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Topic 8

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Endocrine Physiology

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Endocrine Physiology — Key Facts for FMGE Core concept: Hormones act as chemical messengers; they can be steroid (lipid-soluble) or peptide (water-soluble); the hypothalamic-pituitary axis controls most endocrine systems High-yield point: Steroid hormones use intracellular receptors and affect gene transcription; peptide hormones use cell surface receptors and second messengers like cAMP ⚡ Exam tip: The HPA axis is central to understanding endocrine disease - ACTH drives cortisol, TSH drives thyroid hormone, FSH/LH drive gonadal function

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Endocrine Physiology — FMGE Study Guide

Hormone Classification

Peptide/Protein Hormones

  • Water-soluble; stored in vesicles; released by exocytosis
  • Cannot cross membrane; must use surface receptors
  • Half-life: Short (minutes to hours)
  • Examples: Insulin, glucagon, GH, prolactin, TSH, FSH, LH, ACTH, ADH, oxytocin, parathyroid hormone (PTH)

Steroid Hormones

  • Lipid-soluble (from cholesterol); synthesized on demand
  • Cross cell membranes; use intracellular receptors
  • Half-life: Long (hours to days)
  • Examples: Cortisol, aldosterone, estrogen, progesterone, testosterone, 1,25-dihydroxyvitamin D (calcitriol)

Amine Hormones

  • Modified amino acids; some are water-soluble (catecholamines), some are lipid-soluble (thyroid hormones)
  • Catecholamines (epinephrine, norepinephrine): Adrenal medulla, sympathetic neurons
  • Thyroid hormones (T3, T4): Derived from tyrosine; cross membranes; bind intracellular receptors

Hormone Mechanisms

Peptide Hormone Signaling (Second Messengers)

cAMP-PKA pathway (Gs):

  • Hormone → receptor → Gs protein → adenylyl cyclase → ↑cAMP → PKA
  • Examples: Glucagon, ADH (V2), TSH, LH, FSH, ACTH, CRH, β-adrenergic agonists
  • Amplification: 1 hormone → many Gs proteins → many cAMP molecules → many phosphorylations

IP3/DAG pathway (Gq):

  • Hormone → receptor → Gq → phospholipase C → IP₃ + DAG → ↑[Ca²⁺] + PKC
  • Examples: TRH, GnRH, ADH (V1), α-adrenergic agonists, angiotensin II

Tyrosine kinase pathway:

  • Receptor has intrinsic tyrosine kinase activity
  • Examples: Insulin, IGF-1, growth factors
  • Receptor autophosphorylation → intracellular signaling cascades

Steroid Hormone Signaling

  • Hormone enters cell → binds intracellular receptor → hormone-receptor complex → enters nucleus → binds DNA → alters transcription
  • Examples: Cortisol, aldosterone, estrogen, progesterone, testosterone, thyroid hormone

Hypothalamic-Pituitary Axis

Anterior Pituitary (Adenohypophysis)

  • Releases: FSH, LH, TSH, ACTH, GH, Prolactin
  • Regulation: Hypothalamic releasing/inhibiting hormones (hypophysiotropic hormones) reach via portal system

Hypothalamic Releasing Hormones

  • GnRH: Stimulates LH and FSH release
  • TRH: Stimulates TSH and prolactin release
  • CRH: Stimulates ACTH release
  • GHRH/GHIH (somatostatin): Stimulates/inhibits GH release
  • Dopamine: Inhibits prolactin release (tonic inhibition)

Posterior Pituitary (Neurohypophysis)

  • Stores and releases ADH (vasopressin) and oxytocin
  • ADH: From supraoptic nucleus; regulates water balance
  • Oxytocin: From paraventricular nucleus; stimulates uterine contraction, milk letdown

Feedback Loops

  • Negative feedback: Primary mechanism maintaining hormone levels
    • High cortisol → ↓CRH + ↓ACTH (short loop, long loop)
    • High T4/T3 → ↓TRH + ↓TSH
  • Positive feedback: Limited (e.g., estrogen → ↑LH before ovulation)

Specific Endocrine Axes

Hypothalamic-Pituitary-Adrenal (HPA) Axis

  • CRH → ACTH → Cortisol (from adrenal cortex zona fasciculata)
  • Functions of cortisol: Gluconeogenesis, anti-inflammatory, stress response, ↑BP, ↓immune function
  • Cushing syndrome: Excess cortisol (iatrogenic, pituitary adenoma, ectopic ACTH)
  • Addison disease: Deficient cortisol (autoimmune, infection, hemorrhage)

Hypothalamic-Pituitary-Thyroid (HPT) Axis

  • TRH → TSH → T4/T3 (from thyroid follicular cells)
  • T4: More abundant, less active; converted to T3 peripherally
  • Functions: ↑metabolic rate, ↑O₂ consumption, ↑heat production, development (CNS, bone)
  • Hyperthyroidism: ↑T4/T3, ↓TSH (negative feedback); Graves disease (autoantibody stimulates TSH receptor)
  • Hypothyroidism: ↓T4/T3, ↑TSH; Hashimoto (autoimmune destruction, most common cause in developed countries)

Hypothalamic-Pituitary-Gonadal (HPG) Axis

  • GnRH (pulsatile) → LH/FSH → Gonads (testosterone/estrogen)
  • Male: LH → Leydig cells → testosterone; FSH → Sertoli cells → spermatogenesis
  • Female: Follicular development, ovulation, menstrual cycle
  • Estrogen: Feedback on FSH/LH (negative at high levels, positive just before ovulation)
  • Testosterone: Negative feedback on LH (no direct effect on FSH, but inhibin B inhibits FSH)

