrate the important role of adipose tissue in human health May be genetic or acquired

Cholesterol movement

Lipoprotein lipase in the end-organ (cardiac, skeletal muscle and adipose tissue) hydrolyse the triglyceride components of the chylomicrons (made up of cholesterol and TAGs from the diet), allowing the free fatty acids made to be absorbed by the tissues. The chylomicron remnants transport cholesterol to the Liver where they are stored, broken down by Bile Acids and released as VLDL into the circulation VLDL is assembled in the liver (from phospholipids, triglycerides, cholesterol, and apolipoproteins) and goes to adipose, cardiac and skeletal muscle where lipoprotein lipase removes triglycerides from VLDL for storage or energy production. HDL transfers cholesteryl esters to VLDL in exchange for phospholipids and triglycerides turning it into IDL then LDL as they lose more triglyceride- their cholesterol content becomes greater LDL is taken into a cell via the LDL receptor through endocytosis, where the contents are either stored, used for cell membrane structure, or converted into other products such as steroid hormones or bile acids. HDL collects cholesterol particles as they travel through blood vessels and deposits them in the liver where they are transferred to bile acids and disposed of and to steroidogenic organs such as ovaries, testes. Important for the formation of steroid hormones

Liraglutide, exenatide

Liraglutide is a stable GLP1 (glucogon-like peptide -1) receptor agonists. Developed to promote release of insulin for treatment of Type 2 diabetes but weight loss was a notable consequence of drug treatment. This action is now exploited directly in the clinic (e.g. liraglutide - an 'incretin mimetic'

Congenital Adrenal Hyperplasia

Loss-of-function mutations / decreased expression of adrenal steroidogenic enzymes Little or no synthesis of cortisol or corticosterone Decreased negative feedback Elevated ACTH causes hyperplasia Salt-wasting" CAH - Na+ loss due to insufficient synthesis of aldosterone "Salt-sparing" CAH = simple-virilising CAH - sufficient mineralocorticoid (not aldosterone) to stimulate Na+ resorption - Malignant hypertension

Ovary Ap

Low / medium power views of the ovarian cortex, containing primordial and primary follicles, a small secondary follicle, and several large secondary (antral) follicles (in which the oocyte is not visible). The points of interest here are: Box A - epithelium, primordial and primary follicles Box B - primary follicles Box C - secondary (antral) follicles

Stimulation of Glucagon Secretion

Low Glucose Amino acids Adrenaline GIP

Uptake scan - toxic nodule

Low TSH except for one nodule Activity to NIS confined to certain bits that are active

Adiponectin and hypertension

Low adiponectin levels correlate with high blood pressure Endothelial cells express AdipoR 1 and 2 promoting their health Adiponectin increases endothelial NO production via AMPK The NO decreases smooth muscle proliferation and reduces oxidative stress. OxLDL inhibits eNOS activity, but adiponectin suppresses this

Conditions with hyperphosphataemia

Low calcium levels/high phosphate levels occur in renal failure, hypoparathyroidism, and pseudohypoparathyroidism Vitamin D intoxication- high calcium, high phosphate

Adipose tissue during fasting (or exercise)

Low insulin/adrenaline stimulate lipolysis of the stored TAG The released NEFA enter the plasma as fuel for other tissues

Hypothyroid

Low levels of circulating T3 and T4 High levels of TSH Identify a cause atrophic, primary myxoedema, Hashimotos, drugs eg lithium, amiodarone T4 is given- Danger of overdose: angina and heart failure. T3 is reserved for myxoedema coma. Replace the hormone using: LEVOTHYROXINE synthetic T4

Process of glucagon secretion

Low transport of glucose through the GLUT2 transporter means there is a higher ADP:ATP ratio Less activity of ATP-sensitive K+ channel. Low depolarisation leads to activation of a voltage dependent sodium channel, opens a different calcium channel P/Q-type. High intracellular calcium, degranulation of glucagon

Ovarian reserve testing

Lower number of follicles, lower AMH (as this is produced by the granuloma cells of the follicles), higher FSH

Lugol's iodine

Lugol's iodine- bunch of iodine stuns the thyroid into switching off • blocks production of T4/T3 by Wolff-Chaikoff effect • Effective for 10 days • Then becomes hyperthyroid (Jod-Basedow effect)

Catecholamine Metabolism

MAO monoamine oxidase and COMT catechol-O- methyl -transferase break down epinephrine and norepinephrine. The major metabolites of epinephrine and norepinephrine are metanephrine and VMA. These are looked for in urine if we're testing for excess catecholamines, as epinephrine and norepinephrine have very short half lives.

Multiple endocrine neoplasia (MEN)

MEN-I arises from cells that do not develop from the neural crest MEN-II arises from cells that develop from the neural crest

Nephropathy

Macroscopic appearance of end-stage diabetic nephropathy. External surface is granular reflecting extensive sclerosis of cortical glomeruli (left). Cut surface shows destruction of the renal papillae and scarring consistent with previous attacks of pyelonephritis (right Microscopic appearance of diabetic nephropathy secondary to microvascular injury. • Damage to basement membrane and the mesangium and accumulation of mesangial matrix. • Diffuse or focal/nodular (Kimmelstiel- Wilson nodules) glomerulosclerosis.

Pre-existing type 1 diabetes mellitus in pregnancy

Maintenance of a diabetic diet, body weight and exercise are important when considering pregnancy There is a risk of hypoglycaemia and impaired awareness of hypoglycaemia during pregnancy how nausea and vomiting in pregnancy can affect blood glucose control the increased risk of having a baby who is large for gestational age, which increases the likelihood of birth trauma, induction of labour, and instrumental and caesarean section deliveries the need for diabetic retinopathy and nephropathy assessment before and during pregnancy the importance of maternal blood glucose control during labour and birth, and the need for early feeding of the baby, in order to reduce the risk of neonatal hypoglycaemia the possibility of that the baby may have health problems in the first 28 days- the risk of the baby developing obesity, diabetes and/or other health problems in later life.

Gestational diabetes mellitus treatment

Maintenance of healthy weight and exercising before pregnancy assist in prevention. Gestational diabetes is treated with a diabetic diet, exercise, medication (such as metformin), and sometimes insulin injections.

Ideal body weight

Males Allow 48 kg (105 lb) for 1.5 m (4.9 ft) of height. Add 0.8 kg (1.7 lb) for each additional centimeter over 1.5 m (4.9 ft). Then subtract 10% for a small frame or add 10% for a larger frame. Females: Allow 45 kg (99 lb) for 1.5 m (4.9 ft) of height. Add 0.7 kg (1.5 lb) for each additional centimeter over 1.5 m (4.9 ft). Then subtract 10% for a small frame or add 10% for a larger frame.

Malignant FNA

Malignant "THY4 or 5" • papillary cells with cell and nuclear size variation • follicular cells with cell and nuclear size variation Inclusion bodies in the nucleus Some colloid but many more cells

Prolactin and lactation

Mammary gland development during pregnancy is facilitated by oestrogen and progesterone but high levels of these hormones inhibit prolactin stimulation of milk production. Following birth, progesterone levels fall rapidly allowing prolactin to stimulate milk production. Stimulation of the nipples causes oxytocin release as well as increased prolactin availability.

Goals of diabetes management

Manage symptoms Prevent acute and late complications Improve quality of life Avoid premature diabetes-associated death Provide an individualised approach

Factors influencing food intake

Many factors influence food intake and termination of a meal. complex, interacting physiological factors, in the CNS and periphery Habits, learned associations social factors mood

Assessing blood glucose control

Many individuals routinely test their blood glucose either as a finger prick test or via continous monitoring sensor and linked device. A for the A1C test The A1C test shows her average blood glucose level over the past 3 months. The A1C goal for many people with diabetes is below 7 percent. B for Blood pressure The blood pressure goal for most people with diabetes is below 140/90 mm Hg. C for Cholesterol LDL can build up and clog blood vessels. Too much LDL cholesterol can cause a heart attack or stroke. HDL cholesterol helps remove the LDL cholesterol from your blood vessels. If over 40 years of age, she may need to take a statin drug for heart health. Also stopping smoking

Type 2 diabetes- non-insulin dependent

Maturity onset. Reduced insulin secretion and insulin resistance. Serum insulin levels can be high The b-cells do not release enough insulin in response to an increase in blood sugar Treatment is diet, drugs or insulin Often undiscovered

Maturity onset diabetes of the young

Maturity-onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production.[1] Along with neonatal diabetes, MODY is a form of the conditions known as monogenic diabetes. While the more common types of diabetes (especially type 1 and type 2) involve more complex combinations of causes involving multiple genes and environmental factors, each forms of MODY are caused by changes to a single gene (monogenic).[2] GCK-MODY (MODY 2) and HNF1A-MODY (MODY 3) are the most common forms.

McCune-Albright syndrome

McCune-Albright syndrome is a genetic disorder where there is a constitutively active Gsa protein upregulating adenylate cyclase, resulting in the over-production of several hormones including GnRH café-au-lait spots, abnormal bone growth and early puberty.

Phentermine

Mechanism of action resembles that of fenfluramine but this drug has not been linked with fenfluramine's adverse actions. Phen-Fen:- A formulation combining fenfluramine and phentermine. Adverse effects are primary pulmonary hypertension, valvulopathy and, possibly, neuropathy. It is no longer available for clinical use. The reasons for these adverse effects are, as yet, unknown but are unlikely to be linked with inhibition of monoamine reuptake because they are not induced by other monoamine reuptake inhibitors (e.g. the tricyclic antidepressants or sibutramine).

Medullary cancer of thyroid

Medullary cancer of the thyroid is a C cell tumour may be familial or not it may be isolated Or it might be part of MEN II where there is also a tumour of the chromatin cells of the adrenal medulla- very high circulating calcitonin but normal serum calcium

Factors that reduce food intake (anorexigenic):

Melanocortins CART (cocaine amphetamine regulated transcript) 5-hydroxytryptamine (5-HT; Serotonin). Noradrenaline Dopamine Nicotine

Menarche

Menarche is the culmination of physiological and anatomical processes of puberty Sufficient body mass for menses 17-22% body fat Disinhibition of the GnRH pulse generator in the arcuate nucleus of the hypothalamus Secretion of oestrogen by the ovaries in response to pituitary hormones

Metformin

Metformin is an oral biguanide hypoglycemic agent. It causes an increased peripheral uptake of glucose by increasing the efficiency of available insulin.

Mifepristone

Mifepristone works differently than the other medications as it blocks the action of cortisol in the body, rather than decreasing the amount of cortisol that is made. 60% of patients have improvement in blood sugars and 80-90% have improvement of physical features.

Hypoglycaemia management

Mild episodes: sugary drink More severe: Glucogel to buccal mucosa IV 25-50ml 50% glucose IM Glucagon (1mg) - mobilises hepatic glycogen stores

Inflammatory cytokines, leptin and hypertension

Most adipokines including inflammatory cytokines and leptin act by decreasing NO production in endothelial cells. They increase the production of vasoconstrictors and increasing the proliferation of smooth muscle cells which can increase arterial stiffness and therefore blood pressure. The perivascular secretion of adipokine from adipose tissue is altered by obesity and may contribute to hypertension

Cortisol & Hepatic Gluconeogenesis

Must overcome irreversible steps in glycolysis: Glucose > Glucose-6-P (hexokinase / glucokinase) Fructose-1-P > Fructose-1,6-P2 (phosphofructokinase) Phosphoenol pyruvate (PEP) > Pyruvate

Human mammary gland, resting: very low power, H and OG erythrosin

Milk is a complex secretion containing protein, carbohydrate and a high fat content, all secreted by a single type of gland cell and stored within secretory units (alveoli) during pregnancy and lactation In the reproductive female the histological appearance of the mammary glands is determined by the level of secretory activity The functional states are: Resting - non-secretory Pregnancy - preparation for lactation Lactation - milk secretion Regression - the gradual return to the resting non-secretory state Note the preponderance of connective tissue in the non-secretory gland the epithelial component is almost entirely represented by ducts (the big white shapes) few (if any) secretory units (alveoli) are present The terminal ducts are arranged in clusters separated by dense fibrous connective tissue, a typical lobular pattern Identify: intralobular ducts and connective tissue lighter interlobular ducts and connective tissue darker Note the differences in texture and collagen fibre density between the intralobular and interlobular connective tissue Proceed via the interactive areas Box A - secretory tissue Box B - collecting duct

Cellular Actions of Oxytocin: Stimulation of milk ejection (milk letdown)

Milk is initially secreted into small sacs within the mammary gland called alveoli, from which it must be ejected for consumption or storage. Mammary alveoli are surrounded by smooth muscle (myoepithelial) cells which are a target cell for oxytocin. Oxytocin stimulates contraction of myoepithelial cells, causing milk to be ejected into the ducts and cisterns. the neural reflex input caused by suckling stimulates further secretion of oxytocin, which causes further milk ejection, which stimulates further suckling, etc.

Treatments for mineralocorticoid excess

Mineralocorticoid antagonists (e.g. Spironolactone) • Angiotensin converting enzyme inhibitors • K+ (aldosterone drives K+ secretion so may need)

Mineralocorticoid resistance

Mineralocorticoid resistance aka type I pseudohypoaldosteronism (PHA1), is a rare inherited disease The generalized, recessive form of the disease is due to abnormalities in the epithelial sodium channel causing renal resistance to aldosterone The autosomal dominant form and some sporadic cases inactivate the mineralocorticoid receptor causing systemic resistance to aldosterone characterized by salt wasting, dehydration and failure to thrive in the newborn.

List the general actions of mineralocorticoids

Mineralocorticoids (and, under defined circumstances, glucocorticoids) stimulate excretion of potassium, retention of sodium and osmotic resorption of water. Hence, the clinical symptoms of adrenal dysfunction will depend on which adrenal hormones are implicated.

Mineralocorticoids

Mineralocorticoids like aldosterone act in the kidney, colon and salivary glands to control the balance of the "minerals", Na+ and K+ , and indirectly of water

T3 also targets the mitochondria directly

Mitochondria have their own genome, T3 binds to TR in the mtDNA to regulate energy metabolism directly It increases nuclear expression of key regulatory factors such as PGC-1 , nuclear respiratory factor • (NRF-1), mitochrondrial RNA polymerase (Polrmt), mitochondrial basal transcription factor (Tfam) • Binds truncated TR1 in mitochondria triggering copying of mtDNA • Binds AdNT (adenine nucleotide transporter) to promote 'proton leak' and heat generation

Mitotane

Mitotane is a medication primarily used in adrenal cancer, it also blocks the production of cortisol. However in higher doses it may also cause destruction of the adrenal cells. Gastrointestinal problems and some develop problems with confusion and impaired mental function

Factors that stimulate Insulin Release

Mixed meal Increased glucose Increased free amino acids Gut hormones released postprandially GLP-1, GIP = INCRETINS Glucagon Acetylcholine to regulate insulin Alpha1 adrenergic receptors Beta 2 adrenergic receptors

Other types of diabetes

Monogenic diabetes, Gestational diabetes Pancreatic- Surgery, pancreatitis, cystic fibrosis Endocrine- Endocrinopathies- Cushing's, acromegaly Drugs- Glucocorticoids, Thiazide diuretics, ß blockers, Statins Other genetic syndromes

Glucocorticoids and angiotensin

More angiotensin is produced in response to glucocorticoids

Vitamin D deficiency prevalence

More people have low vitamin D levels in the winter and spring because of less exposure to sunlight. For six months of the year October to April, much of western Europe including 90% of the UK lies too far north to have enough UVB rays in sunlight necessary to make vitamin D in the skin. So, many people in the UK are at risk of not getting enough vitamin D unless they get it in their diet.

Desensitisation of GPCRs

Most GPCRs desensitise on continuous exposure to its stimulating ligand. Desensitisation = failure of signalling pathway to respond to stimulus despite continued presence of receptors at cell surface. Desensitisation can be: • homologous (cell ceases to respond to desensitising stimulus, but same signal transduction pathway remains responsive to alternative signalling stimuli) • heterologous (cell loses ability to respond to a particular signalling ligand following exposure to an alternative signalling stimulus, acting through a different receptor type).

Regulation of Sodium Balance

Most abundant cation in ECF • Sodium salts in ECF contribute 280 of 300 mOsm • Only cation exerting significant osmotic pressure • Controls ECF volume and water distribution • Changes in Na+ levels affects plasma volume, blood pressure, ECF and ICF volumes

Insulin-mediated Glucose Uptake

Most cells have insulin receptors but not all cells rely on insulin-dependent insertion into the membrane of GLUT4 transporters for glucose uptake. Insulin enhances glucose entry into adipocytes and cardiac and skeletal muscle cells that use GLUT4 as the major glucose carrier. Human red blood cells express only GLUT1 transporters, so insulin does not affect entry directly. But it does stimulate glycolysis. Although it has important metabolic effects in the liver, insulin does not affect liver glucose uptake which occurs through the GLUT2 carrier. Insulin crosses the blood-brain barrier and affects neuron and glial cell metabolism. But it is it not required for glucose entry to the cells, for these use GLUT3 (neurons) or GLUT1 (glial cells) as the glucose transporter.

Cell calcium

Most of the Ca is found bound to proteins in cell organelles including calmodulin in smooth muscle excitation-contraction coupling, and calsequestrin found in the sarcoplasmic reticulum of skeletal muscle cells. In resting cells, cytosolic free Ca2+ is in the nmol/L range. It rises substantially when Ca2+-activated pathways are stimulated.

Calcium handling in the kidneys

Most of the filtered Ca2+ is reabsorbed passively through the tight junctions through claudin-2 and paracellular pathway in the proximal tubules. Some is reabsorbed passively in the ascending thick limb of the loop of Henle. Only some 8% is reabsorbed actively. This occurs in the distal tubules and involves the same pathways as are used for Ca2+ absorption in the intestine. Around 2% of the filtered load is excreted in the urine.

Body phosphorous content

Most phosphate is in bone, some 99% as part of hydroxyapatite, Ca10(PO4)6(OH)2. Only 1% is readily exchangeable, though in chronic illnesses, much more P can be lost from bone. The non-bone P is found predominantly in cells, where phosphate is the major cell anion; only 0.1% is in the extracellular fluid (ECF).

Adinopectin and muscle insulin sensitivity

Muscle has the receptor AdipoR1. Adiponectin causes an increase in the uptake of glucose in muscle. It also increases beta oxidation via AMPK in the muscles decreasing muscle lipid stores and increasing insulin sensitivity.

Salt-Sparing / Simple-Virilising CAH

Mutation in 11 beta hydroxylase- DOC is produced in excess and has some of the weak DOC is produced in excess. Lack of aldosterone and cortisol raise ACTH drive thus more DOC is produced. Causes malignant hypertension- uncontrolled hypertension

Salt-wasting CAH

Mutation in the 21 hydroxylase enzyme so no aldosterone or cortisol Lack of cortisol drives ACTH, DHEA can be made and is increased Hypoglycaemia, hyponatreamia, hyperkalaemia Vomiting due to salt-wasting, dehydration Hypovolaemia, shock

Achondroplasia

Mutation in the FGFR3 gene resulting in either a glycine or arginine substitution. G to A transition in most, less than 3% G to C transition dominant allele, homozygous affected dies shortly before or after birth

11 beta-HSD mutations

Mutations in 11bHSD gene • Coding sequence (loss of function) • Regulatory region (decreased expression) Known mutations are recessive Significance: • Defectivegeneneedstobehomozygousto generate phenotype • AME usually confined to consanguinous parentage • BUT heterozygotes might have increased ability to conserve sodium under conditions of sodium deprivation giving a selective advantage which may have conserved mutations.

GH and acromegaly

Mutations in the αS subunit of the G-protein for GHRH lead to persistent activation can be a cause of acromegaly

Myxoedema coma

Myxedema coma is an extreme or decompensated form of hypothyroidism. A person may have laboratory values identical to a "normal" hypothyroid state, but a stressful event such as an infection, myocardial infarction, or stroke precipitates the myxedema coma state, usually in the elderly. Primary symptoms are altered mental status and low body temperature. Low blood sugar, low blood pressure, hyponatremia, hypercapnia, hypoxia, slowed heart rate, and hypoventilation may also occur.

Congenital hypothyroidism screening

NHS newborn screen for TSH (heel prick) in the blood, will be high in hypothyroidism Treat with L-T4 as soon as possible

Mild-moderate iodine insufficiency in the UK

National survey of UK schoolgirls 2010 median urine iodine content of 80 μg/L should be >100 μg/L (>150 in pregnancy) This is on background of free school milk being withdrawn from the 1970s salt iodinisation not mandatory in UK Potential impact on fetal brain development during pregnancy is not known

Vitamin D storage

Native vitamin D including cholecalciferol and ergocalciferol vitamin D2, can be converted in the liver to 25 hydroxyvitamin D (calcidol) and stored. Increasing concentrations of 25-hydroxycholecalciferol inhibits further conversion. the liver can store cholecalciferol for months but the half-life of 25-hydroxycholecalciferol is much shorter, so limiting conversion helps maintain the liver's cholecalciferol stores. The intake and production of cholecalciferol can vary widely without this affecting the production of 25-hydroxycholecalciferol.

Symptoms of Pseudohypoaldosteronism

Natriuresis / Anti-kaliuresis Hyponatremia / Hyperkalemia • high plasma renin activity • high [ Aldosterone ]

Cortisol

Near term, cortisol stimulates synthesis of surfactant, to reduce surface tension allowing the alveoli to expand with air at birth and begin gas exchange. dexamethasone is given in premature labour to decrease the incidence of neonatal respiratory distress syndrome.

Necrosis v apoptosis

Necrosis is inflammatory, apoptosis is non-inflammatory

Endocrine regulation of growth

Need for the appropriate setting endocrine: thyroid/adrenal/parathyroid/gonadal social: nutrition / psychological GH is then the dominant endocrine regulator of growth however for first year of life, growth is largely nutrition dependent GH receptors appear at 7 months

Non-Metabolic Actions of Cortisol, endocrine function

Negative feedback on CRH+ ACTH, affects mood and behaviour as POMC makes beta-endorphins Positive ionotropy, abnormal ECG Increased renal blood flow/GFR/water clearance Inhibits fibroblast proliferation/collagen formation- increased bruising / impaired wound healing Increased synthesis of surfactant, cortisol can be used in early delivery to improve the function of the lung in neonates Anti-inflammatory / immunosuppressant Increases serum calcium through increased bone catabolism

Nelson's syndrome

Nelson's syndrome is an iatrogenic condition that occurs as a result of removal of both adrenal glands. Treatment involves trans- sphenoidal surgery to remove the pituitary tumour. The common signs and symptoms include muscle weakness and skin hyperpigmentation due to excess MSH. Nelson's syndrome is now rare because bilateral adrenalectomy is now only used in extreme circumstances.

Neovascularisation in tumours

Neovascularisation occurs early in tumour development. The blood vessels formed are abnormal, being hyper permeable to small molecules, plasma fluid and proteins These vessels are easier for metastatic tumour cells to invade and enter the circulation These cells may reach distant sites and potentially form new tumours, metastasis

Water homeostasis

Neurons in the hypothalamus detect an increase in osmolarity and respond by releasing ADH and thirst. Vasopressin is produced by magnocellular neurosecretory neurons in the paraventricular nucleus of hypothalamus (PVN) and supraoptic nucleus (SON) and stored in the posterior pituitary until it needs to be released.

Factors that increase food intake orexigenic:

Neuropeptide Y AgRP Agouti-related peptide Endocannabinoids Opioids

Neuropeptide Y is orexigenic

Neuropeptide Y is released from neurones with cell bodies in the arcuate nucleus (ARC), which project to the paraventricular nucleus. These neurones are activated by a decline in fat stores and are normally inhibited by negative feedback provided by insulin and leptin. Their stimulation reduces sympathetic outflow to brown adipose tissue and so lowers energy expenditure and stimulates lipogenesis. desensitisation of NPY- releasing neurones may impair satiety regulation of meal size.

Post-menopausal syndrome

No follicles to lack of oestrogen - vasomotor symptoms - urogenital atrophy - ↑ bone resorption (osteoporosis) - ↑ atheroma formation

explain the unique control of prolactin secretion

No releasing factor yet identified for prolactin It appears to be under dominant negative control; decreased inhibition is "stimulus" to prolactin synthesis and secretion. Major inhibitory factor for prolactin appears to be dopamine

Menarche and Fertility

No specific hormonal signal for menarche is known Menarche does not signal ovulation- ovulation can occur before the first menstruation so although unlikely, it is possible for a girl who has engaged in sexual intercourse shortly before the 1st menses to conceive and become pregnant 80% cycles anovulatory in 1st, 50% in the 3rd, 10% in the 6th year post menarche

Non-permissive heterodimers

Non-permissive heterodimers are those that can only be activated by the partner's ligand while RXR is silent By silencing RXR activity and responding only to their own ligands, non-permissive receptors permit transcriptional regulation that is directly proportional to the level of the hormone, thereby meeting the requirements of endocrine physiology.

Actions of catecholamines

Noradrenaline increases both systolic and diastolic BP (so increasing mean BP) adrenaline only increases systolic BP and reduces diastolic BP (hence no change in mean BP). Adrenaline decreases gut motility and can act as a bronchodilator. Effects of noradrenaline on gut motility are less marked and no effect on bronchial tone. Both can dilate the pupil (if applied at high concentrations) and induce piloerection. catecholamines increase glycogenolysis (predominantly adrenaline) and the plasma [ NEFA ] (predominantly noradrenaline). Increase in glucose-6-phosphate results in hyperglycaemia and lactic acidaemia (due to high rate of glycolysis).

Leptin and the immune system

Normal immune function is suppressed during nutritional deprivation but this can be reserved by the administration of leptin In this way, leptin is a chemoattractant, and may be responsible for the infiltration of macrophages into adipose tissue in obesity. Leptin is also involved in the development of the immune system (Leptin also has an effect on the reproductive system)

Parathyroid Glands

Normally 4 glands embedded in the rear face of the thyroid although number and position are variable • Abnormalities may occur in 1 in 10 glands

Incidence of pituitary tumours

Note incidence of pituitary tumours: PRL > ACTH > GH • LH/FSH/TSHveryrare

Human mammary gland, pregnant B

Note that the epithelium of the intralobular ducts has proliferated and many of these ducts now have a two-layered epithelium

Human uterus, promenstrual Bi: stratum compactum

Note the high cellular density of the stroma and the paucity of collagen fibres

Oviduct iA

Note variable appearance, simple or pseudostratified with basal cells, cuboidal or columnar

Height V Chronological Age (Population)

Note: • Appropriate reference population must be used • Generations change, linked to improved nutrition and economic conditions

Contraception: Combined Hormonal Contraceptive

OESTROGEN + PROGESTOGEN e.g. ethinyl-oestradiol + norethisterone • administration: oral, transdermal patch, vaginal ring • traditional: 21 days, followed by 7 hormone-free days • "tailored": less frequent/shorter hormone-free intervals

Explain the risks associated with obesity.

Obesity BMI ›= 30kg/m? is associated with increased risk for: Type II diabetes Hyperinsulinaemia Glucose intolerance Hypertension and stroke Coronary heart disease Some cancers- breast, endometrial, ovarian, gall bladder, colon Obese individuals often suffer from 'metabolic syndrome',

Obesity and Cancer prognosis

Obesity is associated with, for some cancers, increased incidence, increased aggression of tumours, increased recurrence and increased mortality. Cancer cells incubated with adipocytes, or in adipocyte cultured media show increased invasive potential. More aggressive tumours, high number of metastases, increases resistance to chemotherapy. Several studies have shown that exercise during and after treatment can significantly improve survival

Obesity

Obesity significantly reduces life expectancy, and is associated with an increased risk for several conditions including Type 2 diabetes , coronary heart disease, and some types of cancer. Adipose tissue is now recognised as an important endocrine tissue, whose secretory profile is disturbed in obesity.

Oestrogens

Oestrogens give rise to "oestrous" behaviour sexual receptivity in women, and stimulate the development of female secondary sexual characteristics i.e.breast growth.

Ovulation

On day fourteen Oestrogen levels peak causing an LH surge. The LH stimulates the mature follicle to rupture and release the secondary oocyte.

Post-ovulation:

Once ovulation occurs, oestrogen levels fall and progesterone levels rise. Progesterone inhibits further release of GnRH, LH, and FSH. The positive oestrogen-LH loop is now inhibited. If pregnancy does not occur, progesterone levels fall, the hypothalamus secretes GnRH and the cycle begins again.

Plasma calcium

Only some 50% of the total plasma calcium is ionized. The other 50% is bound to proteins or complexed with anions such as phosphate, bicarbonate, and citrate

What histological changes occur in maturing ovarian follicles before ovulation?

Oocyte - increase in size; zona pellucida Follicular epithelium (granulosa), followed by increase in follicular fluid in central cavity ​Development of hormone secreting thecal cells

Secondary hyperparathyroidism treatment

Oral or intravenous administration of calcitriol increases vitamin D receptors in the parathyroid glands and suppresses PTH secretion. It may cause hyperphosphataemia and hypercalcaemia as Vitamin D increases calcium and phosphate uptake from the intestines

Menstrual cycle

Originally, FSH and LH rise, involved in oestrogen synthesis so oestrogen increases. Oestrogen negatively feeds back to reduce FSH and LH The dominant follice continues to synthesise oestrogen even after FSH and LH drop as there is overexpression of the gonadtrophic receptors Oestrogen stimulates the proliferative phase of the endometrium At high oestrogen, LH levels surge, ovulation, corpus luteum forms Corpus luteum releases progesterone- stops prolfieration stimulates differentiation of the endometrium. Glands, high volume low viscocity of secretions No implantation, corpus luteum degeneration, progesterone falls, menstruation

Orlistat

Oristat prevents the absorption of fat by inhibiting pancreatic lipase, preventing the breakdown of fat to fatty acids and glycerols. It increases faecal fat and so patients must adhere to a low fat diet to avoid unpleasant (and antisocial!) side-effects

explain the control of AVP secretion

Osmolality and plasma volume are sensed independently, but act in synergy as in the change in blood volume alters the sensitivity of AVP secretion to changes in plasma osmolality Osmolality is more effective than plasma volume - 15% decrease in plasma volume - 2X increase in [ AVP ], 20% decrease in plasma volume - 4X increase in [ AVP ] - 2% increase in plasma osmolality - 35% increase in [ AVP ], 4% increase in plasma osmolality - 3.5 fold [ AVP ]

Osmolarity

Osmolarity is the total number of dissolved particles in a solution In relation to the standard body fluid osmolarity of 295 mosmol/L (280-300 mosm/L), there are three possible solutions: Isoosmotic: the same osmolarity Hypoosmotic: a lower osmolarity Hyperosmotic: a higher osmolarity

Thirst

Osmoreceptors in the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO) lie outside of the blood brain barrier can detect the increased plasma osmolarity and are triggered by the osmotic shrinkage of cells They activate the median preoptic nucleus which initiates water seeking and ingestive behavior.

describe the effects of GH on fibroblast transformation and long bone extension

Osteoblasts expressing the IGF-1 receptor expand under GH GH directly and indirectly through IGF-1 stimulates the clonal expansion of mature chondrocytes Via IGF-1 also stimulates fat cell expansion

Aspirin

Other anti-inflammatory drugs like aspirin may be able to decrease insulin resistance such as adinopectin does.

