exam 4

• Understand short-loop and long-loop negative feedback mechanisms controlling anterior pituitary hormone release.

-regulate secretion-- too much is bad Neural mechanisms: secretion of catecholamines (pregang neurons synapse on adrenal medulla, which secretes them) FEEDBACKNegativeSome feature of hormone action directly or indirectly inhibits further secretion of the hormoneLong loop: hormone feeds all the way back to the hypothalamic-pituitary axisShort loop: anterior pituitary hormone feeds back on the hypothalamus to inhibit secretion of HRHUltrashort loop feedback: hypothalamic hormone inhibits its own secretion (ex GHRH can inhibit GHRH secretion)Also insulin ex: when blood glucose is high insulin secretion turned on, when blood glucose goes to normal insulin secretion is turned offPositiveUncommon. Some feature of hormone action causes more secretion of the hormoneEx effect of estrogen on secretion of FSH and LH by anterior pituitary at midpoint of menstrual cycle causes more estrogen secretionAlso oxytocin, dilation of cervix causes posterior pit to secrete oxytocin which causes contractions to further dilates cervix etc -phys response driven Endocrine gland produces hormone Hormone acts on target to cause phys response Phys response signals og gland to produce more or less of hormone (most of time its inhibiting) -endocrine axis-driven Hypothal releases RH (releasing hormones) Act on pituitary gland, which produces tropic hormone ('have activity/produce a response") Tropic hormones travel through bloodstream where they act on peripheral endocrine glands to cause additional hormone production (thyroid/adrenal, their hormones can act back negatively at hypothal or pituitary) Which can then act on target organs to produce a response -UNDERSTAND NEGATIVE FEEDBACK Ex: response to blood glucoseDec blood glucose, pos signal to alpha cells of eyelets of longerhon in pancreasProduce glucagon, acts on liver to release glucose to blood streamBlood glucose inc is negative signal to alpha cells to stop producing glucagon There is pos feedback: estrogen (during menstrual cycle, switches to pos feedback at some point to cause LH surge) Regulate hormone secretionHormone acting back from pituitary to hypoothal = short loop feedbackHormone acting back from peripheral gland to pit or hypothal = long loop feedback

Understand the regulation of parathyroid hormone (PTH) and describe its biologic function.

· PTH: parathyroids in the back of the thyroid gland. 2 cells: chief cells produce PTH, oxyphil cells don't have major physiologic role. PTH acts at cortical collecting duct of kidney. o Regulate conc of Ca2+ in ECF (when Ca2+ dec PTH secreted). Acts on bone, kidney,(direct by cAMP, inhibits Na+-phosphate cotransport to dec phosphate reabs) and intestine (indirect through vitamin D) o Located in neck under thyroid gland o Bone: PTH receptors on osteoblasts (inc bone formation) and cytokines from this act on osteoclasts to inc bone resorption (delivers Ca2+ and phosphate to ECF) o Kidney: inhibits phosphate reabs (inhibit Na+ phosphate cotransport in PT—phosphaturia, inc phosphate excretion in urine which allows ionized Ca2+ to inc), also stim Ca2+ reabs in DCT o Small intestine: stim Ca2+ reabs by activation of vitamin D · Regulation o Regulated by plasma Ca2+ (ionized): low secretion when it's normal, high secretion when it dec less than 10 mg/dL o Parathyroid cell membrane has Ca2+ sensing receps that are Gq linked o Chronic changes lead to hyper/hypoparathyroidism o Magnesium has same effect

List the hormones involved in the control of growth from the perinatal stage through adolescence and puberty.

· Thyroid (bone lengthening), GH (postnatal), insulin, sex steroids

Be able to explain the physiologic actions of calcium and phosphate.

· calcium o hypocalcemic- extreme excitation (threshold for Aps lower). Muscle cramps, tingling and numbness o hypercalcemia—constipation, thirst, lethargy, coma o Also table slide (muscle contraction, blood clotting). o Inc protein conc = inc plasma Ca2+ conc · Phosphate o Bone and teeth o Metabolism (ATP and NADPH) o Membrane phospholipids · Our bone is always being turned over, so we keep healthy strong bones. Osteoblasts build bone, osteoclasts break down bone. We need to know what cell within bone has receptors for what hormones (on sacrificial bone slide)

Be able to describe the functions of osteoblasts and osteoclasts in bone remodeling and factors that can regulate their activity.

· estrogen prevents ongoing osteoporosis by limiting amt of activation of osteoblasts by osteoclasts.

• Understand how spermatogenesis is supported by the Sertoli cells and the contribution of the Leydig cells to hormone production.

