9.2 Endocrine Physiology

Secretion, action, regulation — the official three bullets

Endocrine Physiology is 12% of the Physiology domain. The test plan names exactly three nested topics: secretion of hormones, action of hormones, and regulation. That is a mechanism syllabus. Do not turn it into a pathology atlas of Graves disease, and do not duplicate the Chemistry chapter's fuel-pathway maps. Name the gland, the chemical class, how the hormone is stored and released, which receptor and second messenger it uses, and which feedback loop sets the plasma level. Gland histology and development are in 4.3 Endocrine System Anatomy. Metabolic effects of insulin, glucagon, cortisol, GH, and thyroid hormone on glycolysis and lipolysis are in 11.1 Hormones.

Quick Answer: Peptides: vesicles + membrane receptors. Steroids: made on demand + nuclear receptors. Gs-cAMP for ACTH/TSH/LH/FSH/PTH/glucagon/V2. Gq-IP3 for TRH/GnRH/oxytocin/V1/Ang II. Insulin = receptor tyrosine kinase. GH/prolactin = JAK-STAT. Aldosterone follows Ang II and K+, not ACTH. PTH raises Ca2+ and lowers phosphate; 1,25-D3 absorbs both from gut.

Chemical classes and how secretion actually happens

Secretion patterns are testable because they explain sampling and disease kinetics:

• Pulsatile: GH, ACTH, GnRH/LH. A single random GH is often useless; an IGF-1 integrates GH over time.
• Circadian: ACTH and cortisol nadir around midnight and peak near waking. GH peaks in slow-wave sleep.
• Stimulus-secretion coupling: peptides and catecholamines wait in vesicles for a calcium signal.
• On-demand steroids: no granule of cortisol sitting in the zona fasciculata. ACTH (Gs-cAMP) induces StAR and steroidogenic enzymes, then cortisol appears in blood.
• Thyroid colloid: weeks of hormone precursor can sit as iodinated thyroglobulin. That is why a Wolff-Chaikoff iodide load can be buffered, and why thyroid hormone deficiency takes time to declare itself after TSH falls.

C-peptide is cleaved from proinsulin in the beta-cell granule and is released equimolar with insulin. C-peptide in plasma marks endogenous insulin secretion; injected insulin has no C-peptide. That is secretion physiology, not a billing code.

Action: receptor classes and second messengers

Membrane receptors change in minutes. Nuclear receptors change transcription over hours. Permissive, synergistic, and antagonistic pairings are how the same second messenger produces different physiology in different tissues.

Exam trap — ADH receptors. V2 on collecting-duct principal cells is Gs-cAMP and inserts AQP2. V1 on vascular smooth muscle is Gq and vasoconstricts. Naming ADH as 'the water hormone' without the receptor subtype loses the item if the stem is a pressor question.

Exam trap — insulin. Insulin does not use Gs. It does not enter muscle as a passenger on GLUT4. Insulin translocates GLUT4 to the membrane in skeletal muscle and adipose tissue. GLUT1 (RBC, blood-brain barrier), GLUT2 (beta cell, liver, kidney, intestine — bidirectional, high Km), GLUT3 (neurons), GLUT4 (insulin-dependent muscle/fat).

Beta-cell secretion sequence, because it is the cleanest stimulus-secretion story in the domain: glucose enters via GLUT2 → glucokinase phosphorylates it (the glucose sensor) → ATP rises → KATP channels (Kir6.2/SUR1) close → depolarization → voltage-gated Ca2+ channels open → insulin granule exocytosis. Sulfonylureas close KATP; that is pharmacology sitting on a physiology fact.

Permissive example: cortisol maintains vascular responsiveness to catecholamines (enzyme induction, receptor coupling). Synergistic example: glucagon, epinephrine, and cortisol on hepatic glucose output. Antagonistic example: insulin versus glucagon on liver phosphorylase versus glycogen synthase.

Regulation: loops, tropic hormones, and set points

Negative feedback is the default. Long-loop: peripheral hormone inhibits hypothalamus and pituitary (T3/T4 on TRH/TSH; cortisol on CRH/ACTH; IGF-1 on GHRH/GH). Short-loop: pituitary hormone inhibits its hypothalamic releasing hormone (GH on GHRH). Ultra-short: a hypothalamic peptide inhibits its own neurons.

Positive feedback is rare and always named: estradiol on the LH surge, oxytocin in the Ferguson reflex, and (outside this chapter) coagulation thrombin burst. If an item says 'always negative,' it is wrong.

Tropic hormones act on another endocrine gland (ACTH, TSH, LH, FSH). Trophic describes growth effects (ACTH also maintains fasciculata mass). GH is both a metabolic hormone and a tropic hormone for IGF-1 secretion.

Set points move. Estrogen raises TBG, so total T4 rises in pregnancy while free T4 stays near normal if the axis is healthy. Measuring only total T4 in that setting is a trap. Fever raises the hypothalamic temperature set point; that is not thyroid storm.