Adrenal organisation

Outer capsule Outer layers are the cortex The arteries anastomose to deliver the signal and pick up hormone that gets delivered in the vein

Ovary ApA

Ovarian epithelium The cortical surface is smooth, covered with a simple cuboidal epithelium (E), often only patchily preserved Beneath the epithelium is a layer of fibrous connective tissue, the tunica albuginea (TA), be careful of the context, the testis also has a tunica albuginea Primordial follicles (PF) consist of primary oocytes (O) surrounded by a single layer of flattened follicular cells (F) Often the oocyte are out of site, such is the case with the primary follicle here In this image there is a single early primary follicle whose follicular cells have multiplied and have become cuboidal granulosa cells (GC)

Risk factors for Type 2 diabetes

Overweight Poor diet Excess alcohol consumption

Treatments for infertility

Ovulation induction for anovulation Menopur Clonid IVF- injections given to give rise to multiple dominant follicles. Day 5/6 blastocyst inserted back into uterus ICSY (intracytoplasmic sperm injection) - sperm put directly into the egg if there's a problem with the sperm

Delayed puberty treatment

Oxandrolone is an anabolic steroid that is a weak androgen It cannot be aromatised to oestrogen therefore does not advance bone age or lead to growth plate closure. So does not shorten pre-pubertal window of time • Stimulates growth of boys with pubertal delay: increases natural GH • Lower doses used for girls

describe the role for neural reflexes in the control of oxytocin secretion

Oxytocin (OT) elevates intracellular Ca2+ to stimulate contraction of smooth muscles of: breast (to stimulate milk ejection) uterus (to stimulate expulsion of infant at parturition) The secretion of OT from the posterior pituitary is triggered by neural reflex inputs: suckling reflex: The act of nursing or suckling is relayed within a few milliseconds to the brain via a spinal reflex arc. These signals impinge on oxytocin-secreting neurons, leading to release of oxytocin. (plus sensory stimulus of crying infant)

Oxytocin

Oxytocin is a nine amino acid peptide that is synthesized in hypothalamic neurons. It is also secreted from a few other tissues, including the ovaries and testes. Oxytocin differs from antidiuretic hormone in two of the nine amino acids. Both hormones are packaged into granules and secreted along with carrier proteins called neurophysins.

Oxytocin action

Oxytocin, from the posterior pituitary, causes contraction of the myoepithelial cells in the mammary gland that help expel the milk from the lactiferous ducts.

4-gland hyperplasia

Parathyroid scan with technetiumTc99m-MIBI demonstrating uptake in all 4 glands consistent with 4- gland hyperplasia

Regulation Of PNMT Expression And Activity

PNMT expression & activity is increased by: • Sympathetic neural input • Glucocorticoids Chromaffin cells: • Epinephrine output 4X NE output • Noradrenergic neurones lack PNMT

PPARy Mutations May Also Cause Obesity

PPARy stimulates the differentiation of pre-adipocytes to adipocytes. Phosphorylation of Ser114 inhibits its activity. The Pro115GIn mutation disrupts the consensus phosphorylation site for MAPK. The mutant PPARy2 is overactive, resulting in greater differentiation of adipocytes. The affected had substantially greater obesity than the rest of the test subjects (BMI of up to 47.3), but lower fasting insulin levels.

Contraception: Progestogen only

PROGESTOGEN e.g. norethisterone, levonorgestrel, medroxyprogesterone acetate (MPA) • administration: - oral, injectables, patches, implants - continuous administration (irregular bleeding)

PTH action on receptors

PTH acts via cell surface receptors on osteoclasts and the antiluminal surface of the renal tubules • Linked to adenylyl cyclase and formation of cAMP • Continual secretion, rapid clearance (half-life ~5 min)

PTH actions on the kidneys

PTH blocks the reabsorption of phosphate at the proximal tubule stimulating an increase in phosphate excretion increases reabsorption of calcium from the distal tubule (calcium excretion may increase because of the greater filtered load due to hypercalcaemia induced by PTH)

PTH actions on the GI tract

PTH stimulates 1alpha hydroxylation of 25 hydroxyvitamin (25-hydroxy cholecalciferol, an inactive vitamin D metabolite produced from vitamin D in the liver) to produce active 1,25 dihydroxyvitamin D. the active form1,25-dihydroxy cholecalciferol acts in the intestine to increase Ca2+ absorption and phosphate

PTH role

PTH stimulates 1alpha hydroxylation of 25 hydroxyvitamin produced in the liver to active 1,25 dihydroxyvitamin D. the active form 1,25-dihydroxy cholecalciferol acts in the intestine to increase Ca2+ and phosphate absorption It stimulates osteoclasts to increase their RANKL expression, promoting their recruitment and differentiation. they release Ca2+ from bone. PTH blocks the reabsorption of phosphate at the proximal tubule and increases reabsorption of calcium from the distal tubule High calcium, active vitamin D and low phosphate levels all act via negative feedack on the PTH gland to maintain homeostasis

Secondary hyperparathyroidism treatment

PTH stimulates 1α-hydroxylase therefore, calcitriol rather than cholecalciferol or ergocalciferol needs to be given to treat hypocalcaemia secondary to hypoparathyroidism

PTH actions on the bone

PTH stimulates osteoclasts to increase their RANKL expression. This promotes the recruitment and differentiation of osteoclasts, activating them. they break down bone mineral and degrade bone collagen, release Ca2+ from bone.

Paracrine Somatostatin

Pancreatic SST is likely to play paracrine role • Inhibition of pancreatic exocrine secretion • Inhibition of pancreatic endocine secretion insulin, glucagon, ghrelin etc

Factors that suppress Insulin Release

Pancreatic and gastric somatostatin Decreased glucose Epinephrine: Alpha 2 adrenergic receptors

Insulin and vagal nerve stimulation

Parasympathetic vagal nerve stimulation releases some insulin even before food has been ingested in preparation for the anticipated increased glucose absorption from the intestine.

Parathyroid Hormone

Parathyroid hormone (PTH) is released from the chief cell in the parathyroid glands. Chief cells have calcium-sensing protein in their membranes. Decreased plasma Ca2+ stimulates PTH secretion; increased plasma Ca2+ inhibits PTH secretion.

define the sites of synthesis and physiological actions of parathyroid hormone (PTH), calcitriol and calcitonin

Parathyroid hormone is released from the chief cells of the parathyroid glands.

Pasireotide

Pasireotide lowers cortisol in most and normalizes cortisol levels in about 25% of patients. The major side effect of pasireotide is increased blood sugars. 40% of patients had increased blood sugars and ~1:5 develop diabetes.

Tailor-made insulin regimen

Patient choice Age, cognitive abilities Diet and regularity of meal times Exercise, shiftwork Target HbA1C Risk or experience of hypoglycaemia Previous control if already on insulin

Conn's Syndrome treatment

Patients are referred for a laparoscopic adrenalectomy after an abdominal CT scan reveals an enlarged adrenal gland. most patients go home the day after surgery with minimal pain. The surgery occurs through 3-4 small incisions measuring less ~1cm in size. Many patients return to work within 7-10 days.

Lipodystrophy symptoms

Patients often have aspects of metabolic syndrome such as insulin resistance, dyslipidemia and hypertension Some of the symptoms seen in lipodystrophies can be alleviated by the administration of adipocytokines, such as leptin or adiponectin

Tubal factor

Pelvic inflammatory disease (50%) - Chlamydia - Genital tuberculosis Endometriosis Intratubal debris Salpingitis isthmica nodosa

Peptides

Peptides are short chains of amino acids; most hormones are peptides The peptide and protein hormones are all water soluble and act on surface receptors.

Endocannabinoids

Peripheral administration of anandamide increases food intake - probably explains the 'munchies' experienced by users of cannabis. CB1 antagonists reduce food intake. Fasting leads to accumulation of anandamide to drive food intake.

Anorexigenic

Peripheral signals Adiposity signals -leptin, adiponectin, (insulin) Satiety/Satiation signals -GLP-1, PYY, CCK, gastric distension Central signals -serotonin (5-HT), noradrenaline -melanocortins (e.g. a-MSH)

Orexigenic

Peripheral signals Hunger signals -ghrelin Central signals -NPY, orexin, AgRP -hypoglycemia -endocannabinoids Emotions/Stress -Food as reward

Permissive and non-permissive heterodimers

Permissive heterodimers are those that can be activated by ligands of either RXR or its partner An important regulatory feature of permissive receptor partners are Peroxisome Proliferator-Activated Receptors (PPARs). Simultaneous presence of both RXR and partner receptor ligands results in a larger response compared to binding of only a single receptor ligand

Hyperphosphataemia treatment

Phosphate binders dietary restriction of phosphate High PTH results in low serum phosphate levels, as a result of decreased renal tubular phosphate reabsorption

ECF phosphate

Phosphate in the ECF is there as both H2PO4- and HPO42- At the normal pH of blood, 7.4, there is 4 x more HPO42- than H2PO4- . This reflects the fact that the PKa for the reaction HPO42- + H+ ⇄ H2PO4- is 6.8.

Transcellular phosphate intestinal absorption

Phosphate is cotransported into cells coupled to Na+. It leaves cells on a phosphate carrier, the precise details of which are as yet unknown. The Na+ that entered with the phosphate is removed across the basolateral membrane by the Na+K+ATPase. The K+ taken into the cell on the transporters diffuses from the cell through K+ channels.

Phosphorus absorption

Phosphorus-containing foods are readily digested and the phosphorus absorbed. Most of the phosphorus excreted in the faeces is associated with unreabsorbed calcium.

Gonadotropin release in puberty

Pituitary gonadotrophins drives the changes in gonadal steroid activity, the key effectors of puberty During the childhood and juvenile stages gonadotrophin output remains very low in both sexes Initially most gonadotrophin secretion occurs during sleep Puberty-pulses of LH and FSH become evident, and levels rise gradually to reach adult levels

Secondary hypothyroidism

Pituitary/hypothalamic disease e.g. tumour, surgery, head injury TSH is low or low-normal in these cases It can be 'inappropriately normal' given the low T4, T3

Regulation of Labor and Birth

Placenta produced Corticotropin-releasing hormones stimulate increased estrogen secretion just prior to birth. The high estrogen levels overcome the inhibitory effects of progesterone on uterine smooth muscle by promoting the formation of gap junctions between the smooth muscle cells and the myometrium. It also increases the number of smooth muscle cell receptors for oxytocin that promote uterine contractions.

Adiponectin and cancer

Plasma adiponectin levels are consistently lower in cancer patients, and hypoadiponectinaemia is a marker for an agressive phenotype. Adiponectin is also anti-angiogenic

Leptin and cancer

Plasma leptin and cancer risk - inconclusive. Locally increased leptin levels have been reported, mechanism is likely to be paracrine. Tumours are often found to express leptin- leptin can act as a mitogens on many cell types and as an inhibitor of apoptosis Pro-inflammatory cytokines enhance leptin production by pre-adipocytes

AVP and plasma volume

Plasma volume must decrease > 8% A decrease in plasma volume lowers the firing of baroreceptors in the system venous circulation, left atrium and the systemic arterial system of carotid sinus and aortic arch There is less neurotransmission along the afferents IX and X causing less alpha-adrenergic inhibition of the magnocellular neurones. This increases the secretion of AVP. • Exponential relationship (provided plasma volume decreases > 8%): • 15% decrease in volume = 2X increase in [AVP] • 20% decrease in volume = 4X increase in [AVP]

PCOS

Polycystic ovarian syndrome (PCOS) is a common condition, affecting 5 to 10% of women of childbearing age. The disorder is probably the most common hormonal abnormality in women of reproductive age and is certainly a leading cause of infertility. Although the underlying cause is not well understood, PCOS is generally characterised by an excess production of androgens (male hormones - usually testosterone), anovulation (the egg is not released by the ovary) and amenorrhoea, and by a varying degree of insulin resistance. Hormone imbalances also affect the menstrual cycle in PCOS, causing infertility problems. Most women with this condition do not have regular monthly periods. Often they have chronic anovulation and amenorrhoea, but they may also experience irregular periods and uterine bleeding. Most women with PCOS have varying degrees of insulin resistance, obesity, and lipid dysfunction. Insulin resistance tends to be more pronounced in those who are obese and do not ovulate. These conditions put those with PCOS at a higher risk of developing type 2 diabetes and cardiovascular disease. 25% - 50% PCOS patients have no Insulin resistance With PCOS, both ovaries tend to be enlarged as much as 3 times their normal size. In 90% of women with PCOS, an ultrasound of the ovaries will reveal cysts (small immature egg-bearing follicles, fluid-filled follicles) that can be seen on the surface of the ovary. These ovarian cysts are often lined-up to form the appearance of a "pearl necklace." When the egg is not released and a woman is not menstruating, sufficient progesterone is not produced. This leads to a hormonal imbalance in which oestrogen acts "unopposed." This can lead to an overgrowth of the lining of the uterus (endometrial hyperplasia) and increases a woman's risk of developing endometrial cancer. Women with PCOS who do ovulate and become pregnant tend to have an increased risk of miscarriage.

Type 1 diabetes symptoms

Polydypsia Polyuria increased hunger Unexplained weight loss. Other presenting symptoms may include blurring of vision, fatigue, and symptoms and signs of ketoacidosis.

Diabetes insipidus symptoms

Polyuria (up to 20L urine/day with decreased urinary osmolality) Polydipsia check this is not psychogenic Increased plasma renin activity and [ aldosterone ] Hypovolemic hypotension

Polyuria in diabetes mellitus

Polyuria is a result of chronic renal disease, osmotic diuretics and unreabsorbable solute With elevated plasma glucose, more is filtered across the glomeruli. It exceeds the reabsorbative capacity of the proximal tubule resulting in more passing into the distal segments of the kidney that lack glucose transporters. The unreabsorbable glucose holds water with it in the tubular lumen. In addition, the greater volume delivered distally to the distal nephron segments decreases contact time with the tubule cells limiting the contact time for sodium and chloride reabsorption. Therefore the urine contains more glucose more sodium and more chloride which are all osmotically active solutes.

Skin infections

Poor blood supply leads to poor healing High levels of blood glucose give rise to conditions in the skin that permit rapid growth of invading bacteria and yeasts in small cuts and abrasions. This is compounded by the loss of peripheral sensation due to neuropathy so that infections can get hold without pain or sensation, particularly in the extremities. This can give rise to gangrenous infections if the wound becomes anaerobic and requires amputation in many cases.

Osteoarthritis

Poor glucose control can lead to modification of collagen and other structural proteins so that they cannot be readily degraded. The reduced turnover can lead to more radical induced damage to these proteins and give rise to the symptoms.

sleeve gastrectomy

Portion of stomach is removed, leaving a banana-shaped stomach pouch. Removal of the stomach fungus means caloric restriction through decreased absorption and enhanced nutrient/bile delivery to the small intestine

Hypoglycaemia in diabetics

Potential complication of therapy with insulin/sulphonylureas adrenergic and neurologlycopenic symptoms Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death.

Premature thelarche

Premature thelarche is a common disorder; it is characterized by breast development, usually under the age of 2 years, with no other signs of puberty. Growth and bone age are normal. This condition is self- limiting over a few years.

Insulin Synthesis and Processing

Preproinsulin is an 110 amino-acid protein which is encoded on the short arm of chromosome 11. Within the lumen of the rough ER of the pancreatic β cells, preproinsulin is cleaved (at the N-terminus) to generate, proinsulin an 86 amino-acid protein with a molecular mass of 9kDa. It contains a total of 3 intramolecular disulphide bonds. Within 20 mins of translation, the pro-insulin passes (in microvesicles) to the Golgi apparatus, where it is packaged into vesicles that possess a specific endopeptidase (pro-hormone convertase) enzyme. As the vesicles mature (30-120mins), this enzyme hydrolyses the proinsulin to liberate the connecting (C-) peptide, leaving the 21 amino-acid α-chain and 30 amino-acid β-chain of insulin joined by two disulphide bonds. As proinsulin molecules are processed, the insulin molecules form hexamers associated with zinc atoms. Within the secretory β-granule, the insulin-zinc complex forms the crystalline core, surrounded by cleaved C-peptide. On stimulation, the membranes of the β-granule fuse with the plasma membrane of the β-cell to secrete insulin into the pancreatic venules draining the islet. (This secretory process is both Ca2+- and energy-dependent).

define the main roles for 11 beta-HSD type 2 in the placenta

Prevents cortisol from maternal circulation from entering fetus: Cortisone Placental 11βHSD, thus fetal circulation • If placental 11βHSD is compromised Increased transplacental transfer of cortisol into fetal circulation • Stimulates premature differentiation of fetal tissues • Prevents full growth of fetal organs • Culminates in intra-uterine growth retardation (IUGR) Barker hypothesis - increased risk of serious adult disease

Glucocorticoid resistance

Primary generalized glucocorticoid resistance AKA as Chrousos syndrome is caused by mutations in the gene encoding the glucocorticoid receptor. A characteristic of the syndrome is hypothalamic-pituitary-adrenal axis (HPA axis) hyperactivation and adrenal hyperplasia. This results in high levels of cortisol as well as high levels of adrenal androgens and mineralocorticoids and neuropsychiatric symptoms such as depression, anxiety, and chronic fatigue. treated with high doses of mineralocorticoid-sparing synthetic corticosteroids such as dexamethasone.

Conn's Syndrome

Primary hyperaldosteronism - RARE Increased secretion of aldosterone due to over-expression of steroidogenic enzymes and/or expansion of Z.glomerulosa Kaliuresis / anti-natriuresis fluid resorption - hypervol. hypertension

Hyperparathyroidism

Primary hyperparathyroidism is a benign tumour of one or more parathyroid glands Secondary hyperparathyroidism Tertiary hyperparathyroidism has been reported in renal transplant patients.

Case 1. A 20-year old lady presented to her GP with difficulties in sleeping. She had been very irritable for the last 6 months, and had had palpitations, weight loss and sweating over the past year. She had noticed a swelling in her own neck over the past year. On examination she had a fine tremor and looked thin. Her pulse was 105 beats per minute and her blood pressure 110/75 mm Hg. She had a neck swelling which moved with swallowing. It was soft, was symmetrical and was not tender to touch. Her GP sent a blood sample to the hospital for thyroid tests.

Primary hyperthyroidism, the thyroid gland itself is producing too much T3/T4 and suppressing the pituitary causing the decreased TSH 1. Which of the patients above has thyroid overactivity? Which is underactive? Indicate the likely results of thyroid testing in each case.

Case 2. A 57-year old woman presented to her GP with progressive tiredness. constipated, intolerant of the cold and half a stone heavier than previously. Her periods were now heavier and lasted longer than before. There was no other illness in her family. On examination she was pale, was overweight and appeared disinterested. Her pulse was 55 beats per minute, and her blood pressure 105/75 mm Hg. She had slow relaxing reflexes. Her GP sent a blood sample to the hospital for thyroid tests. Low free T4 and T3, high TSH

Primary hypothyroidism Low T3,T4 reduces negative feedback on pituitary, high TRH and TSH

Altered adrenal hormone synthesis

Primary increased hormone secretion results from general gland enlargement hyperplasia or from tumors within the gland Primary decreased hormone secretion results from gland hypoplasia or destruction. symptoms and signs of overproduction of glucocorticoids are also associated with their therapeutic use, largely as anti-inflammatory agents.

Spermatogenesis

Primordial germ cells arrest mitotically as spermatogonia until puberty During mitosis, the basal spermatogonial stem cell renews itself and gives rise to a diploid daughter cell the primary spermatocyte that moves into the adluminal compartment Primary spermatocytes then undergo the first meiotic division to form haploid secondary spermatocytes The second meiotic division produces spermatids, which gradually mature into spermatozoa The spermatozoa are released into the lumen of the tubule and pass to the epididymis towards release at ejaculation.

Causes of decreased glucocorticoid production

Probably the most common acute cause is over treatment with glucocorticoids. This suppresses the adrenal cortex production of these hormones and results in gradual atrophy of the gland. It also suppresses hypothalamic production of CRH and anterior pituitary production of ACTH. If the glucocorticoid treatment is suddenly stopped, the person's own gland can not supply the needed hormone.

Male reproductive system

Production, nourishment and short-term storage of spermatozoa • Introduction of fluid containing spermatozoa into female genital system • Synthesis of male sex hormones (androgens) • Testes (2) - produce spermatozoa (male gametes) and male sex hormones (androgens) • Ducts - efferent ducts (2) → epididymis (2) → ductus (vas) deferens (2) → ejaculatory ducts (2) → urethra → .... • Glands - seminal vesicles (2) + prostate (1) + bulbourethral glands of Cowper (2) • Penis

Progestins

Progestins are required "for gestation" - they stimulate the secretion of uterine nutrients and inhibit contractions of the myometrium

Regulation of Lactation

Prolactin increases steadily throughout the pregnancy. However the high levels of estrogen and progesterone during pregnancy inhibit the action of Prolactin on the mammary tissue so no milk production occurs. After birth the levels of estrogen and progesterone rapidly drop and their inhibitory action ends. The stretch receptors in the breast are activated by the sucking action of the baby and serve to send impulses to the hypothalamus. The impulses from the breast reaching the hypothalamus inhibit a Prolactin - inhibiting hormone (PIH) and stimulate Prolactin-releasing hormone (PRH) Increased PRH triggers the release of Prolactin from the anterior pituitary gland. This circulates to the alveoli of the mammary glands and promotes lactation. The sucking action of the baby stimulates the hypothalamic hormone oxytocin. Oxytocin circulates to the myoepithelial cells that surround the alveoli of the mammary gland and cause contraction. This forces the milk from the alveoli into the ducts where it then can be suckled.

Insulin resistance leads to Type 2 diabetes

Prolonged insulin resistance leads to beta cell hypertrophy, but can only keep up for so long before degeneration. Dynamic process between genetics and the environment will influence the reaction of the beta cells to insulin resistance, obesity and hyperglycaemia. Hyperglycaemia leads to beta cell exhaustion which leads to Type 2 diabetes

Symptom reduction on hyperthyroidism

Propranolol a beta adrenoceptor antagonist is used to reduce tachycardia, tremor, and agitation. Guanethidine may reduce exophthalmos (bulging of the eyes seen in Grave's disease)

Protein Kinase A

Protein kinase A, an R2C2 heterotetramer, is a serine/threonine kinase. The binding of 4 x cAMP to the two R subunits causes them to dissociate from the catalytic subunits, activating them. Protein kinase A phosphorylates several enzymes, such as hormone-sensitive lipase (+), acetyl CoA carboxylase (-), glycogen synthase (-), and the transcription factor CREB (+). Protein kinase A is thus able to immediately alter metabolic pathways, and have longer term effects via gene transcription.

Adrenal Dysfunction - Altered Hormone Actions

Pseudohypoaldosteronism (PHA) Glucocorticoid resistance Apparent mineralocorticoid excess (AME)

Special points re: interpretation of serum GH values

Pulsatile secretion pattern GH secretion naturally declines with age During and after the 3rd decade

glucose oxidation and TAG synthesis

Pyruvate enters the citric acid cycle - citrate exits for FA synthesis via cytosolic acetyl-CoA Glycolysis generates alpha-phosphoglycerate, the backbone of TAG The pentose phosphate pathway generates reduced nucleotide cofactors for FA synthesis

RXR Heterodimers

RXR ligands called retinoids can simultaneously activate several heterodimers Small changes in the ligand partner can be amplified via RXR heterodimerization Receptor heterodimerisation of the retinoid X receptor can be activated by either the RXR ligand or the partner receptor ligand

Radioiodine (131I) treatment

Radioiodine can be used as a treatment for hyperthyroidism It is taken up as is I- by thyroid tissue and decays into high energy beta-particles (plus g-radiation) causing apoptosis It is especially effective for toxic MNG/adenoma and can also be used for Graves' disease

Acromegaly appearance

Raised GH causes raised IGF1 which gives rise to the proliferation of bone, cartilage and soft tissues + increase in the size of other organs Enlarged hands and feet, jaw protrusion and dental malocclusion increased foot and hand size coarsening of facial features: prominent frontal ridge and prognathism

Acromegaly complications

Raised GH opposes insulin Increased risk of diabetes mellitus with associated symptoms: Polydipsia / polyuria / recurrent urinary tract infections / retinopathy / neuropathy

Diagnosis of diabetic ketoacidosis

Raised blood glucose Metabolic acidosis Ketonuria

Laron dwarfism

Rare, autosomal recessive condition where mutations affect the GH receptors Depending on the mutation site it can be less severe where there is reduced binding affinity to the most severe with no binding Recombinant hGH not effective •Trials with recombinant IGF-1 Note: one patient described with partial deletion in gene for IGF-1:

explain how the free concentrations of active hormones to which a cell or tissue is exposed represent the balance between hormone synthesis, secretion, metabolism, clearance and interactions with binding proteins.

Rate of secretion. Steroids are hydrophobic, therefore the rate of secretion (by diffusion) is determined by the rate of synthesis, as they are not stored in cells, as hydrophilic hormones are. control of the rate of secretion is only applicable to hydrophilic hormones whereas hepatic metabolism of a hormone is more important for the clearance of hydrophobic than hydrophilic hormones. One key exception is thyroid hormones, they are stored on a peptide backbone to allow for long-term storage of the hormone

Receptor Tyrosine Kinases

Receptor tyrosine kinases function as dimers, with an extracellular hormone-binding domain, and an intracellular protein tyrosine kinase domain. Upon binding of hormone (many are growth factors), RTK monomers cross-phosphorylate each other. Phosphorylation of the RTK makes it a site of attachment for proteins with SH2 domains, or PTB domains - localising proteins at the membrane. For the insulin receptor, cross-phosphorylation causes the kinase to become fully active.

Metreleptin

Recombinant methionyl human leptin (additional methionine at N') Metreleptin works in lipodystrophy to normalise fat and carb metabolism. It also Increases insulin secretion and sensitivity In obesity it is not as effective as would be expected but may work with amylin to cause weight loss could be used in the future to counteract decrease in resting metabolic rate and help maintain weight lost

Risk of complications ↑as HbA1c increases

Reducing HbA1c reduces risk Lowering HbA1c by 1% significantly reduces: Diabetes- related death Myocardial infarction Microvascular complications Peripheral vascular disease

Risks associated with increased HbA1C

Reducing HbA1c reduces risk Lowering HbA1c by 1% significantly reduces: Diabetes- related death Myocardial infarction Microvascular complications Peripheral vascular disease

Regular ovulation

Regular ovulation -predictable and consistent durations of menses, and predictable and consistent patterns of flow (heaviness/cramping etc.) Continuing ovulation typically requires >22% body fat

Hypothalamic mediators

Regulation of body weight requires the ability to monitor the adipose store and to adjust appetite, satiety and energy expenditure appropriately. there is feedback between the brain and adipose tissue that regulates energy balance. However, long-term changes in energy intake lead to compensatory adjustments in energy expenditure.

Relaxin

Relaxin produced by the placenta inhibits myometrial contraction and increases the flexibility of the pubic symphysis.

Pseudohypoaldosteronism

Resistance to actions of aldosterone due to mutations of aldosterone, non-functional receptor

Significance of adrenal androgens in a "woman"

Responsible for adrenarche: • Growth of pubic and axillary hair prior to puberty • Acne Substrate for post-menopausal oestrogen synthesis in periphery • Important for oestrogen-dependent tumours • Female Pseudohermaphroditism

Papillary thyroid carcinoma

Retain NIS expression • Women > men (2.5:1) • Peak incidence 30-50y • 78% cases of thyroid ca • Present as LNpathy (spread to lymph nodes) 1/3 at presentation • Associated with • RET/PTC and TRK chimeric Tyr kinase genes that activate cell growth • BRAF mutations associated with poor prognosis, also drives cellular growth No colloid. Nucleus has inclusion bodies

Dopamine

Role in regulation of food intake not clear. However, genetically obese Zucker rats have abnormal D1 / D2 receptor expression in the hypothalamus.

What changes occur at or after ovulation?

Rupture of a single follicle and transport of oocyte to oviduct Transformation of ruptured follicle to corpus luteum ​Degeneration of other maturing follicles (atresic follicles) ​If fertilisation of ovum occurs corpus luteum enlarges and is maintained until third month of pregnancy, otherwise degenerates forming a corpus albicans

Selective Oestrogen Receptor Modulators

SERMs block the effects of oestrogen in the breast tissue by binding to the oestrogen receptor, leaving no room for oestrogen SERMs are selective- each oestrogen receptor has a slightly different structure, depending on the cell expressing it So breast cell oestrogen receptors are different from bone cell oestrogen receptors and both of those oestrogen receptors are different from uterine oestrogen receptors.

Switching of the JAK/STAT/ Pathway

SHP1 is a phosphotyrosine phosphatase, that binds the phosphorylated receptor (phosphorylated by the JAK kinases which were phosphorylated due to the Epo simultaneously binds two EpoRs, bringing the JAK kinases close enough for each to phosphorylate the activation lip of the other) and dephosphorylates JAK kinase. The JAK kinases usually phosphorylate the receptors allowing STAT5 to bind via their SH2 domains to the EpoR and also get phosphorylated where the phosphorylated STAT5s then dissociates from the receptor, dimerises exposing a nuclear localisation sequence and the STAT5 dimer enters the nucleus and its DNA-binding domain binds to specific DNA regulatory sequences to control the expression of target genes. SHP1 inhibits the pathway when cytokines are no longer binding to the receptor. A mutant version of the erythropoietin receptor was discovered in an athlete that caused them to have higher levels of RBCs than normal, despite unusually low levels of erythropoietin. This mutant receptor was missing some of the tyrosines normally phosphorylated during signal transduction. Therefore the receptor was able to bind and activate STAT5 as JAK phosphorylates the EpoR allowing this, but was unable to bind the SHP1 phosphatase, resulting in increased intracellular signalling in the erythroid progenitor cells, and more RBCs than usual.

