Endocrine Physiology

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Hormone

Back 1

molecules that alter function of nearby or far away cells that are secreted by endocrine cells into blood. ex: water/plasma soluble (peptides and amines), lipid/membrane soluble (adrenal cortical and gonadal steroids, thyronine T3 T4, calcitrol)

Front 2

Hormone Receptors

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specificity
amplification of hormone action
not rate-limiting
down-regulates receptors according to hormone plasma concentration
up-regulates its own or other hormone receptors

Front 3

Water soluble hormones

Back 3

PEPTIDES, BIOGENIC AMINES, aldosterone
short half-life, freely dissolved in plasma, receptor on cell surface of target cell, modifies production of intracellular 2 messengers

Front 4

Lipid soluble hormones

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STEROIDS, THYROID HORMONES
long half-life, bound to albumin plasma protein, receptor on nucleus of target cell, hormone-receptor complex acts as Tx factor modifying specific mRNA production

Front 5

Enzyme-linked Receptors

Back 5

bind to tyrosine kinase -> phosphorylate receptors ->
cascade
ex: insulin, GH, prolaction

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G-protein coupled Receptors

Back 6

1.Adenylate cyclase-> cAMP
ex: ADH, ACTH, B1 norep, B2 epi, Glucagon, Secretin, PTH, LH, FSH, TSH
2. Phospholipase C -> IP3 + DAG -> Ca2+ -> contraction, secretion, cell division
ex: A1 Norepi, Angiotensin2, CKK, Gastrin, GnRH
3. guanylyl cyclase -> cGMP -> less Ca2+
ex: ANP

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Hypothalamus - Anterior Pituitary Communication

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NS modifies hormone secretion via hypothalamo-hypophysial portal vessels
1. Ventromedial & Arcuate N produce TRH, CRH, GHRH, Somatostatin, PIF; Preoptic N produce GnRH
2. hormones secreted into hypothalamo-hypophyseal portal vessels
3. hormones bind to anterior pituitary receptors
4. hormones modify secretion of TSH, FSH, LH, ACTH, GH, Prolactin
Block: Low Cortisol & ACTH

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Ant. Pituitary Removal

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Low Cortisol & ACTH; Anterior pituitary hormones decreases except Prolactin b/c PIF inhibited

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Negative Feedback

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when plasma tropic hormone concentration (FSH, LH, TSH, ACTH) high, rate of secretion reduces

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Ant pituitary modes of secretion

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1. Pulsatile ex: LH & GnRH
2. Circadian hormones secreted more at specific parts of day
ex: ACTH
3. Episodic/On Demand: secreted in response to hypothalmic afferent input
ex: nipple stimulation-> prolactin in lactating moms

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Adrenal Hormone Categories

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Zona glomerulosa: Angiotensin2 -> aldosterone
Zona fasiculata and reticularis: ACTH -> cortisol and androgens
Adrenal Medulla: ANS -> epinephrine

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Glucocorticoid cortisol

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antagonizes insulin (promotes glucose secretion into blood by liver, inhibits glucose uptake by cells), increases BP, no ADH, Permissive vasoconstrictive effects of EPI and NOREPI, Mobilizes energy stores via glucagon + EPI (glycogen or fat or protein-> plasma fatty acids + glycerol, amino acids -> high gluconeogenic enzymes -> glucose), glycogen synthesis, excretes water load by suppressing ADH, allows one to cope w/ stress (trauma that’s not fatal) by preventing glucose uptake by muscle (like insulin does) and redirects glucose -> brain, inhibits ACTH (low cortisol ex: CAH or drugs increases ACTH)

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Catecholamine Epinephrine

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Adrenal medulla; gluconeogenesis + increases capacity of person to mobilize glycogen or lipids-> glucose & free fatty acids during exercise or cold exposure; increases reuptake of K+ by muscle preventing hypokalemia (normal A.P. na in, k out = hypokalemia), can be compensated for by postganglionic symp-controlled NOREPI in the absence of adrenal medulla/epi, Hypophysectomy: low cortisol/low ACTH = low epinephrine

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Adrenal Steroid Hormone Synthesis

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Cholesterol (mitochondria) --ACTH (ZF+ZR)+StaR<->cAMP--> Cortisol
Cholesterol (mitochondria) --ACTH (ZF+ZR)+StaR<->cAMP--> Corticosterone --Angiotensin 2 (ZG)--> Aldosterone

