5BBL0210: Endocrinology and reproduction
gestational diabetes mellitus (GDM)
any degree of glucose intolerance with its onset or first diagnosis during pregnancy and usually resolving shortly after delivery - no universally agreed clinical definition of gestational diabetes - estimates of prevalence vary hugely!
where do drugs act in the synthesis and secretion of thyroid hormones
at the stage where peroxidase activates iodide
effect of secretion of adrenal androgens
axilla/pubic hair growth - low levels of androgens required - occurs in both sexes adrenal androgens are not sufficient for facial hair growth
how can mental impairment in babies be prevented in congenital hypothyroidism
babies must be treated with replacement thyroid hormone as soon as possible after birth. In developed countries neonatal screening is carried out routinely.
what are thyroid follicles
balls of epithelial cells surrounding proteinaceous (non-cellular) glycoprotein 'colloid' - where thyroid hormones are stored
role of lipoprotein lipase
breaks down the TAG in chylomicrons into FAs and monoglycerides so it can pass through membrane into adipocytes and be converted back into TAG for storage
initial (latent) phase
contractions develop, cervix softens (days), not actual labour
role of LH in females
controls the reproductive cycle and ovulation, stimulates oestrogen
what happens to carbohydrates in absorptive state
converted to glucose
what does the zona fasciculata produce
cortisol (this part of kidney responsible for making hormone in response to stress)
consequence of iodide insufficiency in infants
cretinism (hypothyroidism)
what stimulates glucagon release
decreased blood glucose during the postabsorptive state (insulin inhibited)
effect of GLP-1 on liver
decreased glucagon reduces hepatic glucose output
effect of GLP-1 on islet alpha cells
decreased glucagon secretion
effect of GLP-1 on stomach
delays gastric emptying
effect of slower gastric emptying in T1DM
delays the peak increase in plasma glucose after food intake
disturbances in testes function
disturbances in: • genetic level (klinefelter syndrome) • hypothalamic level (kallmann syndrome) • pituitary levels (hyperprolactinemia) • target tissue level (androgen insensitivity syndrome)
how to tell the difference between inactive and active thyroid
epithelial cells get bigger and follicles actually grow to produce more hormone when thyroid active
what innervates islets of langerhans
extensive sympathetic (adrenergic) and parasympathetic (cholinergic) innervation
what does the urogenital sinus develop into
external genitalia (clitoris, vulva or penis, scrotum)
effect of secretion of testis androgens
facial hair - high levels of androgens required, beard growth in males
origin of obesity
failure to maintain balance between energy intake and expenditure - body weight maintained through complex mechanisms ensuring constant supply of energy for cellular functions
what does the mullerian duct develop into
fallopian tube, uterus, cervix (female reproductive organs)
physical effect of hyperglycaemia
fatigue because muscle cannot uptake sufficient glucose
leptin signalling role in reproduction
one of the main mechanisms for communicating healthy energy homeostasis to the HPG axis, other signals insulin ghrelin PYY involved but to lesser extent
Thyroxine (T4) and Tri-iodothyronine (T3)
thyroid hormones, iodinated derivatives of tyrosine. T3- biologically active, T4- not active and storage
why do the Leydig cells and the seminiferous tubules work closely together
to maintain reproductive function
hyperoxic
too much oxygen
fetal bilirubin
toxic waste from fetus
treatment of thyroid failure caused by lack of iodide in diet
treated with dietary supplement (iodide in salt)
what diseases is obesity associated with an increased risk of
type 2 diabetes, cvd, some cancers, osteoarthritis, fatty liver disease
how steroids affect sperm production
use of steroids suppress HPG axis and reduce fertility
what does the inflation of the gastric band stimulate and how does it relate to weight loss
vagal afferent nerve fibres in the stomach, which project to activate neurons within the nucleus of the solitary tract. This then leads to activation of the arcuate nucleus and the paraventricular nucleus to decrease appetite
physical effect of hyperketoanemia acidosis
vasodilation, hyperventilation leading to hypotension (vasodilation) and hypothermia (vasodilation): - high levels of CO2 recognised by low pH, so acidosis causes respiratory system to hyperventilate - blood vessels also dilate with high CO2, recognised by low pH
physical effect of increased glycogenolysis, gluconeogenesis and lipolysis
wasting, weight loss
BMI
weight (kg)/height^2(m^2)
how does weight loss increase insulin sensitivity
weight loss reduces fat depots that contribute to insulin resistance, improving insulin sensitivity: more effective reductions in blood glucose levels
bariatric surgery
weight loss surgery performed on severely obese individuals unable to reduce weight through diet/exercise/pharmacotherapy: • must be morbidly obese • non invasive (laproscopy)
when does GIP stimulate insulin secretion
when blood glucose levels are elevated (>=6mM)
cyclic recruitment in development of ovarian follicle
when follicles enter reproductive cycle (ovarian cycle)
when is biological impact of leptin probably more pronounced
when leptin levels decreasing (fasting/starvation) rather than increasing (fed)
when does the hyperplasia of the adrenal glands occur
when one is lost, so one gets bigger to replace it/compensate
glucose sparing
when peripheral tissues start using fatty acids and ketones so that CNS can use glucose during periods of starvation
where does spermatogenesis occur
within the seminiferous tubules
half life of insulin and where it is degraded
~5 minutes, mainly degraded in liver by insulin dehydrogenase
IGF-1 receptor signalling pathways
• (mitogen-activated protein kinase) MAPK pathway is coupled to mitogenesis • protein kinase B (PKB) pathway results in cell survival • net effect is growth promotion
counter signals controlling eating behaviour
• AGRP/NPY=hunger signal (low leptin; high leptin inhibits) • POMC/α-MSH=satiety signal (high leptin) • Leptin mediates an adipostat feedback loop from fat cells to the brain to suppress appetite and cause peripheral lipolysis and fatty acid oxidation
characteristics of steroid hormone receptors
• intracellular • translocate to nucleus when hormone binds to receptor • influence gene expression (increases transcription of the gene regulated by that promoter) • relatively long term effects
physical effects from thyroid hormone underproduction in adults
• lack of T3/T4 means no inhibition of TRH/TSH release so elevated levels of TSH • continuous release of TSH stimulates thyroid growth • thyroid goitres form "benign goitre" • not malignant but they cannot release T3/4
role of liver in absorptive state for amino acids
- minority converted to keto acids by deamination, enter TCA cycle or converted to FA - Keto acids not converted to glucose during the absorptive phase because we have enough glucose -- but KA are in the postabsorptive phase because no active supply of glucose
consequence and clinical example of defects in GH receptor
- mutated GHR = GH resistance - Laron syndrome
leptin in starvation
- negative energy balance = low leptin - decreased POMC, increased NPY/AGRP - increased food intake and weight gain - energy balance restored
do excess androgens of PCOS affect insulin
- normally effects on insulin resistance balance out because of simultaneous oestrogen and androgen production - increased androgens (progesterone and cortisol) result in increased insulin resistance - increases plasma insulin - so excess androgens affect insulin
events in late proliferative phase (day 13-14)
- oocyte released from follicle - uterine lining thickens The glands are long and tortuous due to active growth. Stroma is gradually becoming oedematous.
placenta
- organ allowing fetus to access maternal blood - all umbilical blood vessels in umbilical cord enter villus trees which have big SA and are dense with vascularisation so fetus can absorb oxygen and nutrients from mother's blood - placenta has tissues containing trophoblasts that invade mother's blood supply
the incretin effect
a significantly enhanced insulin secretory response to oral glucose than to the same glucose dose administered IV
indices of puberty in girls
a) breast bud b) pubic hair begins c) peak height spurt d) menarche (menstruation) e) pubic hair adult f) breast adult
indices of puberty in boys
a) genital development begins (spermatogenesis begins) b) pubic hair begins c) peak height spurt d) genitalia adult e) pubic hair adult
how do nutrients pass through placenta
aa: several mechanisms including ATP dependent, aa specific and concentration gradients gluc: glucose transfer predominantly by GLUT-1 in second half of pregnancy FA: passive diffusion/membrane carrier proteins
what happens to proteins in absorptive state
absorbed as AA
lipostatic/adipostatic theory
acc to Kennedy 1953: • total body weight maintained by regulating body fat content • hypothalamus senses conc of a CF which provides info on size of fat stores • ob/ob lack cf providing info on fat stores • db/db mice unresponsive to cf providing info on fat stores
main source of information on energy reserves
adipose tissue, the major energy depot
where is glucocorticoid (cortisol) produced
adrenal cortex
what does the medulla of the adrenal glands produce
adrenaline/epinephrine and noradrenaline/norepinephrine
the two major events that cause an increase in circulating reproductive hormones and subsequent pubertal changes
adrenarche and HPG axis
what is the point where no further primary oocytes can be generated
after birth, but newer research says maybe can be due to germline stem cells maintained post birth
what age is ossification usually complete by in humans
age 25
what does the zona glomerulosa produce
aldosterone (regulate Na and K)
why are there sex-specific changes in adolescent bone growth
allows for the hormonal activation of certain genes and are caused by different mechanisms to the pubertal growth spurt
why is the regulation of energy homeostasis and reproduction bidirectional
allows integrated control of both systems in terms of whole body physiology, extremely useful for ensuring successful reproduction whilst maintaining the health of the mother
which cells in islets make which hormones
alpha cells (glucagon) beta cells (insulin) delta cells (somatostatin)
alpha-MSH
alpha-Melanocyte-stimulating hormone, relates to skin pigmentation in Melanocyte 1 but also linked to obesity - suppresses appetite in hypothalamus
physiological stress
an endocrine response: any event that elicits increased secretion of the glucocorticoid steroid hormone cortisol
where is growth hormone produced (polypeptide hormone)
anterior pituitary under control of hypothalamus
gap junctions and labour
- Gap junctions made from CONNEXIN proteins (Cx) - Cx43 and Cx26 up-regulated during labour. - Better transmission of signals between cells Increased GAP JUNCTIONS, intercellular communication, more powerful contractions
adolescent growth spurt and end of growth spurt
- Growth plates generate new bone longitudinally and extend the length of the bone rapidly during the adolescent growth spurt - At the end of the growth spurt the epiphyseal growth plate fuses into bone, preventing the bone from extending in adulthood - with no gonadal steroids - no growth spurt
HPG axis and follicular phase
- High FSH causes proliferation of granulosa cells. - Increased oestradiol release as follicles grow. - Negative feedback causes FSH to fall.