SIADH causes

SIADH is the syndrome of inappropriate ADH secretion CNS diseases that directly stimulate the hypothalamus Ectopic ADH secretion from tumours numerous drugs that chemically stimulate the hypothalamus inherited mutations Hyponatremia is the most frequent electrolyte (1/3rd of all cases)

SOCS

STAT dimerization and translocation to the nucleus modulate target gene transcription such as IGF-1 and SOCS (suppressor of cytokine signaling) • SOCS terminate the GH signal cascade

Ambiguous genitalia in Congenital Adrenal Hyperplasia (CAH)

Salt-wasting CAH also involves symptoms caused by low cortisol and high androgens. These symptoms may include: In female newborns, external genitalia can be ambiguous, i.e., not typical female appearing , with normal internal reproductive organs (ovaries, uterus, and fallopian tubes) Enlarged genitalia in male newborns Development of certain qualities called virilization (pronounced vir-uhl-uh-ZEY-shuhn) in boys or girls before the normal age of puberty, sometimes as early as age 2 or 3. This is a condition characterized by: Rapid growth Appearance of pubic and armpit hair Deep voice Failure to menstruate, or abnormal or irregular menstrual periods (females) Well-developed muscles Enlarged penis (males) Unusually tall height as children, but being shorter than normal as adults Possible difficulties getting pregnant (females) Excess facial hair (females) Early beard (males) Severe acne Benign testicular tumors and infertility (males)

Pancreatic Polypeptide

Secreted after eating and suppresses appetite

Parathyroid hormone regulation

Secretion is regulated via vitamin D Longstanding hypomagnesaemia inhibits PTH synthesis and impairs PTH actions in target tissues Epinephrine and histamine both stimulate PTH release via specific receptors

Monitoring glycaemic control: type I diabetes

Self-monitoring of blood glucose No role for urine glucose testing in monitoring of type I DM Blood glucose monitoring with glucose stix at least x2/daily pre insulin Target pre-meal 4-7 mmol/L post-meal <10mmol/L HbA1C Glycated Hb- Index of glycaemic control over preceding 2-3 months

Steroid hormone receptors are divisible into subgroups on evolutionary grounds

Sequence alignment comparison puts human NR family into six evolutionary groups 1. This large group contains the receptors TRs, RARs, VDR (NR1I1), and PPARs, as well as orphan receptors such as RORs, Rev-erbs, CAR (NR1I3), PXR (NR1I2), LXRs, and others. 2. RXRs, COUP-TF, and HNF-4. 3. This subfamily includes the steroid receptors with ERs, GRs, PRs, and ARs as well as the ERRs. 4.This small group contains the nerve growth factor- induced clone B group of orphan receptors [NGFI-B, (NR4A1), NURR1 (NR4A2), and NOR1 (NR4A3)]. 5.This another small group that includes the steroidogenic factor 1 (NR5A1) and the receptors related to the Drosophila FTZ-F1. 6. This subfamily contains only the GCNF1 receptor (NR6A1), which does not fit well into any other subfamilies. Previously subdivision of the superfamily was on the basis of binding class. • Class I steroid receptors (PR,GR, MR, AR) • Class II non-steroid receptors (VDR & TR related receptors) • Class III orphan receptors (RXR)

5-hydroxytryptamine (5-HT; Serotonin):

Serotonin reduces food intake through the activation of 5-HT2C receptors The actions of serotonin are thought to be mediated in the PVN, possibly by preventing release of Neuropeptide Y. The release of insulin with the dietary intake of carbohydrate promotes the uptake of the serotonin precursor tryptophan, increasing serotonin release in the brain. This might augment the effects of 5-HT on satiety, although this is controversial. Serotonin might also suppress preference for fat intake

Low adinopectin

Several gene polymorphisms of adinopectin have been associated with increased risk of metabolic syndrome or Type 2 diabetes Low levels of adiponectin are associated with hyperinsulinemia, insulin resistance and future risk of Type 2 diabetes

Precocious Puberty

Signs of puberty before age 8 in girls and 9 in boys. There is a tendency to run in families. a problem in the brain, such as a tumour damage to the brain as a result of an infection, surgery or radiotherapy a problem with the ovaries or thyroid gland a genetic disorder, such as McCune-Albright syndrome

Structure of IGF-1

Similar to proinsulin IGF1 (but not IGF2) acts via insulin-like receptors IGF-1 also known as somatomedin C

Thyroid disease

Simple goitre-hypertrophy of the gland in response to low iodine intake Hyperthyroidism- toxic goitre. Diffuse Grave disease - LATS. Nodular. Hypothyroidism - Hashimoto's thyroiditis autoimmune

Transport of steroids

Since the steroid are lipids, they must be transported on carrier proteins. Albumin binds all steroid hormones with low affinity but high capacity. Corticosteroid-binding globulin with a high affinity but has a low capacity. Sex hormone-binding globulin binds the androgens, again with a high affinity but has a low capacity. around 90% of plasma cortisol circulates bound to corticosteroid binding globulin (CBG) while the majority of aldosterone circulates in association with serum albumin.

Inactivation and excretion of steroid hormones

Since the steroid hormones are not water soluble, they are carried on proteins which can not be filtered at the glomerulus. So unchanged hormone can not appear in the urine. Conjugation by liver, and to a lesser extent the kidneys, converts the water-insoluble hormone to an inactive but water-soluble form which can be filtered into the urine. About 75% of the conjugated hormone is excreted through the kidneys and about 25% through the biliary system.

describe the chemical nature of GH

Single chain protein with 2 disulphide bonds- long anti-parallel alpha helices 1/2 life of about 15mins structurally related to leptin and cytokines such as interleukins and erythropoietin having 4 long anti- parallel α-helices very similar to prolactin, secreted from the ant. pituitary lactotrophs

DPP-4 inhibitors- gliptins

Sitagliptin— Advantages over Incretin mimetics oral drugs; no injection needed fewer side effects such as nausea, difficult to overdose Differences to Incretin mimetics no direct CNS effect no effect on satiety, no weight loss not specific for GLP-1 effect on other DPP enzymes

Smooth muscle contraction

Smooth muscle is under involuntary (unconscious) control of the central nervous system. When the concentration of calcium is low, caldesmon forms a complex with tropomyosin and actin restricting myosin binding to actin The filaments are loose bundles of thick and thin filaments at dense bodies in the cytosol With an increase in cytosolic calcium, calcium first binds to calmodulin. The Ca-calmodulin complex binds to the regulatory light chain activating myosin light chain kinase. This phosphorylates the regulatory light chain which removes its inhibition on actin for myosin ATPase activity stimulation This operates more slowly from seconds to minutes than in striated muscle Smooth muscle can also be regulated by humoral factors that activate or inhibit contraction like hormones

the relative concentrations of major electrolytes within each fluid compartment.

Sodium and potassium levels are the inverses of each other. That is, more sodium is present outside the cell than in and more potassium is present inside the cell than out. Na+/K+-ATPase actively pumps sodium out of the cell and potassium into the cell.

relate the follicle to the biosynthesis of T3 and T4

Sodium-iodide symporter (NIS) brings iodide into the epithelial cell Pendrin is a channel that moves iodide into the colloid Thyroglobulin is made by the epithelial cells and is exported into the colloid Organification by thyroid perxoidase and hydrogen peroxide (the oxidising agent made bu dual oxidase) produces organified tyrosine molecules, diodotyrosine DIT and monoiodotyrosine (MIT). Coupling by thyroid peroxidase brings the two phenol groups together (DIT + DIT = T4, DIT + MIT on the outside = T3)

Insulin preparations

Soluble insulin - rapid action but limited duration Lente insulins - slow release preparations of insulin combined with zinc or the protein protamine Route: Subcutaneous for maintenance i.v. (soluble only) for ketoacidosis with NaCl and K

Acromegaly treatment

Somatostatin analog- octeotride Dopamine agonist- bromocriptine Mutated GH which prevents receptor dimerisation/activation

Somatostatin

Somatostatin, which is secreted by the hypothalamic periventricular nucleus inhibits the release of GH from the anterior pituitary growth hormone also stimulates the hypothalamic release of somatostatin, which further inhibits growth hormone secretion.

Human uterus, promenstrual C

Some blood vessels of the enormously vascular region of the uterine wall Recognise arterial and venous vessels The arterial components are the straight arteries, which supply the stratum basalis The withdrawal of progesterone at the end of the menstrual cycle causes these helical arteries to constrict cutting off the blood supply to the stratum compactum to degenerate and be discarded.

The islets of Langerhans

Some cells, which bud off from the pancreatic ducts, proliferate to form the pancreatic islets of Langerhans. In the neonate, these highly vascularised islets receive both sympathetic, adrenergic innervation via the splanchnic nerve from the coeliac plexus and parasympathetic, cholinergic input via the vagus nerve

Sparing Glucose Metabolism

Some tissues like the brain, erythrocytes and the renal medulla are entirely reliant on glycolysis Most tissues are capable of using non- carbohydrates to derive reduced NADH / FADH2 for ATP synthesis the β-oxidation of fatty acids spares the glycolytic oxidation of glucose NEFA - b-oxidation - acetyl CoA (TCA) Amino acids - 6 routes into TCA

Sperm formation summary

Spermatogonia undergo mitosis and differentiation into primary spermatocytes Primary spermatocytes undergo meiosis into secondary spermatocytes Secondary spermatocytes become spermatids connected by a cytoplasmic bridge Spermatids become spermatozoa

Human testis, adult: medium power, iron haematoxylin and eosin

Spermatozoa in seminiferous tubules In this image many tubules are cut obliquely Note how some tubules conatain mature, flagellated spermatozoa while some do not This is because spermatozoa are in different stages of development in different regions of tubules, but are in the same stage of development in any given region.

SD Score

Standard Deviation Score: - a normalised system derived from the position of an individual on the population chart showing height v age i.e. Assessment 5 SD score = (observed - mean height ) SD for that age and sex Normal SDS scores lie between -2 and +2

Statins and diabetes

Statins are associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes due its effect of increasing insulin resistance.

Cholesterol transport for steroid hormone synthesis

Steroidogenesis is catalysed in the inner membrane of the mitochondrion Short half-life proteins such as the steroidogenic acture regulatory [StAR] protein is required to transport cholesterol across the aqueous space between the two mitochondrial membranes

Steroids

Steroids are lipid-soluble and are derived from cholesterol. The adrenal cortex produces a large number of steroids including the key hormones: aldosterone, cortisol and DHEA.

Steroids

Steroids are lipids derived from cholesterol. Testosterone is the male sex hormone. Estradiol, similar in structure to testosterone, is responsible for many female sexual characteristics. Steroid hormones are secreted by the gonads, adrenal cortex, and placenta. They are lipids and are therefore lipid soluble.

Therapeutic strategies to reduce hyperglycemia in type II diabetes mellitus

Stimulate insulin secretion Promote insulin-mediated glucose uptake Reduce glucose production Limit glucose production Increase glucose secretion

T3 action on adipose tissue

Stimulates heat by non-shivering thermogenesis in brown adipose tissue decreasing body weight Activation of the sympathetic nervous system- local NE release in white adipose tissue stimulates lipolysis

Cellular Actions of Oxytocin

Stimulation of milk ejection (milk letdown) Stimulate uterine smooth muscle contractions at birth Establishment of maternal behaviour

Treatment for Hypervitaminosis D

Stop taking vitamin D supplements immediately Reduce the amount of calcium in your diet temporarily In some cases, bisphosphonates can be used to suppress the release of calcium from bone Monitor vitamin D levels frequently until they return to normal.

Monogenic diabetes

Strong family history of diabetes Autosomal dominant Diabetes develops at an early age (<25 years) Multiple genes and counting being discovered Diet or tablet treatment

Adipogenesis and weight loss

Substances that increase adipogenesis, like TZDs and adiponectin can increase insulin sensitivity, without necessarily causing weight loss.

T3 testing alone

T3 levels alone are not appropriate for diagnosing hypothyroidism because increased conversion of T4 to T3 maintains T3 serum levels within the normal range until hypothyroidism becomes severe

Placental oestrogen and progesterone

The estrogens increase uterine blood flow and maintain the endometrium during pregnancy. The high levels of estrogen and progesterone also inhibit the synthesis of milk. Progesterone inhibits myometrial contractions of the uterus to prevent premature birth.

Implantation Success

Successful implantation requires the timely arrival of a viable blastocyst into a receptive endometrium. The endometrium is remodelled throughout the menstrual cycle, and exhibits only a short period of receptivity, known as the 'implantation window'. In humans, during a normal cycle, the embryo enters the uterine cavity ∼4 days after ovulation. The endometrium becomes receptive to blastocyst implantation 6-8 days after ovulation and remains receptive for ∼4 days (cycle days 20-24). The majority of spontaneous human conceptions fail to complete implantation and to achieve ongoing pregnancy. Evidence from sperm donation programmes have indicated that the maximal chance of achieving successful implantations under optimal conditions is ∼40% per cycle, and this rate declines with age. A high incidence of chromosomal abnormalities has been reported for human embryos and a significant proportion of pregnancy wastage is caused by numerical or structural chromosomal abnormalities. The frequency of embryonic genetic abnormality increases with maternal age. Therefore, genetic abnormalities are thought to be a major factor contributing to implantation failure. Failure of the blastocyst to release from the zona pellucida has been identified as a potential cause of implantation failure in assisted cycles, particularly in older women. A potential solution to this is artificial disruption of the zona pellucida or assisted hatching with IVF.

Adrenal crisis symptoms

Sudden penetrating pain in the legs, lower back or abdomen Confusion, psychosis, slurred speech Severe lethargy and generally "not feeling well"[5] Convulsions Fever Hyperkalemia (elevated potassium level in the blood) Hypercalcemia (elevated calcium level in the blood): the cause of hypercalcemia is a combination of increased calcium input into the extracellular space and reduced calcium removal by the kidney, this last caused by decreased glomerular filtration and increased tubular calcium reabsorption. Both renal factors are secondary to volume depletion and, in fact, improve rapidly during rehydration with saline infusion.[6] Hypoglycemia (reduced level of blood glucose) Hyponatremia (low sodium level in the blood) Hypotension (low blood pressure) Hypothyroidism (low T4 level) Severe vomiting and diarrhea, resulting in dehydration Syncope (transient loss of consciousness) and/or orthostatic hypotension (drop in blood pressure on standing, leading to loss of balance)

Structural and functional properties of hydrophobic hormone receptors

Superfamily of steroid/thyroid hormone receptors Hydrophobic hormone receptors • Mineralocorticoid receptor • Progesterone receptor • Glucocorticoid receptor • Androgen receptor • Oestrogen receptor • Thyroid hormone (T3) receptor • Vitamin D3 receptor

IODINE INSUFFICIENCY

Supply of iodine in water depends upon local geology We require a minimum of 50mg of iodide/day Problem typically in mountainous central land masses Cretinism is neonatal Goitre- thyroid responds by hypertrophising Short stature- thyroid hormones work with GH for growth

What are Sertoli cells, where do you find them, and what is their function?

Supportive cells of the germinal epithelium of the seminiferous tubules. Function - support, protect and nourish developing sperm cells; secretion of hormones/growth factors; phagocytosis.

Surgery

Surgery is another option if the patient is not able to take drugs or RAI. Large goitre Complications • Hypothyroidism • Recurrent laryngeal nerve injury (1%) • Hypoparathyroidism (often transient, 2% permanent) • Haemorrhage into the neck the trachea, asphyxiation • Infection

Would you raise baby G as a girl or boy?

Surgical reconstruction to form female genitalia would be the expected course of action. The baby also has normal ovaries, fallopian tubes and uterus and should begin menstrual cycles at puberty and have normal reproductive capacity. Behavioural masculinisation may have occurred and can result in gender identify issues later on in life. Assignment as a male would not provide the patient with future reproductive capacity due to the lack of testes, and ducting.

Suspicious FNA

Suspicious "THY3" No colloid • enlarged follicular cells (=foll adenoma or carcinoma) the cells look the same size so possibly not carcinoma • Hurthle cells (=H cell adenoma or ca)

Activation of the Heterotrimeric G-Protein

Switch II is hidden by the βγ subunits The extra phosphate on GTP stabilises helical switch II The stabilised switch II interacts and activates adenylyl cyclase When the GTP is hydrolysed, switch II becomes disordered

Islets of Langerhans Innervation

Sympathetic adrenergic input from the Splanchnic nerve - from coeliac plexus Parasympathetic: cholinergic input from the vagus nerve

Cretinism

Symptoms may include goiter, poor length growth in infants, reduced adult stature, thickened skin, hair loss, enlarged tongue, a protruding abdomen; delayed bone maturation and puberty in children; and mental deterioration, neurological impairment, impeded ovulation, and infertility in adults.

Synthesis inhibition

Synthesis impeded by: • inhibition of tyrosine hydroxylase (e.g. with a-methyltyrosine) • suppressing release and/or action of ACh (e.g. with hexamethonium).

explain the nature of T3 receptors

T3 receptors are member of the steroid-thyroid hormone receptor superfamily- nuclear receptors They are bound to DNA, a target response element (TRE) in their resting state Then occupancy of the hormone (ligand)-binding domain results in transcriptional activation by RNA polymerase Can bind as a monomer, homodimer or heterodimer

T3 testing

T3 testing, combined with an interpretation of FT4 levels, is useful for diagnosing and monitoring hyperthyroidism a high TT3/TT4 ratio > 20 suggests Graves' disease T3 levels are useful for monitoring the acute response to thyrotoxicosis treatment in Graves' disease; elevated T3 is a common early sign of relapse.

T3R and RXR

T3R often dimerises with receptors for retinoic acid RXR (heterodimer) The ligand T3 binds to the heterodimer RXR and TR (thyroid hormone receptor) which is bound to a TRE. Coactivators recruit and activate RNA polymerase 2, transcribes the DNA to mRNA, translation, protein formation, effector

T4 v reverse T3

T4 can also be converted to rT3 by an "inner-ring" deiodinase (D3: 5-deiodinase - not same as 5' deiodinase). rT3 has no known biological activity.

How to assess T4 and T3

T4 is the primary hormone secreted by the thyroid gland, ~80% of serum T3 results from the peripheral conversion of T4 via 5'- mono-deiodination in various tissues Nearly all THs circulate in the bloodstream bound to plasma proteins FT4 and FT3 levels are more relevant than total hormone levels as the free hormone is the biologically active form of the hormone.

Describe the Smad pathway as initiated by the TGF-β receptor, and its relationship to cancer.

TGFβ binds to TβR-II, whose serine/threonine kinase activity is constitutively active. This allows it to bind to TβR-I, and phosphorylate its glycine-serine rich (GS) domain, activating the S/T kinase activity. TβR-I can then phosphorylate a class of transcription factors called R-SMADs. Upon phosphorylation, two R-SMADs and a Co-SMAD form a heterotrimer, and the nuclear localisation signals are also exposed. In the nucleus, the heterotrimer interacts with transcription factors to cause expression of particular target genes.

TNF-α and IL-6

TNF-α and IL-6 are secreted by infiltrating macrophages IL-6 inhibits adiponectin expression and causes the liver to make inflammatory proteins like CRP. Adinopectin is anti inflammatory (inhibits activation of macrophages and inhibits TNF-a secretion by monocytes and macrophages stimulating them to produce anti-inflammatory cytokines such as IL-10) and improves insulin resistance (causes an increase in the uptake of glucose in muscle and increases beta oxidation decreasing, decreases liver gluconeogenesis) TNFalpha inhibits adipogenesis

Hypothalamo-Pituitary Thyroid Axis (HPT)

TRH (thyroid releasing hormone) is synthesized by the paraventricular nucleus and secreted when plasma thyroxine levels are low. The hypothalamus also controls thyroid hormone secretion in response to body temperature to adjust metabolic rate

TSH secretion in the anterior pituitary

TRH reaches the TSH-secreting basophilic cells in the anterior pituitary through the portal circulation. Here it binds to G protein-coupled receptors, that acting through IP3 and diacylglycerol, elevate cell Ca2+ concentration which triggers the exocytotic release of TSH.

Resistance to thyroid syndrome

TRbeta mutation leads to a decrease in the responsiveness of the hypothalamus and anterior pituitary to T3,T4

Vas deferens

TS through spermatic cord; adult human, H & E, containing the ductus deferens (vas deferens) This image shows a large quadrant of a transverse section of the vas deferens This muscular tube is surrounded by a sheath of connective tissue The adventitia has large blood vessels and nerves. 3 muscular layers- Inner and outer layer of longitudinal muscle with an intermediate circular layer. The lumen lined by columnar epithelium with room to expand during ejaculation

Assessing thyroid function

TSH and FT4 are routinely used to assess thyroid function and to monitor hyper- and hypothyroidism treatment- the body can compensate by making more FT3 so not appropriate for diagnosing hypothyroidism

Prolactin secretion stimulation

TSH released from the hypothalamus stimulates prolactin secretion But the most potent stimulator is stimulation of the nipple by suckling. This information is carried to the hypothalamus via afferent nerves from the nipples and inhibits dopamine release from arcuate nucleus neurons.

TSH, LH and FSH structure

TSH, LH and FSH are heterodimeric glycoproteins: 1 alpha-subunit + 1 beta-subunit. Their alpha-subunits are identical; beta-subunits differ and confer specificity. (TSHbeta, LHbeta & FSHbeta)

Thyroid Eye Disease

TSI are the IgG antibodies in Grave's disease They bind to orbital muscle Ag related to a thyroid antigen causing inflammatory cell infiltration due to T cell recognition Cytokines like IL-1, TNF-alpha and Interferon gamma are released. These act on the fibroblasts between the extraocular muscle cells causing fibrosis Glycosaminoglycans cause oedema due to water retention

Testosterone and DHT

Testosterone and DHT both bind to the same intranuclear receptors. Together, these androgens regulate male prenatal development and the development of male sexual characteristics. These include enlargement of the male sex organs, secondary sex characteristics that begin at puberty and protein synthesis.

Spermatogenesis

Testosterone stimulates the final stages of spermatogenesis. It is also converted to dihydrotestosterone (DHT). DHT may function to promote sperm cell formation. Sertoli cells in the testes release inhibin when the level of spermatogenesis needed for the male reproductive system has been attained. Inhibin acts as a negative feedback control on the anterior pituitary to regulate FSH secretion.

Radio-iodine

The 131 isotope of iodine is a beta and gamma emitter Given orally as iodide - Complete destruction of the gland by beta radiation - decays with half life of 8 days Irradiation can be used to ablate the overactive gland, followed by T4 maintenance therapy.

Chvostek's sign

The Chvostek sign is the abnormal twitching of muscles that are innervated by the facial nerve When the facial nerve is tapped in front of the ear, there is ipsilateral face spasm The muscles that control the nose, lips and eyebrows are often the ones that will spasm. These facial spasms are caused by facial nerve hyperexcitability due to hypocalcemia

Mechanism of gene activation by the steroid hormone receptors (transcription factors) in response to hormones

The DNA binding domain of the receptor is characterised by the presence of two zinc fingers with a beta sheet and an alpha helical structure. DNA interacting residues are in the alpha helix At rest the zinc is masked by the association of the receptor with a dimerised heat shock protein such as hsp70 or hsp90. When the hormone binds the hsp dimer dissociates revealing the Zinc fingers and translocation to the nucleus takes place if required. The receptors themselves dimerise then bind with 4 zinc fingers to short regions of DNA, known as hormone response element (HRE).

Descending limb of the loop of Henle

The Descending limb of the loop of Henle is the first segment of the loop which penetrate only to the outer medulla. The majority of water is removed from the interstitial fluid of the medulla and moves into the tubules so that the interstitial fluid is hyperosmotic. (Table is values for interstitial fluid)

Genetic Mouse Models of Obesity

The Diabetic obese mouse (db/db) - Mutant mice are larger/obese relative to heterozygous littermates by 1 month, with increased fat deposition, and hyperglycaemia by 8 weeks. The Fat mouse (fat/fat) - Obesity develops relatively slowly, increased fat deposition. Hyper(pro)insulinaemia, but not hyperglycaemia, not prone to diabetes.

STAT5

The JAK 2 kinases phosphorylate the tyrosine residues on the GH receptors allowing STAT5 (a member of the Signal Transduction and Activation of Transcription (STAT) family) to bind via their SH2 domains to the GHR. The activated JAK2 phosphorylase the tyrosines on the STAT5s The phosphorylated STAT5s dissociate from the receptor and dimerise, exposing a nuclear localisation sequence. The STAT5 dimer enters the nucleus and its DNA-binding domain binds to specific DNA regulatory sequences to control the expression of target genes such as IGF-1 and SOCS

Significance of the MAPK pathway

The MAPK pathway is unaffected by insulin resistance. It mediates the proliferative, mitogenic effects of insulin such as cell proliferation and in hyperinsulinemia may have atherogenic and cancerogenic effects which could be further exacerbated by insulin administration

Insulin signalling in adipocytes

The PI3-kinase pathway for immediate responses to insulin like GLUT4 translocation, glycogenesis and the inhibition of lipolysis. This pathway shows less activity in insulin resistance. The MAPK pathway for long term effects. Unaffected by insulin resistance.

Parathyroid hormone synthesis and secretion

The PTH gene encodes a longer prepro-hormone , which is cleaved twice at the N-terminus to generate active PTH. The secretion of the PTH protein requires magnesium, deficiency of which can impair PTH secretion in premature babies, resulting in hypocalcaemia.

Rickets v osteomalacia

The age-related differences between the skeletal symptoms of severely impaired intestinal calcium absorption depend on whether or not the bones are still growing. In children, the growing ends of the bone swell with failure of endochondral ossification, culminating in excessively thick epiphyseal cartilage which is soft due to inadequate calcification. In the adult, osteomalacia is characterised by bone pain with decreased bone density, pseudo-fractures and wide layers of poorly calcified osteoid.

Agouti

The agouti protein is normally expressed transiently by the follicular melanocytes and alters pigment production by antagonising the binding of a-MSH to melanocortin 1 receptor (Mc1r)

Human prostate

The Prostate Gland The prostate gland surrounds the urethra between the base of the urinary bladder and the base of the penis This specimen is not normal; there is evidence of previous infection, with epithelial changes in the secretory alveoli and cyst formation. Observe by naked eye the general architecture of the glandular tissue (compound exocrine, alveolar secretory units); cystic areas of glandular tissue can be seen and are patchily distributed Note the relationship of the urethra to the glandular tissue In this region the urethra is called the prostatic urethra and it has a crescentic lumen, its epithelium is transitional (continuous with that of the bladder) and it becomes simple or pseudostratified columnar as it leaves the prostate gland to become the membranous urethra. In the penis the spongy urethra has a simple or pseudostratified columnar epithelium, except at its exit at the end of the penis where it is stratified squamous The prostate gland is encapsulated The capsule contains fibroelastic connective tissue. Connective tissue septa from the capsule divide the gland into poorly defined lobules. The connective tissue also contains irregular bundles of smooth muscle cells (which contract under sympathetic control) The prostatic glands drain into ducts which coalesce and eventually drain into the urethra on each side of the urethral crest. In this image, large prostatic ducts may be seen converging on the urethra

Brown v white adipose tissue

The TAG droplets in brown adipose tissue are multiocular, the mitochondria are larger and higher in density and its is highly innervated by he SNS and the capillary network is denser. Brown adipose tissue is seen in adults as well as infants particularly after cold acclimation.

The TGFβ Receptor and Cancer

The TGF-β receptor pathway often inhibits growth in cells. Loss of either TBRI or TBRII function due to inactivating mutations is found in many human tumours. These tumours are resistant to growth inhibition by TGF-β. Mutations in the Smad proteins also prevent TGF-β signalling, most human pancreatic cancers contain a deletion in Smad4 (a Co-Smad)

Transforming Growth Factor (TGFβ)

The TGFβ family is a large family of proteins involved in regulating development. These signalling proteins normally prevent proliferation of most mammalian cells by inducing synthesis of proteins that inhibit the cell cycle. Most mammalian cells secrete at least one TGFβ isoform, and have receptors on their surface. Bone morphogenetic protein (BMP7) induces bone formation in cultured cells and is now used clinically to strengthen bone fractures. TGFβ proteins also play a role in tissue organisation, promoting expression of extracellular matrix proteins and adhesion molecules.

Chronic stress

The ability of cortisol to stimulate the breakdown of muscle protein and connective tissue contributes to the wasting associated with elevated concentrations of cortisol in syndromes of adrenal hyperactivity e.g. chronic stress. Plasma glucose is increased by chronic, genomic actions of cortisol Increased lipogenesis in the trunk and face

INSULIN

The actions are mediated through the insulin receptor Immediate effects: enzyme phosphorylation Delayed effects: enzyme synthesis and cell proliferation and growth All Cells o Increased glucose uptake o Increased utilization of glucose, amino acids and fats o increased uptake of potassium and calcium Liver o Increased glycogen synthesis o Reduced glycogen breakdown and glucose synthesis Muscle o Increased amino acid uptake and protein synthesis o Increased glucose transport, glycolysis and glycogen synthesis Adipose tissue o Increased glycerol synthesis and triglyceride formation o Reduced lipolysis

Corticosteroid receptor specificity

The actions of mineralocorticoids and glucocorticoids are mediated through type 1 and type 2 corticosteroid receptors

Anti-diuretic action via V2 receptors

The activation of V2 receptors on the base lateral membrane of the collecting duct activates cAMP to stimulate the insertion of aquaporin (AP2) water channels in the renal collecting ducts (and longer term increased AP3 and AP4). AP2 inserts on the apical membrane, AP3 and AP4 on the basolateral membrane. This increases the permeability of the renal collecting ducts to water Na+-driven resorption of water in the kidney requires AVP. BUT the t1⁄2 of AVP in the plasma is approx. 5 min so longer term regulation of salt and water balance also involves aldosterone which has a t1⁄2 approx. 20 min and is dependent on gene expression

Licorice and hyper-aldosteronism

The active ingredient in licorice, glycyrrhizin, inhibits 11-β-hydroxysteroid dehydrogenase 2 and so people habitually consuming licorice can develop secondary hyper-aldosteronism.

Other regulations of 1-alpha-hydroxylase and 24-hydroxylase

The activities of renal 1alpha-hydroxylase and 24-hydroxylase are similarly subject to reciprocal control by the serum phosphate concentration; Moreover, PTH increases 1alpha-hydroxylase activity (such that mobilization of bone calcium reservoirs is accompanied by increased intestinal absorption of dietary calcium) and calcitonin inhibits 1alpha-hydroxylase.

describe and illustrate the structural connections between the hypothalamus, anterior and posterior lobes of the pituitary gland

The anterior lobe of the pituitary gland is connected to the hypothalamus by the hypophyseal portal circulation The posterior lobe of the pituitary gland is connected to the hypothalamus by the supraoptic-hypothalamic tract

Hypothalamic nuclei

The arcuate nucleus (ARC) has different sets of neurones in which NPY and AgRP are colocalised or which contain POMC. Both groups are sensitive to leptin and have reciprocal connections with the, Paraventricular nucleus (PVN), the Dorsomedial nucleus (DMH) and the Lateral hypothalamic area (LHA)

Body Weight and Puberty

The attainment of a body size sufficient to cope with pregnancy (some 50,000 kcal) is a logical signal for puberty Obesity in girls advances puberty, yet in boys it delays it. If body weight is not predictive of puberty onset, what is?

Male development

The average age for girls to start puberty is 11, while for boys the average age is 12.

Phosphate Homeostasis

The balance between phosphate absorption from the intestine, mobilization from bone, and excretion via the kidneys in urine determines the final levels of plasma phosphate In the kidneys, up to 65-70% of the filtered phosphate is reabsorbed via the proximal tubules using Na+-dependent phosphate transporters The renal NaPi transporters are regulated by vitamin D and PTH

GH and the MAPK pathway

The binding of GH to the dimeric receptor forces the PTK domains, the JAK2 together which cross-phosphorylate. Tyrosine-phosphates of JAK2 act as docking sites for Grb-2, which is attached to Sos. Sos is a guanine nucleotide exchange factor (GEF) it only catalyses when it has been recruited to the membrane via Grb-2. Sos catalyses the exchange of GDP for GTP on membrane-bound Ras, activating it. Ras is a small monomeric G-protein. GTP:Ras binds and activates Raf, a membrane-bound protein kinase. A series of protein kinases such as MAPK are phosphorylated and activated, resulting in the phosphorylation of several transcription factors, altering their activity.