Hypothalamic-pituitary unit

The anterior pituitary (adenohypophysis) is epithelial and is controlled by portal venous releasing and inhibiting hormones. The posterior pituitary (neurohypophysis) is a downgrowth of hypothalamus: supraoptic and paraventricular neurons synthesize ADH and oxytocin, axon-transport them, and release them into systemic capillaries. Posterior-lobe hormones are therefore hypothalamic hormones with a pituitary ZIP code.

POMC cleavage yields ACTH, β-endorphin, and MSH-related peptides. That is why a marked ACTH excess can produce hyperpigmentation (MSH activity of POMC fragments on melanocortin receptors).

GH uses JAK2-STAT. It is secreted in pulses, stimulated by hypoglycemia, exercise, deep sleep, and ghrelin, and inhibited by glucose and IGF-1. Direct GH effects include anti-insulin actions (lipolysis, decreased glucose uptake). Many growth effects are via IGF-1. Do not memorize a pediatric growth chart here; do know the receptor class and the glucose relationship (GH rises when glucose falls).

Prolactin is unique among anterior hormones: its dominant hypothalamic control is tonic inhibition. Cut the pituitary stalk and prolactin rises while other anterior hormones fall. That stalk-effect item is regulation, not neurosurgery.

ADH is released by increased plasma osmolarity (osmoreceptors) and by large drops in volume/pressure (baroreceptors). Osmolarity is the finer controller in ordinary life. Ethanol inhibits ADH; nausea stimulates it.

Thyroid: iodide, TPO, and peripheral conversion

Follicular cells trap iodide via the Na+/I− symporter (NIS). Pendrin moves iodide into the colloid. Thyroid peroxidase (TPO) oxidizes iodide, organifies it onto thyroglobulin tyrosines (MIT, DIT), and couples residues: DIT+DIT = T4, MIT+DIT = T3. TSH (Gs-cAMP) stimulates every step plus colloid endocytosis. Lysosomal proteolysis frees T4 and T3.

The gland secretes mostly T4. T3 is the higher-affinity ligand at the nuclear receptor. Peripheral deiodinases: D1/D2 convert T4 → T3; D3 converts T4 → inactive reverse T3. Fasting and severe illness increase rT3 and decrease T3 (euthyroid sick pattern) — a regulation change, not a new gland.

Wolff-Chaikoff: excess iodide transiently inhibits organification. Escape restores hormone synthesis in a normal gland. Jod-Basedow: iodine load can spark hyperthyroidism in autonomous tissue. You do not need the eponyms if you can state the iodide-TPO relationship.

Thyroid hormone raises BMR (Na+/K+ ATPase, mitochondria), is permissive for β-adrenergic receptors (the reason hyperthyroid patients look catecholamine-driven), and is required for CNS development in the fetus and infant. TSH-receptor stimulating antibodies belong in pathology; the receptor being Gs belongs here.

Adrenal: three cortical zones and a modified ganglion

Cortex is mesoderm; medulla is neural crest (modified sympathetic postganglionic cells). Learn the enzyme geography or you will assign the wrong product to ACTH.

Exam trap: physiologic ACTH pulses are not the main aldosterone controller. A patient can have secondary adrenal insufficiency (low ACTH, low cortisol, intact RAAS aldosterone) and still handle potassium better than a primary adrenal failure patient who lacks both cortisol and aldosterone.

Cortisol is gluconeogenic, proteolyzes muscle, redistributes fat, suppresses inflammation (lipocortin/annexin-1 reducing PLA2 activity), and is permissive for catecholamine vascular tone. 11β-HSD2 in the kidney converts cortisol to cortisone so the mineralocorticoid receptor 'sees' aldosterone; licorice inhibits that enzyme and produces an apparent mineralocorticoid excess — a regulation item, not a candy joke.

Medullary PNMT (norepinephrine → epinephrine) is induced by high local cortisol from the cortex-to-medulla portal blood. That is why the adrenal medulla secretes mostly epinephrine while sympathetic endings secrete norepinephrine.

Pancreatic islets

Insulin and glucagon are reciprocal in the fed/fasted switch. Somatostatin is the local referee. Incretins explain why oral glucose raises insulin more than the same intravenous glucose — secretion physiology of the enteroinsular axis.

Calcium-regulating hormones

Plasma ionized Ca2+ is the controlled variable. The parathyroid calcium-sensing receptor (CaSR) is a GPCR: high Ca2+ suppresses PTH (one of the few endocrine glands in which the sensed ion inhibits secretion).

Exam trap: calcitonin comes from C cells, not follicular cells. Adult calcium set-point is a PTH / vitamin D story; calcitonin is more important as a pharmacologic osteoclast silencer and as a medullary-thyroid-carcinoma tumor marker than as the daily Ca2+ thermostat.

FGF23 from osteocytes lowers phosphate by reducing proximal reabsorption and by suppressing 1α-hydroxylase. Phosphate is not a spectator ion.

Worked scenario — low ionized calcium. PTH should rise. Expect phosphaturia, increased 1,25-D3, and RANKL-mediated bone resorption. If PTH is high and phosphate is high, the kidney is not answering (renal failure) rather than the parathyroid being silent. If PTH is low despite hypocalcemia, the gland is failing or the CaSR is overactive.

/practice/nbce-part1Practice questions with detailed explanations