• -Sertoli cells- provides nourishment to developing sperm • -Leydig cells- responsible for testosterone production (intratesticular- drives spermatogenesis: spermatogonium developing to functional and mature sperm) • -Sertoli cell: • -Leydig cell: has receps for LH, Gs coupled (leads to adenylyl cyclase/cAMP/PKA activation). These phosphorylation events give enzymes needed for steroid hormone biosynthesis (cleavage enzyme) • -cells that respond to HP signaling to control spermatogenesis. Know which cell has receps for which pit hormone, what binding of gonadotropin will do (once it binds recept, what is impact on cell) • -aromatase converts testosterone to estrogen • -both males and females have testosterone and estrogen, just differ in which is dominant (ovary estrogen, gonads testosterone) • -ABP binds testosterone. Need intratesticular testosterone to stay very high to drive spermatogenesis (androgen binding protein from Sertoli cell in response to FSH does this) • -inhibin: acts as a negative feedback regulator of FSH alone (when inhibin goes up, AP gonadotropes suppress FSH so dominant gonadotropin is LH)(skews male toward testosterone by turning off FSH, which stims production of estrogen). Doesn't turn FSH off completely, just limits so testosterone is dominant (need some to make ABP for intracell testosterone)

• Identify the disease states caused by altered secretion, or decreased sensitivity to insulin, and describe the principal manifestations of each.

• -acute nausea and vomiting can be a sign of pancreatic dysfunction • Diabetes mellitus type 1: inadequate insulin secretion caused by destruction of beta cells (autoimmune). Inc blood glucose, dec glucose utilization, and inc gluconeogenesis. Inc blood fatty acid and ketoacid conc from inc lipolysis of fat. Inc blood AA conc. Causes ketoacidosis. Osmotic diuresis and thirst. Hyperkalemia. • Type 2: insulin resistance of target tissues, associated with obesity (downregulated receptors)

• Describe the basic organization of the male gonad, the testes, and how the process of spermatogenesis occurs.

• -blood-testes barrier: protects haploid cells from immune system attack and individual from being infertile (what is unique about a gamete that's different from any other nucleated cell in the body: they're haploid) • -so much sperm to inc odds of fertilization • -fertilization of oocyte occurs in fallopian tube (not uterus- sperm have to swim up through uterus and find opening • -seminiferous tubules really long, packed in testes so why they're hard • -compare/contrast: germinal epithelium in each gonad. Maleà seminiferous tubules make sperm throughout whole reproductive life span, femaleà born with all oocytes we will have • -won't be asked about meiosis/crossover/genetic whatever, just know have to go under two meiotic divisions to get haploid • -no blood-oocyte barrier in spermatogenesis: in order to become haploid have to dodge immune system • -acrosome contains very bad things. Acrosomal reaction allows sperm to penetrate the oocyte so that genetic material can be released inside • -movement of tail changes from flagellular to whip like (for corkscrew movement), and once reaches egg lays flat on surface and continues the corkscrew while vibrating so that sperm can start acrosomal rxn • -mid body has a lot of mitochondria- supply ATP needed to move tail

• Understand the functions of estradiol and progesterone on the ovarian follicle and endometrium.

• -estrone weaker than estradiol • -estriol the estrogen of pregnancy • --FSH drives aromatase activity in both gonads (just not theca cells) • -remember that aromatase converts testosterone to estrogen

• Be able to identify the appropriate hypothalamic releasing hormones controlling anterior pituitary hormones.

-characteristics of hypothalamic releasing hormones Secreted in pulses (helps keep homeostasis)Critical for maintained optimal responsiveness of pituitary cells (dec extent of down-regulattion of pit receps, cont release of hypothal hormones actually suppresses the secretion of pit hormones) Act o specific plasma membrane receps Utilize second messenger systems in target cells include Ca cAMP, PKC Stim release of stored target anterior pit hormones via exocytosis Stim synthesis of target anterior pituitary hormones Stim hyperplasia (inc in number of cells) and hypertrophy (inc in size of cells) Can up or down regulate the number of their own receps on target cells (why they're released in pulses, have a constant replenishing/recycling of receps on anterior pit cells) Modulate the bio activity of target anterior pit hormones by post translational effects like glycosylation or phosphorylation -CRH: stim ACTH release -TRH-- release TSH -PRF: inc prolactin -GNRH: stim FSH and LH -GHRH-- GH -dopamine-- suppresses prolactin release

• Describe the importance of hormonal rhythms on endocrine function.

-circadian rhythms Respond to light and dark to regulate sleep schedule Hormones produced in pulses throughout any particular day, important for their secretion -endocrine disorders Peripheral gland not producing hormone-- primary disorder Pit gland over/underproduce: secondary Level of hypothal: tertiary disorder

review notes

-protein in every meal helps fight insulin spikes and diabetes -prolactin—tonically suppressed by dopamine -know which releasing hormone does what -describe negative loops for each organ system (HP or physiologic axes) -know paracrine (different cell, distant) vs endocrine (same cell) -(hormone syn in axon rather than in secretory pathway (what type is that) -don't need to know GS vs Gq, just understand difference in receps -review pathologic conditions of each organ system (just the big ones—those that take up whole slides) -steroid hormone biosyn: P450 cleavage of side chains is rate limiting step (enzyme shit) -don't need to know carnitine acetyl transferase thing, just know that by inhibition of glucagon (acetyl coA carboxylase) initiates mov of fatty acids into mitochon to undergo hydroxylation to get keto bodies (or something like that)

• Be able to identify and understand the chemical nature of the major endocrine Hormones.