IRS-1

The binding of insulin to its dimeric receptor forces the PTK domains together which cross-phosphorylate. These phosphorylated tyrosine residues act as docking sites for IRS-1 (insulin receptor substrate 1), which gets phosphorylated. IRS-1 is a docking protein, as it can bind many proteins other than PI-3K, including Grb-2 thereby activating the MAPK pathway

Insulin signalling: The MAPK pathway

The binding of insulin to its dimeric receptor forces the PTK domains together which cross-phosphorylate. These phosphorylated tyrosine residues act as docking sites for IRS-1 (insulin receptor substrate 1), which gets phosphorylated. Insulin receptor substrate-1 is phosphorylated and dissociates from the receptor It can bind PI-3K (phosphoinositide-3 kinase), which, now located at the membrane, phosphorylates PIP2 at position 3, forming PIP3 (phosphatidylinositol-3,4,5 triphosphate). PIP3 allows both PDK1 (phosphoinositide-dependent kinase-1) and PKB (protein kinase B) to associate with the membrane via their PH (pleckstrin homology) domains where Phosphorylated PKB dissociates from the membrane and phosphorylates its target proteins. There are other proteins that can assemble at the phosphorylated insulin receptor, including IRS-2, a homologous protein. Insulin is therefore capable of simultaneously stimulating numerous pathways, involving short-term and long-term effects

Describe how the PI-3 kinase pathway stimulated by insulin relates to the MAPK pathway

The binding of insulin to the dimeric receptor forces the PTK domains together which cross-phosphorylate. These phosphorylated tyrosine residues act as docking sites for IRS-1 (insulin receptor substrate 1), which gets phosphorylated. Insulin receptor substrate-1 is phosphorylated and can bind PI-3K (phosphoinositide-3 kinase), which, now located at the membrane, phosphorylates PIP2 at position 3, forming PIP3 (phosphatidylinositol-3,4,5 triphosphate). IRS-1 is already associated with the membrane due to its PH domain, which can bind PIP2. Once phosphorylated, it can dissociate from the insulin receptor. PIP3 allows both PDK1 (phosphoinositide-dependent kinase-1) and PKB (protein kinase B) to associate with the membrane via their PH (pleckstrin homology) domains where Phosphorylated PKB dissociates from the membrane and phosphorylates its target proteins. IRS-1 is a docking protein, as it can bind many proteins other than PI-3K, including Grb-2 (thereby activating the MAPK pathway) as Grb-2 attached to Sos binds to the tyrosine-phosphates (which was phosphorylated by the binding of EGF to each EGFR monomer induces a structural change that allows the monomers to dimerize where the proximity of the cytosolic domains allowed cross-phosphorylation). The Sos catalyses the exchange of GDP for GTP on membrane-bound Ras, activating it., GTP:Ras binds and activates Raf, a membrane-bound protein kinase, A series of protein kinases are phosphorylated and activated, resulting in the phosphorylation of several transcription factors, altering their activity. There are other proteins that can assemble at the phosphorylated insulin receptor, including IRS-2, a homologous protein. Insulin is therefore capable of simultaneously stimulating numerous pathways, involving short-term and long-term effects

How is renal function monitored in people with diabetes?

The blood protein, albumin, is monitored in the urine. Other tests include albumin:creatinine ratio and estimated GFR. Albumin leaks into the urine as the kidney filtration mechanisms become stressed and the pressure in the blood vessels of the kidneys increases.

Human prostate B

The capsule (Cap) of the prostate gland is a fairly thick layer of fibroelastic connective tissue with smooth muscle cells (difficult to identify with this stain) In this image, in the surrounding adventitia you should be able to identify these elements: fibrous connective tissue adipocytes blood vessels (arterial and venous) lymphatics nerve bundles a parasympathetic ganglion (terminal ganglion) In older men, the lumen of the glands often become filled with prostatic concretions (Box A)

Adrenal gland zones and hormones

The capsule helps the adrenals glands adhere to the kidney. The cortex includes all the zones outer zona glomerulosa- the mineralocorticoid, aldosterone zona fasciculata- glucocorticoids including cortisol. inner zona reticularis produces androgens- DHT and testosterone. The medulla produces the catecholamines epinephrine and norepinephrine derived from the amino acid tyrosine. These are secreted into the blood

The catecholamines

The catecholamines are synthesized and stored in cell vesicles. These are released by exocytosis when required. The catecholamines are water soluble. The catecholamines act through surface receptors

Catecholamines

The catecholamines epinephrine and norepinephrine are synthesised in the medulla. They are derived from the amino acid tyrosine. The catecholamines are synthesized, stored in cell vesicles and released by exocytosis when required. They are water soluble and act through surface receptors.

Chromaffin Cells

The cells are innervated by cholinergic preganglionic fibres of the sympathetic nervous system Within the cells the granules contain catecholamines, ATP, POMC products and chromogranin • • 80-85% epinephrine • 15-20% norepinephrine Granules produce one or the other usually. The catecholamines are synthesised by a series of reactions and the intermediates move back and forth between the cytoplasm and granules.

The collecting duct

The collecting duct runs all the way through the hyperosmotic medulla to drain into the renal pelvis and ureters. Here, the expression of the epithelial sodium channels ENaC is under the influence of aldosterone. the sodium concentration in urine may be decreased to as low as 50 mmol/L. The water permeability of the collecting duct is determined by ADH

Thyroid follicles

The colloid is a jelly-like pool of thyroid hormones Underactive follicles have flattened thyroid epithelial cells and increased colloid. Overactive follicles have tall columnar epithelial cells and reduced colloid.

Diabetic complications

The complications of long term diabetes include the following: Increases incidence of cardiovascular disease including myocardial infarction More peripheral vascular disease e.g. in the femoral artery (macroangiopathy) and microangiopathy Renal disease (microangiopathy) Retinal disease (microangiopathy) Lens opacity (cataracts) Neuropathy - impaired nerve conductance (e.g. impotence) Skin infections (gangrene, thrush) Osteoarthritis cases the severity of these disorders can be reduced by tight control of blood glucose

Oestrogen and progesterone

The corpus luteum secretes both oestrogen and progesterone, which inhibit the release of LH and FSH. The release of inhibin from the corpus luteum enhances this inhibitory effect. As the levels of FSH and LH decline, the corpus luteum begins to degenerate. This degeneration reduces the production of oestrogen and progesterone. The sharp decline in ovarian hormones triggers the release of GnRH from the hypothalamus and the cycle begins again.

Calcium concentration in the cells

The cytosolic Ca2+ concentration is maintained in the nmolar range (~100 nmoles/L). Concentrations above these activate a variety of signaling pathways and will also lead to cell damage if excessive. Calbindin prevents the ionized Ca2+ concentration from rising

Vitamin D synthesis in the skin

The deepest layer of skin cells the stratum basale or basal layer synthesize 7-dehydrocholesterol. This can either be converted to cholesterol or, through UV-B radiation, be made into the prohormone vitamin D3- cholecalciferol. Vitamins D3 and the closely related D2 can also be obtained in the diet.

Ambiguous genitalia in Congenital Adrenal Hyperplasia (CAH)

The defect causing the condition results in an accumulation of steroid hormone precursors due to a lack of enzyme that produce glucocorticoids and mineralocorticoids. The steroid hormone precursors are then converted to adrenal androgens by the remaining active enzyme cascades resulting in the production of DHEA and androstenedione. These adrenal androgens cause masculinisation of the external genitalia in utero hence the cliteromegaly

Human mammary gland A

The difference in density between intralobular and interlobular connective tissue is readily apparent in this image. The intralobular connective tissue is less dense as it gives the glands room to grow during pregnancy. The milk producing glands are not very well developed as they are in the resting state Note the presence of adipocytes. A few blood vessels can be seen as well.

Distal tubule

The distal tubule contains two parts. The first is lined by the same type of epithelium as the adjacent ascending limb of the loop of Henle so sodium is also re absorbed here. in the latter part reabsorption is increased by aldosterone.

Endometrium

The endometrium is a multilayered, dynamic organ overlaying the myometrium and comprises a functional layer and a basal layer. Each month, cells in the functional layer are separated from the basal layer during menstruation. The basal layer is attached to the myometrium and remains intact during menstruation, serving as a base for endometrial regeneration. Progesterone and oestrogen are the dominant hormonal modulators of endometrial development. Ovarian oestrogen and progesterone condition the uterus for implantation, and knowledge about the precise temporal action of these hormones within the menstrual cycle has allowed the development of hormone-based contraception. Both the epithelial and stromal compartments express progesterone and oestrogen receptors, and the response depends on the levels of these receptors as well as on the concentration of the hormones themselves. It is apparent that the appropriate cyclical pattern of receptor expression is crucial for achieving endometrial receptivity and successful implantation. Hormonal activity depends on not only the levels of progesterone, oestrogen and their receptors, but also on the rates of their metabolism. In addition, a number of other endocrine factors alter endometrial function. Prostaglandins are thought to facilitate increased vascular permeability during implantation, and enzymes involved in their production (COX-1/2) show cyclical changes in expression. hCG is thought to have direct effects on the endometrium. The effects of androgens are often overlooked in the female reproductive cycle. However, androgen receptors are present on stromal and epithelial cells in the endometrium, and both androstenedione and testosterone induce changes in endometrial function that may be important during implantation.

Oviduct iAi

The epithelium is ciliated, but the cilia are not well preserved What are: 1. Columnar epithelium 2. 3. 4. What does the lamina propria contain? Some smooth muscle What types of cell are present in the epithelium? Regular columnar epithelium, some are ciliated, some are not and there are intercalated cells. The cilia will waft the oocyte into the right direction. The non-ciliated cells secrete the fluid in the fallopian tube.

Human mammary gland Bi

The epithelium of the collecting ducts is usually two layers of cuboidal cells Immediately beneath this epithelium the connective tissue is loose and highly vascularised with microvessels The duct contains a secretion which is not milk or colostrum Intralobular and interlobular ducts are affected by ovarian hormones, and as their circulating levels rise during the menstrual cycle the ductal cells are stimulated to secrete slightly and the ducts distend (increasing the firmness of the breast at this time)

How does the testis of a child differ from that of a normal adult?

The epithelium of the seminiferous tubules consists mainly of Sertoli cells and with spermatogonia; the sperm cells develop and differentiate under the influence of testosterone which starts to be secreted at puberty.

Exocrine pancreas

The exocrine pancreatic cells are organised into acini that drain into tubules that eventually open into the main pancreatic duct. These cells produce inactive precursors of the intestinal digestive enzymes. Lobules- Acinar cells secrete enzymes and fluid Intercalated ducts join to form the pancreatic duct which fuses with the common bile duct before emptying in the duodenum

POMC Processing

The expression of Pre-POMC is usually driven by CRH The signal peptide is cleaved to generate POMC PHC/endopeptidases cleave POMC into Pro-ACTH + beta-LPH

Familial Partial Lipodystrophy 3 (MIM 604367): dominant-negative mechanism

The faulty copy is expressed and translocates to the nucleus but interacts with PPARγ binding partners inhibiting the activity of the wild-type Or binds to the DNA binding sites but does not increase expression and outcompetes the wild type PPARγ

Clinical Scenario: Mrs S is a 55 year-old lady of Bangladeshi origin, presented to her GP with various non-specific symptoms including generalised aches and pains, muscle weakness when walking and particularly when going up stairs. Investigation results are shown in the table below to have a low serum calcium level in association with raised alkaline phosphatase and an elevated PTH concentration. Serum vitamin D concentrations were measured and found to be below the seasonal normal range.

The finding suggest vitamin D deficiency, low serum calcium and low calcium excretion. Vitamin D deficiency would be expected to raise parathyroid hormone (PTH) levels and raise calcium and phosphate release from bone and be thus associated with raised alkaline phosphatase levels (marker of the bone activity of PTH). Therefore key treatment involves sunlight exposure. Note with the increased use of creams with high SPF, this may need to be considered. Vitamin D is found in certain foods: liver, some types of fish, and egg yolk. Some cereals or margarines contain added vitamin D. Growing children, pregnant women, and breastfeeding women need extra vitamin D because it is required for growth.

Differential Diagnostic Testing: ACTH testing

The first step in distinguishing the type of Cushing's syndrome is a blood test for the measurement of ACTH obtained in the morning. Patients with ACTH-secreting tumors will either have a normal or elevated level of ACTH. In contrast, patients with adrenal Cushing's will have a subnormal level as the ACTH is subject to negative feedback by the cortisol.

The tips of the loops

The fluid reaches an equilibrium with the adjacent interstitial fluid. At the tips of the loops of juxtamedullary nephrons, the fluid has an osmolarity of approximately 1200 mosmol/L.

Implantation

The free-living blastocyst is bathed in uterine secretions from which it draws the oxygen and metabolic substrates for growth and survival • There is a limit to the size that a free-living conceptus can attain before such exchanges become inadequate • Implantation, the ultimate outcome of which is the formation of the placenta • On entering the uterus, the conceptus is positioned to implant at a site within the uterus that is characteristic for each species • Humans, a single blastocyst normally implants in the posterior uterine wall Attachment has two phases: • Close apposition • Adherence • Zona pellucida must be removed • Proteolytic enzymes come from either the trophoblast cells themselves or uterine secretions • Attachment induces changes in the endometrial epithelium and the underlying endometrial stromal tissue, initiate the maternal portion of the placenta Animal studies and in vitro experiments have improved understanding about the hormonal and morphological changes that occur during implantation in humans.Human implantation involves a number of different stages; prior to implantation, the blastocyst shows evidence of polarity, assuming a particular orientation as it approaches the endometrium. Once the blastocyst is oriented correctly (apposition), the zona pellucida is shed. The blastocyst then comes into contact with the epithelial layer and adheres to the endometrial surface (adhesion). Finally, the blastocyst penetrates the epithelial layer and invades the stroma (invasion).

Fertilisation significance

The gametes are brought into proximity in the oviduct to allow fertilization • Fertilizationhasahighlysignificantstatus: • sets genetic sex • ethical significance - in vitro conceptus has generated legal definitions of fertilization as "the start of life" • However,fertilizationisnotasingleeventbuta protracted process taking many hours to completion.

Human prostate Ai

The glandular epithelium (E) is pseudostratified cuboidal or columnar, and is highly branched or folded The lamina propria (LP) contains a core of connective tissue and carries the services.

Rapid weight loss in Type 1 diabetes

The inability to metabolize glucose caused by the lack of insulin (glucose uptake in muscles and fat, glucose storage in the liver) leads to increased catabolism of fat and protein with inevitable weight loss. The combination of hypernatremia and hyperglycemia, will draw water from cells (not in the brain as glucose can enter brain cells without insulin), so the body is losing both ECF and ICF contributing to the weight loss

Liver cirrhosis, heart failure and secondary hyperaldosteronism

The hepatic portal vein carries blood from the abdomen to the liver. Cirrhosis of the liver means it gets backed up causing portal hypertension and ascites (fluid in the peritoneal cavity). This decreases the effective extracellular fluid volume. Heart failure also does this. This stimulates the RAAS system where angiotensin II causes aldosterone secretion.

Obesity and Genetics

The heritability of obesity is extremely high, at the moment. Genetic variation can also affect numerous obesity-related phenotypes: Appetite regulation Fuel metabolism Body weight distribution Risks associated with obesity Our current environment (high-calorie food, sedentary lifestyle) almost guarantees that any propensity towards obesity will become manifest.

Salt-wasting Congenital Adrenal Hyperplasia

The high ACTH means DOC is produced in excess. The mutations lead to decreased expression of adrenal steroidogenic enzymes that would synthesise cortisol and aldosterone. Lack of aldosterone and cortisol raise ACTH drive thus more DOC is produced.

Growth Hormone Control

The hypothalamus receives information about body metabolism including that related to puberty GHRH is synthesized in the arcuate nucleus and secreted from their nerve endings in the median eminence in a pulsatile manner. it binds to GHRHR in the anterior pituitary, a Gs-protein-coupled receptor that acts via the adenylyl cyclase - cAMP pathway.

The thyroid hormone axis

The hypothalamus receives information about body temperature and adjusts metabolic rate appropriately through its control of thyroid hormone secretion. TRH (thyroid releasing hormone) is synthesized by neurons in the paraventricular nucleus and secreted from their nerve endings in the median eminence when plasma thyroxine levels are low. TRH reaches the TSH-secreting basophilic cells in the anterior pituitary through the portal circulation. Here it binds to G protein-coupled receptors, that acting through IP3 and diacylglycerol, elevate cell Ca2+ concentration which triggers the exocytotic release of TSH. The released TSH feeds back to inhibit further TRH release. It also stimulates the thyroid gland to release thyroxine. In turn, the elevated thyroxine levels inhibit further TSH and TRH release.

Hypothalamo-Pituitary Adrenal Axis (HPA)

The hypothalamus receives information about the levels of stress and adjusts the levels of cortisol appropriately through control of its secretion. CRH (corticotropin releasing hormone) is synthesized by the paraventricular nucleus in response to stress.

The adrenal axis

The hypothalamus receives information about the levels of stress and adjusts the levels of cortisol appropriately through control of its secretion. CRH is synthesised by neurons in the paraventricular nucleus

Hypothalamo-Pituitary Gonadal Axes (HPG) in females

The hypothalamus receives information related to sexual activity and modulates this appropriately through its control of oestrogen and progesterone secretions. GnRH (gonadotropin-releasing hormone) is synthesised by neurons in the preoptic anterior hypothalamus and secreted when plasma LH levels are low.

Hypothalamo-Pituitary Gonadal Axes (HPG) in males

The hypothalamus receives information related to sexual activity and modulates this appropriately through its control of testosterone secretion. GnRH (gonadotropin-releasing hormone) is synthesized by neurons in the preoptic anterior hypothalamus and is secreted when plasma testosterone levels are low.

Hypothalamus-Pituitary-Gonadal axis in females

The hypothalamus secretes GnRH which acts on the anterior pituitary to release FSH and LH Oestrogen is released by the follicles- usually negative feedback on the anterior pituitary but if oestrogen levels remain high for over 36 hours, it starts to postiviely feedback on the anterior pituitary Progesterone secreted by the corpus luteum negatively feeds back on the anterior pituitary

Osteomalacia

The impairment of bone metabolism causes inadequate bone mineralization. Diffuse joint and bone pain (especially of spine, pelvis, and legs) Muscle weakness Difficulty walking, often with a waddling gait Hypocalcemia (positive Chvostek sign) Compressed vertebrae and diminished stature Pelvic flattening Weak, soft bones Easy fracturing Bending of bones

Infertility

The inability to conceive after 2 years of regular unprotected intercourse

Glucose and osmolarity

The increased glucose concentration does result in an increased plasma osmolarity however as glucose unlike sodium can enter brain cells, independent of insulin, its concentration rises in the cells to the same extent as in the ECF; no difference in osmolarity.

Differential Diagnostic Testing: Inferior Petrosal Sinus Sampling

The inferior petrosal sinuses are veins that drain the pituitary. A catheter is placed in both of these veins at the same time and blood sampled for ACTH before and after the administration of CRH. This test can be used to distinguish between Cushing's Disease which is a pituitary defect secreting ACTH and an ectopic source of ACTH In Cushing's Disease there is an exaggerated increase in ACTH In ectopic ACTH syndrome there will be no response

Renal disease and secondary hyperparathyroidism

The kidney is a major site for calcitriol production thus renal disease causes calcitriol deficiency which leads to secondary hyperparathyroidism.

Human prostate Ba

The lamellated object is a corpus amylaceus, and is made out of glycoprotein With age these become calcified to form true prostatic concretions, completely takes up the gland.

Human mammary gland, pregnant i

The large collecting duct contains precipitated colostrum

Oviduct i

The layers are: Adventitia Muscularis propria running in circular and longitudinal directions Mucosa lamina propria epithelium Box A - mucosa Box B - muscularis and adventitia

Ovary A

The left half of this image is ovarian cortex, containing: Primordial follicles (P) Primary follicles (1) Secondary follicles (2) Secondary follicles may be called antral follicles N.B. The definition of primary, secondary and tertiary follicles can be confusing - different texts will tell you different things. For this reason, the terms "pre-antral" and "antral" are preferred, describing follicles without and with an antrum, respectively Graafian follicles are the most mature type of antral follicle and are the follicles that rupture at ovulation In any one cycle, only one antral follicle will become the Graafian follicle Graafian follicles are always towards the cortex and bulge beneath the ovarian epithelium (whose cells flatten) Large antral follicles such as (3) should not be called Graafian follicles unless the oocyte status is known

Ovary C

The left side of this image is ovarian medulla, which is quite vascular The pale pink spots here are corpicus albicans Note also the number of atretic follicles. These are the remains of secondary follicles that have not gone onto ovulation The follicles that began to mature in a menstrual cycle but which did not become the Graafian follicle undergo atresia

The Lethal Yellow Mutant Mouse (A^Y)

The lethal yellow mutant mouse has ectopic expression of the agouti protein due to a deletion in the promoter causing the loss of a tissue-specific promoter element Lethal to homozygotes, heterozygotes have a yellow coat, mature-onset obesity, type II

Insulin in metabolism

The magnitude of the insulin response to oral intake of protein reflects the combined effects of the rise in plasma amino-acids and the increased levels of gastrin, secretin and

Implantation

The main question here is how the mother distinguishes between a fertile and infertile reproductive cycle. In an infertile cycle the demise of the corpus luteum at the end of the 28 day cycle, results in a loss of progesterone and with it, the uterine endothelium. In a fertile cycle the corpus luteum is kept functional by the secretion of an LH-like hormone, human chorionic gonadotrophin (hCG), by the implanting blastocyst. Thus the implanting embryo controls the mother's hormones by hijacking the function of the ovary.

Symptoms of hypernatreamia

The main symptom of hypernatremia is excessive thirst. Others include fatigue and confusion, but usually no symptoms unless severe.

The incretin effect

The major controller of insulin secretion is glucose. However, oral intake of a glucose solution stimulates a greater increase in pancreatic insulin secretion than intravenous administration This points to the importance of the gastro-intestinal hormones in stimulating insulin synthesis and secretion following ingestion of glucose.

Endocrine pancreas

The mature islet comprises 3 distinct cells types α cells secrete glucagon β cells secrete insulin d cells secrete somatostatin

explain the dilemma of the "mineralocorticoid receptor" (MR)

The mineralocorticoid receptor has no inherent specificity for mineralocorticoids. It has a higher affinity for cortisol than the glucocorticoid receptor The concentration of cortisol is 100-1000 times greater than that of aldosterone and displays a diurnal rhythm

Regulation of aldosterone synthesis

The most potent stimulus of aldosterone synthesis is plasma K+ concentration as increased K+ concentration depolarizes the zona glomerulosa cells, thereby opening membrane Ca2+ channels. The increased cell Ca2+ is a potent stimulator of aldosterone production. Angiotensin II seems to work together with K+ to increase aldosterone production. Blood volume and arterial blood pressure also affect it. ACTH does have some small stimulatory effect

Parathyroidectomy

The need for surgical parathyroidectomy in patients with secondary hyperparathyroidism has decreased significantly in recent years due to the increased efficacy of treatments to suppress parathyroid hormone (PTH) secretion, especially vitamin D The main indication for parathyroidectomy is therapy-resistant hypercalcaemia.

Neural stimulation of thirst

The neural stimulation of thirst requires an increase of 3% in plasma osmolality. An increase in plasma osmolality leads to an increase in ECF osmolality causing the osmotic shrinkage of cells. It is this shrinkage that triggers the firing of hypothalamic and non-hypothalamic osmoreceptors. These fire action potentials are relayed to the magnocellular neurones to increases secretion of AVP.

Steroid Complications

The neuropsychiatric complications of steroid treatment are quite common symptoms from anxiety, irritability and impaired cognition to depression, mania, psychosis, and suicidal tendency • It is clear that these symptoms are common enough and potentially very severe so as to warrant aggressive and early intervention by psychiatric consultants

Calcium phosphate precipitation

The normal plasma ion concentrations of calcium and phosphate are such that the system is virtually saturated at normal values. However, the plasma does contain substances including pyrophosphates and citrate that inhibit calcium phosphate precipitation. any increase in calcium or phosphate ion concentrations is likely to result in some calcium phosphate precipitation and there is always a risk of calcification in tissues other than bone which is seen in chronic renal disease where there is loss of precise control over renal calcium and phosphate excretion.

Nuclear Localization of nuclear receptors

The nuclear receptor like all cellular proteins, are synthesized on ribosomes that reside outside the nucleus Import of the NRs into the nucleus requires the nuclear localization signal NLS which is located near the border of the C and D domains of the receptor

The Obese Mouse (ob/ob)

The obese mouse does not express the product of the ob gene leptin gains weight rapidly, to become 3x the size of control mice. Uncontrollable food intake obesity, type II diabetes, insulin resistance and hyperinsulinaemia. When leptin is administered to these mice, they show a dramatic reduction in weight

Female sexual reproduction

The oogonium undergo mitosis in the third trimester to become primary oocytes. The primary oocytes begin meiosis I during foetal development but stops at prophase I After puberty where GnRH pulses more frequently and LH and FSH levels rise, the primary oocytes complete meiosis I which produces a secondary oocyte and a first polar body which may or may not divide again

Pancreas structure

The pancreas lies in the C- curve of the duodenum. Its main duct, the pancreatic duct joins with the common bile duct and goes through the sphincter of Oddi at the ampulla of Vater before entering the duodenum. These ducts carry the pancreatic exocrine secretions from the acinar cells into the duodenum. The pancreas also has an endocrine function with the islets of langerhaan

Secretion of somatostatin

The pancreatic secretion of somatostatin is triggered by each of the components of a mixed meal i.e. carbohydrates, proteins and fats. entry of gastric acid into the duodenum also increases somatostatin release, enabling it to decrease gastric acid secretion in the bulbogastrone mechanism.

Pars Intermedia / Intermediate Lobe

The pars intermedia regresses after childhood It is closely associated with the pars nervosa and separated from the pars distalis by the hypophyseal cleft. Melanocyte-stimulating hormone is the predominant hormone secreted.

GH and the PI3 kinase pathway

The phosphorylated tyrosine residues on JAK2 act as docking sites for IRS-1 (insulin receptor substrate 1), which gets phosphorylated. IRS-1 is phosphorylated and can bind PI-3K (phosphoinositide-3 kinase), which, now located at the membrane, phosphorylates PIP2 at position 3, forming PIP3 (phosphatidylinositol-3,4,5 triphosphate). PIP3 allows both PDK1 (phosphoinositide-dependent kinase-1) and PKB (protein kinase B) to associate with the membrane via their PH (pleckstrin homology) domains where Phosphorylated PKB dissociates from the membrane and phosphorylates its target proteins.

The pituitary gland

The pituitary gland protected at the base of the brain in the sphenoid bone, connected by pituitary stalk The pituitary is connected to the hypothalamus by the infudibulum. The pituitary consist of anterior, posterior lobes, and the pars intermedia that regresses after childhood

TSH — thyroid stimulating hormone.

The pituitary is the body's natural monitoring system for thyroid hormone levels so changes in the TSH level are often the first and most subtle sign that the thyroid is becoming under- or over-active. For this reason, TSH is commonly the first test done by the lab. If it is normal, no further tests are done since it is very likely that the T4 and T3 will also be normal.

Polydipsia in diabetes mellitus

The polydipsia seen in diabetes mellitus is a combination of an increased plasma osmolarity and a decreased plasma and ECF volume. In the kidneys, there is loss of sodium and chloride due to the increased tubular flow limiting their reabsorption. The loss of water is proportionately greater than the loss of sodium and chloride, so extracellular sodium concentration rises- hypernatremia. The decrease in cell volume due to the hypernatreamia is detected by osmoreceptors and stimulates thirst and ADH release. The decrease in extracellular volume also induces thirst and ADH release.

Pathophysiology of gestational diabetes mellitus

The precise mechanisms underlying gestational diabetes remain unknown. The hallmark of GDM is increased insulin resistance. Pregnancy hormones and other factors are thought to interfere with the action of insulin as it binds to the insulin receptor. insulin resistance prevents glucose from entering the cells properly

Initiating Pregnancy

The preimplantation conceptus remains at the site of fertilization initially before transfer through the isthmus of the oviduct into the uterus. This is mediated by the early luteal phase rise in the ratio of progesterone to oestrogen, which affects the oviducal and uterine musculature and relaxes the isthmic sphincter. Conventionally, pregnancy is timed from the last menstrual period. Given that this event marks the beginning of a menstrual cycle rather than ovulation, a pregnancy designated '12 weeks' is in fact only 10 weeks after ovulation and fertilization • Once the conceptus makes contact with the uterine endometrium at implantation it signals its presence to the mother to delay luteolysis • If both actions are successful, pregnancy is initiated • Successful initiation of pregnancy creates a new and extraordinary parabiotic link between mother and conceptus, which last ~9 months

Osmosis

The presence of a solute will lower the relative amount of water available to freely move in a solution. This is called the substance's water activity. As compartment A has less solute, it has relatively more water available to move When there is a difference in the availability of water (water activity) between compartments, there is net water movement from the compartment with the higher water activity to that with the lower water activity. This movement will continue until the activities of water in the two compartments become equalized. This net movement is called osmosis. Hydrostatic pressure increases water activity, solutes decrease it.

Hypocalcaemia presentation

The presentations of patients with hypocalcemia vary widely, from asymptomatic to life-threatening situations. Hypocalcaemia is usually insidious in onset but when serum Ca2+ falls below 1.5 mmol/L (6.0 mg/dL), the condition becomes increasingly dangerous.

Stages of the follicles

The primordial follicle contains the primary oocyte arrested at prophase I during foetal development and follicular cells under the basement membrane The late primary follicle has granuloma cells, a zona pellucida around the primary oocyte and theca folliculi on the basement membrane The secondary follicle has the theca externa and interna and the corona radiata The Graafian follicle has the antrum filled with follicular fluid

Development

The primordial germs cells originate in the yolk sac and migrate into the developing fetus at around 4- 5 weeks of development. The primary differentiation is into oogonia or spermatogonia. They enter meiosis as oocytes or spermatocytes. In males the spermatids are formed after puberty and they differentiate into spermatozoa as haploid cells. In the female, germ cells are arrested as primary oocytes. After puberty small numbers grow and reinitiate meiosis up to metaphase II. Oocytes are ovulated and fertilized at meiosis metaphase II. Activation at fertilization leads to the completion of meiosis of the oocyte.

Glycogen synthesis

The rate-determining step in the synthesis of glycogen is catalysed by glycogen synthetase - an enzyme which is active in the dephosphorylated form but can be inactivated by the kinase-mediated addition of a phosphate group.