HPG axis and ovulatory phase
- High oestradiol switches to a positive feedback effect. • Normally oestradiol has a negative feedback effect on LH release but at high concentrations it has positive feedback effect. • The positive feedback loop between oestradiol and LH causes the "LH surge". • This surge triggers ovulation - "LH surge" in response to positive feedback causes ovulation.
indirect effects of growth hormone
- IGF-1 binds to cell surface IGF-1 receptors: • increased protein synthesis • cartilage formation and bone growth • increased growth of all organs
developing gestational diabetes
- Insulin resistance increases during pregnancy. - Islets adapt to compensate. - Failure to compensate with increased insulin secretion leads to gestational diabetes
hypothalamus and obesity effect on reproductive function
- increased leptin, so chance of leptin resistance increases - causes POMC and NPY to be desensitised - no stimulatory signal from POMC - inhibitory signal from NPY comes through - so no FSH and LH and declined reproductive function
events that happen in adrenarche
- increased production and secretion of adrenal androgens from newly formed zona reticularis in adrenal cortex - Results in the release of weak androgens including dehydroepiandrosterone (DHEA), DHEA sulphate and androstenedione. - leads to peripheral conversion - testosterone and dihydrotestosterone (DHT) - all these hormones cause development in both genders of: • Pubic and axillary hair • Changes in sweat and body odour • Increased oiliness of skin and acne
actions of insulin in target tissues
- increases anabolic actions - decreases catabolic actions
what mechanism of labour does infection and inflammation affect
- inflammation becomes driver of labour - increased COX-2, IL-1beta, decreased PGDH and inc MMPs causes increased prostaglandins and functional P4 withdrawal
absorptive state
- ingested nutrients enters the blood from the GI tract (we are absorbing food) - takes ~3 hours for an average meal - blood travels directly from GI tract to liver via hepatic portal vein
catabolic actions of insulin in liver
- inhibits glycogen phosphorylase to reduce glycogenolysis - inhibits gluconeogenesis - inhibits ketone production
effect of cortisol on inflammatory and immune response and clinical importance
- inhibits inflammatory and immune response - inhibits PG and (leukotriene) LT production - inflammatory cytokines stimulate ACTH, hence cortisol secretion in -ve loop to damp down inflammatory responses - clinically important as anti inflammatory therapy - but prolonged use has severe side effects (Cushings), including down-regulation of ACTH secretion and adrenal atrophy
effect of cortisol on non essential functions and clinical importance
- inhibits non-essential functions like reproduction and growth - reduction in bone density, skin thickness, muscle mass, etc as catabolic processes generate fuel - chronic stress/elevated cortisol in childhood may cause growth retardation - chronic stress in adults may reduce fertility - clinically important as side effects of cortisol therapy
hypopituitarism and treatment
- insufficient GH secretion - e.g. german shepherd dog dwarfism • inherited "pan-hypopituitarism" (undersecretion of hormones from the pituitary gland). • puppies are normal at birth but have a reduced rate of growth due to insufficient GH and IGF-1 secretion. - growth hormone injections are the treatment
what causes hypothalamus to start releasing GnRH under normal circumstances
- kisspeptins (peptides encoded by the Kiss-1 gene), identified as endogenous ligands for the orphan G-protein coupled receptor, GPR54 - Without the GPR54, puberty doesn't occur, so kisspeptin is crucial in controlling onset of puberty
hypothalamus effect on reproductive function when eating normally
- leptin released from adipose cells - cause +ve effect on POMC which causes +ve effect on GnRH and Kisspeptin - causes -ve effect on NPY - kisspeptin has +ve effect on GnRH which has +ve effect on gonadotrophs, which release FSH and LH
leptin and appetite
- leptin released from adipose cells - major satiety signal to hypothalamus - lack of leptin/leptin resistance leads to excessive appetite and obesity
components of breast
- lobules/alveoli where milk is produced and stored, grow during pregnancy to make more milk-producing cells - tubules that allow milk to be delivered to baby
pre-pubertal hypothalamic-pituitary-gonadal (HPG) axis
- low levels of GnRH from hypothalamus to anterior pituitary - low levels of FSH and LH from anterior pituitary to ovary/testis - no eggs/sperm released
anatomy of testes
- made up of dense networks of tubules that all connect into epididymis and therefore vas deferens - two compartments: leydig cells and seminiferous tubules
leptin receptor characteristics
- member of cytokine receptor family - expressed mostly in hypothalamus, also liver, muscle, adipose and other tissues
internal signals for regulating eating behaviour
- metabolic (glucose, lipids, amino acids) - hormonal (leptin, insulin, gastrointestinal) - neural (gastric distension)
thyroid hormone receptors characteristics
• located in nucleus (unlike steroid R) • hormone binding allows receptor to bind to specific DNA sequence(s) • requires heterodimer with RXR to enhance transcription (unlike steroid R) of specific genes • enhanced synthesis of specific proteins • slow response
effects of underproduction of thyroid hormones in adults
• low metabolic rate • weight gain • cold sensitivity (not enough UTP) • deficient growth (fractures, wound healing) • slow mental processes • decreased cardiac activity
lipolysis
TAG in adipose tissue broken down, generates FA and glycerol which travels to liver, liver converts glycerol to glucose
events of menstrual phase
- oocyte disintegrates - Uterine lining sloughs off and is removed from the body, passing through the cervix and vagina - Once the uterine lining is removed the endometrium starts to proliferate again.
hyperprolactinemia in males
- pituitary level disorder - Abnormally high levels of circulating prolactin which inhibits GnRH. - Can be caused by pituitary tumours. - Also often a side-effect of various prescription drugs that affect dopamine. - In males symptoms include decreased libido and reduced fertility
steroidogenesis in pregnancy
- placenta gets cholesterol from mother to produce progesterone - cholesterol crosses through placenta through blood - progesterone is maintained this way - fetus also produces DHEA/DHEAS so placenta can make oestrogens
pro-relaxation
- promote K channel activity, lowering excitability of cell - suppress pathways for muscle contraction at labour onset
basal insulin concentration
0.4ng/ml (~70pM)
humoral regulation
CNS regulatory mechanisms -> caloric intake -> energy balance stored calories -> leptin -> CNS...
how LH and FSH are released, in response to what and where from
Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH) are released together into the circulation from the anterior pituitary in response to GnRH
how does insulin travel in blood
as a monomer
fat redistribution in cushing's
buffalo hump
how is PCOS characterised
by a positive feedback loop between androgens and insulin still unclear which part of this loop is the initial cause of PCOS development - may be multiple factors
what comprises meals
carbohydrates, proteins and fats
role of umbilical vein
delivers oxygen, nutrients and hormones to the baby
atretic
deteriorated follicle
what is proinsulin and explain cleavage of C-peptide from proinsulin
Proinsulin is an insulin precursor peptide. It contains a connecting peptide as well as the A- and B-chains of mature insulin. peptidases in the secretory granules cleave proinsulin to produce active insulin and free C-peptide
insulin biosynthesis in beta cells
nucleus • transcription of insulin gene - preproinsulin mRNA Endoplasmic reticulum • translation of mRNA making preproinsulin • preproinsulin is rapidly cleaved to proinsulin Golgi apparatus • proinsulin packaged into secretory granules Secretory granules • proinsulin converted to insulin and C peptide • mature insulin has low solubility and forms crystals with Zn2+
what does increased testosterone released from the growing testes drive
the formation of secondary sexual characteristics e.g. facial hair, voice breaking
secondary follicle in ovarian development
• Theca cells are recruited by the oocyte to form the basal lamina around the follicle. • The basal lamina differentiates into two layers, the theca externa and the theca interna which provide a blood supply to the follicle. • The antrum, a fluid filled cavity next to the oocyte forms
myometrium
- dense smooth muscle cells embedded in connective tissue and well vascularised. - Sparsely innervated in pregnancy
leptin receptor gene mutation
- mutation in leptin receptor gene resulting in truncated receptor - patients eat nearly all the time
which part of the HPG axis triggers the start of puberty
- we know that the pituitary, ovaries and testes can all function earlier (precocious puberty) - so we know that GnRH release is responsible
how does leptin resistance develop in obesity
1) Expansion of adipose tissue 2) Increased secretion of leptin 3) Increased serum leptin concentration 4) continuous stimulation of leptin receptors 5) down-regulation of leptin receptor signalling
spermiogenesis
4-phase process that converts the symmetrical spermatids into mature sperm. 1) golgi phase 2) cap phase 3) acrosome phase 4) maturation phase
how much does insulin concentration rise when glucose levels increase
5-10 fold
when does the fetus synthesise insulin
9-11 weeks
what binds to testosterone to stimulate spermatogenesis
ABP
maturation phase of spermiogenesis
Excess cytoplasm is phagocytosed by Sertoli cells to produce mature sperm.
what are the sertoli cells regulated by
FSH
what stimulates the sertoli cells to produce ABP and inhibin
FSH
receptors of melanocortin system
MC1R (skin and hair) MC2R (adrenal) MC3R (hypothalamus) MC4R (hypothalamus)
what two cell types comprise the seminiferous tubules besides sperm cells
both sertoli cells and spermatogonial stem cells
effect of resistance to stress response
chronic: cortisol levels elevated
why was sibutramine banned
due to increased risk of serious cv events
why was rimonabant banned
due to increased risk of serious psychiatric problems and suicidal tendencies
when do the early stages of gametogenesis occur
during development before birth
sperm transport post ejaculation
ejaculation: deposition of sperm in vagina (acidic) cervix: mucous barrier and crypts as sperm reservoirs - sperm motility important uterus/fal tubes: mild contraction to propel the sperm towards egg
two main control systems
endocrine (long term) and sympathetic nervous system (short term)
effect of cortisol on cardiovascular reactivity and clinical importance
enhances CV reactivity to catecholamines - so allows vasoconstriction in response to (nor)adrenaline - clinically important because chronic stress can cause hypertension; low/absent cortisol can cause hypotension
effect of GLP-1 on islet B cells
enhances glucose dependent insulin secretion which in fat/muscle the increased insulin stimulates glucose uptake and storage
what does the wolffian duct develop into
epididymis, vas deferens, seminal vesicles (male reproductive organs)
sympathetic nervous system
fight or flight
hypothalamus effect on reproductive function when fasting
leptin release decreases, so POMC not stimulated, NPY stimulated, results in less FSH and LH and reproductive function turned off
how do pregnant women adapt to insulin resistance
like in obesity, islets must adapt to compensate • Increased glucose-stimulated insulin secretion • Increased β-cell mass • Increased insulin synthesis • Increased gap junctions between β-cells • Increased cAMP metabolism
organs involved in fuel homeostasis
liver, adipose, muscle
location and characteristics human adrenal glands
located above kidneys, cortex split into zona glomerulosa, zona fasciculata and zona reticularis, medulla under cortex
plasma levels of GIP and GLP-1 in fasting state
low
where are L cells found
lower GI tract, in ileum and colon
treatments for type 2 diabetes
lower blood glucose • diet • a-glucosidase inhibitors increase insulin secretion • sulphonylureas/glinides • exenatide/DPPIV inhibitors increase insulin sensitivity • thiazolidinediones • biguanides increase glucose exertion • SGLT2 inhibitors
main products of proglucagon from L-cells
main product is GLP-1 (also some GLP-2)
what is the role of spermatogenesis
maintaining species
liver in fuel homeostasis
major glycogen store
main precursor for testosterone
pregnenolone
where is GIP (glucose dependent insulinotropic polypeptide) synthesised from
proGIP in K cells of proximal GI tract (duodenum and proximal jejunum)
puberty end goal
production of viable gametes
effect of GLP-1 on brain
promotes satiety and reduces appetite
what is stress
psychological, emotional, with stressors generating similar responses, an endocrine response
thyroid hormones and the seasonal regulation of body mass
short days = winter = reduced body weight, restricted = reduced food intake, returns to normal. T3 reverses effects of short day on body weight, short day decreases body weight
function of glucocorticoid (cortisol)
• maintains liver and adipose enzymes required for gluconeogenesis and lipolysis
catabolic
'break down' aka glycolysis
immune system effects of cushing's syndrome
• immunosuppression, infections
anabolic
'build up' aka storing glucose or aa
characteristics of type 1 diabetes
• ~ 10% of all cases of diabetes • autoimmune destruction of pancreatic b-cells by lymphocytes 'insulitis' • progressive disorder • almost total destruction when clinical symptoms present • genetic susceptibility • environmental factors may trigger immune response - fasting plasma glucose higher than normal person
characteristics of type 2 diabetes
• ~ 90% of all cases of diabetes • many causes leading to similar pathology • insulin resistance in peripheral tissues • b-cell dysfunction, impaired insulin secretion • genetic susceptibility • environmentally associated with obesity/excessive energy intake of "Western" diet • alarming increase of T2DM in children/adolescents • risk reduced by exercise
cardiovascular effects of cushing's syndrome
• vasoconstriction, hypertension
General Adaptation Syndrome (GAS)
(1) Alarm • Fight or flight: short term, adrenaline (2) Resistance to stress • Chronic: cortisol levels elevated (x10) (3) Exhaustion • immune suppression, illness, death
body's responses to prolonged fasting/starvation
(1) fatty acid and ketone utilisation by peripheral tissues: glucose sparing for CNS as described for postabsorptive stage (2) short-term: protein catabolised to generate amino acids that are converted to glucose by the liver via the keto acid pathway (3) long term (> 3-4 days) brain metabolism alters to utilise ketones as well as glucose: ketone production predominantly from FA derived from TAG, so much less protein catabolism is required, so less muscle wastage (4) efficient mechanisms: after 4 days starvation BG reduced by only a few %, after 1 month by only 25% (5) prolonged starvations: body uses skeletal muscle protein and eventually breaks down protein in other tissues i.e. vital organs, which is when irreversible
the tanner scale
- 1-5 scale of physical development defined to objectively measure sexual maturation - 5 stages of physical development are defined, based on measurements of external primary and secondary sex characteristics such as breast development, genital development and pubic hair
triple X syndrome
- A genetic disorder in which a female has three X chromosomes. - Individuals will have 47 chromosomes instead of the normal 46 with XXX. - Effects vary between individuals, many people will not show any symptoms, but it can result in underdeveloped ovaries and reduced fertility. - Affects around 1:1000 females.
