4.2 Endocrine Physiology: Hormone Chemistry, Axes, Calcium & Fuel Regulation

Why this area matters

The 2025 TOS asks about:

• the roles of endocrine systems and their interaction with the nervous system;
• hormone synthesis, transport, action and regulation;
• the anatomy of the hypothalamus, pituitary, thyroid, parathyroid and adrenal glands;
• measurement of hormone concentrations;
• hydrophilic versus hydrophobic hormones and how they reach their receptors.

The same physiology later supports diabetes, thyroid and adrenal disease in Medicine, Pharmacology and Pathology.

Hormone classes and transport

Second messengers:

• Gs (cAMP): ACTH, TSH, LH, FSH, glucagon, PTH, ADH at V2, beta-adrenergic receptors.
• Gq (IP3, DAG, Ca2+): TRH, GnRH, ADH at V1, oxytocin, alpha-1 receptors, gastrin.
• Gi (lowers cAMP): alpha-2 receptors, somatostatin, dopamine D2.
• Receptor tyrosine kinase: insulin, IGF-1.
• JAK-STAT: growth hormone and prolactin.
• cGMP: ANP and nitric oxide.

Only the free hormone is biologically active. High estrogen states (pregnancy, oral contraceptives) raise thyroxine-binding and cortisol-binding globulins. Total T4 and total cortisol then rise, but the free levels and the patient's thyroid and adrenal status stay normal.

Measuring hormones

• Immunoassays measure most hormones; free T4 and TSH are the usual thyroid tests.
• Many hormones are pulsatile or circadian. Cortisol peaks in the early morning, and growth hormone surges in deep sleep. A single random level can mislead.
• Dynamic testing follows one rule: stimulate when you suspect deficiency, suppress when you suspect excess.
  • The ACTH (cosyntropin) stimulation test diagnoses adrenal insufficiency.
  • Insulin-induced hypoglycemia tests the GH and ACTH axes.
  • The overnight dexamethasone suppression test screens for Cushing syndrome.
  • A glucose load that fails to suppress GH confirms acromegaly.
• Interpret a hormone together with its regulator. Low free T4 with high TSH points to primary hypothyroidism; low free T4 with low or normal TSH points to central (secondary) hypothyroidism.

Endocrine Control & Hypothalamic-Pituitary Axes

Endocrine homeostasis is maintained via negative feedback across anterior pituitary axes and independent mineral/nutrient feedback systems.

Hypothalamic-Pituitary Axes

1. Hypothalamic-Pituitary-Adrenal (HPA) Axis:
   • Hypothalamic Corticotropin-Releasing Hormone (CRH) stimulates anterior pituitary corticotrophs to cleave pro-opiomelanocortin (POMC) into Adrenocorticotropic Hormone (ACTH) and $\alpha$-MSH.
   • ACTH acts on the adrenal cortex via $MC2R$ ($G_s \rightarrow \text{cAMP}$):
     • Zona Glomerulosa: Mineralocorticoids (aldosterone). Regulated primarily by Angiotensin II and extracellular $[K^+]$; only minimally by ACTH.
     • Zona Fasciculata: Glucocorticoids (cortisol). Regulated strictly by ACTH; exhibits circadian secretion peaking at 08:00.
     • Zona Reticularis: Adrenal androgens (DHEA, androstenedione).
   • Cortisol exerts negative feedback on both pituitary ACTH and hypothalamic CRH.
2. Hypothalamic-Pituitary-Thyroid (HPT) Axis:
   • TRH stimulates TSH release from anterior pituitary thyrotrophs ($G_q \rightarrow IP_3$).
   • TSH binds follicular cell basolateral receptors ($G_s \rightarrow \text{cAMP}$), stimulating iodide uptake via the Sodium-Iodide Symporter (NIS), thyroid peroxidase (TPO) oxidation/organification/coupling, and thyroglobulin endocytosis.
   • Releases predominantly $T_4$ (90%) and $T_3$ (10%). Peripheral 5'-deiodinase converts $T_4$ to active $T_3$. Free $T_3$ and $T_4$ exert negative feedback on TSH and TRH.
3. Hypothalamic-Pituitary-Gonadal (HPG) Axis:
   • Pulsatile GnRH triggers pulsatile LH and FSH secretion.
   • Males: LH stimulates Leydig cells to synthesize testosterone; FSH stimulates Sertoli cells to support spermatogenesis and produce inhibin B (which selectively suppresses FSH).
   • Females: LH stimulates theca interna cells to produce androstenedione ($17\alpha$-hydroxylase); FSH stimulates granulosa cells to express aromatase, converting androgens to estradiol.