*ACTH not rate limiting; in its absence, aldosterone levels unaffected b/c A2 is rate limiting

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Adrenal Cortex Hormone Transport

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aldosterone = free/h20 soluble
cortisol: CBG-bound cortisol in equilibrium w/ free cortisol (diffuses into target cells)
CBG secretion stimulated by estrogen
high CBG=high total plasma cortisol ex: pregnant woman
low CBG=low total plasma cortisol ex: liver damage, renal disease
cortisol levels normalize in high or low CBG conditions

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DHEA

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androgen; masculinizing hormone in women and children when secreted in large amounts from adrenal cortex; bound to albumin so long half life + high DHEA conc, in fetus: ACTH -> DHEA -> placenta: estriol/estrone/estradiol -> estrogen (blood & urine of pregnant mom)

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Mineralocorticoid Aldosterone

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Increases ECF volume, Increases BP, K+ secretion, Na+ reabsorption, stimulated by Estrogen and Plasma K+

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Cushing's Syndrome

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pituitary tumor -> ACTH, cortisol
fat pads, poor muscle development, big abdomen, bruising, thin skin due to proteinolysis

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Hyperaldosteronism

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Primary: hypokalemia, high HCO3, metabolic alkalosis, high plasma Na+ & H20 retention, low Filtration Fraction -> Na+ escape 1/2 L -> increased ECF volume, hypertension, 25 aldosterone: 1 renin
Secondary: low BP (due to volume depletion ex: hemorrhage, diarrhea, vomiting, low cardiac output, dehydration) -> renin, Angiotensin 2, Aldosterone -> retain fluid, increased ECF volume, edema, no hypokalemia or alkalosis, no Na+ escape (HYPERNATREMIA), 10 aldosterone: 1 renin

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Hypoaldosteronism

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Primary/Addison's Disease: low BP-> high renin, angiotension 2, low aldosterone, hyperkalemia, low HCO3, Na+ and H2O loss, decreased ECF volume, hypotension
Secondary: due to bed rest or weightlessness, low renin -> low angiotensin 2 -> low aldosterone, low ADH, high ANP, lose Na+ and H2O-> decreased ECF volume

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Parathyroid Hormone/PTH

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4 glands posterior to thyroid gland; chief cells secrete PTH; low Ca2-> high cAMP-> high PTH secretion; high Ca2-> low cAMP -> low PTH; only the intact PTH binds both Antibodies in sandwich assay (used to monitor PTH levels)
PTH increases serum Ca2 and decreases serum Phosphate
BONE: breaks down bone by increasing osteoclast function via osteoblast receptors to remove Ca2 to increase plasma [Ca2] levels back to normal + releases hydroxyproline + Phosphate too
KIDNEY: inhibits P reabsorption by inhibiting Na/P cotransporter on apical memb, stimulates transcellular Ca2 reabsorption by opening up Ca2 channel on apical memb, increases hydroxylase activity which increases active Vit D production
INTESTINES: no PTH receptors, PTH makes Vit D in kidney & Vit D increases Ca2 reabsorption

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Familial Hypocalciuric Hypercalcemia

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mutation causing high plasma Ca2 levels, normal PTH levels b/c it reduces Ca2 channel's sensitivity to changes in Ca2 levels so you need more Ca2 to suppress PTH

Front 23

Parathyroid Hormone Related Peptide (PTHrP)

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secreted by normal & malignant tissues/tumors, mimics PTH effects on bone & kidney

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Vitamin D

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Binds to receptors of target cells; not hormone or essential vitamin; hydroxylated in liver and then in kidney to active 1-25 dehydroxy Vit D form when plasma Ca2 is low, PTH is high. PTH increases hydroxylase gene activity in kidney.
BONES: bone remodeling by breaking down old old bone thus increasing plasma Ca2 and Phosphate, which helps mineralize new bone
decreases PTH secretion (negative feedback loop)
INTESTINES: Increase Ca2 absorption

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Rickets

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low Vitamin D levels -> weak bones; bowing of legs

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Ca2+ and Phosphate Homeostasis

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Ca2 and Phosphate readily combine to form hydroxyapatite (mineral part of bone); Both regulated by Vit D and PTH