-proteins and peptides (GH, ACTH): synthesized from amino acids as a preprohormone, cleaved and stored in secretory vesicles; rise in ICF Ca2+ is required for exocytosis **pay attention to what causes rise in calcium to trigger hormone release in diff situations, connect w function -amines (derived from tyrosine (catecholamines from adrenal medulla, thyroid hormones from thyroid gland): not stored long term (made as needed), not synthesized as a preprohormone (derived from tyrosine, chemical modification of that gives cat or thyr) -steroids (derived from cholesterol (cortisol from adrenal ctx, testosterone from reproductive glands)): synthesized in cytoplasm and mitochondria, not stored (v short half life, produced when needed)

• Understand the significance of hormone/receptor interactions and second messenger pathways.

-regulation of receptors Responsiveness of a target tissue to a hormone is expressed in the dose-response relationship (magnitude of response is correlated with hormone concentration) Sensitivity: the hormone concentration that produces 50% of the maximal responseThis and responsiveness can be changed by changing # of receps or affinity of receps for the hormoneDownregulation: # receps or affinity has dec (upregulation opposite) DownregulationOccurs by dec synthesis of new receps, inc degradation of existing receps, or inactivating recepsReduce sensitivity of target tissue when hormone levels are high for an extended pd of time (ex effect of progesterone on its recep in uterus, also how progesterone down regulates receps for estrogen) UpregulationBasically opposite of aboveEx prolactin inc number of its receps in breast, also GH and estrogenEstrogen also upregs receps for LH in ovaries -exert their effects through binding to various types of receptors (G protein coupled-- G alpha s, i, or q) -s: activation of adenylyl cyclase, rise in cAMP, activates PKA to phosphorylate proteins and influx of Ca2+ from ECF to ICF, allows for exocytosis (stimulator) -when no hormone is bound subunit binds GDP (inactive), when hormone binds conf change replaces that with GTP (GAP and GRFs facilitate GTP hydrolysis and dissoc of GDP, respectively) -q: activates phospholipase C, inc IP3 and diasoglycerol (releases them from PIP2), inc ICF calcium by inc releasing it from intracellular stores (endo or sarc reticulum). Calcium and diacylglycerol activate PKC which phosphorylates proteins and produces final phys actions -i: "inhibitory", no activation of adenylyl/cAMP and does not cause rise in calcium -**stim or inhibitory activity resides in the alpha subunit -goes receptor, effector enzyme, second messenger which amplifies hormone signal to produce final physiologic actions -insulin receptor: has intrinsic enzymatic activity (when it binds recep, the recep has tyrosine kinase domains which can start phosphorylation event) -GH recep-- has associated enzymes. When it binds recep activates a specific pathway ( -also a steroid hormone mechanism? -insulin and insulin-like growth factors (IGFs) act on target cells through a tyrosine kinase mechanism -several hormones activate guanylate cyclase w second messenger cGMP -catalytic receps (hormones bind to cell surface receptors that are assoc with intracell enzymatic activity) Guanalyl cyclase and serine/threonine and tyrosine kinases. Cyclase converts cMGP to GTP and kinases phosphorylate proteins on those locations (neg chrg) and conf change → phys action ANP can stimulate the pathway, same w NO (pathway to relax vasc SM) STh kinases use adenylyl and phospholipase C Tyrosine specific receptors -steroid/thyroid hormone mech Act slowly bc involves protein synthesis Inner nuclear receptor that binds SREs and transcribes

endocrine vs paracrine

Endocrine-- ability of a hormone to be produced by one cell, released into blood stream to travel and act on a distant cell Paracrine-- produced by one cell, released to act on neighboring cell Autocrine-- produces hormone to act on that cell itself Neuroendocrine-- production of hormones by tissue of CNS (hypothalamus)

Have a basic understanding of the causes and consequences of excess and deficiency of Thyroid Hormones

HyperthyroidismGraves disease—inc circulation of thyroid stimulating immunoglobulins (antibodies to TSH receptors, stim)Diagnosis depends on whether TSH/TRH levels are inc or decSymptoms: weight loss w increased food intake, heat production and sweating, rapid heart rate, tremor/nervousness/weaknessInc activity of thyroid gland causes it to enlarge—goiterTreated by drugs that inhibit syn of TH, removal of gland HypothyroidismMost common cause is autoimmune destruction of thyroid gland (destroy gland or block TH synthesis)Also removal of gland, iodide deficiency, hypothalamic/pituitary failureAgain diagnosis based on levels of TSH and shitOpp symptoms of hyperGoiter can form when the cause is thyroid defect (unrelenting stim of thyroif gland by high circulating levels of TSH)Perinatally—cretinism GOITERHigh levels of TSH and analogues have a trophic effect on the thyroid (cause it to grow)

• Be able to describe how the chemical nature of a hormone can influence its synthesis, storage, mechanism of action and clearance.