Cushing's syndrome
- Adrenal cortex tumour ↑ cortisol - Pituitary adenoma ↑ ACTH (>70%, Cushing's disease) - Net effect generates symptoms similar to chronic stress
blastocyst stage
- After 5 days the zygote has reached the uterus and become a blastocyst. - An inner cell mass that will become the embryo. - The trophoblast surrounding the inner cell mass, which will become the placenta.
role of oestrogens in pregnancy
- CV adaptation to pregnancy (more low resistance so more blood flow) - growth of uterus - 'priming' uterus for labour - weak anti-insulin activity in loner (via increased cortisol) - onset of labour and cervical ripening
what causes SPTB
- Clinical/sub-clinical infection - Cervical weakness/shortening - Decidual haemorrhage/abruption - Multiple fetuses - Bacterial vaginosis - Maternal age - Genetics (gene-environment) - Prenatal BMI and diet - Environment - Social/psychological stress
how does myometrium contract in labour
- Contraction dependent on calcium - Changes in calcium handling at term - Uterotonins (PGs or oxytocin) augment contractions so that contractions are stronger
events in proliferative phase (day 5-13)
- Endometrium proliferates and thickens, tubular glands and arteries form. - Stimulation of progesterone receptors synthesis in endometrial cells. - oocyte matures in follicle - uterine lining renews
environmental changes for regulating eating behaviour
- Food palatability - Adversive food behaviours both lead to psychological factors (cortical)
effect of peptides secreted by K and L cells on underlying weight loss and glycaemic improvements as a result of weight loss from gastric band
- GIP: stimulates insulin secretion - GLP-1: reduces food intake stimulates insulin secretion reduces glucagon secretion - PYY: reduces food intake enhances insulin-stimulated glucose uptake • L-cell peptide levels are increased within days after surgery and remain elevated for many years
effect of orexigenic hypothalamic peptides (NPY, AGRP, MCH, Orexins)
- increased food intake - decreased sympathetic tone (decreased energy expenditure) - increased fat intake
congenital adrenal hyperplasia (21-hydroxylase deficiency)
- Mutation leading to an inactivation of the enzyme 21-hydroxylase, responsible for cortisol synthesis. - The adrenal gland cannot produce cortisol and instead produces an excess of androgens. - Excess androgens in females cause male physical development, including development of external male genitalia or ambiguous genitalia - Can still have normal uterus and ovaries
examples of orexigenic peptides
- NPY (Neuropeptide Y) - AGRP (Agouti-related peptide) - orexins - MCH
examples of anorexigenic peptides
- POMC (pro-opiomelanocortin) - CART (cocaine and amphetamine-regulated transcript)
ligands of melanocortin system
- POMC -> alpha-MSH - AGRP
effect of L cells secreting peptides underlying weight loss and glycaemic improvements
- PYY: reduces food intake enhances insulin-stimulated glucose uptake • L-cell peptide levels are increased within days after surgery and remain elevated for many years
eunuchoid gigantism
- Rare form of gigantism related to undeveloped sexual organs and associated lack of pubertal development. - in absence of gonadal steroids, specifically oestrogens (usually oestrogen receptor deficiency) - however, gigantism is far more commonly due to excess growth hormone
androgen binding protein (ABP)
- Spermatogenesis requires very high levels of testosterone around the developing sperm. - ABP binds to testosterone in the lumen, making testosterone less lipophilic. - Concentrates testosterone in the lumen, increasing fertility
advantage of treating T1DM with GLP-1 analogues
- T1DM patients suffer weight gain - T1DM consequence of loss of islet B-cells - but insulin use associated with weight gain - GLP-1 associated with weight loss, therefore can help control their weight - delivery of GLP-1 analogues = reduced requirement of insulin for controlling blood glucose levels - but then delayed gastric emptying and reduced glucagon secretion reduce risk of hypoglycaemia
HPG axis and end of luteal phase
- The corpus luteum degenerates. - Oestradiol and progesterone levels fall. - LH and FSH rise. - The cycle starts again...
HPG axis and luteal phase
- The follicle collapses causing oestradiol levels to fall and resume negative feedback. - The follicle becomes the corpus luteum, releasing oestradiol and progesterone. - LH and FSH are suppressed.
implantation
- The trophoblast layer attaches to the surface of the endometrium (implantation) - The blastocyst invades the endometrium. - Trophoblast cells release human chorionic gonadotropin which maintains the corpus luteum during early pregnancy (prevents menstruation)
3 subtypes of spermatogenesis
- Type A(d): Replicate by mitosis around edge of sem tubules to provide a constant supply of Type A(d) and Type A(p) cells. - Type A(p): Divide by mitosis to provide Type B cells and replace themselves. Called p because pale - Type B: Divide by mitosis into primary spermatocytes.
effects of reproduction on fuel homeostasis
- Under normal circumstances reproductive function does not strongly regulate fuel homeostasis. - There are slight changes in insulin sensitivity and energy homeostasis across the female reproductive cycle and at puberty. - However, during pregnancy the reproductive axis has a large effect on energy homeostasis.
hypogonadotrophic hypogonadism
- a condition in which there is impaired pubertal maturation and subsequent lack of reproductive function - different forms: sometimes a hereditary genetic defect - without kisspeptin receptor (GPR54), puberty does not occur and reproductive organs remain undeveloped
addison's disease
- adrenal cortex damaged by tuberculosis or by autoimmune destruction - adrenal insufficiency causes: • hypotension, hypoglycemia, tiredness, weakness, anorexia, vomiting, depression • Progressive, maybe misdiagnosed as chronic fatigue syndrome • inability to respond to stress = Addisonian crisis, fatal if untreated • Treated by steroid replacement therapies
discoid placenta
- area of transfer in one disk, shaped like oval - rodents, primates
Hashimoto's thyroiditis
- autoimmune destruction of thyroid • About 1 in 1000 occurrence, 8-15 times more common in women, most often middle aged (40-60). • Circulating antibodies against thyroid peroxidase, thyroglobulin and/or TSH receptors. • TSH is increased as the pituitary tries to compensate for decreased T4. • Treated with T3/T4 replacement (oral).
gastric band
- band with an inflatable balloon is inserted around the upper stomach to create a pouch - restricts passage of food and leads to prolonged fullness after feeding - balloon diameter regulated by injecting saline through subcutaneous port and this adjusts the degree of gastric restriction - absence of any anatomical changes mean that procedure is readily reversible but the band usually remains in situ for life
what mechanism of labour does decidual/placental haemorrhage affect
- bleed out very quickly because of low-resistance placenta blood supply - thrombin for blood clotting induces labour
thyroid
- butterfly shaped gland over the windpipe - made up of little follicles - good blood supply as use blood to transport hormones
GH gene mutations consequences and treatments
- can lead to proportional short stature - treated with GH injections
how is glucose-6-phosphate converted to glucose in muscle
- can't be converted in muscle as no glucose-6-phosphatase - undergoes glycolysis to produce lactate and pyruvate - these are released and travel in blood to liver - in liver they are converted to glucose
effect of circulating leptin proportional to fat cell mass first order neuron POMC/CART
- circulating leptin activates POMC/CART neuron - encourages alpha-MSH expression - alpha MSH receptors therefore stimulated - leads to less food intake
what initiates/times labour
- in rodents/goats/sheep it is functional progesterone withdrawal (drop in progesterone) mediated by HPA axis - in humans/monkey/guinea pigs: • fetal HPA involvement • functional progesterone withdrawal • inc oestrogen concentrations actually probably many phys events pushing towards labour to ensure survival - no single trigger
effect of circulating leptin proportional to fat cell mass on first order neuron NPY/AGRP
- circulating leptin inhibits NPY/AGRP neuron - low circulating leptin stimulates NPY/AGRP neuron - more NPY/AGRP expressed - more NPY and AGRP released so more food intake. - AGRP also inhibits alpha MSH receptors via paraventricular nucleus (more food intake by inhibiting receptors that cause less food intake)
characteristics of islets of langerhans
- comprise ~2% of total pancreatic mass - 100 µm in diameter - adult pancreas contains ~10^6 islets - contain ~1,000-2,000 cells, of which: • ~ 60-80% are insulin-secreting b-cells • ~20-40% are: • glucagon-secreting alpha-cells • somatostatin-secreting delta-cells • pancreatic polypeptide-secreting PP-cells
two types of hypothyroidism
- congenital thyroid failure (from birth) - acquired later in life (lack of iodide in diet/Hashimoto's)
insulin hexamers
- consist of six insulin molecules surrounding a zinc ion - insulin molecules interact with the zinc ion via B-chain histidine residues
effect of anorexigenic hypothalamic peptides (POMC -> α-MSH, CART, CRH, TSH)
- decreased food intake - increased sympathetic tone (increased energy expenditure) - increased fat oxidation
human leptin gene mutation
- deficiency or inactive leptin leading to insatiability and overeating - results from being homozygous for deletion mutation in leptin gene (inactive protein) (maybe from consanguineous marriage) - treated by administering leptin
Effect of leptin deficiency
- drives hunger - suppresses energy expenditure - failing serum leptin levels primarily act to inform brain that body is starving
how do the physiological signals of nutritional status affect reproduction
- fasting and obesity impair reproductive function - obesity linked with decline in reproductive function
what mechanism of labour does multiple fetuses affect
- fetal HPA and CRH-placenta - cervical/uterine distension
insulin in fetus
- fetal insulin determines glucose metabolism - excess glucose = excess growth and fat deposition - inadequate glucose = emaciation
how to remove fetal bilirubin
- fetus cannot convert bilirubin to glucuronide because no enzyme - fetus builds up bilirubin, high concentration - bilirubin travels down concentration gradient across placenta to maternal blood - mother has enzyme to convert bilirubin to be excreted as bile/converted to glucuronide
why does a fetus depend on the mother for glucose
- fetus have little capacity for gluconeogenesis - necessary enzymes don't function at ambient low pO2
what are the multiple functions of the sertoli cells
- forms the blood testis barrier - release androgen-binding protein (ABP) - release inhibin for feedback on the pituitary - secrete supporting fluid into the lumen - phagocytose residual cytoplasm from spermiogenesis - release a range of other proteins such as GDNF and anti-mullerian hormone
disturbances in ovarian function
- genetic level (triple x and turner syndrome) - hypothalamic level (kallmann syndrome) - pituitary level (hyperprolactinemia) - ovary level (PCOS) - other tissues (congenital adrenal hyperplasia)
klinefelter syndrome
- genetic level disorder - male with X and Y chromosome also has additional X chromosome - individuals have 47 chromosomes (46 is normal) with XXY - effects vary, many people don't show symptoms, can result in hypogonadism + reduced fertility
adipose's role in the absorptive state for glucose
- glucose converted to fatty acids and a-glycerol phosphate, essential for TAG synthesis in adipocytes - excess CHO stored as fat
hormonal release in early fetal and placental growth
- hCG and hPL from syncytiotrophoblasts stimulate progesterone from corpus luteum - progesterone stimulates progesterone receptor and releases prolactin - prolactin from mother and hCG and hPL from fetus stimulate glandular epithelium of mother - GE produces nutrients (glycodelin A) for fetus and GF (VEGF and EGF) to allow proliferation
effect of GHR knockout in mice
- heterozygous mice were very similar to wild-type mice - homozygous mice showed: • no expression of GHR • severe postnatal growth retardation • proportionate dwarfism • delayed puberty • severe postnatal growth retardation
synthesis and secretion of thyroid hormones
- hormone synthesis takes place outside thyroid cells in colloid on a protein template (thyroglobulin) - thyroid peroxidase enzyme activates iodide from diet - tyrosine residues on thyroglobulin are iodinated (forming DIT/diiodotyrosine) - two DIT molecules couple together to form T4 - hormones stored in colloid (attached to thyroglobulin)
turner syndrome
- hypothalamic level disorder - A genetic disorder in which a female only has one X chromosome. - The vast majority of Turner syndrome embryos either spontaneously abort or are stillborn. - Results in many health problems, including non-functional ovaries and lack of reproductive function.