Roux-en-Y gastric bypass

The stomach is stapled then the jejunum is shortened and directly connected to the smaller stomach bypassing the duodenum Causes caloric restriction by decreasing the pathway of food through the intestine, thus reducing absorption of calories and fats There is enhanced nutrient/bile delivery to the mid/distal jejunum and ileum

Hormone response elements

The receptor dimers are bound to the HRE that is upstream from the target gene and its promoter region. DNA dependent RNA polymerase action is controlled by this promoter region This promotor region is subject to enhancing or occasionally suppressive influence by the dimerised hormone complex. co-activators or co-repressors are recruited by the ligand occupied dimerised receptor to enhance or repress the function of the transcription initiation complex. The mRNA produced is then translated to protein and number of regulations can occur at this post-transcriptional stage

Hormonal regulation of the female reproductive cycle

The regulation begins in the hypothalamus with the release of gonadotropin releasing hormone. At the beginning of the month the levels of GnRH slowly rise. The GnRH binds to receptors in the anterior pituitary and stimulates the release of the gonadotropins, follicle-stimulating hormones (FSH) and luteinizing hormone (LH).

The ovarian cycle luteal phase

The release of LH is inhibited, which suppresses the ovulation of another secondary oocyte. The corpus luteum, stimulated by LH, secretes progesterone and oestrogen which supports uterine endometrial changes in preparation for implantation of an embryo in the event that fertilization occurs. Progesterone increases the growth and development of the uterus and prepares it for possible implantation.

Ionised Ca2+ concentration

The release of ionized Ca2+ into the blood contributes to the maintenance of the plasma ionized Ca2+ concentration when this is low. When ionized Ca2+ concentration is normal or high, calcium phosphate is deposited on bone surfaces. In this situation, PTH levels are low and so the kidneys are not forming significant quantities of 1,25-dihydroxycholecalciferol. • So there is not stimulus from 1,25-dihydroxycholecalciferol for osteoclastic bone breakdown.

ACTH action

The released ACTH feeds back to inhibit further CRH release. ACTH also stimulates the adrenal cortex to release cortisol. In turn, the elevated cortisol levels inhibit further ACTH and CRH release.

ACTH inhibition

The released ACTH feeds back to inhibit further CRH release. ACTH stimulates the adrenal cortex to release cortisol. In turn, the elevated cortisol levels inhibit further ACTH and CRH release.

TSH action

The released TSH feeds back to inhibit further TRH release. It also stimulates the thyroid gland to release thyroxine. In turn, the elevated thyroxine levels inhibit further TSH and TRH release

receptors that detect changes in blood pressure (baroreceptors) and blood volume influence sodium excretion or retention.

The renin-angiotensin-aldosterone cascade detects the decrease in renal perfusion pressure and increases the amount of sodium reabsorbed by the kidneys through the release of aldosterone by angiotensin III. Atrial natriuretic peptide (ANP) increases natriuresis sodium in the urine.

When cells produce either hydrophobic or hydrophilic hormones how does this affect hormone secretion?

The same rules that govern the ability of hormones to enter target cells also constrain their ability to pass across the plasma membranes of the cells in which they are synthesised. Hence, hydrophilic hormones are unable to diffuse across the plasma membrane of cells in which they are produced, and instead must be packaged in vesicles that fuse with the plasma membranes prior to secretion.

Secondary oocyte pathways

The secondary oocyte begins meiosis II, stopping at metaphase II High levels of oestrogen cause the LH surge, where the Graafian follicle ruptures and the secondary oocyte and first polar body is ovulated The collapsed follicle becomes the corpus luteum secreting large amounts of progesterone, oestrogen and inhibin to promote endometrial proliferation and secretion. High levels of inhibin stop the production of LH and FSH by the anterior pituitary. If the secondary oocyte is not fertilized the corpus luteum degenerates and the cycle begins again. If fertilisation occurs, meiosis II resumes and the oocyte splits into an ovum and a second polar body

Calcitonin role

The secretion of calcitonin is increased in response to hypercalcaemia and it acts to decrease the amount in the body by inhibiting osteoclasts and reducing uptake in the intestine and kidney

Promenstrual uterus

The stratum functionalis is what is lost during menstruation Th drop in progesterone and oestrogen during menstruation constrics the vessels suppyling the endometrium leading to their degenration

Human testis- germinal epithelium

The seminiferous epithelium is an example of a germinal epithelium Spermatogonia are found in the basal layers resting on the basement membrane, they divide mitotically to give rise to further stem cells called Type A spermatogonia, and Type B spermatogonia Type A spermatogonia (SA) have large dark nuclei (condensed chromatin) with peripheral nucleoli (if visible) Type B spermatogonia (SB) have large pale nuclei (dispersed chromatin) with central nucleoli. Type B cells enter mitosis and become spermatocytes Primary spermatocytes (S1) are the largest cells here, with distinctive nuclei in which the chromatin is in clumps or threads. They divide in the first meiotic division to yield two daughter cells, secondary spermatocytes. The first meiotic cycle takes about three weeks, but the secondary spermatocytes (rarely observed) rapidly undergo the second meiotic division to produce the gametes, spermatids (ST) Spermatids mature during spermiogenesis and become spermatozoa (SZ), changing their appearance from small round cells to smaller pointed cells Sertoli cells (SC) support the spermatogenic cells They rest on the basement membrane and extend to the lumen, their nuclei are usually oval or triangular, pale with a prominent nucleolus above the basal level. Their cytoplasm surrounds the spermatogenic cells and Sertoli cells make tight junctions with each other, thus providing a cellular barrier between the circulation and the spermatogenic cell, the so-called blood testis barrier The germinal epithelium with is basal lamina sits on a thin layer of fibromuscular connective tissue, with fibromyocytes (myoid cells, myoepithelial cells) dispersed amongst collagen and elastin fibres that they have laid down

What would be the appearance of an undescended abdominal testis in an adult, and why?

The seminiferous tubules will contain Sertoli cells and interstitial cells secreting testosterone will be present; the temperature sensitive germinal cells will however not develop, so no spermatogenesis.

Steroid hormone classes

The simplest respect in which the classes of steroid hormone differ is in the number of carbon atoms as follows: progestins have 21 carbon atoms; therefore "C21 steroids" glucocorticoids C21 steroids mineralocorticoids C21 steroids androgens C19 steroids oestrogens C18 steroids

pH and the solubility product

The solubility product is given by the cation x anion concentrations. Increasing pH increases it, decreasing pH decreases it.

Fertility Through Life

The start of fertility - puberty The end of fertility - menopause Inhibiting fertility - contraception Increasing fertility - treatment of infertility

outline the negative feedback loops within the hypothalamo-pituitary axes that control the thyroid gland, gonads, adrenal glands and growth

The stimulus to anterior pituitary function is controlled largely by "short-loop" negative feedback from anterior pituitary gland itself. Increased trophic hormone feeds back to inhibit the hypothalamic secretion of releasing hormone. Increasing peripheral concentrations of gland hormone feedback to inhibit the release of trophic hormone by the anterior pituitary cells and secretion of releasing hormone by the hypothalamus. For example: gonadotrophins decrease frequency and amplitude of GnRH pulses from median eminence GH suppresses subsequent synthesis and secretion of GHRH. Hormonal signals arising outside hypothalamo-pituitary complex also control synthesis and secretion of peptide and glycoprotein hormones from the anterior pituitary gland. This is exemplified within the thyroid, gonadal and adrenal axes. Activity of hypothalamo-adenohypophyseal axis can also be over-ridden by higher centres of brain. For example, in chronic stress, (with loss of negative feedback to CRH and ACTH) and other elements of anterior pituitary (e.g. gonadotrophs and somatotrophs) repressed following withdrawal of hypothalamic releasing hormones.

Human uterus, menstrual A: stratum compactum

The surface epithelium is absent; eroded uterine glands and raw endometrial stroma from the ragged exposed surface Glycogen can be seen in the glands which serves as nutrition for the blastocyst (pale orange smudges) This tissue makes up the bulk of the menstrual flow.

Justin, a 23-year-old machine operator, has been experiencing weight loss, increased thirst, increased urination, increased appetite, and some blurred vision over the past few weeks. Why would today's clinical measurements be appropriate? What are the normal values for blood glucose levels, and what might we expect to find with Justin?

The symptoms that Justin describes are symptoms of diabetes mellitus. Testing his blood glucose level will indicate whether he has high blood glucose levels. Normal blood glucose levels are between 4-7 mmol/L (72-126 mg/dL). You'd expect to find a random blood glucose level of > 11 mmol/L (> 200 mg/dL).

explain how the synthesis and secretion of anterior pituitary hormones is controlled by specific hypothalamic releasing hormones and inhibitory factors

The synthesis and secretion of adenohypohyseal hormones is stimulated by hypothalamic releasing hormones which are synthesised in the cell bodies of the hypothalamic parvicellular neurones: TRH Thyrotrophin releasing hormone targets Thyrotrophs - TSH. also stimulates prolactin release from lactotrophs CRH Corticotrophin releasing hormone Corticotrophs - ACTH (GnRH Gonadotrophin releasing hormone Gonadotrophs - LH & FSH GHRH Growth hormone releasing hormone Somatotrophs - GH)

Secondary/Graafian follicle

The theca interna cells are the endocrine cells

Why don't we monitor body sodium content by measuring plasma sodium concentration?

The thirst/ADH mechanism already regulates the concentration of sodium in the ECF through water This means that sodium concentration is now independent of the amount of sodium in the body.

Release of thyroid hormones

The thyroglobulin still attached is endocytosed at the apical border Lysosomal degradation releases the hormone, and T4 and T3 diffuse into the capillary The uncoupled MIT and DIT is recycled to make more iodide

Embryological abnormalities

The thyroid develops between the anterior 2/3 and posterior 1/3 of the tongue and tracks down the middle of the neck. Balls of thyroid cells may be left behind anywhere down this track PAX8 mutation causes failure of the gland to develop- congenital hypothyroidism Migration of the thyroid- lingual, retrosternal thyroid Failure of thyroglossal duct to atrophy- thyroglossal cyst

The thyroid makes two types of hormone

The thyroid follicles make T4 and T3 The C cells make calcitonin

Mechanism of action of the thyroid hormone

The thyroid hormone receptors are nuclear receptor that regulation gene transcription on activation Like steroids T3 and T4 are internalised Receptors activation increases glucose and amino acid uptake. Translation yields proteins that have a regulatory effector function.

describe, with the aid of diagrams, the gross morphology of the thyroid gland

The thyroid is made up of two lobes connected by the isthmus It is situated below the larynx It has a follicular structure with parafollicular C cells There are four small parathyroid glands attached to its posterior surface

Paracellular absorption of calcium

The tight junctions contain cation channels claudins that allow Ca2+ to diffuse through them down their electrochemical gradient.

Pregnancy

The transition from a maternal source of progesterone, albeit stimulated by the embryo, to it being supplied by the conceptus is complete by the end of the first trimester. The main hormones of pregnancy are progesterone, oestrone, placental lactogen and prolactin. These hormones are secreted from the conceptus from 2-3 weeks of implantation Progesterone is synthesised by the placenta. Oestrogens are synthesised by co- operation between the fetus and placenta (conceptus). Parturition Parturition requires an increase in uterine contractility and ripening of the cervix. The fetus determines the timing of parturition through increasing secretion of glucocorticoids. Glucocorticoids lead to modifications in the oestrogen/progesterone ratio that results in an increase in uterine contractility. The increased oestrogen upregulates oxytocin receptors and prostaglandin production. In addition, the action of oxytocin on the myometrium also stimulates PG production. Stimulation of the cervix leads to oxytocin secretion from the posterior pituitary via a neuroendocrine reflex. The combined effects of oxytocin and PGs on uterine contractility and cervical ripening lead to parturition.

Phaeochromocytoma

This tumor is named for its colorful reaction in fixatives containing chromic acid salts. Individual chromaffin cells usually only secrete either norepinephrine or epinephrine, but phaeochromocytomas usually over-secrete both hormones.

Epididymis B

The tubules contain agglomerated spermatozoa (is this real or artefactual?) The wall of the tubule consists of: an external adventitia of connective tissue that merges with the connective tissue between the tubules an outer layer of smooth muscle, oriented predominantly circularly or obliquely (spirally) subepithelial connective tissue (a thin layer) an inner lining of simple columnar epithelium Note the presence of blood vessels in the connective tissue between the tubules At the top right there is a small segment of the tunica albuginea. What is its construction?

D is a 44 year old woman who presents at her GP's after an abnormal eye test complaining of visual problems. On questioning she had been increasingly tired over the last few months. She had lost interest in sex but put this down to exhaustion. She had noticed a number of occasions of feeling dizzy on standing up. She has visual field loss in the exterior regions of both visual fields. she has menstrual irregularities and a discharge from her breasts.

The visual field defect detected bilateral hemianopia. In this case the lesion would be at the optic chiasm. This suggests pituitary gland pathology such as a pituitary tumour, which is growing outside the pituitary fossa causing compression of the optic chiasm. When asked about other signs and symptoms D tells her GP that The menstrual irregularities and discharge from her breasts suggests prolactinoma.

Seminal vesicles B

The wall of the seminal vesicles consists of (from the outside to the inside) Adventitia Muscularis- inner circular and outer longitudinal layer Submucosa Mucosa What are: A B C D- adventitia with nerve bundle What are the major components of these layers?

Metabolism in the adrenal glands

The zona glomerulosa produces aldosterone Zona fasciculuta- cortisol Zona reticularis- DHEA (dehydroepiandrosterone) P450CSCC cholesterol side chain cleave P450C21 21-hydroxylase P450C11B1 11-betahydroxylase

Primary/primordial follicles

Thecal cells around the primary follicle ~ 500,000 PF in human ovary at birth - arrested in 1st meiotic division ~ 20 / month begin maturation... only 1 ovulates usually

How would you collect a urine sample from an infant or young child who doesn't have voluntary control?

There are a number of plastic disposable collection bags available for this purpose. Just follow the instructions and be careful not to irritate the sensitive perineal skin.

Phosphate

There are many organs involved in phosphate regulation and these include the kidney, gastrointestinal tract, parathyroid glands and bone. Phosphate is required for numerous cellular functions such as : DNA synthesis Membrane lipid synthesis Generation of high-energy phosphate esters Intracellular signaling.

SERMs

Three key SERMs: • tamoxifen • raloxifene • toremifene Tamoxifen is the oldest, most well-known, and most-prescribed SERM.

What are some other dangers of sensation-loss in the feet?

There are many possible dangers including: - Standing on something sharp and not realizing until it has punctured the skin. - Walking on slippery surfaces and having no perception of how slippery it is. - Allowing the feet to get too cold for long periods, can lead to tissue damage and death. - Being unaware of large cuts or abrasions until they become quite bad.

Paracellular phosphate intestinal absorption

There are no known specific phosphate-accessible channels at the tight junctions, it can just diffuse.

Incorporation of glucose into Triglycerides

There are several biochemical pathways linking the oxidation of glucose to the synthesis of triglycerides: glycolysis yields pyruvate which can enter the Kreb's cycle and exit as citrate for fatty acid biosynthesis (via cytosolic acteyl-CoA) glycolysis yields α-glycerophosphate - to which fatty acids can be esterified in the formation of triglycerides via the pentose phosphate pathway, glucose-6-phosphate yields the reducing equivalents necessary for fatty acid biosynthesis.

Cardiovascular disease and diabetes

There are several ways in which this can be enhanced by diabetes. 1. Increased VLDL - increased blood coagulation by activation of Factor VII 2. Impaired endothelial function - i.e. reduced release of nitric oxide, therefore greater arterial contraction and reduced blood flow. Also increased platelet activation due to lack of NO. Endothelial dysfunction may be due to effects of elevated VLDL, osmotic effects of glucose and by modification of LDL (see below) 3. Modification of lipoproteins. LDL can be glycated non-enzymatically as well as collagen. This can give rise to cross-linking of LDL to matrix proteins in the arterial intima and therefore deposition of lipid. Macrophages in atherosclerotic plaque accumulate lipids because they are able to recognise and take up modified lipoproteins e.g. glycated LDL and AGEP LDL. These cells have receptors for these AGE proteins called RAGE, which lead to the uptake and accumulation of LDL, and therefore cholesterol and cholesterol esters, in the macrophage-derived "foam cells" of the atherosclerotic plaque (1). 4. 5. Proliferation of smooth muscle cells - part of development of atherosclerosis due to activation of macrophages and release of chemokines and growth factors from macrophages. Hyperinsulinaemia seen in some Type II diabetics may also have independent effects which enhance atherosclerosis.

Phosphate intestinal absorption

There are two pathways for phosphate absorption- diffusion through the paracellular pathway and transport through the cells, transcellular

Calcium absorption in the digestive system

There are two possible pathways; through the cells transcellular or between the cells across the tight junctions paracellular.

Ascending limb of the loop of Henle

There are two sections (thin and thick) to the ascending limb. They are impermeable to water In the thin ascending limb there is NaCl reabsorption via the net passive diffusion from the tubule to the interstitial fluid. In the thick ascending limb there is active reabsorption of NaCl from the tubules. The solute removed by this process is what creates the hyperosmolarity of the medulla. Overall the imbalance between the amount of sodium and water reabsorbed in the loop of Henle produces a hyposmotic filtrate.

Vitamin D

There are two sources of vitamin D; dietary and skin synthesis. Vitamin D' is used to describe vitamin D at varying stages of hydroxylation; the stage of hydroxylation has a profound effect of the activity of the hormone and therefore is important to state which 'vitamin D' is being referred to. Vitamin D refers to a group of related steroid-based compounds in which one of the bonds in the steroid ring is broken. Neither vitamin D2 or D3 is physiologically active.

GH-induced Insulin Resistance

There is GH-mediated induction of insulin resistance GH-induced increase in FFA flux from the adipose tissue has been associated with impaired insulin action at target tissues • SOCS-1 and SOCS-3 have been associated with insulin resistance and down-regulation of insulin signaling

Gigantism pathophysiology

There is delayed puberty as the somatotrophs compress the other pituitary cells in the restricted space of the sella turcica giving reductions in other pituitary functions Poor prognosis if untreated • The high SD score should be picked up in childhood and the tumour, which can be imaged with an MRI scan, removed surgically

Glycation and retinopathy

There is distortion of the structure of the collagen leading to the formation of nodular structures that enhance the permeability of the blood vessels. This leads to haemorrhage of the vessels in the eye and to blindness (diabetes is the most significant cause of blindness in the U.K).

Autoimmunity in Type 1 diabetes

There is likely to be a genetic element in Type 1 which allows a greater susceptibility. This may predispose to a viral infection and then an inflammatory reaction An autoimmune reaction is set up involving cytotoxic antibodies and T lymphocytes which leads to the destruction of the insulin-secreting cells.

Monitoring compliance with hypothyroidism therapy

This is a classic presentation of someone who has stopped taking their thyroid medication (levothyroxine) for a while, then gets a call-up letter saying they are due for a routine thyroid blood test. What do they do? Well they start taking their levothyroxine of course. Remember it took many months for the TSH levels to normalise, therefore in the presentation shown the TSH is raised giving us a measure of compliance in taking the levothyroxine. But we see the raised T3 and T4 as the levothyroxine is converted to these hormones in the bloodstream. The outcome make sure the patient knows they need to keep taking the medication, even though they feel better, this will be life-long medication to replace their thyroid function.

Microfocus of PTC

This is a common postmortem finding - relatively benign course?

PCOS treatment

There is no cure for PCOS. Although there have been cases involving the spontaneous resumption of menses, most women will have progressive symptoms until after menopause. Treatment of PCOS is aimed at reducing its symptoms and helping to prevent future complications. The goals are to promote ovulation, prevent endometrial hyperplasia, counterbalance the effects of androgen, and reduce insulin resistance. Treatment options depend on the type and severity of the individual patient's symptoms and on the patient's desire to become pregnant. Low-dose oral contraceptives are often used to stabilize hormones and oppose oestrogenic stimulation of the endometrium. Over several months, low-dose oral contraceptives can usually regulate menstrual periods, eliminate or minimise uterine bleeding, and reduce androgen levels (improving hirsutism and clearing up acne). Anti-androgens, such as spironolactone (aldactone), flutamide (Drogenil) and cyproterone (Androcur, Cyproterone acetate) are sometimes combined with oral contraceptives to help address more severe hirsutism and acne. Waxing, shaving, depilatory and electrolysis may be used to remove unwanted hair, and antibiotics or retinoic acids may be used to treat acne. Metformin (Glucophage) is used to reduce insulin resistance. It has also shown promising initial results in women with PCOS hirsutism and in helping to regulate menstrual cycles, but its effects on infertility and other symptoms are not yet known. This drug has not been licensed in the UK for use in non-diabetic patients. Weight loss and exercise are recommended to help decrease insulin resistance and to minimize lipid abnormalities. Weight reduction can also decrease testosterone, insulin, and LH levels. If a woman with PCOS wants to become pregnant, she is usually given clomiphene citrate (Clomifene, Clomid), a drug that helps induce ovulation. She may also be given human menstrual gonadotrophins (Merional, Menopur), although this drug increases the risk of multiple pregnancies.

Age

There's also a decline in the number of follicles Higher rate of chromosomal abnormality with age

Nuclear receptors

These intracellular receptors function as hormone-regulated transcription factors, controlling the expression of specific target genes by interacting with regions known as hormone response elements located close to the promoter in the regulatory region.

Receptor Enzymes

These receptors have an extracellular ligand-binding domain, and an enzyme active site on the intracellular section, connected by a single transmembrane segment. Many of these enzymes are tyrosine kinases (RTKs), e.g. the insulin receptor. There are also some with serine/threonine kinase activity. Another group have guanylyl cyclase activity (convert GTP to cGMP). In these receptors, ligand binding either activates the enzyme activity, or brings it in proximity to its target.

Thiazolidinediones

Thiazolidinediones are synthetic ligands to PPARy, and have been shown to improve insulin sensitivity, lower plasma glucose, and alter the secretory profile of adipose tissue away from the pro-inflammatory direction.

Human mammary gland B

This collecting duct is embedded in interlobular connective tissue What type of connective tissue is this, and what does it contain?

Seminal vesicles

This image is of a section of a segment of seminal vesicle, showing surrounding connective issue (bottom left), the fibromuscular wall (diagonally) and a part of the lumen (top right, containing precipitated fluid)

Human testis

This image shows seminiferous tubules cut in various planes Each seminiferous tubule is surrounded by a sheath (collagen plus contractile myoepithelial cells) Vascular connective tissue stroma contains clumps of interstitial cells (Leydig cells). Grey-purple cells are the Leydig cells

PPARγ

This transcription factor is necessary and sufficient for adipogenesis. An increase in adipogenesis is associated with smaller adipocytes, less ectopic deposition ie in muscle and liver, and improved insulin sensitivity. PPARy is also needed for maintenance of the adipocyte's differentiation.

Cervix

This is a midline section and therefore includes the cervical canal and its opening into the vagina (the external os); only a limited amount of vaginal wall is included (on the right) Follow the continuity of the vaginal cervix with the wall of the vagina, along the stratified squamous epithelium over the vaginal surface of the cervix to its orifice (the external os): at this point, or a short way along the cervical canal, there is an abrupt change to the simple cuboidal/columnar epithelium which lines the rest of the uterine lumen (Box A) Note the branched mucous secretory glands (G) opening into the cervical canal, and the secretions in the cervical canal (a mixture of mucus and shed cells) The stroma of the cervix is made of fibromuscular tissue Proceed via the interactive areas Box A - vagina/cervix junction Box B - wall of cervix Box C - vaginal stroma Box D - vaginal epithelium

Ovary ApC

This is a young-ish antral (secondary) follicle The main difference between a primary follicle and a secondary follicle is the development of the antrum (A), which is filled with follicular fluid, due to proliferation of the granulosa cells The granulosa cells become endocrine at this stage, secreting follicle stimulating hormone (FSH) and converting androstendione (secreted by thecal cells) into oestrogen Note that the pituitary gland secretes far more FSH than the granulosa cells, whose output is very low At ovulation the granulosa cells secrete inhibin F which inhibits pituitary FSH production The primary oocyte has reached its maximum size The zona pellucida (ZP), which is present in late primary follicles, is well developed, surrounding the oocyte and separating it from the granulosa cells The theca folliculi differentiates into the theca interna (TI) and the less distinct theca externa (TE) The cells of the theca interna tend to round up and form a layer a few cells thick. These are endocrine cells, they secrete oestrogen and progesterone to promote proliferation of the uterine mucosa, preparing it for implantation of a fertilised ovum The cells of the theca externa become flat and fusiform, merging with the stroma

Ovary B

This is an antral follicle at a late stage The antrum has enlarged, surrounded by an even layer of zona granulosa a few cells thick The region where the granulosa cells maintain the attachment of the oocyte is the cumulus oophorus

Human vaginal cervix C: stroma

This is vaginal stroma Type 1 collagen fibrils Blood vessels Fibroblast Nerve bundles What are the two main tissue types present here? What other structures are present?

Sorbitol Pathway

This pathway has little importance in normal metabolism other than to permit inter-conversion of some sugars where required or to metabolise minor dietary constituents such as sorbitol. In diabetes, there is a big increase in the pathway because of the mass action effects of large amounts of glucose. The intermediates and products accumulate intracellularly because there are no active or facilitated transport systems for them. This gives rise to osmotic effects and damage to the cells. One approach to treatment has been the inhibition of the aldose reductase enzymes that form the polyols, with rather variable success. When glucose levels are high, sorbitol and fructose accumulate in the cells since they diffuse relatively slowly. This causes osmotic effects which may damage cells such as lens cells and nerve cells. Damage in nerve cells contribute to neuropathy. Distortion of the lens cells contribute tw

Satiety factors

This process recruits peripheral receptors in the gut, distension and chemo-receptors and metabolic changes send signals to the brain via the vagus Receptors in the CNS detect circulating levels of nutrients, such as glucose Neuroactive factors which cross the blood-brain barrier and/or are released in the brain.

ACTH action

This second messenger then elevates adrenal steroid biosynthesis by increasing: The uptake of cholesterol substrate in the form of plasma lipoproteins The expression of the StAR protein The expression and activity of key steroidogenic enzymes

Thyroid function

Thyotropin Releasing Hormone (TRH) released from the hypothalamus stimulates the release of thyrotropin TSH- thyroid stimulating hormone from the anterior pituitary. Thyrotropin regulates iodide uptake by the thyroid gland.

Thyroglobulin

Thyroglobulin is a glycoprotein with tyrosine that is synthesised by the thyroid epithelial cells and secreted into the lumen of the follicle 1 thyroglobulin = 134 tyrosines, only a handful of these are actually used to synthesize T4 and T3.

TSH levels in pregnancy

Thyroid hormone is required for CNS development • High levels of hCG in the first trimester stimulate the thyroid, as it mimics TSH; the α-chain is identical between hCG, LH, FSH and TSH. This offsetting of TSH action leads to lower serum TSH levels, which is physiological but needs to be remembered when interpreting thyroid function tests in the first trimester.

Thyroid Peroxidase

Thyroid peroxidase is in the apical (colloid-facing) membrane of the thyroid epithelial cells. It organifies- iodisation of the tyrosines on thyroglobulin Then couples the organified molecules for the synthesis of T4 or T3

Uptake scan- thyroiditis

Thyroiditis involved the breakdown of thyroid hormone and colloid in the thyroid The scintigram picks up no thyroid Poor uptake Also seen in iodine overload

T3 and T4 production

Thyroperoxidase with hydrogen peroxide, mediates the oxidation iodide to iodine and linking of iodide to tyrosine residues in thyroglobulin. One mono-and di-iodo forms yield the thyroid hormone T3 (tri-iodothyronine) Two di-iodo forms yield T4 or thyroxine. Thyroxine (T4) has large reserves and slow turnover. T4 is converted to T3 in the periphery. T3 is the main ACTIVE thyroid hormone.

list the major cell types present in the anterior pituitary gland and the protein hormones produced in and secreted from each of these cell types

Thyrotrophs secrete TSH (thyroid-stimulating hormone) Gonadotrophs secrete Gonadotrophins: LH (luteinizing hormone) & FSH (follicle-stimulating hormone) Corticotrophs secrete ACTH (adrenocorticotrophic hormone) Stimulates steroid biosynthesis in adrenal cortex Somatotrophs secrete Somatotrophin = GH (growth hormone) Lactotrophs secrete Prolactin Stimulates lactation

Signs and symptoms of hypothyroidism

Tiredness- Pale, pasty complexion 'Slowed down' Dementia- Disinterested, slow to speak, bradycardia, slow- relaxing reflexes, confusion ... coma Neck swelling- Goitre Constipation Weight gain Obesity Cold intolerant- Hypothermia (extreme cases) Dry skin Subfertility, menorrhagia GOITRE CAN OCCUR IN HYPER AND HYPOTHYROIDISM

Calcium Sensing Receptor

Tissue distribution: • Parathyroid chief cells • Renal proximal tubule • Nephron segments • Gastrointestinal tract • Osteoblast/osteoclast • Monocytes/macrophages • Nervous system • Bone marrow • Cardiovascular tissue

Regulation of aldosterone secretion

To regulate plasma osmolarity, when we retain extracellular Na+ we don't increase its concentration as we are retaining water with it. Plasma volume and blood pressure increase inhibiting aldosterone secretion. Conversely, when extracellular Na+ is lost, plasma volume and blood pressure fall. Now, aldosterone secretion is enhanced. These effects on aldosterone secretion result largely from changes in angiotensin II levels in the plasma. There is no hormonal feedback control.

Hypervitaminosis D

Too much vitamin D can cause abnormally high levels of calcium in the blood; affecting: bones, tissues, and other organs. Leading to high blood pressure, bone loss, and kidney damage.

Hypervitaminosis D causes

Too much vitamin D does not come from food or exposure to the sun It is usually due to taking more than the recommended daily value of vitamin D Some prescription medications used to treat high blood pressure (thiazide diuretics) and heart diseases (digoxin) can cause an increase in vitamin D in the blood Oestrogen therapy, long-term antacids and isoniazide, an antituberculosis medication, can all cause elevated levels of vitamin D. Hypervitaminosis D is more likely with vitamin D supplements combined with other existing health problems such as: kidney disease, liver disease, Tuberculosis, and hyperparathyroidism.

Acromegaly surgery

Transphenoidal route guided by MRI scan usually Transfrontal route if tumour is large Radiotherapy Conventional supervoltage: slow effect in tumour reduction: often results in eventual hypothyroidism

Prevention of hyponatraemia

Treat associated conditions- such as adrenal gland insufficiency • Patient education- with diuretic, anti depressant etc. • High intensity activities- replace water with sports beverages that contain electrolytes in endurance events and demanding activities • Drink water in moderation. Drinking water is vital for health, so make sure you drink enough fluids. But don't overdo it. Thirst and the colour of urine is usually the best indications of how much water the body needs. If you're not thirsty and your urine is pale yellow, you are likely getting enough water.