Peptide/protein -mRNa transcribed in nucleus → in cytoplasm translated on ribosomes to preprohormone→ removal of signal peptide makes prohormone→ packaged in secretory vesicles in Golgi apparatus→ proteolytic enzymes cleave some peptides to make final hormone→ stored in secretory vesicles until exocytosed steroid -steroid hormone biosynthesis: need cholesterol in diet (aldosterone, cortisol, testosterone, and estrogen) -conversion of cholesterol to pregnenolone (P450 side chain cleavage enzyme does this)(this is the rate limiting step) -what cell type makes this conversion determines what hormone is made -steroid action: released by passive diffusion, transported in blood bound to proteins, interact w ICF (nuclear) receptors that are transcription factors, net result is stim or repression of gene transcription

Be able to describe the regulation of Thyroid function and understand the regulatory feedback loop in Thyroid hormone production

TRH secreted from hypothalamus acts on anterior pituitary thyrotrophs (cells in AP that make TSH--secreted. Also transcribes TSH gene to stim prolactin secretion). TH inhibit secretion of TSH by downregulating TRH receptor on thyrotrophs (dec sensitivity)(mediated by free T3) Steady secretion rate due to reciprocal regulation (TRH and TH affect TSH) TSH travels through blood to act on thyroid gland. Gs receptor, adenylyl cyclase and cAMP Stim syn and sec by influencing every step of pathway (Inc production of thyroglobulin and TPX activity) Grows thyroid gland (trophic effect) TSH receptor activated by thyroid-stimulating immunoglobulins (antibodies to TSH recep, produce same response)(high levels can cause Graves disease) Remember negative feedback system for each gland/hormone system and what receptors are involved. Review how rise in ICF calcium comes about for this (in lecture recording).

Describe the physiological effects of Thyroid hormone.

TSH binds G2 coupled recep, activates adenylyl cyclase/cAMP/PKA. Effects slide. Inc expression and activity of Na/I symporter, expression of megalin, proteolytic enzymes that release free T3 and T4. thyroid hormone inc metabolism. Caloric vs thermal challenges pathway slide go over this again). Act synergistically with growth hormone and somatomedins to promote bone formation. Inc BMR/body temp/o2 consumption by inducing synthesis and activity of NaKATPase Cardiac: induce synthesis of beta1 adrenergic receptors (SNS effect on heart rate) In perinatal period its essential for normal maturation of CNS

• Understand the physiologic and anatomic relationship between the hypothalamus and the anterior and posterior pituitary.

The functional connections between the hypothalamus and the anterior lobe of the pituitary now can be understood in the context of the anatomic connections Q -hypothal regulates anterior pituitary (as well as other subsequent specialized glands) -endocrine access (regulation of peripheral hormone production) -pituitary gland connected to hypothal via pituitary stalk (infundibulum) -anterior pit: epithelial drive (hormonal) -posterior pit: neuronal drive -tissue types determine function and response to stimuli -anterior regulation: Axons from hypothal (cell bodies in hypothal make RH) Blood from hypothalamus goes directly to anterior pit-- long and short portal vessels (direct delivery of hormone to anterior pit, concentration control in systemic circ.)(SHORT CIRCUIT) RH released into pituitary stalk Then released in median eminence (axons from hypothal terminate here)(central part of anterior pit) Enter capillary beds/bloodstream, direct RH to anterior pit Find receptor/cell typeCorticotropes: production of ACTHLactitropes: production of prolactinGonadotropes: LH and FSH (gonadotropins)Also GHPROTEIN OR PEPTIDE HORMONES (transcript in nuclei + then protein) -posterior regulation Cell bodies in hypothal make hormones (beginning of posterior pituitary neurons)1 Axons travel through stalk and terminate in posterior pituitary itself (no RH for this) Oxytocin and ADH (kidney and arterioles/breast and uterus)(neuropeptides) Does post pit synthesize and secrete hormones? No-- only secrete, synthesized in hypothal Post pit releases to cap beds/bloodstream

explain how GH levels change during aging

decrease as you age

Understand how iodide availability can regulate thyroid hormone production.

if you're in iodine excess, you dec the activity of TPX and megalin to buffer colloid activity. If you're in iodine deficiency, Na/I symporter activity goes up to increase trapping of the little iodide in blood stream (Wolff effect thing). -T3 and T4 circulate bound to thyroxine-binding globulin (hepatic failure = TBG decrease, inhibits TH synthesis by inc free T molecs and starting neg feedback)(opp can occur in pregnancy)(T3 resin uptake test assesses circulating levels)

· Be able to describe the difference btw the adrenal cortex and the adrenal medulla

o adrenal ctx: made of 3 zones. Adrenal medulla- neural tissue, these areas respond to stimuli differently. Ctx will respond more to peptide/protein stimuli, medulla will respond to neural input. Medulla produces catecholamines (ep and norep, 90% is ep. Primary ep site for whole body). MEDULLA- blood flows thru ctx before medulla so cortisol can be picked up to convert norep to ep and noradr to adr.