Growth Hormone Axis

  • GHRH → GH → Liver (IGF-1 production) → Growth effects
  • GH functions: ↑linear bone growth, ↑muscle, ↓fat; diabetogenic (↑blood glucose)
  • Gigantism/Acromegaly: Excess GH (pituitary tumor)
  • Dwarfism: GH deficiency (pituitary dysfunction in childhood)

Prolactin

  • Dopamine inhibits (tonic); ↑TRH, ↓dopamine → ↑prolactin
  • Functions: Breast development, milk production
  • Hyperprolactinemia: Galactorrhea, amenorrhea, infertility, hypogonadism

Adrenal Glands

Adrenal Cortex

Zona Glomerulosa: Aldosterone (mineralocorticoid)

  • Regulated by: Renin-angiotensin-aldosterone system (RAAS) + K⁺ levels
  • Functions: Na⁺ retention, K⁺ excretion, water balance

Zona Fasciculata: Cortisol (glucocorticoid)

  • Regulated by: ACTH (HPA axis)
  • Functions: Gluconeogenesis, stress response, anti-inflammatory

Zona Reticularis: Androgens (DHEA, androstenedione)

  • Precursors to sex steroids

Adrenal Medulla

  • Chromaffin cells (modified sympathetic neurons)
  • Catecholamines: Epinephrine (80%), Norepinephrine (20%)
  • Functions: Fight or flight response; ↑HR, ↑BP, ↑blood glucose, bronchodilation

Pancreatic Islets

Cell Types

α cells: Glucagon (↑blood glucose)

  • Secreted in response to: Low glucose, sympathetic stimulation, ACh
  • Actions: Glycogenolysis, gluconeogenesis, ↓insulin secretion

β cells: Insulin (↓blood glucose)

  • Secreted in response to: High glucose, amino acids, fatty acids, parasympathetic
  • Actions: ↑glucose uptake, ↑glycogenesis, ↑lipogenesis, ↓gluconeogenesis

δ cells: Somatostatin (inhibits GI and pancreatic secretions)

Insulin and Glucagon Effects

Insulin (anabolic):

  • ↑GLUT4 translocation (muscle, fat)
  • ↑glycogen synthesis
  • ↑lipogenesis
  • ↑protein synthesis
  • ↓gluconeogenesis
  • ↓glycogenolysis

Glucagon (catabolic):

  • ↑glycogenolysis
  • ↑gluconeogenesis
  • ↑ketogenesis
  • ↑lipolysis

Diabetes Mellitus

  • Type 1: Autoimmune β cell destruction → absolute insulin deficiency
  • Type 2: Insulin resistance + relative insulin deficiency
  • Diagnostic: Fasting glucose ≥126, 2hr post-prandial ≥200, HbA1c ≥6.5%
  • Complications: Retinopathy, nephropathy, neuropathy, cardiovascular disease

Calcium Metabolism

PTH (Parathyroid Hormone)

  • Secreted by: Chief cells of parathyroid glands
  • Regulated by: Serum Ca²⁺ (low Ca → ↑PTH)
  • Actions:
    • ↑bone resorption → ↑Ca²⁺ release
    • ↑renal Ca²⁺ reabsorption
    • ↓renal phosphate reabsorption
    • ↑1-alpha-hydroxylase → ↑active vitamin D (1,25(OH)₂D)

Vitamin D (Calcitriol)

  • Sources: Skin (sunlight converts 7-dehydrocholesterol to cholecalciferol), diet (fatty fish)
  • Activation: Liver (25-OH) → Kidney (1-alpha-hydroxylase → 1,25(OH)₂D)
  • Actions: ↑intestinal Ca²⁺ absorption, ↑bone mineralization, ↑renal Ca²⁺ reabsorption

Calcitonin

  • Secreted by: C cells of thyroid
  • Actions: ↓bone resorption, ↓renal Ca²⁺ reabsorption
  • Role in humans: Minor compared to PTH and vitamin D

Calcium Balance

  • Total Ca: 8.5-10.5 mg/dL
  • Ionized Ca: 4.5-5.5 mg/dL (active form)
  • Hypocalcemia: Tetany, seizures, cardiac arrhythmias (prolonged QT)
  • Hypercalcemia: “Stones, bones, groans, psychiatric overtones” (kidney stones, bone pain, abdominal pain, confusion)

Thyroid and Parathyroid

Thyroid Hormones

  • T4 (thyroxine): Major secretory product; converted to T3 in tissues
  • T3 (triiodothyronine): More potent; binds nuclear receptors
  • Storage: In colloid (thyroglobulin); very large reserve
  • Iodine: Essential for hormone synthesis; concentrated by thyroid

Thyroid Tests

  • TSH: Most sensitive for primary thyroid disease; elevated in primary hypothyroidism, low in primary hyperthyroidism
  • Free T4/T3: Direct measurement of active hormone
  • Thyroid antibodies: Anti-TPO, anti-thyroglobulin (Hashimoto); TSI (Graves)
  • Radioactive iodine uptake (RAIU): High in Graves (diffuse uptake), low in thyroiditis (damage causes “leaky” hormone release)

Parathyroid Hormone

  • Functions: ↑serum calcium, ↓serum phosphate
  • PTH-related peptide (PTHrP): Mimics PTH; secreted by some cancers → hypercalcemia of malignancy

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