Growth Hormone deficiency treatment

Treat with rGH if there is a sufficient window of pre- pubertal time for catch up growth Daily subcutaneous injections - usually at night On a Tanner Chart SD score will improve

Case 2: TYPE TWO Causes Often associated with obesity, but not all patients are obese. A man aged 51 visits his general practitioner, who he had not visited for many years, with a number of apparently unrelated complaints. He is clinically obese (B.M.I.36), did not exercise and has complained of rheumatism of the joints to friends in his pub for a number of years. He was a smoker. He had some lack of sensation in his feet and has open sores on his toes, as well as pains in his calves. With a high level of embarrassment, he also admits to loss of libido and has erectile dysfunction (his wife had read about "Viagra" in the newspapers). He also complains of poor vision. On questioning by the GP, he agrees that he is often thirsty and does need to urinate more frequently than a few years ago. The GP believes this to be case of TYPE TWO and sends him to the hospital for more tests. These reveal that he does indeed have diabetes, although his insulin levels are normal to high. His glucose levels are elevated (16mM) and there was glucose and albumin in the urine. There was no evidence of significant ketoacidosis. There was evidence of peripheral vascular disease associated with hyperlipidaemia. There were fungal infections of the skin, which could be treated. His eyes shown evidence of early cataracts and also there were clear microvascular lesions in the retina. Nerve conductance velocity was also reduced. ESR-008

Treatment The patient was put on a weight-loss regime and given dietary advice to increase his consumption of fresh fruit and vegetables and to lower the amount of fat in the diet. He was not given insulin, but biguanides, which increase tissue responses to insulin. He was told to monitor his urine glucose with Clinistix. He was also told to stop smoking forthwith. The man was not a model patient - did not give up smoking and did not change his diet. He did take the drugs, but there were few improvements in his condition. One year later he developed severe renal disease, which was worrying. However, he died shortly afterwards of a myocardial infarction.

Baby G is found to have a congenital defect of the enzyme 21b- hydroxylase. What hormone replacement therapy would be given?

Treatment would involve the administration of glucocorticoids and mineralocorticoids to correct the deficiencies in these hormones. Correcting the feedback to ACTH will reduce the over production of adrenal androgens. Additional anti-androgens can also be given.

Trousseau's sign

Trousseau sign of latent tetany is a medical sign observed in patients with low calcium. To elicit the sign, a blood pressure cuff is placed around the arm and inflated to a pressure greater than the systolic blood pressure and held in place for 3 minutes. This will occlude the brachial artery. In the absence of blood flow, the patient's hypocalcemia and subsequent neuromuscular irritability will induce spasm of the muscles of the hand and forearm. The wrist and metacarpophalangeal joints flex, the DIP and PIP joints extend, and the fingers adduct. The sign is also known as main d'accoucheur (French for "hand of the obstetrician") because it supposedly resembles the position of an obstetrician's hand in delivering a baby.

The posterior pituitary hormones

Two major posterior pituitary hormones: vasopressin (AVP arginine vasopressin) = anti-diuretic hormone (ADH) and oxytocin (OT). Both 1.1kDa nonapeptides Some AVP is synthesised in the parvicellular neurones -these are co-secreted into the anterior lobe with CRH. This means that there is some effect of AVP on ACTH secretion and there is limited AVP secretion if supra-optic hypothalamic tract disrupted.

Two Main 'Types'

Type 1 Diabetes: ß-cell destruction absolute lack of insulin Type 2 Diabetes: Defective insulin secretion due to ß-cell dysfunction, insulin resistance, relative lack of insulin NIDDM, IDDM etc. outdated

Type 1 diabetes

Type 1 diabetes is an autoimmune disorder with onset in childhood or adolescence There is genetic and environmental predisposition. It may be triggered by a viral infection Autoantibodies destroy pancreatic insulin-secreting ß islet cells. Treatment: insulin therapy

Diabetes is a continuum

Type 1- autoimmune destruction of beta cells Type 2- also have some beta cell failure

describe the pathway for the synthesis of catecholamines

Tyrosine into DOPA by tyrosine hydroxylase. This is the rate limiting step and occurs in the cytoplasm. DOPA carboxylase converts DOPA into dopamine in the cytoplasm. Dopamine is translocated into the vesicles. In the granules, dopamine is converted into noradrenaline by dopamine hydroxalase. If we want adrenaline, phenylethanolamine-N-methyltransferase (PMNT) converts noradrenaline into adrenaline in the cytoplasm. PNMT expression depends on high [glucocorticoid] that are only present in the adrenal medulla because of the drainage of venous blood from the outer adrenal cortex.

explain the clinical significance of maintaining tight control over plasma calcium concentrations: the life cycle and mineral balance

Under normal circumstances Ca2+ is in equilibrium across the different 'pools' in the body During childhood the intestinal absorption of calcium is greater than the renal excretion- positive balance In post menopausal women, output from bone is greater than input Ca2+ is in part regulated with phosphate. However, a higher proportion of PO43− than Ca2+ is absorbed from the diet and so more PO43− is excreted in the urine

Use of Insulin

Used to maintain type I diabetics. Used to treat hyperglycaemic ketoacidosis. Used in severe type II diabetics where diet and other anti-diabetic drugs fail. Sources: Bovine, Porcine, Human. Dose: International units.

CT neck

Useful to assess extent of retrosternal goitre Squashed trachea can cause stridor Contrast contains iodine, therefore do scan without contrast

Type 2 diabetes aetiology

Usually > 30 yrs Polygenic Environmental triggers? Usually overweight/obese Insufficient insulin secretion & resistance Symptoms insidious & vary in severity

Metabolism-linked insulin release (triggering pathway): Sulphonylureas

Usually with food intake, the metabolism of glucose increases the ATP:ADP ratio opening the K+ channel. Block KATP channel so that there is depolarisation, Ca2+ channels open, insulin is released.

Name the components of the female genital tract and relate to function. ​What type of epithelium lines each part?

Uterine tubes (oviducts, Fallopian tubes); simple cuboidal/columnar epithelium of ciliated cells and secretory cells; conduct ova towards uterus, fertilisation occurs along tube. Uterus where embryo implants and grows; simple and secretory columnar epithelium with uterine glands; cervix; simple columnar epithelium with mucous secreting glands. Vagina; stratified squamous epithelium

Changes in TH transporters

Various acquired or inherited changes in transporter proteins alter TT4 and TT3 (total levels) serum levels, T3 and T4 need transporters to move in and out of the cell FT4 is not susceptible to changes in the expression of TH transporters and has little intra-individual variability TT4 should be measured when discrepancies exist

the actions of AVP

Vasopressin exerts two different actions via two different GPCR: Pressor action - via V1 receptors (decrease GFR) And Anti-diurectic actions - via V2 receptors

Vasopressin synthesis

Vasopressin is synthesised in the hypothalamic magnocellular neurones where it is packaged into neurosecretory granules with neurophysin. These travel along the supraoptic-hypothalamic tract, axons, to the posterior pituitary. The neurosecretory granules fuse with the membrane of neuronal terminals. AVP is then released from neuronal terminals into the posterior pituitary via fenestrated capillaries into the inferior hypophyseal circulation of the posterior lobe.

Larson dwarfism appearance

Very low SD score/ growth velocity Proportionate growth but with a very immature face NORMAL GH LEVELS Low IGF-1 Hypothyroidism short limbs not achieving full growth potential

Describe the structure of AVP

Very similar to Oxytocin - both 1.1kDa nonapeptides

Human uterus, menstrual B: permanent stroma of the endometrium

Vessels under the stratum basalis (straight arteries) are unaffected by menstruation

Renal handling of phosphate

Virtually all of the reabsorption of the filtered phosphate occurs in the proximal tubule. Mechanisms are similar to those for phosphate absorption in the intestine.

Visceral Adipose Tissue

Visceral adipose tissue products drain directly into the portal vein, to the liver. They are more resistant to insulin signalling and sensitive to adrenaline and therefore release more fatty acids- hyperlipolytic This leads to the increased production of VLDL and glucose in the liver

Calcitriol (Vitamin D) Deficiency risk factors

Vitamin D deficiency is common in children, pregnant women, breastfed babies, and anyone who stays indoors or covers their skin. People with conditions that affect the way the body handles vitamin D such as those with coeliac disease, Crohn's disease, and some types of liver and kidney disease. People taking certain medicines: carbamezepine, phenytoin, primidone or barbiturates. People with dark skins or of South Asian origin, elderly people, and those with a family history of vitamin D deficiency. It is important to treat and prevent deficiency to ensure good health, growth and strong bones.

Waist circumference

Waist circumference is a good indicator of abdominal fat, and provides an estimation of relative risk for heart disease, diabetes, and hypertension. A waist measurement of > 80 cm in women and > 94 cm in men increases the risk for these diseases.

How is fluid distributed within our bodies?

Water makes up about 60% of lean body weight approximately 2/3 of our fluid is intracellular. The remaining 1/3 is ECF. This is either contained within the vascular system (plasma) which is 20% of ECF or bathes the cells (interstitial fluid) 80% of ECF. For women, 55% of lean body weight is fluid. Women have relatively less water because of a higher body-fat content, as fat cells contain low amounts of water.

Phosphorus balance

We ingest around 40 mmol of phosphorus in our food. As it passes through the GI tract, 5 mmol of phosphorus is added through GI secretions, giving a total of 45 mmol added to the GI tract each day. Of this, 31 mmol is absorbed from the small intestine, giving a net absorption of (31 - 5) = 26 mmol. This leaves (40 + 5 - 31) = 14 mmol to be excreted in the faeces. The absorbed phosphorus enters the blood and is distributed through the extracellular fluid (ECF). The ECF exchanges some 10 mmol/day with bone phosphorus. An unknown amount exchanges each day between cells generally and the ECF, shown here as ??. In a steady state, the net quantity absorbed from the GI tract (26 mmol) must equal the quantity excreted in the urine. We filter around 180 mmol of phosphorus each day but only 26 mmol is excreted in the urine. The other 154 mmol is reabsorbed by the tubules.

Calcium intake and excretion

We ingest calcium in our food. As it passes through the GI tract, calcium is added through GI secretions Of this, 20 mmol is absorbed from the small intestine, giving a net absorption of (25 - 20) = 5 mmol. This leaves (25 + 18 - 20) = 23 mmol to be excreted in the feces. The absorbed calcium enters the blood and is distributed through the extracellular fluid (ECF). The ECF exchanges some 8 mmol/day with bone calcium. In a steady state, the net quantity absorbed from the GI tract (5 mmol) must equal the quantity excreted in the urine. We filter around 250 mmol of calcium each day but only 5 mmol is excreted in the urine. The other 245 mmol is reabsorbed by the tubules.

Protirelin

a tripeptide derivative of TRH is used to test for sub-clinical hyperthyroidism.

Urinalysis process

Wear clean gloves. Clean the meatus with soap and water. Have the patient void ~30 mL of urine and discard. Collect urine into a sterile container, being careful not to touch any part of the body. Stop collecting urine before the bladder is empty. Allow the patient to finish voiding and discard urine. Label the container, and send to laboratory.

describe the development of the adrenal gland

Week 5: Embryonic adrenal cortex, at anterior of mesonephros, originates from mesothelium; invades retroperitoneal mesenchyme at week 5 of development. • Week 7: Progenitors of chromaffin cells = phaeochromafinnoblasts, derived from neural crest. Week 7 of development, phaeochromafinnoblasts colonize centre of developing adrenal cortex to establish medulla.

Weight bias and obesity stigma

Weight bias is defined as negative attitudes towards, and beliefs about, others because of their weight. These negative attitudes are manifested by stereotypes and/or prejudice towards people with overweight/obesity. But can also be associated with underweight. Internalised weight bias is defined as holding negative beliefs about oneself due to weight or size. Weight bias can lead to obesity stigma, which is the social sign or label affixed to an individual who is the victim of prejudice. Obesity stigma involves actions against people with obesity that can cause exclusion and marginalisation, and lead to inequalities - for example, when people with obesity do not receive adequate health care or when they are discriminated against in the workplace or in educational settings.

Cushing's Syndrome Symptoms

Weight gain of the upper body and trunk Skin changes including darkening of the skin, easy bruising and purple stretch marks Excess hair growth or acne in women due to increased adrenal androgens Menstrual disorders, especially infrequent or absent periods Fatigue and muscle weakness, numbness Personality changes or mood swings Headache High blood pressure

Weight loss

Weight loss is considered significant if it falls into any of the following parameters, and may indicate poor nutritional status and/or health problems: 1-2% in 1 week. 5% in 1 month. 7.5% in 3 months. 10% in 6 months.

Human mammary gland, pregnant iA

What are the labelled items 1. 2. 3. 4. 5. 6. 7. 8.

Human uterus, promenstrual A: stroma

What are the labelled items: 1. Endothelial cell 2. Nucleus of muscle cell 3. Nucleus of fibroblast 4. Fibromuscular cells of the stroma 5. 6. Smooth muscle wall of blood vessels 7. Fibrous connective tissue which the blood vessels run in 8. Capillary Note the difference between the connective tissue around the two blood vessels and the uterine stroma These are probably spiral arteries, which, like the straight arteries, are derived from the uterine artery. They supply the endometrium with a rich vascular plexus that degenerates, and bleeds, during menstruation

Lactating mammary gland iB

What are: 1. 2. 3. 4. 5. 6.

Lactating Mammary gland i

What are: 1. Septa 2. Secretory unit (sometimes referred to as alveolar) 3. Lumen of a duct

Lactating mammary gland iA

What are: 1. Lipid material creamy component of the milk, split from the aqueous component 2. Blood vessel

Lactating mammary gland iC: duct

What are: 1. Surrounding septa- collagenous connective tissue 2. Duct

Polly was found not to be pregnant. Further questioning revealed a long history of complaints about her periods. Her GP observed some increased body hair growth (hirsutism) on her face and arms. On questioning she admitted to a constant battle to keep her weight down and her BMI was 30. The GP referred her to the local infertility clinic.

What hormones would your measure to establish any hormonal imbalances in the patient? Luteinizing hormone (LH) Oestrogen Follicle Stimulating Hormone (FSH) Progesterone Testosterone (androgens) Finding Increased secretion Persistent (rather than cyclic) secretion May be normal or low. LH:FSH ratio changes from 1:1 to 2:1 or 3:1 Absent or low secretion Increased secretion of male hormones

Oviduct iB: adventitia

What is the orientation of the smooth muscle in the muscularis propria? Both longitudinal and circular What can you say about the innervation of the fallopian tube? Subject to sympathetic Innervation, small nerve bundles are seen.

Human vaginal cervix B

What type of epithelium is present at the edge on the right? Squamous epithelium What apical specialisation does it have? What is present immediately beneath this epithelium (beneath its basal lamina)? What feature is evident in this region? What are the labelled items: 1. 2. 3. Lumen of the cervical canal 4. Lumen of cervical mucous glands 5. Capillary 6. Capillary

Human vaginal cervix D:

What type of epithelium is this? Is it keratinised? The "peg" at the base of this epithelium is a papilla, similar to those found in skin. Papillae can reach deep into the epithelium and contain blood vessels, i.e. capillary loops (Cap), and autonomic and sensory nerve fibres. The nerves are involved in controlling the capillary permeability and are thought to control the transudation that performs the function of lubrication

Ovary Ci

What type of follicle is this? Secondary follicle, antral follicle What are the labelled items: 1. Antrum 2. Zona granulosa 3. Theca interna 4. Theca externa 5. Oocyte 6. Zona pellucida 7. Corona radiate 8. Capillary 9. Ovarian stroma What is the status of the oocyte?

Human vaginal cervix D

What types of epithelium are: 1. 2. 3. 4.

Human vaginal cervix Di

What unfortunate event often happens at A? Why? What are the labelled items: 1. 2. 3. 4. 5. 6.

describe the major endocrine systems employed to decrease plasma calcium concentrations

When blood calcium level rise, the C cells in the thyroid gland releases calcitonin, lowering blood calcium levels Glucocorticoid excess results in decreased bone density.

describe the major endocrine systems employed to increase plasma calcium concentrations

When blood calcium levels fall, the parathyroid gland releases parathyroid hormones (PTH), to raise blood calcium levels The major hormones that increase calcium and phosphate uptake and excretion are PTH and calcitriol (active vitamin D). Gonadal steroids maintain skeletal mass. For example, oestrogen deficiency is linked to post-menopausal osteoporosis. Insulin, growth hormone, and thyroid hormones promote skeletal growth and maturation.

Type 1 diabetes and other conditions

When blood glucose is poorly controlled over long periods the blood vessels in various tissues throughout the body undergo structural changes resulting in inadequate blood supply to the tissues. This leads to increased risk of myocardial infarction, stroke, kidney disease, retinopathy and blindness. Chronic high glucose causes damage to other tissues and results in autonomic and peripheral neuropathy.

Delayed Puberty

When boys have no signs of testicular development by 14 years and girls have not started to develop breasts by 13 or no by 15 then the puberty is delayed More common in boys.

Oral Glucose Tolerance test

When diagnosis is uncertain an oral glucose tolerance test is performed to confirm diabetes mellitus and to aid in diagnosing hypoglycemia Check blood glucose before and after 2 hours of a sugary drink.

ADH secretion

When plasma osmolarity begins to rise above 280 momol/L, ADH secretion begins and increases linearly as osmolarity rises. We begin to feel thirsty when the osmolarity reaches 290 mosmol/L thus the kidneys begin to conserve water first before we are stimulated to drink. This ensures that the water we do drink is retained rather than excreted in the urine.

Growth Velocity Chart

When puberty ends: Sex steroids have increased • androgens in boys • oestrogens in girls These close the growth plates and growth stops!

Leptin in obesity

Where obesity is caused by chromosomal mutations causing leptin deficiency, the administration of leptin results in weight loss. In most obese humans, leptin levels are high, and they appear to show leptin resistance, which may be due to decreased uptake across the blood brain barrier.

Cortisol lipogenesis

While elevated concentrations of cortisol (and synthetic glucocorticoids) increases lipolysis in the limbs, they increase lipogenesis in the trunk and face. Hence, chronic elevation leads to a marked redistribution of body fat- abdominal adiposity with "buffalo hump" and "moon face" The loss of subcutaneous adipose coupled with loosening of connective tissue underlies the increased tendency to bruise with elevated plasma cortisol. The excess cortisol is responsible for the symptoms of Cushing's syndrome as shown.

ACTH and aldosterone

While the synthesis of aldosterone is not ACTH-dependent, it is ACTH-sensitive an increase in the ACTH concentration will increase aldosterone biosynthesis, but aldosterone production is relatively unaffected by a decrease in the ACTH concentration the synthesis of aldosterone is controlled predominantly by the renin-angiotensin axis and by the concentration of potassium.

demonstrate an awareness of the social consequences of short stature

Why is short stature a problem? As children/adolescents it causes bullying etc As adults it is a disadvantage in our competitive society

Dynamic Function Tests for GH secretion

Widely used: Deals with the problem of irregular secretion (a) Provocative tests (b) Suppression tests

how do the mineralocorticoid receptors in the distal nephron, colon and parotid gland selectively respond to the renin- angiotensin-aldosterone axis?

With 11 beta-HSD, the target cell guardian of the MR

Why does Addison's disease result in hyperpigmentation?

With Addison's disease, there is decreased cortisol resulting in decreased negative feedback on ACTH and CRH Increased CRH increases the expression of the gene encoding pre-pro-opiomelanocortin (pre-POMC) and the processing of the POMC to generate pro-adrenocorticotrophic hormone (ACTH) The subunit ACTH undergoes further cleavage to produce alpha-MSH, the most important MSH for skin pigmentation.

CT scan of PCOS

With PCOS, both ovaries tend to be enlarged as much as 3 times their normal size. In 90% of women with PCOS, an ultrasound of the ovaries will reveal cysts (small immature egg-bearing follicles, fluid-filled follicles) that can be seen on the surface of the ovary. These ovarian cysts are often lined-up to form the appearance of a "pearl necklace." When the egg is not released and a woman is not menstruating, sufficient progesterone is not produced. This leads to a hormonal imbalance in which oestrogen acts "unopposed." This can lead to an overgrowth of the lining of the uterus (endometrial hyperplasia) and increases a woman's risk of developing endometrial cancer. Women with PCOS who do ovulate and become pregnant tend to have an increased risk of miscarriage.

Signs & symptoms of Type 2 diabetes

With Type 2 diabetes, there is often no symptoms Polyuria with polydipsia as a result Lethargy & general malaise Recurrent infections

Bariatric surgery

With both surgeries, there is caloric restriction, the rapid emptying of nutrients into the small intestine and enhanced nutrient/bile delivery to the mid/distal jejunem and ileum

Control of transcription in detail

With no T3 there are no coactivators, instead corepressors which recruit HDAC. There is histone deacetylation. TR/RXR on DNA = ACTIVE REPRESSION • + T3, TR/RXR on DNA = ACTIVE ↑TRANSCRIPTION • No TR/RXR on DNA = PERMISSIVE TRANSCRIPTION as there are coactivators

Inflammation in obesity

With obesity, there is more hypoxia with expanding adipose tissue and higher levels of free fatty acids, which stimulate inflammation through toll-like receptors Many markers of inflammation including CRP, IL-6 and serum amyloid A (SAA) are at higher levels in the plasma in obesity

explain the consequences of positive feedback

With positive feedback a hormone (X) exerts a positive action on a physiological process (Y) and that process exerts positive feedback on the production of hormone "X"in a vicious endocrine spiral. Hence, if the concentration of the solute "X" departs from the normal physiological concentration for that solute, a homeostatic chain of events will be initiated whereby the concentration of the hormone "X" will increase "Y". Until the initial stimulus is removed and "X" returns to normal, then so will "Y". 1. OT secretion in the Fergusson reflex to expel foetus 2. OT secretion to stimulate contraction of milk glands in the suckling reflex (milk let down reflex).

Small v large adipocytes

With smaller adipocyte size, adipokines are anti-inflammatory and insulin sensitising Larger- adipokines are pro-inflammatory, insulin desensitising and there is more cell death with recruited macrophages

Central obesity

Within BMI categories, central obesity can vary greatly and correlates with increased risk for diabetes, CVD etc The size of visceral adipocytes correlates more closely with measures of metabolic health than those of subcutaneous AT.

Glucagon synthesis and processing

Within the rough ER of the pancreatic alpha cells, preproglucagon is processed by prohormone convertases 1 and 2 glucagon. Glucagon is a single polypeptide chain. It is stored as granules in cytoplasmic vesicles until release is stimulated. zinc is not an absolute requirement (like with insulin) but metal complexes with glucagon increase its half-life an increase in the plasma glucose concentration suppresses glucagon release whereas a fall in plasma glucose increases the synthesis and secretion of glucagon in pancreatic α-cells.

Sperm formation

Within the seminiferous tubules, spermatogenesis takes place. Some spermatogonia remain as precursor stem cells The others are pushed away from the basement membrane and undergo mitosis and differentiation to become primary spermatocytes The primary spermatocytes undergo DNA replication, tetrad formation and crossing over at Meiosis I to become secondary spermatocytes The secondary spermatocytes undergo meiosis II to become spermatids, connected by a cytoplasmic bridge The spermatids become spermatozoa which are in the lumen of the seminiferous tubule

Ketoacidosis

Without enough insulin, glucose cannot be metabolised properly and the body begins to break down fat as fuel Lipid catabolism produces increasing quantities of acetyl-CoA. Lack of citric acid substrates diverts acetyl-CoA to the ketogenic pathway in liver cells, where non-esterified fatty acids are oxidised leading to ketone body formation. Blood pH falls resulting in metabolic acidosis.

V1 and V2 receptor antagonists

Would want to antagonise V2 receptors if a patient has AVP hyper-secretion induced by intracranial trauma / infection, pneumonia, malignant disease, cytotoxic therapies, selected narcotics or analgesics. AVP hypersecretion results in hypervolemia with hyponatremia -potentially fatal. Syndrome of inappropriate ADH secretion (SIADH)

Turner's Syndrome

XO short stature webbed neck

fine needle aspiration biopsy

You cannot distinguish a follicular carcinoma from an adenoma from FNA as you can only see the cells sucked out rather than whether they are invading anything Diagnosis depends on assessing the entire tumour

The RAAS system

a decrease in arterial and/or venous pressure increases renal sympathetic nervous activity this constricts the afferent arterioles which decreases renal blood flow and lowers GFR. decreased Na+ in the distal tubule sensed by the Macula densa cells renal nervous activity and decreased renal perfusion pressure stimulates renin release from the JGA. renin is released from the granular cells surrounding the afferent arterioles and next to the Macula densa cells next to a distal tubule renin stimulates the conversion of angiotensinogen in the liver to angiotensin I angiotensin converting enzyme (ACE) on the surface of pulmonary and renal endothelium converts angiotensin I into angiotensin II

Metabolic syndrome

a group of risk factors that typically occur together, and increase the risk for coronary artery disease, stroke and type 2 diabetes. central obesity insulin resistance high blood pressure dyslipidaemia hyperglycaemia mild chronic inflammation, etc.

Causes of delayed puberty

a long-term illness - cystic fibrosis a problem with the ovaries, testes, thyroid gland or pituitary gland a disorder of sexual development - androgen insensitivity syndrome Kallman's -lack of GnRH, hypogonadtrophic hypogonadism- nose is affected so often lack of smell anosmia Kleinfelter- XXY, low testosterone, infertility.

Sibutramine metabolism

a prodrug that undergoes extensive first-pass metabolism. It has two active metabolites both of which reduce food intake and increase through inhibition of reuptake of both monoamines.

Growth Rates

adolescent growth can be divided into 3 stages: The minimum growth velocity or 'age at take-off' peak height velocity (PHV) decreased growth velocity and oestradiol driven epiphyseal fusion

Factors affecting the frequency and amplitude of GH pulses

age, geneder, pubertal status, menstrual cycle phase, body composition, sleep, nutrition, and exercise. In diseases such as obesity, type I diabetes mellitus, hypothyroidism, hyperthyroidism, Turner's syndrome, liver failure, acromegaly, and dwarfism the pulsatile secretion of GH and/or its metabolic clearance rate are altered.

Amine/hydrophilic hormone secretion

amines are unable to diffuse across the plasma membrane of the cells that produced them- instead they must be packaged in vesicles that fuse with the plasma membranes for secretion This means the plasma concentration of a peptide/protein hormone or catecholamine can be controlled at the level of hormone synthesis and at the level of secretion.

Amino acids, glucagon and insulin

an increase in the free amino-acid concentration on digestion of protein increases the secretion of both insulin and glucagon. While the rise in insulin stimulates the uptake and incorporation of amino-acids, the co-elevation of glucagon prevents insulin from suppressing glucose below the normal concentration range.

describe the regulation of GH secretion

androgens and oestrogens sensitize somatotrophs to GHRH which accounts for the pubertal rise in GH and growth spurt metabolic products influence GH release - used for clinical tests amino acids such as arginine stimulate GH release glucose and free fatty acids suppress GH release

Lobes of the pituitary gland

anterior lobe- adenohypophysis posterior lobe- neurohypophysis

CART (cocaine amphetamine regulated transcript)

appears to have several roles in addition to regulation of food intake

Growth plate closure

at the end of puberty the increased sex steroids cause closure of the growth plates aromatase activity in the growth plates locally aromatise androgens to oestrogens in boys, oestrogen causes growth plate closure in girls. aromatase inhibitors can be used to delay plate closure in boys

Prolonged activation of the beta-adrenceptor

bAR stimulates b-adrenoreceptor kinase (bARK). This catalyses the phosphorylation of specific Ser and Thr residues in the third intracellular loop + C-terminal tail. This causes conformational changes in bAR allowing the receptor to interact with b-arrestin (peripheral membrane protein - associates with third intracellular loop and C-tail) Therefore, subsequent interactions between the desensitised receptor and GS are blocked. Similar mechanisms are implicated in the desensitisation of all GPCR; bARK only one of family of G-protein receptor kinases (GRKs).

Balance in synthesis and secretion of growth hormone

balance between GHRH and inhibition by somatostatin, a peptide arising in the hypothalamus and/or peripheral tissues Higher brain centres and "stress" can also inhibit the release of GHRH and GnRH from the hypothalamus

the important mechanisms which govern growth:

balanced limb growth important chondrocytes important for extension of long bones need adequate nutrition stress inhibits - importance of hypothalamic function anterior pituitary/ somatotrophs/GH vital/prepuberty window of time for growth hormone treatment - prepuberty

Prolactinoma

benign tumor of the pituitary gland that releases prolactin menstrual irregularities and a discharge from the breasts.

Charcot joint

bone and joint destruction secondary to a neuropathy and loss of sensation stiff, can't dorsiflex too much themselves someone else can manipulate Detected by X-rays 6D's: Deformities Degeneration of the bones Dense bone Destruction of the articular cartilage Dislocation Debris Not all always seen (debris not seen here)

Hypocalcaemia effects

calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibers, reduced calcium lowers the threshold for depolarization CATs go numb - convulsions, arrhythmias, tetany, and numbness in the hands and feet and around the mouth. increased excitability of nerve tissue paraesthasia tetany sometimes epilepsy. Treated with calcium supplements and calcitriol.

Urinalysis

can be used to identify infections and diseases. It provides health care professionals with valuable information about a person's health status including indications of renal, urological and liver disease, diabetes, urinary tract infections (UTIs), and general hydration. It can also be used to screen for substances that would not usually be expected to be present in urine such as glucose, leukocytes, nitrate, and blood. Cloudy urine or the presence of debris can indicate the presence of pus, protein, or white blood cells.

Detection of sodium content

changes in sodium content is signaled by changes in the effective ECF volume the volume that perfuses our tissues. Therefore, regulation of sodium balance is linked to blood pressure and blood volume.

Chronic illness

congenital cardiac disease chronic obstructive or infective pulmonary disease chronic renal failure

Unexplained weight loss

could be caused by a number of medical problems including cancer, celiac disease, chronic obstructive pulmonary disease (COPD), depression, diabetes, overactive thyroid, tuberculosis, Chrohn's disease, or Addison's disease.

The menstrual phase

days one to five of the female reproductive cycle is the menstrual phase. Progesterone and oestrogen levels are at a low level and menses occurs. GnRH pulses more frequently promoting FSH and LH levels to rise. Primary follicles are stimulated to develop.

Gonadotropin Releasing Hormone (GnRH)

decapeptide, released from hypothalamic neurones. Acts on Gq receptors - Low frequency: favours FSH release - High frequency: favours LH release Continuous release of GnRH non-physiological downregulates GnRH Receptors inhibiting of FSH & LH release

RAAS system

decreased Na+ in the distal tubule sensed by the Macula densa cells renal nervous activity and decreased renal perfusion pressure stimulates renin release from the JGA. renin is released from the granular cells surrounding the afferent arterioles and next to the Macula densa cells next to a distal tubule Renin converts angiotensinogen into angiotensin I.

describe the direct physiological actions of GH

decreases glucose metabolism- opposing insulin increases lipolysis increases protein synthesis (anabolic) Increases IGF production from liver etc Increases differentiation of chondrocytes and cartilage formation

Melanocortins

derived from POMC (pro-opiomelanocortin e.g. a-melancyte stimulating hormone aMSH. reduces food intake and increases energy expenditure through activation of MC4 receptors. Synthesized in ARC neurones that project to other hypothalamic areas.