· Be able to describe the physiologic actions of aldosterone, cortisol, and adrenal androgens

o cells in kidney have default pathway to keep too much cortisol from circulating- revisit this part of the lecture (basically 11-hydroxy enzyme converts corticol to cortisone). How does cortisol handle glucose?- liver primary site for liver reentering blood stream, also muscle (if we take glucose into muscle you can deplete blood glucose really quick). Free fatty acids a component of energy, can contribute to gluconeogenesis. Excess cortisol leads to lipogenesis (acts on brown adipose tissue). Don't need to know all of systems cortisol affects, just know that it affects a lot. If you stay stressed out (high cortisol) you can decrease your immune response and inc susceptibility to sickness. o Mineralicorticoids: inc Na+ reabs, inc K+ (principal) and H+ sec (alpha intercalated) o Glucocorticoids: (catabolic) inc lipolysis/gluconeogenesis/GFR, dec glucose utilization/insulin sensitivity/immune response/inflammatory response/bone formation/REM sleep. Addison's disease is hypocortisolism/hypoglycemia, Cushing syndrome is hyperglycemia. Also Cushing disease (excess ACTH) o ACTH LOW IN SECONDARY ADRENOCORTICAL INSUFF, also aldosterone levels normal (only need small ACTH) so hyperkalemia/metabolic acidosis/ECF vol contract don't occur

· Have a basic understanding of the pathophysiology resulting from under or over production of the adrenal hormones

o disorders of aldosterone secretion. Salt craving (we excrete sodium if aldosterone not present).

· Understand the biosynthesis of the adrenocortical hormones and feedback regulation of these hormones

o precursor is cholesterol, circulates bound to proteins, esterified and stored in cells o Rate limiting step in all biosyn is conversion of cholesterol to pregnenolone (done by P450 side chain cleavage enzyme). Question: someone showing deficiency in testosterone production, look at rate limiting step, it is that step (and for all other hormones of the adrenal gland). Stim by ACTH o Pregnenolone to either progesterone or 17 hydroxyprogesterone, 21-hydroxylase converts each to deoxy something and then to aldosterone or cortisol, respectively. In another pathway 17 hydroxyprogesterone converted to DHEA and androstendione to make testosterone (most important in females—male testes make their own testosterone) o Corticosterone can make up for cortisol blockage o Mineralocorticoids can still be produced if blockage is below DOC step (bc at this point the shit still has that activity) o Don't need to know each hormone pathway but a few steps important. Fasciculatas cells have enzymes to produce cortisol, glomerulosa don't (only aldosterone enzymes). o Q: what would happen in 21 alpha hydroxylase deficiency?-- o Synthesis and secretion depend on stim of cholesterol conversion by ACTH § Fasciculata/reticularis are under exclusive control of HP axis (CRH and ACTH) · Pulsatile and daily secretion · Low before sleep, high right before waking up · Stim cholesterol conversion—ACTH (pulsatile) · Neg feedback: cortisol inhibits CRH sec indirectly and directly, also inhibits CRH action on AP (inhibit ACTH) · Other stim: stress, ADH, serotonin, inhibit: opiods, somatostatin § Glomerulosa depends on ACTH for first step but otherwise controlled by RAS · Diurnal · Regulated by changes in ECF vol (RAS)(AGII) · Stim aldosterone sec which stim Na+ reabs by kidney · Also controlled by serum K+ conc: inc K+ inc sec (inc intracell Ca2+ by depo cell)

· Be able to discuss the functional anatomy of the adrenal gland including the three zones and the appropriate hormones secreted from each zone

o sit directly on top of kidneys, get one of highest blood flow rates of tissues in body (primary stress responder), don't need to know vasculature. Blood flow comes from outside and goes through before leaving. o 3 zones: glomerulosa, reticularis, and fasciculata (know what zone makes what hormone/their function). Mineralicorticoids (aldosterone) produced in glomerulosa. Middle and biggest layer, fasciculata, produces glucocorticoids (regulate glucose metabolism, cortisol). Reticularis- produces androgens (testosterone, others, play role in libido in males and females. Also precursor for estrogen in premenopausal women). Middle is medulla, produces catecholamines (epinephrine and norepinephrine) o Adrenal cortical hormones are STEROIDS. GLOMERULOSA- movement of sodium and water. AGII stims conversion of cholesterol to pregnenolone (pathway on slide). Cells of glomerulosa can respond to high potassium- protect against hyperkalemia. Aldosterone inc Na channel expression on apical mem of CCD (also inc expression of NaKATPase on basolateral for gradient). BP response pathway on slide. FASCICULATA- cortisol for stress response. Pathway on slide. HPA axis slide too. Both long and short loop feedback. Cell receptor binding pathways on slide. LDL receptors upregulated by ACTH binding- it brings constant source of cholesterol, particularly if stress is chronic. RETICULARIS- adrenal androgens.

Understand the effects of Thyroid hormones on Development

physiological effects slide and following few. Perinatal = time around birth (mental deficits and shit happen if fetus is hypothyroidic). In primary, low TSH bc negative feedback (how you know its primary). BMR = basal metabolic rate.