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Parathyroid Hormone Pathophysiology

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Primary Hyperparathyroidism: urine has high Phosphate, hydroxyproline, cAMP, Ca2, alkaline phosphatase; high Ca2-> increased gastric acid + ulcers + kidney deposits; due to benign parathyroid adenoma
Secondary Hyperparathyroidism: when low Vit D or Ca2 or renal failure -> high PTH -> low/normal serum Ca2
hypoparathyroidism: associated w/thyroid & parathyroid surgery due to damage; low PTH; low Ca2, high Phosphate
Pseudohypoparathyroidism (hormone resistance): defective receptor can't respond & cause cascade

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Renal Failure & Vitamin D

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low GFR, low Phosphate filtration, Phosphate retained, Phosphate/ Ca2 complexes deposit in soft tissue and skin causing itching and causes low serum Ca2-> low 1,25 active dihydro vitamin D -> low Ca2 absorption -> high PTH -> high bone resorption to increase serum Ca2, also increases bone pain
treatment: inject Vit D, limit Phosphate intake, remove parathyroid tissue to remove high PTH

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Calcitonin

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opposite of PTH (decreases plasma Ca levels); secreted from thyroid gland consistent w/ Ca2 levels; high Ca2, high calcitonin; osteoclasts don't have calcitonin receptors; calcitonin binding decreases osteoclast activity and slows bone turnover rate

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Ca2+ as Hormone

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Ca2 activates Ca2 sensing receptor in TAL of nephron & acts as its own negative feedback regulator

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Dietary Effects of eating dairy

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high plasma Ca2-> low PTH-> low Ca2 and phosphate release from bone-> low alpha1 hydroxylase activity -> low intestinal Ca2 uptake + low renal Ca2 absorption
OR
low plasma Ca2-> high PTH -> increased Ca2 & Phosphate release from bone-> high renal Ca2 absorption-> high alpha1 hydroxylase activity -> high intestinal Ca2 uptake

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Dietary Effects of eating Phosphate/Coke

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high Phosphate -> complexes w/ Ca2-> low Ca2-> high PTH ->high bone Ca2 and Phosphate mobilization/resorption-> Phosphaturia-> high alpha 1 hydroxylase activity-> high Ca2 absorption

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Islets of Langerhans

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B-cells 60-75%/central: preproinsulin->insulin + c peptide (marker 4 insulin secretion in T2D); insulin inhibits glucagon
A-cells 20%/periphery: Glucagon (stimulates insulin)
Delta cells 5%/periphery: somatostatin (inhibits insulin + glucagon)

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Feasting & the anabolic hormone

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high a.a., glucose, fatty acids, K+
LIVER: high glycogen, protein, lipid synthesis; low glycogen breakdown, low synthesis of glucose, ketones, urea
MUSCLE: glut 4; insulin: high glycogen and protein synthesis, glucose oxidation to Co2, H2O, ATP; low glycogen and protein breakdown; Na+out/K+in ATPase
FAT: glut4; insulin: high lipid synthesis, low lipid breakdown

Front 35

Control of Insulin Secretion in Pancreatic B cell

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(+)Glucose uptake, ATP, high Ca2 conductance, hyperkalemia (depolarizes Beta cells), AIR; Glucagon; Growth Hormone; Intestinal Hormones GIP, GLP (jejunal, promotes insulin, inhibits glucagon); Amino Acids Arginine; Parasymp Innervation Ach
(-)hypokalemia (hyperpolarizes B-cells), Symp Innervation epi Norepi; Somatostatin

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weight & insulin secretion

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highest: obese/normal, obese/diabetic (type 2), thin/normal, thin/diabetic (type 2): lowest

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Type 2 Diabetes mechanism

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increased food intake, high insulin levels, insulin receptors on fat/muscle lose their sensitivity to insulin, less glucose uptake, inadequate glucose uptake by fat/muscle, increase plasma glucose, high insulin levels

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Glucagon

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Increases insulin secretion, glycogen breakdown, glucose & ketone & urea synthesis

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Control of Glucagon Secretion in Pancreatic A Cell

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(+) Arginine/a.a., low glucose, parasymp, symp output
(-) high glucose, insulin, somatostatin