Kallman syndrome
- hypothalamic level disorder - GnRH neurones originate from olfactory region of brain - genetic mutations affecting olfactory bulb also stop GnRH neurones developing - lack of GnRH neurons results in no reproductive function - also causes loss of smell because olfactory bulb affected
why are there arterial plugs in the placenta before the end of the first trimester
- hypoxic conditions needed in early pregnancy to ensure angiogenesis and protection of fetus because fetus sensitive to oxidative stress - so arteries plugged until embryo is developed enough to withstand oxygenated environment
beneficial effects after bariatric surgery
- improvement of diabetes and glucose homeostasis - improved glucose tolerance after gastric bypass
protein in postabsorptive state
- in fasting or starvation skeletal muscle protein catabolised - amino acids converted to glucose in liver - protein becomes the major source of glucose a few hours into the post-absorptive period
effect of UCP-1 in thermogenesis
UCP-1 causes heat loss as energy in proton gradient is dissipated without being stored in reactive molecules like ATP
polycystic ovarian syndrome (PCOS)
- ovary level disorder - causes of PCOS unclear, but it may be genetic. - the 'cysts' are some follicles at the early antral stage halt development and release excess androgens. - Severity of effects vary, from just slightly irregular cycles to infertility, hirsutism and susceptibility to other diseases such as diabetes. - can get excess hair growth, acne etc - The most common female endocrine disorder - affects around 5-10% of females.
Acromegaly characteristics and treatment
- over secretion of GH post-puberty - excess GH in adulthood (usually pituitary adenoma causes acromegaly) - as bone epiphyseal growth plates have closed, acromegaly is characterised by lateral thickening of bones in jaw, fingers and toes - treated by surgical removal of pituitary tumour or administration of somatostatin analogues
cause of gigantism, and possible treatment
- oversecretion of GH pre-puberty • Excess GH in childhood (usually pituitary adenoma) causes gigantism. It is extremely rare. • As the bone epiphyseal growth plates have not closed, gigantism is characterised by excessive height, with proportionate growth. - treated by Surgical removal of pituitary tumour or administration of somatostatin analogues
potential mechanisms for preterm birth
- placental/vascular problems - inflammation reaction - maternal stress - hormonal signals/uterine stretch
leptin in fed state
- positive energy balance = high leptin - increased POMC, decreased NPY/AGRP - decreased food intake and weight loss - energy balance restored
LH secretion at puberty
- pre-puberty: low levels of LH - mid puberty: night time increase in LH pulses, but no change during the day - late puberty: regular pulses of LH throughout the day and night
why do women become insulin resistant in pregnancy
- pregnancy hormones - Glucose in the maternal blood is transported across the placenta via GLUT3 transporters - maternal insulin resistance = increased glucose available to the fetus - can be useful as long as blood glucose maintained at healthy level
role of progesterone in pregnancy
- prepares and maintains endometrium to allow implantation - produced initially by CL then placenta - potential role in suppresing maternal immunulogic response to fetal antigens to prevent maternal rejection of trophoblast - plays role in parturition - substrate for fetal adrenal gland production of gluco/mineralocorticoids - Growth of mammary glands - Maintenance of pregnancy - Inhibition of uterine contractility - Prevention of ripening of cervix - Induces overbreathing and lowering of maternal CO2
cells in initial recruitment in development of ovarian follicle
- primary follicle (100µm) - secondary/antral follicle (200-4000µm) - mature follicle (20mm)
two main physiological functions of the testes and what are they controlled by
- production and release of testosterone - spermatogenesis - controlled by the hypothalamic-pituitary-gonadal axis
how progesterone and oestrogen affect insulin sensitivity
- progesterone/cortisol have neg effect on insulin sensitivity (stop insulin binding to receptor) - oestrogen beneficial effect on insulin binding - cancel each other out but - progesterone/cortisol inhibit post-receptor signalling
role of prolactin in male reproduction
- prolactin released from pituitary and affects male fertility - increases LH receptor expression on the Leydig cells resulting in increased testosterone release and increased spermatogenesis and fertility
precocious puberty
- puberty occurs very early on in life - as soon as birth can notice secondary sexual characteristics - caused by hypothalamic hamartoma (benign tumour). - Puberty triggered earlier than intended due to inappropriate GnRH release from the hypothalamus
events in secretory phase (day 15-22)
- remaining cells of follicle develop into corpus luteum - oocyte travels through tube - lining continues to thicken - The growing endometrium becomes dependent on progesterone released from the corpus luteum. - Enlargement of tubular glands which begin secreting mucus and glycogen in preparation for implantation of the fertilized ovum.
why is diabetes during pregnancy a problem
- risks to baby: • Macrosomia (big ass baby) • Risk of birth injury • Hypoglycaemia • Respiratory problems - risks to mother • High blood pressure • Preeclampsia (high BP and potential damage to organs) • Urinary tract infections • Caesarian section
effect of IGF-1 knockout in mice and what does it mean
- severe growth retardation, proportional dwarfism akin to GHR knockout mice - so IGF-1 plays important roles in promoting/mediating growth hormone effects
phenotypic sexual dimorphism
- sexual dimorphism develops from changes in body composition - higher levels of oestradiol or testosterone in f/m respectively cause changes in tissue development • marked increase in muscle mass in boys and increase in body fat in girls therefore differences in muscle strength • androgens stimulate growth of larynx and lengthening and thickening of vocal cords resulting in deepening of voice in both males and females, though effect is much more dramatic in males due to higher androgen levels
why does the uterus change during labour
- signals from fetal HPA and placental hormones/CRH causes increased PG - functional progesterone withdrawal from sudden reduced reception of PG causes expulsion of uterus
gastric bypass
- small gastric pouch with a volume of around 15-30ml separated from the rest of the stomach (gastric remnant) - this pouch is surgically connected to the lower jejunum, so food bypasses most of the stomach, the duodenum and upper jejunum - the gastric remnant remains in situ, but no longer comes into contact with food
why do we need fuel homeostasis
- sporadic intake of food but constant requirement of tissues for nutrients (absorptive and post absorptive states) - CNS is almost entirely reliant on glucose as a metabolic substrate so we need a regular level of glucose - short and long term storage of fuels, mobilisation of stores in postabsorptive state when needed
Maturity onset diabetes of the young (MODY) treatment
- sulphonylureas that bypass limit for glucose metabolism but lead directly to insulin secretion (increase insulin secretion) - inject insulin like in T1/T2DM
Androgen insensitivity syndrome
- target tissue level disorder - Genetic defects in the androgen receptors reduce sensitivity to testosterone and other androgens. - The extent of androgen insensitivity can vary resulting in a wide range of severity. - Sometimes only very mild effects, but complete androgen insensitivity can result in female body development despite XY chromosomes
how would DPP-4 inhibitors work in treating T2DM
- they would work by increasing endogenous GLP-1 - DPP-4 removes two amino acids from the N-termini of GLP-1 and GIP, which renders them inactive - DPP-4 inhibitors maintain GLP-1 (and GIP) levels by blocking cleavage of the N-terminal dipeptide that inactivates the incretins - Blood glucose levels fall in the presence of DPP-4 inhibitors due to elevation in insulin secretion and reduction in glucagon release. - DPP-4 inhibitors now used to treat T2DM (since 2006) - DPP-4 inhibitors also inc circulating GLP-1 half-life
blood testis barrier
- tight junctions between Sertoli cells forms a barrier between the lumen of the seminiferous tubules and the BVs - Allows the Sertoli cells to control the environment within the lumen. - Protects developing sperm from any toxins. - Separates the developing sperm from the immune system which would otherwise mount an autoimmune response. - spermatogonial stem cells outside BTB, but when they mature they are protected by moving into BTB
effect of pharmacological blocking of peroxidase
- treats hyperthyroidism - block first stage of thyroid hormone synthesis - adjust to prevent hyperthyroidism but also hypothyroidism
difference between umbilical arteries and veins
- two umbilical arteries blue, umbilical vein is red - vein is red because carrying oxygenated blood from mother to baby's heart - arteries carry deoxygenated blood away from baby's heart to mother
pro-contraction
- upregulation of pro-contractile pathways - increase calcium channels and ability to release calcium from stores - cells communicate with each other via gap junctions to amplify response
role of skeletal muscle and other organs in absorptive state for amino acids
- used to synthesise proteins and replace proteins lost by catabolism - excess AA converted to fat - other organs need AA to maintain tissue size and healthy cells
gastric sleeve
- vertical gastric 'sleeve' of ~200ml is formed by the lateral excision of up to 80% of the stomach - food bypasses most of the stomach, but has a normal passage down the GI tract - the excised portion of the stomach is removed
pubertal changes
1) Adolescent growth spurt • involving skeleton, muscle and viscera 2) Sex specific increases in growth rate • leads to phenotypic sexual dimorphism 3) Changes in body composition • particularly muscle and fat 4) The development of reproductive function • gonadal activity, secondary sexual characteristics
controlling fuel homeostasis during pregnancy
1) Increased progesterone / cortisol causes impaired insulin signalling in muscle and adipose tissue 2) increased prolactin causes increased insulin release and increase beta-cell mass 3) Insulin resistance results from progesterone and cortisol, but islets cope with the insulin resistance because of prolactin no adverse effects unless islets fail to cope
regulation of food intake and energy expenditure
1) Leptin binds to leptin receptors in hypothalamus, causing release of neuronal signals to region of the brain that reduces appetite 2) Once stimulated by leptin, the hypothalamus directs signal via sympathetic neuron to increase thermogenesis in adipose tissue
oogenesis
1) Migratory germ cells • Divide by mitosis to produce oogonia. • Starting from week 4-8 of foetal development. 2) Oogonia • Diploid cells with 46 chromosomes. • Divide by asymmetric mitosis to produce one oogonia and one primary oocyte. • Starting around week 10-20 of foetal development until birth. 3) Primary oocytes • Diploid cells with 46 chromosomes. • Start meiosis, but stop at prophase I. • Become dormant, halted at this stage of development.
what is it about the Y chromosome that is important in determining a male
1) Normally, XX chromosomes pair up and cross-over all along their length 2) but X and Y cannot - match at top (pairing region) but in non pairing region is sry gene 3) sry gene influences primordial gonads to become testes, which produce anti-mullerian hormone (AMH) and testosterone 4) testosterone ensures wolffian duct is maintained from positive feedback and also development of male external genitalia 5) AMH prevents mullerian duct using negative feedback
what happens to oocyte in ovulatory phase
1) Oocyte undergoes cell division. 2) Follicle wall thins and ruptures. • Just before ovulation the oocyte completes meiosis I. • Forms one secondary oocyte (23 chromosomes) which has all of the cytoplasm and is released • The remaining DNA forms a polar body which then degenerates. • The secondary oocyte immediately starts meiosis II, but stops at metaphase II. 3) Oocyte enters abdominal cavity near fimbriae of fallopian tube.