Be able to explain the biosynthesis of Thyroid Hormones

v different from other hormonal systems. Made in thyroid follicle. TH is only endocrine hormone produced extracellularly. Colloid is center portion (gelatinous, thick substance) where TH production takes place. C cells produce calcitonin. Precursor of TH is tyrosine- iodination of benzene ring, 1 is MIT and 2 is DIT. Our bodies don't make iodine, so we have to take it in diet. Iodine prevents hypothyroidism. MIT and DIT can combine into a T3, two DITs is a T4. out of thyroid gland 90% is T4 and 10% is T3, but T3 is active form- this is due to stability (T4 has longer half life and can be transported through the blood stabily)(T3 has very high affinity for recep and acts quickly/affects quickly). All tissues in body have deiodinases (1,2,3 types- 1 and 2 present in a lot of tissues), which convert T4 to T3. have to be specific where they deiodinate- deiodinating the outer ring is T3, inner ring is reverse T3 (inactive—like an antagonist to TH receptor, binds but doesn't produce a response). Deiodinase 3 gives reverse t3, overactivity of this creates too much and competes with T3 to create hypothyroidism. 7 steps for biosyn: 1: iodide comes into follicular cell through Na/I symporter (ATP dependent). taken into colloid by pendrin. iodide oxidized to iodine catalyzed by TPX (thyroperoxidase). 2: thyroglobulin synthesis (made by follicular cell). 3: iodination (organification)—iodide oxidizes to iodine (req H2O) and iodinate all of tyrosines on thyroglobulin, make MITs and DITs. 4: coupling (combining MIT and DIT or two DITs)(TPX does all of these reactions in colloid- drug that blocks TPX dramatically inhibits TH synthesis, ie PTU). T3 and T4 then expressed on surface. 5: endocytosis- megalin receptor on surface, binds thyroglobulin (that has T3 and 4 on surface), fuse w lysosome, can cleave T3 and T4 off of surface (6: proteolysis). 7: secretion and recycling of T3 and T4 out to blood stream, thyroglobulin and MITs and DITs can be recycled (by thyroid deiodinase, contributes to more TG formation)

Identify disease states caused by the oversecretion or undersecretion of GH

· Achondroplasia—gene mutation, affects bone formation · Gigantism—caused by pituitary adenoma, · Acromegaly—excess GH after growth plates close, treat with somatostatin

Describe the regulation of GH secretion and its target actions in visceral tissue

· GH induces secretion of somatomedins (mediate its actions)(IGF1 and IGF2)

Have a basic understanding of the consequences of abnormal PTH and Vitamin D production.

· Hyperparathyroidism: primary mostly caused by tumors. Inc PTH, hypercalcemia, and hypophosphatemia, and hypercalciuria (bc high filtered load of Ca2+ needs to be excreted). Secondary is excessive PTH as a secondary condition to hypocalcemia · Hypoparathyroidism: consequence of thyroid or hyperparathyroid surgery. Low PTH, hypocalcemia, hyperphosphatemia · Vitamin D deficiency: rickets, insufficient Ca2+ and phosphate to mineralize growing bones (growth failure and skeletal deformities)(children—in adults deficiency results in osteomalacia, which is bending and softening of weight bearing bones) · Vitamin D resistance: kidney unable to produce active metabolite (hydroxylation in kidney absent or inhibited)(common cause is chronic renal failure)

List the target organs and cell types for GH and IGF's.

· Muscle · Liver · adipose

Be able to describe the pathways for the production of the active or inactive form of Vitamin D and the actions of these metabolites.

· cholecalciferol hydroxylated in liver (by 1alpha hydroxylase), not active form. Second hydroxylation in kidney makes it become active (via hydroxylases and P450). Main site of action of vitamin d is the gut. · Active: 1,25 hydroxy D3 (when Ca2+ insufficient) Not active: 24, 25 hydroxy D3 (when Ca2+ sufficient) · Promotes mineralization of new bone, inc both Ca2+ and phosphate conc in plasma so they can be deposited in new bone material. Intestine: calbindin stim Ca2+ reabs to make vitamin D. · Stim by PTH, dec in Ca2+ and phosphate · Ingested in diet or made from UV and skin component

Understand the production and actions of calcitonin.

· inhibits bone turnover/osteoclast activity (osteoclastic bone resorption—dec plasma Ca2+) · synthesized by parafollicular cells of thyroid gland · sec stim by inc plasma Ca2+

Define the pathways of calcium and phosphate metabolism.

· soda has a lot of phosphate, can cause hyperphosphatemia. Turns on active form of vitamin d, shuts off calcium and phosphate reabs in the gut, which in turn affects growth in children. · Calcium homeostasis o Bone/kidney/intestine and PTH/calcitonin/vitamin D o Gut absorbs calcium via vitamin d 1,25 dihydroxycholecalciferol. Also secretes a bit o No net gain or loss of calcium for bone, but continuous bone remodeling stim by PTH o Kidneys have to excrete same amt of Ca2+ abs from GI

• Describe the physiologic changes occurring in the female reproductive track throughout the menstrual cycle and how oral contraceptives can impact.