Diabetes mellitus v diabetes insipidus

diabetes is Greek for siphon- production of copious amounts of urine Urine in diabetes insipidus is insipid because it is dilute and tasteless due to the underproduction or lack of sensitivity to anti-diuretic hormone vasopressin In diabetes mellitus the urine is sweet because of the presence of sugars, mellitus refers to honey

Cellulitis

diffuse, acute infection of the skin marked by local heat, redness, pain, and swelling Presents as a hard, red, painful swelling of the skin tissue. The most common bacteria is streptococcus. Can occur after human or animal bites. Can occur after surgery. Can occur even on skin that has not been broken. It can lead to meningitis when the skin of the face is infected.

Achondroplasia appearance

disproportionate short stature Shortening of proximal limbs rhizomelic shortening Short fingers and toes with trident hands Large head with prominent forehead frontal bossing Small midface with a flattened nasal bridge Spinal kyphosis (convex curvature) or lordosis (concave curvature) Varus (bowleg) or valgus (knock knee) deformities

the postovulatory and secretory phases

during days fifteen to twenty-eight are the postovulatory and secretory phases. The collapsed follicle becomes the corpus luteum secreting large amounts of progesterone, oestrogen and inhibin. These promote endometrial proliferation and secretion. High levels of inhibin stop the production of LH and FSH by the anterior pituitary. If the secondary oocyte is not fertilized the corpus luteum degenerates and the cycle begins again.

the preovulatory and proliferative phases

during days six to thirteen is the preovulatory and proliferative phases. The production of oestrogen increases stimulating further follicular development. The endometrial cells proliferate, increasing the thickness of the endometrium. Rising oestrogen levels stimulate increased pulsing of GnRH and increased secretion of FSH and LH. The primary oocyte undergoes meiosis to form the secondary oocyte.

Hormonal regulation of pregnancy

during the first week of pregnancy, the corpus luteum releases progesterone and oestrogen to maintain the endometrium. When the blastocyst imbeds itself in the lining of the uterus it secretes human chorionic gonadotropin - hCG. hCG prevents the ovarian corpus luteum from degenerating. Because the estrogen and progesterone levels are maintained, menses does not occur

Cranial irradiation and GH

e.g. for leukaemia or brain tumours The pituitary is particularly radiation sensitive- results in low GH

Precocious puberty

early sexual and reproductive maturity initial rapid growth but stops early premature epiphyseal fusion

Psychosocial deprivation

emotional and social upheaval hypothalamic turn off? lack of GHRH?

Amygdala

emotional influences?

Glucocorticoids

endogenous antagonists of leptin and insulin

evidence of peripheral vascular disease

feels for pulses, asks about symptoms of claudication or rest pain, and looks for evidence of an ischemic foot.

Nucleus accumbens

food as reward. Dopamine receptors affect motor activity and duration of feeding bouts but not total food intake.

Hyperprolactinaemia

galactorrhea (production and spontaneous flow of breast milk), infertility, and disruptions in the normal menstrual period in women hypogonadism, infertility and erectile dysfunction in men.

The major endocrine disorders that women face during pregnancy

gestational diabetes mellitus pre-existing type 1 diabetes mellitus thyroid disorders adrenal disorders- Adrenal insufficiency, has been associated with maternal and fetal morbidity and mortality if untreated, while phaeochromocytoma is associated with considerable maternal mortality. the effects of maternal obesity on pregnancy outcomes and infant obesity predisposition

Type 2 corticosteroid receptor

glucocorticoid receptor (GR): cortisol, dexamethasone, prednisolone, etc.

Glucocorticoids and fat metabolism

glucocorticoids like cortisol increase fat metabolism by up-regulating expression of the HSL enzyme to spare glucose.

Diabetic coma- hyperglycaemia

glycosuria and the loss of electrolytes, particularly Na+ and K+ cause dehydration and electrolyte disturbances which, along with the low pH and hyperglycaemia, cause the coma.

GnRH Agonist- gonadorelin

gonadorelin- used for female and rarely male infertility pulsatile dosing has the same effect as GnRH antagonists, shutting down the body's release of FSH and LH to give at the prefferred concentration on the preferred days for ovulation induction. + gonadotropins, for ART artificial reproductive technology - prostate cancer- these cancers need androgens, testosterone to proliferate. initial flare in testosterone with treatment with agonists so often given with an anti-androgen - endometriosis - precocious puberty

hCG production

hCG production increases and peaks about 8 weeks and triggers the corpus luteum to produce ever increasing levels of estrogen and progesterone. After the 4th month the levels of hCG significantly decrease and stay at a low level.

relate this to its clinically important species specificity

hGH differs from bGH by about 35%, non-human GH is not active in man hGH does however act on lower mammalian orders e.g. cattle must treat GH defficient children with hGH pre-1985, hGH extracted from human pituitaries, risk of Creutzfeld-Jacob Disease hGH now manufactured by recombinant technology

achondroplasia

hereditary congenital disturbance of chondrocyte growth in growth plates, leading to short long bones and limbs due to defective receptors for fibroblast growth factor (FGF)

Gonadotropins: FSH, LH,hCG

heterodimeric glycoproteins common alpha + different beta HCG is released by the placenta Gs receptors

Homologous desensitisation of bAR

homologous desensitisation is where the cell ceases to respond to desensitising stimulus, but the same signal transduction pathway remains responsive to alternative signalling stimuli For beta-adrenceptors, this relies on interaction with GS via regions in • third intracellular loop • C-terminal tail of receptor

human chorionic somatomammotropin (hCS)

human chorionic somatomammotropin (hCS) enhances maternal breast growth and development by increasing protein synthesis. It also prepares the mammary glands for lactation and inhibits glucose uptake by the maternal cells leaving more glucose for the fetus.

Steroid/hydrophobic hormone secretion

hydrophobic steroid hormones can pass freely across the plasma membrane of the cells that constitute the endocrine glands so their rate of secretion is directly proportional to the rate of their synthesis.

Iatrogenic Cushing's

hypercortisolism from long-term pharmacologic glucocorticoids

Apparent Mineralocorticoid Excess symptoms

hypertension (high blood pressure) hypernatremia (increased blood sodium concentration) hypokalemia (decreased blood potassium concentration).

Anorexia nervosa

hypothalamic turn-off low GnRH release fasting GH and cortisol elevated

Jaundice in hypothyroidism

hypothyroidism induces cholesterol gallstone formation by promoting cholesterol biosynthesis." low thyroid hormone may precipitate low gallbladder functioning. The Sphincter of Oddi, which controls the release of bile into the small intestine, has receptor sites for thyroid hormones. When thyroid hormones are low, the sphincter may be unable to fully relax and release bile. Thus, bile can accumulate and cause gallstones or bile duct stones to form. Hypothyroid patients usually have a notable increase in low-density lipoprotein (LDL) cholesterol. Cholesterol hyper-saturation of the bile and cholesterol crystallization are two of the major factors contributing to the formation of gallstones. In addition, low thyroid slows metabolism. This can delay gastric emptying and cause bile flow to back up, creating a kind of biliary sludge that quickly results in stone formation. Obstruction of the biliary tract results in jaundice due to the blockage of bile excretion from the biliary tract, which leads to increased conjugated bilirubin and bile salts there.

Loss of peripheral autonomic function: sweat glands

in a person with loss of peripheral autonomic function following electrical stimulation of sweat glands there would be a diminished change in skin potential difference. Sympathetic activity causes an increase in sweat production, commonly assessed by measuring an increase in skin conductance as sweat contains electrolytes (ions like Na+ and Cl- that give sweat it's salty taste)

T4 v T3

in target cells, outer-ring deiodinases D1 or D2 immediately converts T4 to T3 T3 then acts on its nuclear receptors different tissues express different outer ring deiodinases (5'-deiodinases) providing subtle local regulation of effective T3 concentrations at the level of the target cell. 3,3'T2 is excreted

Metabolic effects of insulin in the liver

increase glucose uptake Glucose storage by cells initially as glycogen- decrease in glycogenlysis and gluconeogenesis in the liver

Hyperphosphataemia causes

increased phosphate intake, decreased phosphate excretion, or a disorder that shifts intracellular phosphate into the extracellular space Hyperphosphatemia is mostly asymptomatic

Angiotensin II

increases afferent and efferent arteriolar resistance (efferent more than afferent) via AT1 receptorswhich keeps GFR constant whilst dramatically decreasing renal blood flow filtration fraction is increased increasing peritubular capillary colloid osmotic pressure arteriolar resistance decreases peritubular capillary hydrostatic pressure increased proximal Na+ reabsorption. decreases water and sodium excretion. decreases vasa recta blood flow leads to washout of the urea from the medullary interstitium urea increases and Na+ decreases in the medullary interstitium increased gradient for passive NaCl reabsorption in the thin ascending limb of Henle increased sodium reabsorption The major stimulus for aldosterone secretion comes from angiotensin II

Aldosterone action

increases the number of Na+/K+ pumps in the principal cells of the collecting duct aldosterone is bound to proteins in the plasma. its receptor allows endocytosis at the basolateral membrane induces transcription of regulatory proteins (ubuquitination) for the ENaC channels on the apical membrane this leads to more Na+ absorption. also leads to K+ excretion as it is basically a Na+/K+ exchanger

Sulphonylureas

insulin secretagogue Blocks ATPase-sensitive potassium channels depolarising the beta cell of the Islet of Langerhans. calcium entry stimulates insulin release These drugs may also increase tissue sensitivity to insulin in long -term use Protein bound - potential for drug interaction Excreted via the kidney Cross the placenta Orally active Tolbutamide is short-acting Glibenclamide is longer acting Gliclazide shows greater b-cell specificity than glibenclamide

Sources of vitamin D

key treatment involves sunlight exposure. Note with the increased use of creams with high SPF, this may need to be considered. liver, some types of fish, and egg yolk. Some cereals or margarines contain added vitamin D. Growing children, pregnant women, and breastfeeding women need extra vitamin D because it is required for growth.

Classic Growth Hormone Deficiency Tests and results

little or no GH: low rate of growth, low SD score No or poor GH response to an ITT provocation test Nil or feeble peaks in a 24hr profile Low IGF1

Endocrine somatostatin

mainly released from gastric D-cells • Inhibition of gastric acid secretion • Inhibition of gastric emptying • Reduces small bowel contractions

Opioids

may promote rewarding aspects of food.

Type 1 corticosteroid receptor

mineralocorticoid receptor (MR): aldosterone, DOC

Metformin

most widely used anti-diabetic drug in type 2 diabetes reduces hepatic glucose production decreases insulin resistance in skeletal muscle enhances peripheral glucose uptake by phosphorylating GLUT-4 enhancer factor decreases glucose absorption in the GI tract -Not metabolised; cleared by kidneys

Vitamin D deficiency symptoms

muscle or bone pains recurrent infection such as coughs or colds due to immune suppression. With chronic hypocalcaemia attributable to deficiency of vitamin D- you get rickets in children or osteomalacia in adults

Newer Vitamin D analogues

new vitamin D analogues are relatively selective for the parathyroid gland with lesser effects on intestinal absorption of calcium and phosphate, therefore decreasing PTH secretion without affecting bone turnover

Thyroid autoantibodies

not a standard thyroid function test however, it suggests that any changes in your thyroid gland are caused by an immune reaction. Overactive thyroid- Graves' disease. Under active thyroid- Hashimoto's disease. (also called thyroid antibodies, antithyroid microsomal antibodies, anti-thyroid peroxidase antibodies, anti-TPO and anti-thyroglobulin)

Oestrogen and progesterone secretion in pregnancy

over the first two- three months of pregnancy, estrogen and progesterone are primarily secreted by the corpus luteum, maintaining nutritional support for the embryo and fetus. By the 9th week the placenta becomes the primary source of estrogen and progesterone.

list the hormonal products secreted from the posterior pituitary gland

oxytocin and vasopressin / antidiuretic hormone (ADH) Synthesised in cell bodies of magnocellular neurones (PVN & SON) • Axonal transported from hypothalamus to posterior pituitary

Intrauterine growth retardation

placental insufficiency? poor catch up growth Post-natal growth failure •Sensorineural deafness/mental retardation/GH resistance

placental produced corticotropic releasing hormone

placental produced corticotropic releasing hormone stimulates the fetal anterior pituitary gland to secrete ACTH. ACTH stimulates fetal cortisol production. The release of fetal cortisol triggers fetal lung maturation and surfactant production. through months 4-9 levels of placental CRH increase toward the end of pregnancy and stimulate the fetus and the placenta to produce more estrogens. Increased levels of estrogen act as a timer for birth and for lactation.

Insulin pump

portable, battery-powered device that delivers insulin through the abdominal wall in measured amounts sterilize the area and resite the cannula herself, how to care for wounds, how to estimate and count carbohydrate, and provide instructions in the use of the pump itself.

hCG

produced by placenta almost identical to LH acts on LH receptor maintain corpus luteum (CL) function in 1st trimester of pregnancy the corpus luteum produces oestrogen and progesterone

Peptide YY

produced in the gut - inhibits feeding

'Minor' controllers of AVP secretion

progesterone - pre-menstrual and gestational anti- diuresis alcohol-induced diuresis Deep sleep increases ADH secretion Starting exercise increases ADH secretion- By increasing ADH secretion at the start of exercise, we decrease the rate of urine formation and retain water. This will help keep us hydrated when our body gains heat and sweating begins.

Cholecystokinin

promotes satiety cessation of feeding and increases release of serotonin in the hypothalamus. CCK-B receptors are thought to be critical in mediating satiety and their antagonism increases food intake.

Delayed puberty

puberty delayed beyond age 15, slowing growth around 10 yrs height falls below 3rd centile bone age delayed - 2 yrs behind chronological LH/FSH low GH normal catch-up growth occurs reaches full growth potential

Anastrozole for breast cancer prevention

randomized, controlled trial (IBIS-II): Anastrozole (aromatase inhibitor) or placebo daily for 5 years (7 years follow-up) to ~3000 high-risk, post-menopausal women • ↓ risk of cancer (breast + other) • no change in risk - cardiovascular disease - bone fractures

Noradrenaline

reduces food intake through the activation of a1-adrenoceptors and J3-adrenoceptors in the hypothalamus.

Myxedema

refers to the increased deposition of mucopolysaccharides, a component of connective tissue in the dermis, which results in swelling of the affected area. Fibroblast stimulation by TSH increases glycosaminoglycan deposition- osmotic edema and fluid retention In Grave's disease, lymphocytes react against any tissue expressing the TSH receptor, leading to tissue damage and scar tissue formation pretibial myxedema and exophthalmos are hallmarks of Graves disease Myxedema can also occur in Hashimoto thyroiditis and other long-standing forms of hypothyroidism.

Relaxin and oxytocin

relaxin which is produced by the placenta promotes the dilation of the cervix and increases the flexibility of the pubic symphysis. Initial contraction of the uterus begins the cycle and pushes the fetus towards the cervix. As the fetus enters the cervix, it stretches and stimulates stretch receptors.

RAAS and aldosterone

renin is secreted by the kidneys in response to decreased renal perfusion pressure or decreased plasma Na+ concentration. It converts angiotensinogen, synthesized in the liver, to angiotensin I. ACE converts angiotensin I i to angiotensin II Activation of angiotensin receptors in the zona glomerulosa stimulates aldosterone release

Growth-promoting agents

rhGH, insulin-like growth factor-I (IGF-I), anabolic steroids An alternative approach are products to stop oestrogen production (in both sexes), which is responsible for ultimate epiphysial fusion such as GnRH agonists and aromatase inhibitors • These approaches have been used as sole treatments or in various combinations, with varying efficacy and safety

Measure blood glucose level from a capillary specimen using a glucometer.

samples should be obtained from the edges of fingers as fingertips are more sensitive. The skin should be cleaned with water and dried and should be warm. Remember to rotate puncture sites to prevent skin damage.

Ghrelin

secreted by the stomach and thought to be regulated by leptin. Its secretion is increased by fasting and falls after eating. In obese individuals its levels are reduced, and are not reduced by feeding, as in lean individuals. Ghrelin also inhibits serotonin release. Blockade of the gastric vagal afferents abolishes ghrelin-induced feeding.

CRH, ACTH and cortisol levels

secretion of ACTH is dependent upon CRH, and CRH production is under negative feedback control from cortisol. Therefore cortisol inhibits further endocrine stimulation of the zona fasciculata & reticularis by ACTH. Hence, all 3 hormones show parallel circadian rhythms. the peaks and nadirs of CRH and ACTH precede those for cortisol by up to 1 hour

Growth hormone and other hormones

sex steroids play a role other hormones e.g. PTH, T3/T4/ cortisol modulate GH production and influence genetic factors set growth potential Balanced growth depends upon a balanced environment and a balanced endocrine system.

Selective Estrogen Receptor Modulators (SERMs)

single molecule that acts as agonist in some tissues recruiting co-activators, antagonist in other tissues recruiting corepressors • Raloxifene to prevent osteoporosis - antagonist in breast and uterus (no stimulation and potential cancer) - partial agonist in bones and liver (blood lipids) • Tamoxifen to treat breast cancer - antagonist in breast - partial agonist in bones, liver, uterus

Brainstem nuclei

source of neurones that regulate hypothalamic function Integrate and respond to afferent signals from the digestive tract. Is a target for leptin, especially the nucleus tractus solitarius which is innervated by the vagal afferents

Anti-androgens

spironolactone (aldactone) flutamide (Drogenil) cyproterone (Androcur, Cyproterone acetate)

Classic Steroid Signalling

steroids enter cells through the plasma membrane and bind to their receptors localized in the cytoplasm androgen receptor (AR) and glucocorticoid receptor (GR) or in the nucleus oestrogen receptor-α (ER) Steroid-bound receptors translocate to the nucleus (cytoplasm receptors) and bind DNA to regulate gene transcription • This drives changes in mRNA expression, protein expression and cell biology

ANP

stimulate vasodilation ANP is released from the atria in response to atrial stretch and sympathetic stimulation. It usually decreases the release of renin and aldosterone which has the effect of increasing sodium excretion. With a lower effective circulating volume there is decreased atrial stretch and decreased sympathetic stimulation. ANP is released from the atria Renal afferent arteriole are dilated increasing GFR, decreases NCC activity and ENaC activity and inhibits renin secretion (as renin is released from the granular cells surrounding the afferent arterioles when constricted under sympathetic activity and next to the Macula densa cells which sense a decrease in Na+ in the distal tubule)

LH

stimulates androgen synthesis in follicle as oestrogen precursors, 1st half of cycle stimulates dominant follicle development and rupture ovulation Stimulates the conversion of a ruptured follicle into the Corpus Luteum (CL) directs steroid production, 2nd half of cycle stimulates testosterone production

Human uterus, promenstrual B: stratum compactum

surface epithelium (E) is only patchily preserved uterine glands (UG) - simple tubular, lined with cuboidal epithelium. Secrete glycogen for nutrition of the blastocyst. endometrial stroma (densely cellular connective tissue with numerous blood vessels) beneath surface epithelium The stratum spongiosum above has fibromuscular tissue.

CRH action

the expression of the gene encoding pre-pro-opiomelanocortin (pre-POMC) processing of the POMC glycoprotein by endopeptidase enzymes to generate pro-adrenocorticotrophic hormone (ACTH) and β-lipotrophic hormone (β-LPH) secretion of ACTH by fusion of ACTH-containing vesicles with the plasma membrane of the corticotroph cells

Glycosalation and free radicals

the formation of free radicals is increased in diabetes Superoxide dismutase is an enzyme which removes superoxide anions formed as a byproduct of metabolism. It becomes inhibited when glycated. The glutathione-redox cycle an important mechanism for removing hydrogen peroxide is also impaired. This leads to more protein damage, especially in the presence of metals or haem containing compounds.

The menstrual cycle

the function of the uterine endometrium is to sustain the growth and development of the implanted embryo. The uterine cycle is under the control of the ovarian hormones.

Corticosteroids

the glucocorticoids and mineralocorticoids are the steroid hormones synthesised exclusively in the cortex of the adrenal gland. Hence, they are collectively referred to as corticosteroids.

Glycogen breakdown

the rate-determining enzyme in glycogen catabolism, glycogen phosphorylase, is active in the phosphorylated form and is rendered inactive by the action of a phosphatase enzyme.

Regulating calcium and phosphate levels

the solubility product = calcium x phosphate concentrations. So, if we decrease phosphate concentration, we will increase ionized Ca2+. When bone is broken down both calcium and phosphate are released. If the kidney did not excrete this phosphate, plasma phosphate concentration would rise and calcium phosphate would precipitate in the tissues.

Thyroid problems in pregnancy

thyroid disturbance is associated with adverse pregnancy outcomes such as preterm delivery, low birthweight infants, miscarriage, gestational hypertension and stillbirth

Thyroid hormones

thyroid hormones are stored in thyroid follicles as thyroglobulin. When required, the thyroid cells release the hormone from this store and it enters the blood. They are carried in the blood bound to a plasma protein - thyroxine-binding globulin. the thyroid hormones are lipid soluble and act through nuclear receptors.

Regulation of meal number and size:

timing and the size of meal can vary to maintain energy balance. The end of feeding is promoted by 'satiety factors' that increase during feeding. These generate signals in the brain through peripheral nerves like the vagus innervating the nucleus of the solitary tract, as well as directly by activating their own receptors. This information is then transmitted to the hypothalamus and forebrain areas.

FSH

timulates follicle development and oestrogen production in the follicle from androgen precursors, 1st half of cycle Increases LH receptor expression in the follicles stimulate Sertoli cells to nourish sperm

Pseudohypoparathyroidism

tissue resistance to PTH action, defect of bone and kidney PTH receptors High circulating PTH, hypocalcaemia and hyperphosphataemia.

Adrenal crisis treatment

urgent administration of IV/IM hydrocortisone and IV fluids Patient education regarding preventive measures, i.e. "stress dosing" when sick, parenteral hydrocortisone as necessary and seeking medical assistance promptly

Urine testing

urine must be tested within a few hours of voiding as urinary constituents can become unstable, and may affect test results. If a delay in testing is anticipated, the sample should be kept in the fridge to limit the speed at which the constituents become unstable.

Gonadotrophin medication

urofollitropin uFSH follitropin rFSH, lutropin rLH, choriogonadotropin rhCG USES: male infertility hypogonadotropic hypogonadism ovulation induction + GnRH, for ART diagnostic: hCG detected by pregnancy kits LH detected in ovulation kits

explain how GH is measured: bioassay

used to measure potency of new batches of rec hGH specialised use to check bioactivity of patient GH in vivo / hypophysectomised rats / increase growth plate thickness insensitive and imprecise in vitro / immortalised target cells / hGH receptor colorimetric/ luminescent responses via reporter genes etc very precise and capable of sensitivity

Classic growth hormone deficiency (GHD)

usually iodiopathic hypothalamic disorder? proportionate growth immature face truncal obesity

Beta-adrenoceptors

very short extracellular N-terminus; inadequate to serve as ligand-binding domain. Instead, 7 transmembrane helices form hydrophilic binding pocket which accommodates ligand. Because cellular responses are mediated through the AC-cAMP-PKA pathway, actions potentiated and/or mimicked by increasing half-life of cAMP e.g. with caffeine which inhibits the hydrolysis of cAMP by cyclic nucleotide phosphodiesterases

Rickets

weak or soft bones in children Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone deformities, bone pseudofractures and fractures, muscle spasms, or an abnormally curved spine.

Androgens

when the androgens are secreted from the zona reticularis , enzymes in the peripheral tissues produce oestrogens in adipose tissue and dihydrotestosterone in skin

How would the ovary of a prepubertal female differ histologically from that of a young adult female?

​ Primordial follicles and small antral follicles would be present; no maturing follicles, Graafian follicles present, no corpora lutea or corpora albicantia

What hormones are secreted by the ovary and which structures produce them?

​Oestrogens, progesterone, inhibin (actually a growth factor of the TGFß family) ​Oestrogens are produced by the maturing ovarian follicles and corpus luteum; progesterone by the corpus luteum

Thyroid scintigraphy

• 'Cold' nodules- don't take up tracer • Majority still benign • But will require evaluation for malignancy • 'Hot' nodules • 10-15% still malignant • Therefore not useful to distinguish benign vs malignant

Medullary thyroid ca

• A cancer of the C-cells • A "neuroendocrine tumour" • Flushing and diarrhoea probably due to the calcitonin • Characteristically secretes calcitonin, also CEA • Associated in 25% with mutations in RET (a tyrosine kinase, fused with PTC in cancer) = Multiple Endocrine Neoplasia Type 2

Spermatozoa

• Acrosomal cap - vesicle containing cocktail of enzymes (esp. hyaluronidase) to break up cells surrounding ovum and dissolve zona pellucida for fertilisation • Nucleus - containing half complement (haploid number) of chromosomes • Neck - contains residual cytoplasm • Middle piece - first part of flagellum (tail) containing usual "9 + 2" arrangement of microtubules seen in cilia (axoneme) + 9 longitudinal coarse fibres + close-packed mitochondria • Principal piece - remainder of tail containing "9 + 2" microtubules + coarse fibres, tapering to end piece

Regulation of catecholamine synthesis

• Acute sympathetic stimulation activates the first rate- limiting reaction • Chronic stimulation induces an increase in tyrosine hydroxylase and therefore increases catecholamine output • Cortisol specifically stimulates the last step to generate epinephrine, the high local concentration from the cortex ensures production.

Hypoaldosteronism

• Addison's disease,-autoimmune or infectious destruction of adrenal tissue • CAH (P450C21 or P450C11B2 deficiencies - enzymes on pathway to aldosterone) Symptoms = Hyponatremia / Hyperkalemia, fatigue, weakness, hypotension NOT due to acute decrease in ACTH - often associated with pigmentation because of increased release of ACTH and melanocyte stimulating hormone as there is a lack of negative feedback.

Milk Secretion

• After parturition, when steroid levels, particularly progesterone, fall, prolactin levels fall much more slowly In the absence of suckling, the newly initiated milk secretion will last, for 3-4 weeks, during which period blood prolactin concentrations remain well above normal non-pregnant levels

Lactation

• Among the many changes occurring in the mother during pregnancy are those that involve the breast • In most mammals, this process is as vital to the success of reproduction as gamete production, fertilization and pregnancy, since the failure to lactate results in early postnatal death • Humans have freed themselves from absolute dependence on mothers (wet nurses/formulae) • Consequences of non-human milk?

Diagnosis

• As release is episodic then excess catecholamines can be determined by assay of urine collected over 24h • Most laboratories will assay a range of substances as the end products can vary Front Back • Imaging with uptake scans with meta- iodobenzylguanidine (mIBG), also MRI or PET scanning

Endometrial factor

• Ashermans • Genital tuberculosis (50%) Isthmic occlusion Beaded tubes Adhesion

Primary thyroid lymphoma

• Associated with Hashimoto thyroiditis- the inflammatory filtrate turns into a lymphoma • Treatment • Ext beam radiotherapy Infiltrate of mononuclear lymphoid cells

Follicular thyroid ca

• Associated with iodine deficiency • Peak incidence 40-60y • 10% thyroid ca • Present as enlarging solitary nodule or in context of MNG • Spread via bloodstream (mets in 50%) Cancer cells surrounding the normal follicles with colloid. Invades the blood vessels and capsules (compressed tissue on the outside of the lump)

Breast Development

• At birth, the mammary gland consists mainly of lactiferous ducts with few alveoli • Breast remains in this state until puberty • Oestrogens induce lactiferous ducts sprouting alveoli development • As menstrual cycles establish oestrogen and progesterone induces additional, ductal-lobular- alveolar growth, and the breasts increase in size as a result of the deposition of fat and growth of connective tissue.

Parturition

• Birth (parturition) signal unclear • Progesterone levels fall, oxytocin and prostaglandins become important • Oxytocin action on the uterus increases the contraction of the myometrium during labour causing expulsion of the fetus and the placenta • Progesterone antagonises and oestrogen potentiates the uterine response to oxytocin • Local prostaglandins stimulate uterine contractions • Clinical trials have demonstrated that prostaglandins increase the compliance of the cervix- widening of the pelvis, softening of pelvic bone etc

Adrenal Vasculature

• Blood supply to adrenal medulla via superior, middle and inferior arteries • Divide to form medullary, cortical and capsular arterioles • Additional blood supply to medulla from cortical capillaries (delivery of corticosteroids) • Medullary venules drain to central vein • Left adrenal vein to left renal vein • Right adrenal vein to inferior vena cava

Investigation

• Body mass index • Bloods - Day 2 - 5 serum gonadotrophins (early part where FSH and LH are meant to be on the lower side) - Thyroid function test - Serum prolactin - Serum testosterone - AMH (released by the granuloma cells, reflective of ovarian pool) - Day 21 progesterone (28 days cycle, progesterone rise due to the corpus luteum after ovulation, so if low hasn't ovulated. But only for 28 days) - Semen analysis: amount of sperm, motility of sperm, appearance tail morphology

The Human Life Cycle

• Born physically and sexually immature • 10 years growing • In adolescence, sexual maturity • Reproductive capacity (fecundity) • Distinct differences between men and women in fecundity • Male fecundity, once achieved, persists throughout life, mainly • Female fecundity, in contrast, is 'time limited', declining steeply from about 35 years until ending at the menopause at around age 50 years.

Oestrogen Antagonist

• Clomiphene - at anterior pituitary and hypothalamic receptors - used to induce ovulation in infertility (oestrogen negatively feeds back on the hypothalamus and anterior pituitary to lower LH levels)

Multiple Endocrine Neoplasia: Type 2B MEN

• Comprises ~ 5% of cases of MEN 2 • MEN 2B is characterized by the early development of an aggressive form of MTC in all affected individuals • Individuals with MEN 2B who do not undergo thyroidectomy at an early age (<1 year) are likely to develop metastatic MTC at an early age • Before intervention with early prophylactic thyroidectomy, the average age of death with MEN 2B was 21 years • Phaeochromocytomas occur in 50% of MEN 2B patients • Clinically significant parathyroid disease is absent in MEN 2B.

Tanner Stages

• Conceptually, pubertal maturation can be described in terms of sequence, timing, and tempo (Puberty consists of a series of predictable events, and the sequence of changes in secondary sexual characteristics has been categorized by several groups). • The staging system utilized most frequently is that published by Marshall and Tanner and the sequence of changes, commonly referred to as "Tanner stages".