stages leading up to and after fertilisation
1) acrosome reaction 2) fertilisation 3) blastocyst 4) implantation
two endocrine responses to stress
1) alarm 2) resistance to stress
proposed mechanism of human labour
1) baby ready to be delivered, stretching and affecting local production of oxytocin and prostaglandins, also inducing neuroendocrine reflex causing mother to produce oxytocin 2) fetus still growing, still producing CRH, ACTH and cortisol 3) cortisol feeds into placenta increasing PG production in placenta 4) PG promotes contractions and cervical ripening 5) fetal adrenal gland also produces DHEA and DHEAS, allowing for oestrogen production in placenta 6) placenta produces more CRH in pregnancy, feeding into fetal adrenal gland, stimulating more cortisol 7) all contributes to labour 8) hormone only has effect when changing concentration, progesterone concentration plateaus, causing functional progesterone withdrawal and inducing labour
what is adult female reproductive function controlled by after puberty
a hormonal cycle and interactions between the ovary and the hypothalamus/pituitary
anovulatory cycle
a menstrual cycle characterized by varying degrees of menstrual intervals and the absence of ovulation and a luteal phase. In the absence of ovulation, there will be infertility
development of placenta
1) blastocyst attaches 2) blastocyst cells send trophoblasts to invade maternal tissue to make contact with maternal BVs by making migrating columns 3) on day 7, trophoblasts differentiate into cytotrophoblasts (stem cell layer) and syncytiotrophoblasts (multinucleated and fused) 4) syncytiotrophoblasts forms basis primary villus trees/villi stems/framework for chorionic villi/outer layer 5) cytotrophoblast (stem cell layer) have buds that grow to become blood vessels in villus trees 6) endovascular trophoblasts invade maternal spiral arteries and make them low resistance blood vessels so blood pours into placenta 7) day 17 embryo has contact with mother's blood but not fully established
three phases of ovarian cycle
1) follicular phase (days 1-10) 2) ovulatory phase (days 11-14) 3) luteal phase (days 14-28)
stages of labour
1) initial (latent) phase and active phase 2) propulsive phase 3) placental delivery
adiposity signalling by leptin
1) leptin circulates at levels proportional to body fat 2) in fed state elevated leptin stimulates hypothalamic neuronal pathways to increase energy expenditure and inhibit eating 3) as fat mass decreases, serum leptin levels fall, feeding stimulated and energy expenditure suppressed 4) fat reserves return to set point
gas exchange between mother and fetus
1) maternal uterine artery - maternal blood pours into pools around villus trees 2) fetal umbilical vein - maternal blood comes in oxygenated but mixes with fetal waste, so oxygen content decreases 3) fetal umbilical arteries - oxygen content of blood reduced as it passes through fetal heart - blood is deoxygenated 4) maternal uterine vein - before getting back to maternal vein, blood passes again through pool, increasing oxygen content in blood again
HPA axis and stress
1) neurons in hypothalamus send axons to median eminence 2) CRH released at median eminence, enters portal veins to control release of ACTH from anterior pituitary 3) ACTH released from the anterior pituitary enters the venous drainage to be transported to the adrenals
why is being female the default pathway in humans
1) no sry gene 2) no AMH and no testosterone 3) wolffian duct doesn't develop, instead female external genitalia 4) mullerian duct is maintained
phases of menstrual cycle
1) proliferative phase 2) secretory phase 3) menstrual phase
rationale for progesterone use to treat PTL
1. Functional progesterone withdrawal 2. Medroxyprogesterone acetate (MPA) prevents PTL in animals 3. Progesterone antagonist RU486 induces delivery in animals and women 4. Progesterone thought to be anti-inflammatory
how does suckling ensure milk production
1. Neuroendocrine reflex 2. Suckling • Stimulates production of vasoactive intestinal peptide • Reduces dopamine release (VIP = prolactin releasing factor) (dopamine = prolactin inhibitory factor) 3. Strength and duration of suckling determines amount of prolactin released (determines amount of milk available for subsequent feeds)
three main mechanisms of weight loss and T2DM improvement with bariatric surgeries
1. Reduced food intake and absorption 2. Decreased food intake through central effects 3. Increased insulin secretion/action
treatments of preterm labour
1. Smooth muscle relaxants 2. Inhibition of contractile pathways 3. Treat infection 4. Stop bleeding or response to bleeding 5. Inhibit inflammation related events (COX-2? PGR?) 6. Increase progesterone (not ideal because it doesn't actually drop)
aims of treatment for preterm labour
1. Stop uterine contractions 2. Reversal of cervical shortening/ripening 3. Prevention initiation of PTL
preventing preterm labour
1. Treat Infection: Prophylactic antibiotics (disease preventing) 2. Inhibit inflammation related events: COX-2 inhibitors, TLR antagonists, PG receptor inhibitors 3. Prevent progesterone withdrawal: Synthetic progesterone, natural progesterone 4. Maintain active cAMP system: Inhibit PDE activity
how long does the placenta take to be established
10-13 weeks, then corpus luteum degenerates
how many sperm are made per day and per sec
120 million sperm / day or 1,500 / sec
when is a woman prepared to produce milk and when does full lactation occur
16 weeks gestation, lactation doesnt happen until post-partum
why is fight or flight in terms of seconds/minutes
A/NA has short half life
cocaine and amphetamine-regulated transcript (CART)
Anorexigenic peptide co-expressed with POMC in ARC neurons
what causes myometrial contractions
CRH, oestrogen, oxytocin, uterine distension (uterus gets too stretched/big so muscles trigger labour) - Functional progesterone withdrawal - inflammation and influx of immune cells, prostaglandins from the fetal membranes
Maturity onset diabetes of the young (MODY) causes
Causes • single gene mutations • glucokinase • transcription factors HNF1a, HNF4a, HNF1b, PDX-1, Neuro D1 • mutations cause b-cell defects, insufficient insulin synthesis/secretion • not common: 1-2% of all cases of diabetes • people with MODY are generally not overweight
propulsive phase
Cervix fully dilated - 10 cm Strong propulsive contractions 1-2 hours
function of closed cervix and cervix structure
Closed cervix maintains pregnancy - barrier to ascending infection cervix: - elastic tissue with some smooth muscle - Collagen fibrils in a proteoglycan matrix. - epithelial cell lining and mucous plug
mechanisms initiating ripening of cervix
Due to inflammation - inc iNOS, COX-2 - inc Prostaglandin production (PGE2) - Matrix metalloproteinases 2 & 9, cytokines and immune cells - PGE2 induces cervical ripening - PGE2 causes membrane weakening and rupture and collagen breakdown Cervix softens and more likely to dilate/efface ready for labour
non hormonal factors affecting sperm production
Environment: • Climate (heat) • Radiation • air pollution • food chain pollution • stress • oxidative stress affecting rapid sperm production
muscle's role in absorptive state for glucose
• uses glucose for energy • stores some glucose as glycogen
how increased insulin affects HPG axis to cause PCOS
Follicular phase of ovarian cycle: • Hypothalamic pulses of GnRH control both LH and FSH release through changing pulse amplitude or pulse frequency - Increased GnRH pulse frequency causes a shift towards increased LH and decreased FSH - High insulin levels act together with LH to stimulate androgen release from the theca cells - insulin resistance further impairs action of FSH on granulosa cells - Follicles do not develop properly - halting growth at the antral stage (ovarian cysts) and causing lack of ovulation. - high insulin levels may also be involved in increased GnRH pulse frequency - so insulin affects ovarian function
direct effects of growth hormone
GH is a counter-regulatory hormone that antagonises the effects of insulin. Under conditions of fasting, GH causes: • increased lipolysis - release of free fatty acids from adipocytes - these provide an energy source • increased gluconeogenesis - mainly in liver • decreased glucose uptake
why are the growth-promoting effects of GH largely indirect
GH stimulates growth via IGF-1 secretion • The growth-promoting effects of GH are largely INDIRECT via secretion of IGF-1 from the liver • IGF-1 circulates in plasma bound to binding proteins • at least 6 IGF binding proteins identified • they increase T1/2 of IGF-1 from ~10 min to 3h
female specific changes in adolescent bone growth
High oestradiol levels relative to testosterone cause a widening of the pelvis.
male specific changes in adolescent bone growth
High testosterone levels relative to oestradiol cause growth of the jaw, widening of the shoulders and changes in the shape of the skull.
what instigates inflammatory process leading to cervical ripening
Hormonal Changes: functional progesterone withdrawal - inflammation and influx of immune cells, fetal HPA, placental corticotropin releasing hormone CRH, oestrogen, cervical distension → oxytocin → PGR (Ferguson reflex).
what two hormones maintain the corpus luteum
Human chorionic gonadotropin (hCG) and human placental lactogen (hPL)
events of late secretory phase
If fertilization does not occur, the corpus luteum degenerates, progesterone levels fall and the endometrium degenerates. Uterine glands are wide. Arteries begin contracting and capillary beds begin leaking blood into the endometrium and uterus.
leptin and control of appetite
In hypothalamus, leptin binding to receptor: • increases release of anorexigenic (appetite suppressing) peptides • down-regulates release of orexigenic (appetite-enhancing) peptides
outcome of no/low insulin
Increased catabolism - inc glycogenolysis, gluconeogenesis, lipolysis - hyperketonaemia acidosis - diabetic ketoacidosis (fatal if untreated) decreased anabolism - hyperglycaemia - glycosuria - osmotic diuresis - water and salt depletion
HPG axis effect
Increased hypothalamic pituitary-gonadal axis function resulting in increased hormone secretion from the ovaries/testes
adrenarche
Increased secretion of androgens from the adrenal gland (related to onset of puberty)
which cells are in the core of the islet and which are in the periphery
Insulin-expressing b-cells are often in the core of the islet while glucagon-expressing a-cells are in the periphery
what stimulates the interstitial Leydig cells to produce testosterone
LH
role of LH and FSH in females
LH controls the reproductive cycle and ovulation, stimulates oestrogen FSH stimulates the growth and maturation of ovarian follicles
function of LH and FSH in males
LH stimulates production of testosterone in the testes FSH stimulates the growth and maturation of the testes and spermatogenesis
leydig cells function
LH stimulates the synthesis and release of testosterone and other androgens from Leydig cells
in HPG axis, what hormones are released together into the circulation as a response to GnRH and from where
Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH) are released together into the circulation from the anterior pituitary
what does the ablation of POMC gene result in
Mutations in human POMC with recessive pattern of inheritance - red hair - hyperphagia (excessive eating) - obesity Mouse POMC knockout - obesity - impaired pigmentation
mechanisms initiating myometrial contractions
Myometrium primed for contraction - increased 'contraction associated proteins' e.g. prostaglandin receptor COX-2, oxytocin receptor, gap junctions, calcium signalling proteins and ion channels
current treatments for preterm labour
Oxytocin receptor antagonist - atosiban B2 receptor agonists - ritodrine - salbutamol - terbutaline Ca2+ channel inhibitors - nifedipine Magnesium sulphate
which female reproductive diseases are strongly linked to insulin resistance and hyperinsulinemia
PCOS and hyperandrogenemia
what is used to clinically ripen cervix
PGE2
which are the first order neurons
POMC/CART and NPY/AGRP
what signals tell the islets to adapt to pregnancy
Prolactin/placental lactogen: - both act at the same receptor (PRLR)
active phase
Regular contractions (~3 every 10 min) and steady dilation of the cervix (~3-4 cm to 10 cm) (hours)
why do the beta-cells of some women fail to compensate with insulin resistance
Risk factors: • Race • High BMI • Age • Family history of diabetes i.e. similar risk factors for development of Type 2 diabetes
spermatocytogenesis
Spermatogonial stem cells (diploid cells - 46 chromosomes) divide by mitosis to replace themselves and produce spermatocytes, cells that go on to become sperm.