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Growth Hormone

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stimulates liver to secrete IGF-1 and Insulin; lipolysis (+ hormone sensitive lipase), protein synthesis, maintains blood glucose w/in narrow range by gluconeogenesis and inhibiting cellular uptake of glucose (insulin antagonist)
too much: gigantism, acromegaly
too little: dwarfism

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IGF-1

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helps you grow better than GH; inhibits GH secretion (high IGF1, low GH, low insulin); protein hormone w/ long half-life because its bound to IGFBP-3 carrier so it doesn't get filtered through glomerulus and get chopped up

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Body Fuels & fasting

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glucose: 1 day's worth, source: proteinolysis and glycerol
glycogen: 1 day's worth, stores: liver and muscle
protein: death a/f 1/2 body proteins used, store: muscle
fat: 40 days fuel, transported w/proteins as chylomicrons b/c not H2O soluble, brain can't use it, O2 req. for fat metabolism, fat converted to ketone bodies

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Control of Growth Hormone Secretion

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(+) GHrH in hypothalamus, sleep, low blood glucose, stress, exercise, thyroid hormones, a.a. arginine
(-) somatostatin, high blood glucose/free fatty acids, IGF-1

Front 44

Thyroid Hormones

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Effects: thermogenesis, protein synthesis, growth/development
TSH actions: iodide uptake by Na/I cotransporter, synthesis/release of Thyroid hormones, Na/K ATPase synthesis w/in thyroid, synthesis of Thyroglobulin & TPO, stimulates D1 (type 1 deiodinase)
overriding effects on metabolism: ??????

Front 45

Thyroid hormone regulation

Back 45

SYNTHESIS:small fluctuations/ increase in iodide intake increases rate of hormone synthesis; gland limits its ability to use free iodide= Wolf Chaikoff effect (free iodide decreases cAMP response to TSH binding & prevents thyroglobulin degradation) iodide levels then normalize, thyroid hormones deiodinated->active
SECRETION: TRH in hypothalamus secreted to ant pituitary, which secretes TSH to Thyroid-> T3, T4 in plasma-> negative feedback stops Hypothalamus & Ant Pituitary TRH secretion
INHIBITION: somatostatin, dopamine, glucocorticoids

Front 46

Thyroid gland

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endocrine; stores hormone product, follicular structure

Front 47

Hyperthyroidism/ Grave's Disease

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low TSH, high T3/T4; nervous, weight loss, increased appetite, heat intolerance, sweating, high cardiac output, arrhythmia/tachycardia (loss of vagal input to heart's pacemaker cells), no menstruation

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Hypothyroidism/myxedema/ Hashimoto's disease

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high TSH, low T3/T4; fatigue, lethargic, memory loss, concentration, constipation, abnormal menstrual cycle, low cariac output, cold intolerance, high cholesterol, weight gain, loss of appetite

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Thyroid Hormone Transport

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plasma; binds to TBG (thyroid binding globulin); T4 (inactive) has longer half-life b/c has higher affinity for TBG than T3 (active; higher affinity for receptor)
TBG increase: pregnancy, estrogen, oral contraception, hepatitis.. decrease: steroids, cirrhosis, kidney disease w/proteinuria, glucocorticoids

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Congenital Adrenal Hyperplasia

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Low cortisol, high ACTH
treat w/cortisol

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exogenous Insulin overdose

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high insulin, low c-peptide, low glucose

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normal plasma Na+ and K+ levels

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Na 135-145
K 3.5-5.5

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Cushing's disease

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High Cortisol & ACTH

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Addison's disease

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Low Cortisol, High ACTH
low aldosterone (low BP too) so low Na/K ratio = hyperkalemia and Na urine excretion w/H20 following Na so ECF and ICF volume depleted

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Dexamethasone

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Low Cortisol & ACTH
glucorticoid not on cortisol assay; high doses=suppression test; lowers CRH

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Autonomous Cortisol Tumor of ZF

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High Cortisol, Low ACTH
CRH secreted originally by hypothalamus is instead secreted by ZF

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Prednesone

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glucocorticoid 20X stronger than cortisol, causes HIGH glucose, shows up in cortisol assay;
Low Cortisol & ACTH, insulin normalizes glucose levels

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24 hour urinary free cortisol

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Equal to Mean Plasma concentration of free cortisol in 24 hr

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XY female external genitals

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17a hydroxylase missing b/c low testosterone