PENIS

• Contains 3 cylinders of erectile tissue - two dorsal (corpora cavernosa) and one ventral (corpus spongiosum). Erectile tissue contains large, irregular vascular channels, lined by endothelium; surrounded by fibrous tissue with some smooth muscle bundles • Sympathetic nervous stimulation causes partial closure of normal a-v shunt and diversion of blood from helicene arteries into cavernous spaces; outflow of blood is restricted because thin-walled veins are compressed • Corpus spongiosum becomes somewhat less turgid, allowing urethra to remain sufficiently open for passage of semen during ejaculation

List major syndromes of adrenal dysfunction

• Cushing's disease • Cushing's syndrome • Addison's disease • Adrenal insufficiency • Congenital adrenal hyperplasia (CAH) • Primary hyperaldosteronism (Conn's syndrome) • Pseudohypoaldosteronism (PHA) • Glucocorticoid resistance • Apparent mineralocorticoid excess (AME)

The renin-angiotensis-aldosterone system -reliance on AVP

• Decrease renal perfusion pressure (RPP) increase fluid resorption • Aldosterone release from the adrenal cortex is stimulated primarily by angiotensin II, but its release is also affected to a smaller extent by local potassium levels, and ACTH. • The normal levels of aldosterone release are not sufficient to cause negative feedback control of ACTH secretion by the pituitary

Propylthiouracil

• Reserved for those intolerant of carbimazole • Higher rate of agranulocytosis • Inhibition of peripheral de- iodination

Non-goitrous congenital hypothroidism

• Defect in thyroid embryological development (athyreosis) • PAX8 • NKX2-5 • Defect in TSH-R or TSH itself • TSHR loss of function mutation • TSHB • Distinguished from dyshormogenesis as there is no goitre

Pubertal Stages

• Delayed or precocious puberty? • Assessed by staging : Pubic and auxillary hair Development of boy's external genitalia Girl's breast development

Window of Opportunity

• During fertilization the genetic material from a spermatozoan (haploid) and a secondary oocyte (haploid) become a single diploid nucleus • ~200 million sperm delivered, ~1% reach the cervix, only about 200 reach the secondary oocyte • Fertilization normally occurs in the fallopian tube within 12-24 hours after ovulation • Sperm viable (48 hours), secondary oocyte viable (24 hours after ovulation) • Pregnancy is most likely during a 3-day window - 2 days before to 1 day after ovulation.

Oxytocin and Parental Bonds

• During parturition, there is an increase in csf [oxytocin], establishing maternal behaviour • The hormonal changes at the end of pregnancy (declining progesterone, and increasing oestrogen, prolactin, and oxytocin) induce maternal urges i.e. nesting • Hormonal and neurochemical changes facilitate maternal moods and promote social-bonding with offspring • Post-partum depression (18%) reduced touch, reduced oxytocin (Feldman, 2009)

Cellular Actions of Oxytocin: Stimulate uterine smooth muscle contractions at birth

• During the later stages of gestation, oxytocin receptors increase on uterine smooth muscle cells, which is associated with increased "irritability" of the uterus At parturition, oxytocin (in concert with prostaglandins) stimulates the contraction of the myometrium to expel the infant from the uterus. Passage of the infant across the cervix leads to distension of the vaginal walls, which, in turn, triggers further secretion of oxytocin in the Fergusson reflex. In cases where uterine contractions are not sufficient to complete delivery, oxytocin analogues can be given.

Psychosexual factors

• Dyspareunia- difficult or painful intercourse • Vaginismus • Erectile dysfunction

EPIDIDYMIS & VAS DEFERENS

• Epididymis is a very long, convoluted duct leading from testes to vas deferens. Site of storage / maturation of spermatozoa (motility develops here). Smooth muscle at distal end has sympathetic innervation and contracts during ejaculation • Vas (ductus) deferens is a thick walled smooth muscular tube that transports spermatozoa to urethra; sympathetic innervation; intense contractions during ejaculation

TESTES

• Fibrous capsule - tunica albuginea - gives rise to fibrous septae that separate testes into 200+ lobules. • Seminiferous tubules - tightly packed into lobules of testes. Tubules lined by multilayer germinal epithelium. Each tubule 0.1-0.2 mm diameter; up to 100 cm long. spermatogenesis (formation of spermatids) + spermiogenesis (maturation to spermatozoa) occurs in co- ordinated waves along each tubule. Sertoli cells rest on basement membrane of tubules and support development of spermatic cells via complex cytoplasmic processes. • Interstitial (Leydig) cells - found in spaces between tubules close to capillaries - secrete androgens (mainly testosterone) in response to luteinising hormone from pituitary. Local concentrations of androgens therefore very high in testes.

Sperm Penetration

• For fertilization to occur, a sperm cell first must penetrate two layers: • Corona radiata- the granulosa cells that surround the secondary oocyte • Zona pellucida- the clear glycoprotein layer between the corona radiata and the oocyte's plasma membrane

Examination

• Galactorrhea- hyperprolactinaemia • Acanthosis nigricans • Acne • Hirsuitism- androgens Turner's syndrome • Short stature • Webbed neck

SEMINAL VESICLES

• Glands formed by long (~15 cm), convoluted tubular outgrowths from ductus deferens • Responsible for 50% of volume of seminal fluid - thick yellowish-white secretion containing fructose, proteins, amino acids, prostaglandins, citric and ascorbic acids • Thick smooth muscle wall contracts in synchrony with other parts of the genital tract to expel glandular contents during ejaculation (sympathetic innervation)

Foot infections

• High levels of glucose make a rich medium for organisms infecting the skin • Contributed to by damage to small blood vessels • Sensory neuropathy leads to foot numbness and damage e.g. from ill-fitting shoes. This is very important as the loss of protective sensation means that microtrauma can happen, and if that injury is not detected it can lead to an ulcer and even amputation.

Diagnosis

• History - Menarche - Cycle • Regularity • Symptomatology - Coital frequency • Dysmenorrhea - Past medical/gynaecological/obstetric history - Medications

Gastric bypass surgery

• Restrictive "can't eat" • Malabsorptive • Endocrine effects? Etc. Ghrelin, GLP-1, PYY3-36? "don't want to eat"

Capacitation

• If matures permatozoa recovered at ejaculation are placed with oocytes in vitro, fertilization either does not occur or does so only after several hours • Spermatozoa recovered from the uterus or oviduct a few hours after coitus are capable of immediate fertilization • Full fertilizing capacity is achieved within the female tract is called capacitation • Capacitated spermatozoa: 1. a change to a hyperactivated motility state 2. further change in the spermatozoa called the acrosome reaction.

Milk Secretion

• If prolactin levels are to remain elevated and full lactation is to continue nipple stimulation is essential • Suckling achieves this postpartum release of prolactin from the anterior lobe of the pituitary via a neuroendocrine reflex • The amount of prolactin released is determined by the strength and duration of nipple stimulation • Suckling at both breasts simultaneously, when feeding twins for example, induces a greater release of prolactin than occurs during stimulation of one breast.

Who gets Type 2 diabetes?

• Incidence increasing in all age groups • Many people are at risk • Many people do not know they have diabetes • Inequalities in ethnic distribution

Anticipated changes in plasma [aldosterone] following:

• Increase in plasma [K+]. Increases • Decrease in plasma volume . Increases • Increase in plasma volume. Decreases. • Increase in [ACTH]. Increases. • Decrease in [ACTH]. Stays the same. • Increase [angiotensinogen]. Stays the same. • Administer ACE inhibitors. Decreases

Invasive Implantation

• Invasive implantation occurs in the human, primates dogs, cats, mice and rabbits • The free-living phase of blastocysts is short-lived • Within a few hours of attachment, the surface epithelium underlying the conceptus becomes eroded • The depth to which the conceptus invades maternal tissues varies in pathological conditions • The conceptus invades the stroma so deeply that the surface epithelium becomes restored over it (interstitial).

Lactation and Menstruation

• Lactation can continue for months. During this period, menstruation and ovulation return more slowly than in non-lactating women • Normal reproductive cycles are re-established by 3-6 months Cessation of lactation • Lactation will cease spontaneously as suckling declines • Pharmacological blockade is not recommended • There is no strong evidence to support alternatives such as binding or cabbage leaves.

Tubal patency

• Laparoscopy and dye test (Gold standard) • Hysterosalpingo contrast sonography (HyCoSy) • Hysterosalpingogram (HSG)

PROSTATE GLAND

• Large gland surrounding bladder neck + first part of urethra • Glandular epithelium is irregular pseudostratified / columnar • Glandular units produce thin milky fluid that make up 50% of seminal fluid volume. Enzymes in prostatic fluid (esp. fibrinolysin) liquefy coagulated semen some time after ejaculation • Glandular units surrounded by supporting tissue which is a mixture of smooth muscle + fibrous tissue. Contracts in synchrony with other parts of the genital tract to expel glandular contents during ejaculation (sympathetic innervation) • Increases in size (hypertrophy) with age due to androgen stimulation. Growth of innermost part may constrict urethra, reducing urinary outflow. Hypertophy of outermost part may lead to malignant transformation - prostate carcinoma is most common male malignancy (~10% of men affected) • "Prostatic concretions" - calcified lumps - common in lumen of glands, esp. in older men

Multiple Endocrine Neoplasia

• MEN syndromes • Pediatric and adult • Rare, autosomal dominant mutations: Menin/Ret Current classification recognizes: MEN I: Pituitary, Parathyroid, Pancreatic MEN IIa: Phaeochromocytoma, Parathyroid, Medullary Thyroid Carcinoma MEN IIb: Phaeochromocytoma, Medullary Thyroid Carcinoma, Marfanoid habitus/mucosal neuroma

Causes of hyponatreamia

• Medications- diuretics, antidepressants, pain control Pink Himalayan rock salt (from Pakistan) • Heart, kidney and liver disease- Congestive heart failure etc. can cause fluid accumulation, which dilutes the plasma sodium • Syndrome of inappropriate anti-diuretic hormone (SIADH)- high ADH causes water retention • Chronic, severe vomiting or diarrhoea and other causes of dehydration- loss of electrolytes, such as sodium, and also increases ADH levels. • Drinking too much water- excessive amounts of water can causes low sodium by overwhelming the kidneys' ability to excrete water. Because you lose sodium through sweat, drinking too much water during endurance activities, such as marathons/triathlons, can dilute the sodium • Hormonal changes. Adrenal gland insufficiency (Addison's/CAH) affects sodium, potassium and water balance. Low levels of thyroid hormone cause a low sodium. • The recreational drugs -. the amphetamine ecstasy increases the risk of severe and even fatal hyponatremia.

Fertility and Lactation

• Menstruation is a poor indicator of fertility during this period, and conception often occurs in lactating women without an intervening menstruation • Approximately half of all contraceptively unprotected nursing mothers become pregnant during 9 months of lactation • This variable period of postpartum lactational amenorrhoea and anovulation is probably mediated primarily by prolactin, which can suppress the initiation of cyclical release of gonadotrophins, as discussed more fully in the contexts of hyperprolactinaemia

Progestogen Antagonist

• Mifepristone: - antagonist at Progesterone Receptors in uterus Prevents ovulation, prevents suppression of uterine contractility, stimulates endometrium breakdown - Uses: - early pregnancy termination (+ prostaglandin)

Hyponatraemia signs and symptoms

• Nausea and vomiting • Headache • Confusion • Loss of energy, drowsiness and fatigue • Restlessness and irritability • Muscle weakness, spasms or cramps • Seizures • Coma

Benign multinodular goitre

• Non-toxic (↔TFT) or toxic (↑T4, T3) or hypothyroid • Slow growing: ↑prevalence with age • occurs in iodine deficient areas like Africa, the Alps... • Dyshormonogenesis- e.g. defective Na/I symporter, thyroid peroxidase leading to hypertrophic response of the thyroid • Goitrogens e.g. chronic Li Rx (lithium therapy, need to monitor TFTs), Brassica vegetables (inhibits the production of thyroid hormone, have to eat a lot), antithyroid medications

Menopausal Hormone Therapy (HRT)

• Oestrogen + progestogen • Oestrogen alone (hysterectomized women) (don't need progesterone as there is less risk of cancer, progesterone would oppose the oestrogen driven endometrial proliferation) • Raloxifene: SERM Oestrogen agonist in bone, antagonist in uterus and breast • Tibolone: prodrug metabolized to low potency oestrogen, progestogen and androgen

Establishment of Pregnancy

• On reaching the uterus, the conceptus must communicate with the mother • This interaction has two important and distinctive components: one short range and one long range • First, the conceptus establishes physical and nutritional contact with the maternal endometrium at attachment and implantation; failure to do so properly would deprive the conceptus of essential nutritional substrates and delay or arrest its growth • Implantation involves short-range messages • Second, the conceptus signals its presence to the maternal pituitary-ovarian axis • Failure to do so would result in the normal mechanisms of luteal regression, causing a fall in progesterone levels and loss of the conceptus • The conceptus must convert the mother's cyclic pattern of oscillating oestrogens and progestagens, to a non-cyclic pregnant pattern, in which progestagens dominate throughout • The maternal recognition of pregnancy involves long-range signals • Thus, pregnancy is not initiated with fertilization but only when the conceptus has signalled its presence successfully to the mother.

Pronuclei

• Once a sperm cell enters a secondary oocyte, the oocyte complete meiosis II • The oocyte divides into a larger ovum (mature egg) and a smaller second polar body, and disintegrates • The nucleus in the head of the sperm develops into the male pronucleus, and the nucleus of the fertilized ovum develops into the female pronucleus • After the male and female pronuclei form, they fuse to restores the diploid number (2n) of 46 chromosomes • The fertilized ovum is now called a zygote.

Female reproductive system - components

• Ovaries (2) - produce oocytes (female gametes) and female sex hormones (oestrogens, progestogens) • Uterinetubes(oviducts,Fallopiantubes)(2) - conduct ova towards uterus; fertilisation occurs along tube • Uterus - where embryo implants and grows; cervix • Vagina - site of introduction of spermatozoa; birth canal • Breasts - produce of colostrum & milk - nutrition of newborn

Causes

• Ovulatory disorder (25%) • Tubal damage (20%) • Uterine or peritoneal disorders (10%) • Male factor (30%) • Unexplained (25%)

Evaluation of thyroid nodules

• Palpation: is it retrosternal? • TFTs (thyroid function tests), thyroid antibodies • useful if Hashimoto's • hyperthyroidism reduces but does not eliminate possibility of malignancy (if anything cancer cells will produce less hormones) • Calcitonin and Carcinoembryonic Antigen- Raised in medullary thyroid carcinoma • Ultrasound • Thyroid scintigraphy • Fine needle aspiration • CT scan if concerned about airway

Treatment of diabetes

• Patient education • Nutritional control • Pharmacological treatment • Monitoring of glycaemic control • Screening for complications

Multiple Endocrine Neoplasia: Type 1 MEN

• Patients usually have a family history of MEN I • Inheritance is autosomal dominant • Hyperparathyrodism is most likely • MENI gene mutations identified in 70-95% of MENI patients • Heterozygous MenI-/MenI+ mice develop endocrine tumours similar to humans, while MenI-/MenI- mice die in utero • Clinical manifestation usually hypercalcemia: polydipsia, polyuria, constipation, and fatigue.

Catecholamine Tumours

• Phaeochromocytomas are catecholamine producing tumors of chromaffin cells, that can occur sporadically or as part of a familial syndrome • The majority are found in the adrenal glands, although phaeochromocytoma can be found anywhere with chromaffin tissue (these cells migrate from the neural crest during development) • 97% are abdominal, 2% thoracic and 1% in other regions • Most secrete a number of hormones, including: norepinephrine, epinephrine, dopamine, vanylmandelic acid, metanephrines. • Phaeochromocytomas are usually benign (non- cancerous), but can cause dangerously high blood pressure

Pituitary Tumours

• Pituitary tumors show a range of hormonal and proliferative behaviors • Mutations in classic oncogenes and tumor-suppressor genes are however rarely associated with pituitary tumours • Instead, tumourigenesis is promoted by hormones and growth factors that are implicated in pituitary development

Breast

• Production of colostrum & milk - nutrition of newborn • Epithelia - ducts & glands • Connective tissue - intra-, interlobular + BVs, nerves and lymphatics, fat

Multiple Endocrine Neoplasia: Type 2A MEN

• RET gene mutations in 70-80% of cases of MEN 2 • 70-95% develop medullary thyroid carcinoma (MTC) • 50% develop phaeochromocytoma • 15-30% develop hyperparathyroidism • MTC is generally the first manifestation, followed by phaeochromocytomas

Alternatives to thioureylenes

• Radioactive iodine

What do you need to know from the history

• Rapid growth of mass? • Are they old >60 or young <16?, tend to present with thyroid cancer • Previous neck irradiation • I-131 from Chernobyl 1986, Fukushima 2011 • Iatrogenic: Hodgkin's lymphoma treated with mantle DXT (radiotherapy) • Radiographers, radiologists • Dysphagia (something pressing on oesophagus), stridor (something pressing on trachea) • Lymphadenopathy (metastatic disease, swelling of neck lymph nodes)

Dietary sources of iodine

• Salt (not in UK) • Seafood and seaweed • Dairy products from iodine used for tank cleaning • IODIZED OIL injections for mass public health treament

Hypothyroidism

• Shorter limbs • Not achieving full growth potential • GHlow • T3/T4 low

RATE OF GROWTH v AGE

• Smooths-out single measurements • Very high in year 1 • Plateau followed by growth spurt • Falls to zero at end of puberty

Milk-Ejection Reflex

• Somatosensory pathways in the suckling-induced reflex release of oxytocin • Milk removal involves transport of milk from the alveolar lumina to the nipple where it is removed by the suckling infant • Nipple touch and pressure stimulate oxytocin release and milk let-down, can also be conditioned to occur in response to a baby's cry.

Sperm Changes

• Sperm swim from the vagina into the cervical canal by the movements of their tails (flagella) • The passage of sperm through the rest of the uterus and then into the uterine tube results mainly from contractions of the walls of these organs • Prostaglandins in semen are believed to stimulate uterine motility at the time of intercourse, to aid sperm move of from the uterus to the fallopian tube • Sperm can reach the oocyte within minutes • BUT are not capable of fertilization for several hours

Spermatogenesis

• Spermatogonia - germ cells (present in small numbers before puberty) - multiply by mitosis to give continuous supply of cells for meiosis... type A spermatogonia undergo asymmetric division (mitosis) → more type A cells + type B spermatogonia → 1o spermatocytes • Primary spermatocytes - undergo 1st meiotic division (takes ~3 wks), producing.... • Secondary spermatocytes - daughter cells of 1st meiotic division - (hard to see) rapidly undergo 2nd meiotic division to produce.... • Spermatids - undergo ~7 wk maturation process (spermiogenesis) to produce.... • Spermatozoa - final stages of maturation take place in epididymis

Cushing's Treatment

• Surgery directed at the adrenal or pituitary is the first and most important treatment; however, many patients do not have a sustained remission after surgery. Ketoconazole Mitotane Metyrapone- 1 in 5 individuals have side effects such as increased facial hair growth in women, swelling, low potassium levels, and dizziness.

Hypothalamic-Releasing Hormones

• TRH(3aa)- stimulates thyrotrophin (TSH) • GnRH(10aa)- stimulates gonadotrophins (LH&FSH) • CRH(41aa)- stimulates corticotrophin (ACTH) • GHRH(44aa)- stimulates GH

TSH-R Abs do not always stimulate!

• TSI = Thyroid stimulating antibodies • TBII = TSH-R binding inhibitory immunoglobulins • Patients can produce both- polyclonal antibodies • In different proportions during history of disease • RELAPSING - REMITTING

Acrosome Reaction

• The acrosome sits around the head of a sperm • Acrosomal enzymes (hyaluronidase and acrosin) and strong tail movements by the sperm help it penetrate the cells of the corona radiata and come in contact with the zona pellucida • One of the glycoproteins in the zona pellucida called ZP3 acts as a sperm receptor • ZP3 binding to specific membrane proteins in the sperm head, triggers the acrosomal reaction, the release of the contents of the acrosome • The acrosomal enzymes digest a path through the zona pellucida as the sperm tail pushes the sperm cell onward. Although many sperm bind to ZP3 molecules and undergo acrosomal reactions, only the first sperm cell to penetrate the entire zona pellucida and reach the oocyte's plasma membrane fuses with the oocyte • Fusion of a sperm cell with a secondary oocyte sets in motion events that block polyspermy (fertilization by more than one sperm) • Within a few seconds, the oocyte cell membrane depolarizes to prevent fusing with another sperm

Adrenal Medulla

• The adrenal medulla is essentially a specialised sympathetic ganglion, but instead of axons they release their products directly into the bloodstream, thus their endocrine status • The medulla is the source of circulating epinephrine, whereas NE is primarily a neurotransmitter • The catecholamines act to mobilize fuel, increase the release of glucose and free fatty acids during acute stress. They stimulate the heart, alter the tone in the smooth muscle of the respiratory, gastrointestinal and urinary tract. • The medulla is usually activated along with the sympathetic portion of the autonomic nervous system in the "fight or flight" response. • Some of the neural actions of NE are amplified by the hormonal actions of epinephrine, plus it has its own effects.

Human Chorionic Gonadotrophin

• The blastocyst prolongs the life of the corpus luteum by production of a luteotrophic factor of its own (hCG) • Successful implantation leads to development of the trophoblast, which begins to secrete hCG into the maternal bloodstream • hCG is similar enough to LH to act via the LH receptor, and it maintains the corpus luteum and early pregnancy, and postpones the next cycle of ovulation • High levels of hCG are associated with excessive early morning vomiting (hyperemesis gravidarum). • "Morning sickness" • hCG excreted into the maternal urine forms the basis of most pregnancy tests. • Levels can be detected by urine strip assays soon after menstruation / a period is delayed (~3 weeks of embryo development).

Aromatase

• The enzyme aromatase is found in the growth plates of boys and girls • Aromatase inhibitors are a class of drugs that prevents conversion of androgens to oestrogens • The fusion of the growth plates is oestrogen-dependent in both boys and girls • Aromatase inhibitor administration may help to slow down epiphysial maturation and allow for greater height potential • Aromatase inhibitors can be used to delay plate closure in boys, but you would not use them for girls!

Human GH Gene Family

• The human GH/ chorionic somatomammotropin (CS) locus is located on chromosome 17 • GH-N is expressed preferentially in the somatotropes of the anterior pituitary, while GH-V and the CS genes are expressed in the syncytiotrophoblasts of the placenta • HS I and II are pituitary specific • HS IV is placenta specific, and HS III and V are found in both pituitary and placenta but nowhere else

Corpus Luteum

• The life of the corpus luteum in the non-pregnant female is ~14 days • Luteolysis involves progressive cell death with a consequent fall in the output of progestagens • The whitish scar tissue remaining, the corpus albicans, is absorbed into the stromal tissue of the ovary over a period that varies from weeks to months • Luteolysisis caused by inadequacy of the luteotrophic hormones. Within 2weeks of fertilization the human conceptus synthesizes and releases the hormone hCG • This hormone then maintains the progestagenic activity of the corpus luteum • Within a further 2-3 weeks, the conceptus is also synthesizing all the steroidal hormones required for pregnancy, and although the maternal corpus luteum remains active for the whole of pregnancy, it can be dispensed with after only 4-5 weeks and plays only a trivial role in total progesterone output at later stages.

Oxytocin

• The major roles of oxytocin are during birth and lactation • Like vasopressin, oxytocin circulates largely unbound and so is removed rapidly by the kidney (t1/2 2~5 min) • Outside parturition and breastfeeding, it circulates in very low concentrations and is normally undetectable in the blood • Oxytocin binds to its cell-surface G-protein coupled receptor and signals intracellularly via phosphatidylinositol metabolism and calcium.

The Ferguson reflex

• The movement of the fetus down the birth canal is an example of positive feedback • Oxytocin stimulates uterine contraction which moves the fetus into the distending vagina, which in turn sends neural inputs back to the brain to enhance oxytocin secretion • This positive feedback loop is only broken once the infant is born.

MEN Epidemiology

• The prevalence of MEN in adults is about 0.02-0.2 cases per 1000 population • The male-to-female ratio for MEN is 2:1. • Patients with hyperparathyroidism in type 1 MEN most often present at age 20-40 years, but the disease may appear in children younger than 10 years. However, all MEN syndromes are rare in children. • Hyperparathyroidism is the most common manifestation of type 1 MEN (~80% of presentations) • Type 2 MEN affects ~1 in 40,000 individuals, peak (40yrs) • Type 2A MEN, most cases of type 2, 5% 2B • Phaeochromocytomas are bilateral in ~70%.

What if fertilization takes place?

• The two-cell conceptus in the oviduct now has to perform a heroic task • It must somehow communicate its presence to the mother and convert the whole of her physiology and anatomy from a cyclic reproductive state to a pregnant one • The preimplantation conceptus remains at the site of fertilization for a further few days • Transferred through the oviduct and enters the uterus • Transfer is facilitated by the changing endocrine milieu of the early luteal phase, with its rising ratio of progesterone to oestrogen.

Female Fecundity

• This reduction in female fecundity is due to egg quality- reactivation of the genetic system as eggs were frozen during mitosis, see more trisomy 21 in later years • A perceived 'public health problem' in Western societies (Childbirth >30) • Shifted social life cycle but somatic life cycle i.e. the aging process remains the same! Rates of fertility (red range) and childlessness (blue bars) by age of woman. The fertility rate data were collected from populations of married women who reported no efforts were made to limit reproduction. Note the steep decline in fertility from 35 years. The histograms show the proportions of women remaining childless, note the sharp rise above 35 years

Symptoms pecific to Graves' disease

• Thyroid Eye Disease (TED) • Periorbital oedema • Proptosis • Diplopia (double vision) • Corneal ulceration • Loss of visual acuity • Pretibial myxoedema • Thyroid acropachy (clubbing)

Diagnostic tests for hyperthyroidism

• Thyroid autoantibodies • Anti Thyroid peroxidase (TPO) and Anti Thyroglobulin (TG) are non-specific and insensitive • Anti TSH-R Abs: specific for Graves' disease (95%) Thyroid scintigram

Rx (treatment) of differentiated TC (thyroid cancer)

• Total thyroidectomy (+ any enlarged lymph nodes may also contain the cancer cells) • 131 I ablation (radioactive iodine taken up by the follicular cells, radiation targeted) Follow-up • Suppression of TSH with T3 or T4 to reduce stimulation of thyroid cancer cell growth by TSH (as TSH binds to stimulate follicular cell growth) • Palpation of neck ± USS (ultrasound scan) • Measure thyroglobulin levels with rTSH stimulation (only follicular cells make thyroglobulin, if detected means still cancer cells present) • I-123 scans with rTSH stimulation • Repeated treatments with I-131 if necessary

Feto-placental unit

• Towards the end of the first trimester, fetal steroidogenesis occurs across several organs, leading to the term, the 'feto-placental unit' • Placental secretion of progesterone takes over from the corpus luteum.

There is more than one type of TR

• Two genes: TR alpha and TRbeta Each can be alternatively spliced • TRalpha1,2 and TRbeta1,2 Tissue specific

Bone Age / Bone Maturation

• Use wrist radiographs • Compare epiphyseal growth plates v age related reference ranges • Cumulative scores for several bones (2% CV) • Difficult with skeletal dysplasias

Ultrasound

• Uterine morphology • Ovarian morphology & antral follicle count by transnational ultrasonography

Ultrasound scan

• Very sensitive technique • Unsuspected nodules in 44% women, 20% men • Can image nodules 1-2 mm in size • Can not definitively distinguish benign or malignant • Used to guide FNA

Clinical features general to thyrotoxicosis - hyperthyroidism

• Weight loss despite a normal appetite • Sweating and heat intolerance • Agitation • Tremor • Fatigue • Palpitations / tachycardia / atrial fibrillation Angina • Generalized muscle weakness -proximal myopathy • Diarrhoea • Oligomenorrhoea (lack of periods) and infertility • Eyelid retraction and lid lag

Summary Calcium & Phosphate

• When blood calcium becomes too low, calcium-sensing receptors in the parathyroid gland become activated. This results in the release of PTH, which acts to increase blood calcium (e.g. by osteoclasts) and increased calcium reabsorption from urine and the GI tract. • Calcitonin, released from the C cells in the thyroid gland, works the opposite way, decreasing calcium levels in the blood by causing more calcium to be stored in bone • PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney, increasing phosphate excretion • PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the intestines, absorption of both calcium and phosphate is mediated by an increase in activated vitamin D.

Uterus

• Where embryo implants and grows - simple and secretory columnar epithelium with uterine glands; cervix • Cyclical monthly changes • Proliferation - endometrium doubles in thickness; simple tubular glands form • Secretion - begins with ovulation - glycogen main nutritive product endometrium reaches maximum thickness; highly vascular • Degeneration (menstruation) - in absence of implantation of fertilised ovum

Iodine insufficiency compensation

• increased iodide uptake by NIS • increased iodide recycling in thyroid • MIT preferentially formed over DIT due to lack of iodide • so the T3 : T4 ratio increases • This will maintain euthyroid status for a while • With time a goitre forms due to high TSH • 'drive' to nodular growth

Hypernatraemia

• insufficient fluid intake • too much water loss • in rare cases, consuming too much sodium Risk groups include intravenous (IV) treatments or undergoing nasogastric feeding, altered mental state and infants and older adults. Risk conditions: Dehydration, vomiting, extreme diarrhoea, kidney disease, uncontrolled diabetes mellitus, diabetes insipidus, dementia, fever, delirium and large areas of burned skin.

Menopausal Hormone Therapy (HRT): Adverse Effects

• large randomized controlled trials - older women (Women's Health Initiative; Million Women Study): ↑ risk of breast cancer ↑ risk of cardiovascular disease • recent studies/analyses - perimenopausal ↓? risk of cardiovascular disease small ↑ risk of ovarian cancer

General phenomenon of target tissue steroid metabolism

• metabolism to increase / decrease potency in target cells. • HSD is only one example of this general phenomenon.

Oestrogens

• natural: 17-b oestradiol, oestrone, oestriol • synthetic: e.g. mestranol, ethinyl-oestradiol •produced by -ovaries (follicle,CL) - placenta ▪receptors : - ligand-activated transcriptional factors (ERa, ERb) - GPER1: oestrogen-responsive GPCR

Progestogens

• natural: progesterone • synthetic: levonorgestrel, norethisterone, desogestrel, medroxyprogesterone acetate (MPA) • produced by CL and placenta ▪receptor: - ligand-activated transcription factors

Ovaries

• produce ova (female gametes) by the process of oogenesis • produce female sex hormones - oestrogens (via action of aromatase in granulosa cells on androgen precursors produced by thecal cells) - inhibin (inhibits FSH; granulosa cells) - progestogens (corpus luteum)

Targets for antiobesity agents

• reduce energy (food) intake - Target central transmitters and/or their receptors - Target peripheral satiety/hunger hormones and/or their receptors - Inhibit fat/nutrient absorption • enhance energy expenditure - 'burn' energy at cellular level - Stimulate fat mobilization - exercise

Aldosterone Mechanism of Action:

• salt & water retention • binds to cytoplasmic MRs • in the distal convoluted tubule of the kidney, aldosterone stimulates the active reabsorption of sodium and associated passive reabsorption of water. • thus aldosterone plays an important role in the chronic regulation of blood pressure as a major component of the RAAS (Renin-Angiotensin-Aldosterone System).

TSH-R STIMULATION

• ↑ cAMP via GSa/adenylate cyclase Stimulates the follicle cells • ↑DNA synthesis (proliferation) • ↑ protein synthesis • including thyroglobulin • ↑ iodide influx into the cell via NIS • ↑ thyroid hormone synthesis • ↑ iodination of thyroglobulin • ↑ microvilli number and length at luminal cell surface • ↑ in intracellular volume and endocytosis of colloid droplets ↑ thyroid hormone release

Aims of management of diabetes

✓Treat hyperglycaemia ✓Prevent long-term complications ✓Limit the adverse effects of treatment