how uncoupling of ATP synthesis generates heat
UCP (uncoupling protein) take H+ (protons) and convert energy into heat instead of letting them go through oxidative phosphorylation - helps regulate body temperature
First and second order neuronal signalling
first - fat cells stimulate arcuate nucleus of hypothalamus(ARC) - either NPY/AGRP (which stimulates lateral hypothalamus (LHA) and maybe paraventricular nucleus (PVN)) second - NPY/AGRP affecting Y1 receptor leads to release of MCH and orexin, increasing weight, also inhibits MC4 receptor - POMC/CART stimulates MC4 receptor which causes release of CRH and TRH which decrease weight
what leads to irregular menstrual cycles
frequent post-menarcheal variations • Anovulatory (lack of ovulation) • Missing luteal phase • Variable oestrogen levels from developing follicles
which direction does blood flow in the adrenal glands
from cortex to medulla
where is GLP-1 synthesised
from proglucagon in L-cells of the distal GI tract (ileum and colon) (proglucagon is also the precursor of glucagon in a-cells)
main products of proglucagon from islet alpha cells
glucagon main product (also glicentin-related polypeptide)
fuels present at end of digestion
glucose (galactose, fructose), TAGs, AAs
what happens to glucose following digestion
glucose transported in blood, glucose used as fuel
disease from overproduction of thyroid hormones
graves disease
how do pregnancy tests work
hCG is the indicator
Hyperandrogenemia and hyperinsulinemia
hyperandrogenemia causes: - increased insulin resistance in muscle - increased insulin resistance in adipose tissue leads to hyperinsulinemia which causes: - increased androgen release from theca cells - impaired follicle development - possible effects on GnRH which leads to positive feedback loop (PCOS)
where are the polypeptide fuel homeostasis hormones made
in beta and alpha cells of pancreatic islets of Langerhans
when is GLP-1 released
in response to nutrient absorption in the GI tract (mainly carbohydrate and fat)
where is milk stored
in the alveoli of breast
where does fertilisation occur
in the ampullary region of the fallopian tube
how is GIP carried to the islets
in the circulation
where are K cells found
in the upper GI tract, in the duodenum and proximal jejunum
where are T3/T4 iodinated tyrosine derivatives produced
in thyroid follicles
effect of all stressors
increase glucocorticoid secretion
how does presence of leptin cause weight loss
increased leptin leads to decrease in food intake and increase of energy expenditure (sympathetic activation)
why is hyperoxia important in the unplugging of the arterial plugs stopping maternal blood entering intervillous space in placenta
increased maternal blood so that fetus has increased oxygen leading to - increased oxidative stress - increased apoptosis - decreased proliferation stops placenta from continuing to grow and allows it to regress and form discoid shape
what happens to circulating levels of GIP in response to nutrient absorption (mainly carbs and fat)
increases
what can happen with chronic stress
infections due to suppression of immune system
forms of energy intake
ingestion of protein, fat or carbohydrate
catabolic actions of insulin in adipose
inhibits adipocyte lipolysis by reducing intracellular lipase activity
catabolic actions of insulin in muscle
inhibits glycogen phosphorylase to reduce glycogenolysis
what stimulates insulin release
insulin release stimulated by increased blood glucose during the absorptive state (glucagon inhibited) above 4mM
what is the role of inhibin produced by the sertoli cells
it feeds back to suppress FSH secretion
role of IGF-1R
key role in embryonic development: defect in the IGF-1 receptor is embryonically lethal
when are we normally postabsorptive
late morning and afternoon, and all night
what separates maternal blood and fetus
layer of syncytiotrophoblasts
adipose in fuel homeostasis
major triacylglycerol store
muscle in fuel homeostasis
majority of body mass, major consumer of fuel, some glycogen storage
which mechanism of labour does maternal stress affect
maternal cortisol affects fetal HPA/CRH-placenta
what are the two steps in spermatogenesis
mitosis followed by meiosis
definition of morbid obesity, obesity and overweight
morbid obesity: BMI>40 obesity: BMI>30 overweight: BMI>25
function of insulin and glucagon
most important hormones controlling fuel balance
spontaneous preterm birth (SPTB)
natural births that occur between 24-37 weeks of gestation
the liver's role in absorptive state for glucose
net uptake of glucose, which is converted to: • glycogen for storage (major store) • alpha-glycerol phosphate and fatty acids which form TAG, packed into VLDL and transported to adipose
why does eunuchoid gigantism occur if the hormones lacking are oestrogen receptor deficiency, not growth hormones
no epiphyseal fusion therefore continued bone growth
result of MC4R deficiency
obesity, typically seen in early childhood and is severe
two steroid hormones of the female reproductive cycle
oestrogens and progesterone
catabolic effects of cortisol and clinical importance
opposite to insulin, maintains metabolic enzyme expression - stimulate protein breakdown in muscle, bone, liver etc - stimulate hepatic gluconeogenesis - stimulate lipolysis to generate FA and glycerol - Clinically important because of protein catabolism associated with illness/surgery; insulin requirement in diabetes
what is used to induce labour at term
oxytocin
placental delivery
oxytocin important, high risk because postpartum haemorrhage happens to prevent mother from bleeding out
oxytocin in labour
oxytocin increases and expression of oxytocin receptor increases during labour
what constitutes the endocrine system
pancreatic hormones, cortisol, growth hormone, thyroid hormones, others
pathways for milk secretion
pathway I: exocytotic secretion of milk proteins (Lactose, calcium, aqueous phase components) Pathway II: Milk fat secretion. Cytoplasmic lipid droplets move to apical membrane - secreted as a membrane bound milk fat globule Pathway III: Vesicular transcytosis - proteins e.g. immunoglobulins from the interstitial space. Pathway V: Paracellular transport for plasma components and leukocytes. Open only during pregnancy, involution, inflammation. Pathway IV: Transporters - direct movement of monovalent ions, water and glucose across apical and basal membranes.
in type 1 diabetics, why does plasma glucose increase and plateau rather than continue increasing
patient exceeds renal threshold for glucose reabsorption and excrete it in urine
forms of energy expenditure
physical activity, diet induced thermogenesis, basal metabolic rate
how placenta acts as endocrine gland
placenta can produce wide array of hormones like neuropeptides, pituitary-like hormones, monoamines/adrenal like peptides and steroid hormones
trophoblasts
placental epithelial cells that differentiate into cytotrophoblasts (stem cell layer) which form syncytiotrophoblast (multinucleated cells) - the site of nutrient transfer
what is testis volume directly linked to
plasma testosterone levels
when do GH levels rise
puberty
when does spermatogenesis start
puberty
parasympathetic nervous system
rest and digest
incretins
small peptide hormones stored and released from specialised enteroendocrine cells in GI tract in response to food intake that enhance insulin secretory response to glucose
role of other organs in the absorptive states of triacylglycerols
some ingested fat is oxidised to provide energy (not a big source of energy provision in absorptive state)
what happens to absorbed amino acids in absorptive state
some protein synthesis, excess amino acids converted to fat
what is the function of the spermatogonial cells
sperm production - they are stem cells that produce mature sperm
role of LH in males
stimulates production of testosterone in testes
role of FSH in females
stimulates the growth and maturation of ovarian follicles
role of FSH in males
stimulates the growth and maturation of the testes and spermatogenesis
role of glycodelin A
suppresses activity of natural killer cells and is a nutrient source
what is the site of placental nutrient transport
syncytiotrophoblast - any nutrition for baby has to pass through this layer
what in the placenta produces hCG and hPL
syncytiotrophoblasts
role of two umbilical arteries
take waste and carbon dioxide from the baby
function of glucagon
targets liver to generate glucose by glycogenolysis, gluconeogenesis and ketone production
function of insulin
targets liver, muscle and fat to take up, utilise and store glucose (anabolic)
what do the primordial gonads develop into
testes/ovaries
what suppresses LH secretion in HPG axis
testosterone, which feeds back
what does glucose homeostasis ensure
that plasma glucose is maintained between 5mM and 10mM in normal adult humans
colloid
the proteinaceous fluid filling the follicles containing the prohormone thyroglobulin
where are the non motile sperm in the seminiferous tubules transported and why
the sperm are mature, but not motile, so they are transplanted to the epididymis for storage and where they gain mobility
what happens to the uterus across the ovarian cycle
there are a series of changes in the endometrium in response to changes in the hormone levels
physical effect of osmotic diuresis
thirst, polydipsia
how is body weight maintained
through complex mechanisms ensuring constant supply of energy for cellular functions
effect of thyroid hormones on thermogenesis
thyroid hormones regulate body temperature in humans • uncouple ATP synthesis from metabolism by increasing expression of uncoupling protein (UCP): generates heat • direct effect on mitochondria in brown adipose tissue and skeletal muscle • maybe most important role of T3/4 in humans
effect of thyroid hormones on metabolic rate
thyroid hormones set BMR in most tissues • increase mitochondrial oxidative phosphorylation (so regulate fuel usage) • increase plasma membrane Na/K ATPase activity • regulate the expression of many enzymes involved in metabolic processes (gene regulation) • regulate seasonal changes in body mass in mammals
set point hypothesis
• Blood-borne factor controls body weight at a defined level (the "set point") by interaction with hypothalamus • Factor regulates food intake and energy expenditure • Signals proportional to size of fat stores integrate with other regulators of food intake to keep energy reserves constant (lipostat/adipostat) • Depletion of energy stored in adipose tissue increases food intake to maintain energy homeostasis • Deficiency/defect in factor may lead to weight gain
long term regulation of body mass
• Body weight is relatively constant throughout adult life - 10 kg increase from age 25 to 75 years • Energy intake = energy expended + energy stored • 10 kg increase over 50 years = 4 kcal per day (out of ~1500 to ~3000 kcal daily)
how does bone growth occur
• Bone growth occurs through the activity of cartilage growth plates (epiphyseal plates) located between the bone shaft and head. • IGF-1 induces the formation of new cells that cause the shaft to increase in length at both ends.
risks of bariatric surgery
• Ca2+ absorption is reduced after all bariatric procedures - increased risk of metabolic bone disease and hyperparathyroidism - Ca2+ replacement is usually recommended • Patients with sleeve and bypass (and occasionally band) surgeries are at risk of deficiencies in folate and iron, and vitamins B1, B6, B12 and D because of reduced nutrient absorption. Supplements are recommended • Severe protein calorie malnutrition may occur in a minority (~5%) of bypass patients, requiring nutritional support
characteristics of GnRH neurons
• Cell bodies in the preoptic area of the hypothalamus extend to the median eminence and release GnRH into the pituitary portal blood system. • GnRH is released in regular pulses - gonadotroph cells in anterior pit stimulates release of LH and FSH in regular pulses
agouti yellow obese mouse
• Dominant agouti mutation Agamma results in over-expression of agouti protein in skin cells • Agouti blocks action of α-MSH at the melanocortin-1 receptor in the hair follicle, resulting in yellow pigment • Agouti blocks action of α-MSH at the melanocortin-3 and melanocortin-4 receptors in the hypothalamus, resulting in obesity
role of adipose in absorptive state for triacylglycerols
• FA released from chylomicron TAG, converted to TAG in adipose by combining with alpha-GP (from glucose) • FA released from VLDL (from liver) converted to TAG
mature/antral follicle in ovarian development
• FSH stimulates growth of the follicle and causes the release of inhibin from the granulosa cells. (dependent on FSH now) • Follicles compete for FSH as follicles grow • Competition for FSH causes weaker follicles to be destroyed (atresis) • Continues until only one dominant follicle remains. • mature follicle ready for ovulation
fertilisation
• Fertilisation causes the secondary oocyte to finally complete meiosis II. • Another polar body is formed and degenerates. • The sperm cell chromosomes fuse with the remaining oocyte chromosomes to form the diploid zygote (46 chromosomes) - the zygote starts to divide as it travels along the fallopian tube towards the uterus
effect of alarm
• Fight or flight: short term, adrenaline/noradrenaline • increased sympathetic activation, adrenaline release from medulla, increased circulating noradrenaline • increased glycogenolysis (liver, muscle), provide glucose • increased lipolysis, provide glycerol and fatty acids • increased cardiac output • divert blood flow from viscera to skeletal muscle • increase ventilation (bronchodilation, respiration rate)
oocyte activation in fertilisation
• Following fertilisation cortical granules are released - oocyte membrane becomes impermeable to other sperm. • Formation of the male and female pronuclei.