Calcium & Phosphate Regulation

Endocrine Pancreas: Insulin vs. Glucagon

• Insulin Synthesis & Beta-Cell Secretion:
  1. Synthesized as preproinsulin in the rough ER, cleaved to proinsulin, and packaged in secretory granules.
  2. Cleaved into mature insulin and C-peptide, which are secreted into portal circulation in equimolar ($1:1$) concentrations. Because C-peptide bypasses hepatic first-pass extraction and has a longer plasma half-life, it serves as the definitive clinical biomarker of endogenous beta-cell reserve (and differentiates factitious insulin injection from insulinoma).
  3. Stimulus-Secretion Coupling: Extracellular glucose enters beta-cells via GLUT2 $\rightarrow$ glucokinase phosphorylates glucose $\rightarrow$ glycolysis and Krebs cycle elevate intracellular $[ATP] / [ADP]$ ratio $\rightarrow$ closes ATP-sensitive potassium channels ($K_{ATP}$) $\rightarrow$ membrane depolarizes $\rightarrow$ opens voltage-gated L-type $Ca^{2+}$ channels $\rightarrow$ $Ca^{2+}$ influx triggers quantal exocytosis of insulin granules.
  4. Pharmacology: Sulfonylureas (glimepiride, gliclazide) bind the SUR1 subunit of the $K_{ATP}$ channel to force closure, stimulating insulin secretion independently of ambient glucose.
• Glucagon: Secreted by islet alpha-cells in response to hypoglycemia, amino acids, and sympathetic beta-2 stimulation. Binds hepatic Gs-coupled receptors to stimulate glycogenolysis and gluconeogenesis while inhibiting glycogen synthesis.

Growth hormone, prolactin and the posterior pituitary

• Growth hormone (GH) comes from somatotrophs. Hypothalamic GHRH and ghrelin stimulate it, and somatostatin inhibits it. GH acts through the JAK-STAT pathway and makes the liver produce IGF-1, which mediates growth. GH is anti-insulin: it raises blood glucose and lipolysis. Excess causes gigantism before epiphyseal closure and acromegaly after it.
• Prolactin comes from lactotrophs and is under tonic inhibition by dopamine from the hypothalamus. Stalk section, a pituitary adenoma compressing the stalk, or dopamine-blocking drugs (haloperidol, metoclopramide) raise prolactin. TRH stimulates it, which explains the hyperprolactinemia of primary hypothyroidism. High prolactin suppresses GnRH and causes amenorrhea, galactorrhea and infertility.
• Posterior pituitary. Supraoptic and paraventricular hypothalamic neurons make ADH (vasopressin) and oxytocin, which travel down their axons to the posterior pituitary.
  • ADH is released when plasma osmolality rises (osmoreceptors respond to changes of about 1% to 2%) or when blood volume falls substantially.
  • At V2 receptors, ADH inserts aquaporin-2 into collecting-duct cells; at V1 receptors it constricts vessels.
  • Oxytocin contracts the uterus in labor and the myoepithelial cells of the breast during milk ejection.
• Adrenal medulla. Chromaffin cells, which are modified postganglionic sympathetic neurons, secrete mainly epinephrine (about 80%) in response to preganglionic cholinergic nerves. Cortisol reaching the medulla through the portal blood induces PNMT, the enzyme that converts norepinephrine to epinephrine.
• Thyroid hormone actions: higher basal metabolic rate and heat production (more Na+/K+ ATPase), more beta-adrenergic receptors in the heart, brain development in fetal and neonatal life (congenital hypothyroidism), and bone growth.