• -estrogen can have cardiovascular effects • -during ovulation, hypothalamic pituitary axis component inc (more FSH, LH, and GnRH). Also signals ovary to make inhibin- suppresses FSH specifically • -primary hormone from anterior pituitary is LH during ovulation (LH surge) • -after ovulation reminants of follicle produces progesterone: inhibitor of hypothal and pituitary (almost turn entire axis off)(progesterone stops us from entering another ovulation cycle) • -corpus luteum falls away and forms scar tissue (corpus albicans) on cell if fertilization doesn't occur. Scar tissue accumulates over time, debatable if it contributes to menopause • -myometrium contracts during follicular phase (due to estrogen) to propel sperm upward toward fallopian tube (favors fertilization). Extends into fallopian tube, contractions close off opening from fallopian tube to uterus (why oocyte gets stuck here in high estrogen). • -want myometrium to stay quiet once fertilization occurs • -day 14 ovulation: follicular phase follicles are maturing, • -know what progesterone and estrogen do for contraction • -estrogen causes servical mucus to be more watery so sperm can swim better • -cervical becomes thick (post ovulation) with rise in progesterone (blocks sperm entry) • -pH of vagina buffered during ovulation to help sperm survival (cervical mucus) • -if you're not making estrogen, gonadotropins rise (GnRH, LH, FSH) bc nothing is feeding back to it (feedback loop) • -q: what happens to hypothal and pituitary if no estrogen is present

• Understand how oogenesis is supported by Granulosa and the contribution of Theca cells to steroid hormone production in the ovarian follicle.

• -follicle houses developing oocyte within ovary • -antrum: fluid filled space, characteristic of mature follicle. Once it fills up w so much water it bursts, one of the things that causes ovulation • -primary follicle has primary oocyte. Undergo mitosis and then MEOI, get halted in prophase of this so that it will never become haploid (can't have a haploid oocyte, no blood oocyte barrier. So immune system cant attack haploids). Doesn't complete first MEO until it is ovulated- when it ovulates it completes MEOI, then goes into MEOII but halted. Completes MEOII if fertilization occurs (have haploid oocyte very briefly) • -all follicles contain a primary oocyte***** • -theca cells present in secondary and mature, what allows them to make hormone • -once you get granulosa cells, you get primary follicle • -granulosa have aromatase but can't make testosterone

• Describe the neural process associated with erection, emission, and ejaculation.

• -in sexual excitation some sperm from epididymis enter ejaculatory duct, where it meets up with reproductive secretions • -once sperm enter epididymis, can be 48 hrs to a few weeks before release into ejaculatory duct • -parasympathetic relaxes smooth muscle surrounding penis (that normally doesn't allow blood flow) to cause erection (fills up spongey tissue) • -point and shoot: parasympathetic for erection (point) and sympathetic for ejaculation (shoot) • -vas deferens transports sperm to ejaculatory duct where it becomes a component of semen • -emission: getting sperm through tube and combined with various secretions to make semen • -ejaculation is expulsion of semen out of penis • -symp stim closes bladder/urethra opening so retrograde ejaculation doesn't happen (where semen goes backwards into bladder)(sphincter cuts it off) • Erection: parasympathetic nerves, nitric oxide (NO). • Lubrication: parasympathetic nervous function. • Emission & ejaculation: sympathetic nervous function. • -cowper gland neutralizes pH of urethra before sperm enter it (sperm hate acidic conditions, can damage them) • -seminal vesicle and prostate gland make up bulk of semen, make neutral environ for sperm and help keep it that way even upon deposition into vagina (vag typically acidic)(semen thick to protect sperm) • -byproduct of parasymp act is NO production (relaxes corpus cavernosum SM cells- spongey filled chambers in penis that are normally empty, once stim SM relaxes and allows blood to flow into them for erection to occur) • -viagara and related drugs block phosphodiesterase 5 (so upon sex stim you accumulate and keep cGMP for a long time)(half life differs btw drugs: 2 hrs to 2 days)

• Discuss endocrine regulation of ovarian function by the hypothalamic-pituitary-ovarian axis.

• -know and understand progesterone • -both estrogen and progesterone can neg feedback to hypothal in long loop fashion • -go over short vs long loops in each system • -estrogen switches from neg to pos feedback at a point during menstrual cycle, allows for ovulation to occur • -stress (cortisol) inhibitor of hypothal to produce GnRH. People under chronic stress can render themselves infertile/impotent • -pineal gland makes melatonin for sleep cycle • -when females around eachother they start to cycle in sync, due to pheromones (due to nasal mucosa, can affect HP ovarian axis and estrogen production timing)

• Describe the anatomy of the ovary and the development of the ovarian follicle.

• -think of compare/contrast btw male/female, when find different why is it different? • -no blood ovary barrier: during ovary development female makes all of oocytes she will have for entire reproductive lifespan (4-6 million made, at birth a few 100,000 remaining then at puberty less) • -at birth oocytes undergo atresia: programmed cell death • -stim of primary follicle by FSH from pituitary, get more layers of granulosa cells and expression of theca cells (make testosterone to go to granulosa cells to make aromatase to convert to estrogen)

• Understand the nutrient, neural, and hormonal mechanisms that regulate pancreatic hormone release.