regulation of GH secretion
• GH is synthesised and secreted by anterior pituitary somatotrophs • GH secretion is stimulated by GHRH and ghrelin • its secretion is inhibited by somatostatin
metabolic effects of growth hormone and IGF-1
• GH opposes the metabolic effects of insulin • IGF-1 has insulin-like effects to decrease glucose levels
GH receptor signalling pathways
• GH receptor is widely expressed • GH receptor number increases around birth and plateaus in adulthood • GH binding causes receptor dimerisation and activates the JAK2/STAT signalling cascade
Laron syndrome characteristics and treatment
• GH receptor mutation • leads to grossly impaired postnatal growth • low plasma IGF-1 (because mutated GH receptor means GH can't stimulate IGF-1 production) • usually high plasma GH (because no IGF-1 negative feedback to somatotrophs to suppress GH secretion) - treatment: IGF-1 injections
why is GIP not an ideal candidate as drug therapy for T2DM
• GIP levels are not substantially decreased in T2DM • but GIP has a reduced effect to stimulate insulin secretion in T2DM • also T1/2 for GIP is ~ 5 minutes; degraded by DPP-4 so not a good option
why might GLP-1 be a good drug treatment for T2DM
• GLP-1 secretion in response to nutrients may be decreased • the GLP-1 that is present in T2DM works properly
effect of oestradiol on puberty
• Growth spurt • Fused epiphyses • Growth stops in adulthood • Normal bone mineral density
what happens in follicular phase
• Hormonal signals: 10 to 20 follicles grow. • Levels of FSH are high from the end of the previous cycle • Antral follicles become dependent on FSH to continue growing and enter the oestrus cycle. • LH stimulates the theca cells to produce androgens. • The granulosa cells convert these androgens to oestradiol. • As the follicles grow oestradiol levels increase... • One oocyte selected, remainder become atretic
what causes hyperpigmentation in addison's disease
• Hyperpigmentation • α-MSH normally acts on melanocytes to generate melanin • α-MSH sequence is in ACTH • pathologically high levels of ACTH act on melanocytes to generate melanin
Corticotropin-releasing hormone (CRH) anorexigenic peptide in second order signalling
• Peptide secreted by the PVN • acts on anterior pituitary, releasing adrenocorticotropic hormone (ACTH), which stimulates release of corticosterone/cortisol from the adrenal cortex, leading to reduction of appetite (stress hormone)
proposed biological roles of Corticotropin-releasing hormone (CRH)
• Immunosuppression? • Rising levels of CRH seen near the end of gestation - induction of myometrial contractions? • CRH may be involved in the initiation/timing of parturition (feeding into fetal HPA stimulation): role as 'placental clock?' • Prostaglandin formation in the placenta, amnion, chorion laeve, and decidua is increased by treatment with CRH
metabolic actions of hPL
• Induces maternal lipolysis to increase free fatty acids (NEFAs) - a source of energy for maternal metabolism and fetal nutrition • Increases maternal insulin - promoting protein synthesis and mobilisation of amino acids • Later gestation - this leads to decreased insulin sensitivity (increased insulin resistance) - increasing maternal glucose (whilst reducing maternal glucose utilization) to enhance glucose availability for transport to the fetus • Potent angiogenic hormone - may play an important role in the formation of foetal vasculature • Prolactin-like actions - but role in lactation unclear
advantages of endobarrier
• Insertion of the sleeve is a simple procedure (< 1hour) • There is no alteration to the anatomy of the GI tract • It is a reversible procedure • It is cheaper than commonly used bariatric surgery procedures
structure of insulin
• Insulin A-chain has 21 amino acids; B-chain has 30 amino acids • The chains are connected by two disulphide bonds • Insulin is highly conserved between species
paracrine interactions of islet hormones
• Insulin inhibits glucagon and SST release • Glucagon stimulates insulin and SST release • SST inhibits insulin and glucagon release
can GLP-1 analogues be used to treat T1DM
• Islet b-cells are destroyed in T1DM so GLP-1 analogues can't be used to stimulate insulin secretion • But GLP-1 analogues will inhibit glucagon secretion in T1DM • GLP-1 analogues can also delay gastric emptying in T1DM • GLP-1 analogues can lead to weight loss in T1DM • Preliminary clinical trials have given GLP-1 analogues in T1DM (in combination with insulin)
interpretation of parabiosis experiments
• Leptin from wt (normal) mouse replaces defective leptin in obese ob/ob mouse, reducing appetite and weight • db/db mouse unresponsive to leptin: obese. High circulating leptin reduces appetite and weight (a) in wt mouse (b) in ob/ob mouse • No hypothalamic centre with leptin receptors in lesioned mouse: obese. High circulating leptin reduces appetite and weight in control mouse
MC4R and food intake
• MC4R stimulated by α-MSH and inhibited by AGRP • Leptin stimulates POMC and inhibits AGRP production, increasing MC4R inhibition of food intake
effects of testosterone
• Male hormone - anabolic • Primary and secondary sexual characteristics • Libido and sexual behaviour • Stimulates spermatogenesis
milk ejection reflex (MER)
• Milk is transported from alveoli to nipple • Neuroendocrine reflex • Suckling stimulates paraventricular and supraoptic nuclei to produce and release oxytocin (from posterior pituitary) • Oxytocin causes contraction of myoepithelial cells surrounding alveoli full of milk • Milk propelled into ducts and intramammary pressure builds up • Milk spurts through nipple • Response can be conditioned
the diabetes db/db mouse
• Mouse db gene encodes leptin receptor protein • Homozygous mutant db/db results in the production of a defective receptor protein • The db/db mouse produces leptin, but is incapable of signalling binding to receptors in the hypothalamus, which results in obesity
the obese ob/ob mouse
• Mouse ob gene encodes leptin protein • Binding to leptin receptor in hypothalamus inhibits feeding • Homozygous mutant ob/ob results in the production of a truncated inactive protein • Absence of functional protein to inhibit feeding results in obesity
morbid obesity associated with human MC4R mutations
• Mutation of the MC4R gene is the most commonly occurring monogenic cause of inherited morbid obesity in humans • Phenotype: - hyperphagia starts at ~ 8 months - tendency toward tall stature - hyperinsulinemia - increased bone mineral density
Neuropeptide Y (NPY)
• NPY is a powerful orexigenic peptide (appetite stimulant) • NPY neurons in ARC nucleus • NPY binds to Y1R receptors on POMC neuron to prevent anorexigenic action and on LHA neurons to stimulate orexigenic action
primary follicle role in ovarian development
• Oocyte genome activates, causing gene transcription and signalling between the oocyte and follicle. • Granulosa cells change from a flat to a cuboid structure. • Oocyte and follicle grow in size. • Zona pellucida forms around oocyte. • Follicles develop FSH receptors, though FSH is not required yet.
Agouti related peptide (AGRP)
• Orexigenic peptide • Similar to the agouti protein which is responsible for yellow hair pigment in mice • AGRP is co expressed with NPY in the ARC nucleus of the hypothalamus • Acts as an antagonist of MC3 and MC4 receptors, preventing binding of α-MSH
Orexins A and B: orexigenic peptide in second order signalling
• Orexins exclusively produced in the lateral hypothalamic area (LHA) • Orexin deficiency causes narcolepsy; possible survival link between energy homeostasis and wakefulness
melanin concentrating hormone (MCH) orexigenic peptide in second order signalling
• Over-expressed in the hypothalamus of ob/ob mice • Fasting increases expression in both normal and obese animals
how parabiosis experiments provide evidence for humoral control of body weight
• Parabiosis experiments involve surgical connection of the circulations of two experimental animals • Test the effect of substances carried in the blood of one animal on outcome in the other - between ob/ob mouse and wild type (wt) mouse, circulating factor from normal mouse causes weight loss in ob/ob mouse - between db/db mouse and wt mouse, circulating factor from db/db mouse causes weight loss and wild type mouse stops eating - between ob/ob and db/db mouse, ob/ob mouse loses weight due to circulating factor - hypothalamic lesion mouse and lean control mouse, circulating factor from lesioned mouse causes control mouse to stop eating
acrosome phase of spermiogenesis
• The axoneme extends to become the tail of the sperm. • Temporary cytoskeleton structures called manchettes support the growing tail.
Thyrotropin-releasing hormone (TRH) anorexigenic peptide in second order signalling
• Peptide secreted by the PVN, down-regulated during fasting • Leptin increases the production of α-MSH which in turn stimulates TRH release • TRH acts on anterior pituitary, releasing thyroid-stimulating hormone TSH, which stimulates release of TH from thyroid gland, a major stimulant of metabolic rate
prolactin
• Primarily released from the pituitary • Most commonly associated with controlling lactation • Has many other functions: o Immune system regulation o Growth factor o Anti-apoptotic
spermatidogenesis
• Primary spermatocytes produce spermatids through meiosis. • get from full set of genetic information to half set by two rounds of meiosis • will get 23 chromosomes instead of 46
parturition
• Process of giving birth • Involves softening and effacement of the cervix and development of uterine contractions (rupture of membranes not essential).
hormonal changes at onset of lactation
• Prolactin secreted from 16 weeks' but breast tissue unresponsive - steroid block • Withdrawal of oestrogen and progesterone are essential for prolactin to act on breast tissue • Prolactin also drops but a steady production maintained (if no suckling - small amount of milk produced 3-4 weeks) • Suckling ensures prolactin secretion - Full lactogenesis - Copious milk production
drugs to treat obesity
• RIMONABANT: CB1 receptor antagonist • SIBUTRAMINE: NA and 5-HT re-uptake inhibitor • ORLISTAT: lipase inhibitor, reduces fat absorption • associated with unpleasant side effects (oily, loose stools) • CONTRAVE: combination of naltrexone and bupropion • approved by FDA, but increased risk of psychiatric events and suicidal tendencies • LIRAGLUTIDE: GLP-1 receptor agonist • Available for use in chronically obese patients
mechanisms of weight loss/T2DM improvement in gastric bypass
• Re-routing food through a shorter GI tract allows more rapid delivery of food to the L-cells of the distal GI tract: nutrients reach the ileum within 5 minutes of food ingestion • The L-cells secrete peptides that may underlie weight loss and glycaemic improvements • Bypass of the mucosal cells of the lower stomach (gastric remnant) leads to lower concentrations of the stomach-derived orexigenic peptide, ghrelin
characteristics of LH and FSH
• Released from gonadotroph cells in the anterior pituitary in response to release of GnRH • Also released as regular pulses.
placental lactogen
• Released from the placenta • Stimulates development of the mammary glands in late pregnancy • Similar range of functions to prolactin
functions of established placenta
• Respiratory organ • Nutrient transfer • Excretion fetal waste products • Hormone synthesis
role of leptin in pregnancy
• Secreted by cytotrophoblast & syncytiotrophoblast • Maternal concentrations higher than in non pregnant women and that in the fetal circulation • Stimulates placental amino acid/fatty acid transport • Fetal Leptin concentrations - correlated positively with fetal birthweight • Probably plays an important role in fetal development and growth
effect of absence of thyroid hormones on growth and development
• Severe growth retardation, reduced bone elongation • Undeveloped CNS, axonal retardation (maybe via ↓Nerve Growth Factor), mental retardation • T3/4 permissive (required) for actions of other hormones such as growth hormone, insulin-like growth factors
cap phase of spermiogenesis
• Spermatid DNA is condensed in the nucleus. • The golgi apparatus surrounds the nucleus and the enzyme vesicle forms the acrosomal cap
function of progesterone in females
• Steroid hormones derived from the same precursor as testosterone and oestrogen (cholesterol). • Involved in the menstrual cycle and pregnancy
function of oestrogens in females
• Steroid hormones that function as the primary female reproductive hormones • In non-pregnant women the primary naturally occurring oestrogen is oestradiol • Mainly synthesised from androgens and released by the ovaries
oestrogens
• Steroid hormones that function as the primary female reproductive hormones • In non-pregnant women the primary naturally occurring oestrogen is oestradiol • Synthesised from androgens and released by the ovaries
androgens characteristics
• Steroid hormones that stimulate male physical and reproductive characteristics • Testosterone is the primary biological androgen • Mainly synthesised and released by the testes (M) and the adrenal glands (M&F) • Can be converted into oestrogens
functions of the sertoli cells
• Support • Nutrition • Protection • Regulation
HPT axis/control of thyroid function
• TRH from hypothalamus stimulates TSH release from pituitary • TSH stimulates production and release of T4 and T3 from thyroid. T4 deiodinated to T3 at target tissues • TSH also stimulates growth of thyroid • 99% of T4 in plasma is bound to Thyroid binding globulin (TBG) • free (unbound) fraction is biologically active • 'free' hormone (mainly T3) feeds back to inhibit TSH secretion at the level of the pituitary and hypothalamus
sperm capacitation
• Takes place in the uterus. • Cholesterol and glycoproteins are removed from the sperm cell surface by enzymes such as heparin in the uterus. • "Switching on" of sperm through increased calcium influx. • causes hyperactivity in sperm - Increased motility.