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XX female enlarged clitoris

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11b hydroxylase missing b/c high testosterone

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adrenal glands enlarged/hypertrophied

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high cortisol, high aldosterone, high tesosterone/estrogen, high StaR

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XY salt-losing hypotension

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21b hydroxylase missing b/c low aldosterone

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Insulinoma

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high insulin, high c-peptide, low glucose + shock

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congestive heart failure

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increased ECF volume

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Diabetic Ketoacidosis (T1D) - betaOHbutyrate

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No insulin, high glucagon, high lipolysis, high epie, high cortisol, Ketone synthesis by liver, less ketone excretion, High glucose b/c ACTH and cortisol levels increase to increase plasma glucose; high ketoanions in filtrate, less H+ ions to couple w/ketoanions, high Na+/K+ cation urinary excretion

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osteoporosis

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treat w/bisphosphonate (side effect: jaw bone necrosis)

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deiodinase 1

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rT3, LIVER T3; micromolar

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deiodinase 2

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PITUITARY T3; nanomolar

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TPO

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iodine production to incorporate into thyroglobulin

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Lithium

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increases plasma Ca2+

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ACTH

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high cholesterol uptake in ZF

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Cortisol-> Cortisone

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cortisone doesn't bind mineralocorticoid receptors

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Goiter

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caused by high TSH

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thyroid hormone receptors

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dna-binding domain + high affinity for T3

Front 75

Acute Insulin Response

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peaks of insulin in response to rapid glucose intake; loss of AIR occurs a/f glucose IV due to less Glut2 transporters that can rapidly transport glucose into B cells

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Type 2 diabetics

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low sensitivity of muscle & fat cells to insulin

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Common feature of Hypo and Hyperthyroidism

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high [antibody] to thyroid gland proteins

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starvation

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decreases T3, T4, increases rT3

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DIT and MIT

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T3=MIT + DIT
T4=2 DIT
low Iodine uptake, high MIT, low DIT, high T3

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Pregnancy

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GH decreases women's insulin sensitivity so more insulin secreted so baby gets more glucose
normal: 2X as much insulin secretion, normal glucose
diabetic: high insulin, high glucose

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Adrenal Gland Removal

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decreased aldosterone, low Na/K ratio, hyperkalemia (acidosis), pigmentation

Front 82

Adrenal Tumor

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1 adrenal gland enlarged (high cortisol, aldosterone produced), negative feedback causes other adrenal gland to atrophy

Front 83

Volume Changes

Back 83

Blood loss: low ecf/icf vol
Diarrhea: low ecf vol
sweat loss: low ecf/icf vol, high osmolality
compulsive H2O drinker: high ecf/icf vol, low osmolality

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hypothalamus

Back 84

secretes CRH

Front 85

anterior pituitary

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secretes ACTH

Front 86

adrenal gland of kidney

Back 86

secretes epi/norepi (medulla)
cortisol (cortex)

Front 87

Ectopic Lung Carcinoma/Tumor

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High Cortisol & ACTH; 1/1 ratio of ACTH in petrosal sinus/periph vein

Front 88

High cortisol states

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pregnancy
stress
early morning (high acth dawn effect)
cushing's adrenal tumor

Front 89

Metyrapone

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Low Cortisol, high ACTH

Front 90

block STaR

Back 90

Low Cortisol, high ACTH

Front 91

Low cortisol states

Back 91

Liver or kidney glomerulus damage

Front 92

Steroid Enzyme deficiency Effects

Back 92

Remove 17alphahydroxylase: affects genitalia
Remove 21betahydroxylase: hypotensive, salt losing, low ECF vol - give prednesone
Remove 11betahydroxylase: salt retain, hypertensive, hypokalemic - give cortisol

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Low filtration fraction

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Low renal plasma flow of ion-> Increased ECF volume -> low Filtration Fraction -> Lose Na+ (Na+ Escape)

Weightlessness causes blood that used to pool in legs to circulate upwards/freely throughout body -> Increased atrial blood Pressure -> high ANP -> high Stroke volume -> more blood flow through kidney -> low renin -> low aldosterone

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Weightlessness

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blood circulates freely throughout body -> increased atrial blood pressure -> high ANP -> high stroke volume -> more blood flow through kidney -> high BLP -> low renin, aldosterone, etc