• Inc in blood glucose conc stim secretion of insulin • GLUT2 transports glucose into beta cell, undergoes phosphorylation and oxidation. ATP inc (powers this process) depo cell membrane (K+ channels close). Depo opens Ca2+ channels, Ca2+ flows into cell. This causes insulin secretion. • Stim by inc glucose/amino acid/fatty acid/ketoacid conc, glucagon, cortisol, K+, vagal stim, obesity. Inhibited by fasting, exercise, somatostatin, dec glucose. • Nutrient? Neural? Hormonal? • Glucagon (inc and maintain blood glucose) • Stim: fasting, inc AAs (ingestion of protein), acetylcholine. Inhibit: insulin, somatostatin, other shit that it acts to do

• List the principal target organs for insulin and glucagon action and their major physiologic effects.

• Insulin: target is insulin receptor (alpha subunits), receptor taken into cell and dealth with (insulin downregulates its receptor). Dec blood glucose conc (by inc glucose transport into muscle and adipose cells(GLUT4), promoting formation of glycogen, and inhibiting gluconeogenesis), basically opposite of stimulants. Anabolic effect. Inc NaKATPase activity. • Acetyl coA forms ketoacids • Glucagon: alpha cells, mirror image of insulin. Promotes mobilization and utilization of metabolic fuels. Single straight polypeptide with 29 amino acids. • Gs protein coupled recep • Major actions on liver • Stim glycogenolysis • Inc lipolysis • Somatostatin inhibits secretion of insulin and glucagon

• Identify the principal hormones secreted from the endocrine pancreas, their cells of origin, and their chemical nature.

• Insulin—peptide hormone of two straight chains (A and B). from beta cells. Metabolized in liver and kidney by enzymes that break disulfide bonds. also a peptide molec, comes from precursor. Exogenous insulin doesn't have c peptide in it.

• Discuss the endocrine regulation of testicular function by the hypothalamic-pituitary-testicular axis.

• LH induces testosterone production by stimulating Leydig cells. • FSH stimulates spermatogenesis by activating Sertoli cells. • Testosterone is necessary for spermatogenesis. • Testosterone inhibits GnRH secretion. • Activated sertoli cell secretes inhibin that inhibits secretion of FSH.

• Compare and contrast the mechanisms of secretion and physiologic functions of insulin and glucagon

• glucagon- we won't be tested on gluconeogenesis or glycolysis. Green contributes to gluconeogenesis, red inhibited by glucagon (bc glycolysis). Glucagon helps breakdown glycogen to get gluc 6 phosphate (go over this slide again). Deep in glycolytic pathway- what's happening to acetyl coa/malonyl coa/acetyl coa carbox (this rxn helps to store fat as energy in body as adipose tissue). • When fatty acids brought into mitochon they can go through fatty acid oxidation which produces ketone bodies (can be used as energy but usually not bc acidic. Dn't want them to accumulate in blood)(KNOW LIVER KETOGENESIS PATHWAY). • Gluc and insulin differ in how they handle energy sources in the body. Remember: as glucagon comes up blood gluc rises, also causes rise in insulin. • INSULIN-What regulates insulin secretion: component slide- gluc level primary regulator of insulin sec. GLUT2 is insulin independent.

• Describe the location and structure of the pancreas, and the morphology and function of the pancreatic islets

• located next to stomach and intestine, majority of pancreas has an exocrine function (deals with digestion) but also has endocrine function. Pancreatic eyelets/islets of longerhon- regulate levels of glucagon. • Secretes insulin and glucagon (regulate glucose, fatty acid, and amino acid metabolism) • Islets of Langerhans: beta cells secrete insulin, alpha cells secrete glucagon, delta cells secrete somatostatin, and others secrete peptides. Innervated by neurons. • Beta cells mainly in center, others in periphery (so blood comes in contact with beta cells first-- know whether or not we need to produce insulin). • Alpha cells produce glucagon, delta is somatostatin which is a neg inhibitor of something. After eating a big meal, we get sleepy bc glucose being taken up by brain (?)

• Discuss the organization of the male reproductive tract, including the accessory glands, and the process of semen formation.

• removal of cytoplasm starts formation of sperm as we know it (round to actual shape) • Spermatids attach themselves to large sertoli cells which extend from base to lumen of tubule. • Sertoli cells provide nourishment for spermatids • Sertoli cells remove excess cytoplasm as spermatids become spermatozoa, the process called spermiation. • Sperm form in seminiferous • tubules but mature in epididymis. • Sperm here are non-motile at first.18-24 hrs later, sperm start developing the capability of fertilization; called maturation. • Epididymis secrete fluids containing hormones, enzymes, and nutrients for sperm maturation. • Gain motility, lose cytoplasm, aquire forward mobility protein and acrosomal stabilizing factor