what happens when there is an oestrogen receptor deficiency
• Tall stature • Unfused epiphyses • Continued growth in adulthood • Osteoporosis
agouti in mouse obesity
• The agouti gene encodes the secreted agouti protein that normally antagonizes the melanocortin-1 receptor in peripheral hair follicles to control pigmentation • Genetics of the dominant agouti yellow obese mouse mutation revealed roles for melanocortin peptides and melanocortin receptors in pigmentation and obesity
what does the A(gamma) mouse tell us about human obesity
• The agouti protein blocks melanocortin receptor actions in mice • Melanocortin receptors are blocked by agouti-like protein in humans • Melanocortin receptors are essential for control of body weight
why can't leptin therapy be used to treat human obesity
• The blood levels of leptin are usually higher in obese animals (and humans) than in animals of normal body weight • In clinical trials, the injection of leptin did not result in any weight-reducing effect • Effective only in very rare humans with extreme obesity who have a defective leptin (ob) gene; the ob gene is normal in most obese individuals
golgi phase of spermiogenesis
• The golgi apparatus creates a vesicle of enzymes around the nucleus. • Mitochondria start to move to the other side of the cell. • The centriole starts to form an axoneme, the cytoskeletal core of the tail.
hormones and energy status
• The hypothalamus in the brain coordinates input (signals giving information on nutritional status) with output (nervous stimuli) to control feeding and energy expenditure • The signal must travel from the adipose tissue to the brain in the blood stream, i.e. an endocrine signal or hormone
endobarrier
• This is a thin plastic sleeve that is inserted endoscopically via the mouth, through the stomach. • A metal anchor at the duodenum holds it in place. • It lines the first 60cm of the small intestine and stops contact of food with the duodenum and jejunum.
acrosome reaction
• Triggered by contact with oocyte. • Interaction with ZP3 protein on oocyte membrane prevents cross-species fertilisation. • Acrosome releases hyaluronidase and acrosin enzymes break through egg coating allowing fertilisation.
what happens in luteal phase
• With the oocyte released the follicle collapses and becomes the corpus luteum. • The corpus luteum releases oestradiol and progesterone. • After 14 days the corpus luteum degenerates. Progesterone and oestradiol levels fall. • Falling oestradiol and progesterone levels remove negative feedback on FSH, which increases. • Egg travels through fallopian tube towards uterus. The cycle starts again...
examples of experimental responses
• adrenal hyperplasia • atrophy of immune system organs (thymus, spleen, lymph) • peptic ulcers
effect of sympathetic nervous system in neural hormone control on fuel homeostasis
• adrenaline from adrenal medulla and sympathetic innervation (noradrenaline = neurotransmitter) of islets inhibit insulin release and stimulates glucagon release • both A/NA affect liver directly to increase glycogenolysis and gluconeogenesis so increase plasma glucose • both increase lipolysis in adipose • circ. adrenaline increases glycogenolysis in skeletal muscle (no sympathetic innervation)
which two groups of steroid hormones cause sexual differentiation
• androgens • oestrogens
function and effect of growth hormone
• catabolic hormone • makes adipose more sensitive to lipolytic stimuli • increases gluconeogenesis in liver • reduces the effects of insulin to promote glucose uptake in peripheral tissues • opposes the metabolic effects of insulin - too much growth hormone can cause diabetes
how does GH travel in body and what is its half life
• circulates in plasma bound to GH binding protein • T1/2 of GH ~50 minutes
diseases associated with cortisol overproduction or deficiency
• cortisol deficiency prevents metabolic responses to postabsorptive stage (Addison's disease) • high concentrations of cortisol elicit postabsorptive changes and oppose the effects of insulin (Cushing's syndrome)
what can reduced cell growth arise from
• decreased GH secretion: - GHRH receptor gene mutations - anterior pituitary failure - GH gene mutations - defects in GH receptor - defects in IGF-1 secretion - defects in IGF-1 receptor
exenatide (exendin 4)
• drug to treat T2DM • It has ~50% amino acid homology with GLP-1 • It has a longer half life than GLP-1 in vivo (T1/2 ~2h) and it is not a DPP-4 substrate • It stimulates insulin secretion in a glucose-dependent manner • This leads to more rapid reductions in blood glucose levels: improved glucose tolerance
what happens to fat in absorptive state
• fat absorbed through lymphatics in chylomicrons (transfer fat from GIT to adipose) • fat used for energy • excess fats stored in adipose
risk factors for development of obesity
• genetics • increased food intake • reduced physical activity (sedentary lifestyle)
two main incretins in humans
• glucose-dependent insulinotropic polypeptide (GIP) • glucagon-like peptide-1 (GLP-1)
primordial follicle
• immature dormant oocytes • surrounded by flat granulosa cells • can remain dormant for up to 50 years until initial recruitment
why might GLP-1 replacement therapy be a good drug treatment for T2DM and why may it only be of limited usefulness
• in T2DM, GLP-1 secretion in response to nutrients may be decreased but the GLP-1 that is present works properly • but GLP-1 is a short-lived peptide: • it is degraded by dipeptidyl peptidase-4 (DPP-4) • T1/2 for GLP-1 is ~ 2 minutes So GLP-1 has limited usefulness for treating T2DM
anabolic actions of insulin in liver
• increases glucose uptake by increasing glucokinase activity • activates glycogen synthetase to promote glycogen production • inhibits glycogen phosphorylase to reduce glycogenolysis • inhibits gluconeogenesis • inhibits ketone production
anabolic actions of insulin in muscle
• increases glucose uptake by increasing transporters • activates glycogen synthetase to promote glycogen production • increases amino acid uptake and protein synthesis • inhibits glycogen phosphorylase to reduce glycogenolysis
anabolic actions of insulin in adipose
• increases glucose uptake by increasing transporters • promotes synthesis of FA and a-glycerophosphate, which combine to form TAG for storage • induces expression of lipoprotein lipase to generate triglycerides from circulating lipoproteins • inhibits adipocyte lipolysis by reducing intracellular lipase activity
treatments for type 1 diabetes
• insulin administration - formerly beef/pork, now recombinant human - by injection or infusion • human islet transplantation - not widely available - may provide a temporary "cure"
graves disease
• most common form of hyperthyroidism • autoimmune disease with antibodies that stimulate the thyroid to secrete T3 and T4 (agonist antibody mimics effect of TSH) • high metabolic rate, weight loss, heat sensitivity - increased mitochondrial activity in BAT and muscle - uncoupling of ATP synthesis to generate heat - CNS effects to increase catabolism • increased cardiac activity • hyperactive nervous system, tremor, anxiety • thyroid growth (toxic goitre) exacerbates symptoms and exophthalmos (fluid gathering behind eyeball causing bulging eyes)
when do we utilise fat to spare glucose in postabsorptive state
• most organs (except CNS) reduce glucose utilisation in PA state and increase use of FA which enter TCA cycle as acetyl CoA • in liver the acetyl CoA from FA is mainly converted to ketones and released into blood for fuel use by many tissues • spares glucose for use by CNS
why is there high plasma ACTH in addison's disease
• no -ve feedback from cortisol • continued CRH secretion • continued ACTH secretion • very high plasma ACTH
postabsorptive state
• no glucose being absorbed from GI tract • synthesis of glycogen, fat and protein stops • plasma glucose concentration must be maintained as CNS normally only uses glucose for energy, achieved in two ways: - generating glucose from stored fuels (gluconeogenesis) - glucose sparing (fat utilisation)
catabolic effects of cushing's syndrome
• opposite those of insulin, diabetogenic • protein/fat breakdown, wasting, hyperglycemia, fat redistribution • bone catabolism, osteoporosis, spinal deformity • skin thinning, bruising
glycogenolysis
• part of postabsorptive state • glycogen stores in liver, muscle broken down (storage process stops) • rapid but short-lived response • hepatic glycogenolysis is the first response to maintain plasma glucose levels
main actions of thyroid hormones
• permissive effects on growth and development • increased O2 consumption in most body tissues resulting in increased basal metabolic rate and heat production • increased responsiveness to catecholamines, particularly in the cardiovascular system, leading to increased heart activity • increased nervous system excitability
GHRH receptor inactivating mutation and treatment
• pituitary GHRH receptors do not respond to GHRH. • this results in "isolated GH deficiency" because only peptide affected is GH • severely reduced GH and IGF-1 levels - treat with growth hormone injections
leptin
• polypeptide hormone controlling body weight mainly expressed in adipose tissue • Circulating levels proportional to total fat mass • Decreases feeding and increases metabolic rate • Levels increase after a meal in rodents and after several days of overfeeding in humans • Levels decrease rapidly with food restriction • Leptin treatment in rodents decreases food intake, increases energy expenditure and reduces weight • More important role is to protect against consequences of starvation rather than against obesity
Pro-opiomelanocortin (POMC)
• pre-POMC is precursor peptide • Leptin binding to receptor initiates production POMC in arcuate nucleus neuron (1st order signal) • POMC is processed to form α-melanocyte stimulating hormone (α-MSH) • α-MSH binds to melanocortin-4 receptor (MC4R) on paraventricular nucleus neuron, leading to decrease in appetite (2nd order signal)
congenital hypothyroidism
• produces severe developmental abnormalities if untreated • cretinism: severely stunted physical and mental growth owing to untreated congenital deficiency of thyroid hormone (congenital hypothyroidism) usually owing to maternal hypothyroidism
characteristics of catecholamine receptors
• receptors cross membrane (transmembrane receptors) • hormone binds to extracellular domain • receptor transmits signal to intracellular domain via GTP-binding protein • activates intracellular 2nd messenger (cyclic AMP, DAG, Ca2+ etc) • rapid/reversible responses
function and effect of T3/T4
• set "basal metabolic rate" in most tissues - higher T3/4 higher BMR • increase mitochondrial oxidative phosphorylation (so regulate fuel usage) • increase plasma membrane Na/K ATPase activity • regulate the expression of many enzymes involved in metabolic processes (gene regulation) - opposes action of insulin
IGF-1 gene deletion characteristics and treatment
• severe growth retardation • undetectable plasma IGF-1 because of gene deletion/mutations • high plasma GH (no IGF-1 negative feedback to suppress GH secretion) - treatment: IGF-1 injections
body response to exercise
• similar to responses to fasting but short term and more rapidly • large, rapid amounts of fuel needed by contracting muscles • relatively minor changes in blood glucose because utilise SNS • plasma glucagon rises and plasma insulin decreases because of (i) decreased glucose; (ii) increased circulating adrenaline; (iii) increased sympathetic discharge in islets of Langerhans • circulating adrenaline and sympathetic activity increases catabolic processes in liver, fat and muscle to release fuels
molecular structure of growth hormone
• single chain polypeptide • 191 amino acids, 22kDa in humans • high structural homology with PRL and PL
why can't we use growth hormones from other species to treat GH deficiencies in humans
• species-specific • human GH differs markedly from non-primate GHs -> hGH must be used for treatment of GH deficiencies
beneficial effects of GLP-1
• stimulates insulin secretion • decreases glucagon secretion • delays gastric emptying • decreases appetite/reduces food intake • increases b-cell mass by decreased apoptosis/increased proliferation
structure of IGF-1 receptor
• structurally and functionally related to the insulin receptor • transmembrane tyrosine kinase - intrinsic tyrosine kinase activity meaning can transfer phosphate groups to tyrosine residues of substrate proteins in cell
effect of GLP-1 inhibiting glucagon secretion in T1DM
• this will lead to less glucose production by the liver and thus reduced circulating glucose levels
examples of experimental stressors
• toxic injection • trauma • infection • cold environment • swimming to exhaustion
