Chapter 16 - General Principles of Endocrine Physiology

16.1 - Hormones: Overview and Classification

1. Peptide/Protein hormones (e.g., insulin, GH, ACTH) - synthesized as precursor preprohormones, cleaved post-translationally. They are water-soluble and act on cell surface receptors, triggering second messenger cascades (cAMP, IP3/DAG, tyrosine kinase).
2. Steroid hormones (e.g., cortisol, estrogen, testosterone) - derived from cholesterol. They are lipid-soluble, circulate bound to plasma proteins, and act on intracellular nuclear receptors to regulate gene transcription. Only the free (unbound) fraction is biologically active.
3. Amine hormones (e.g., epinephrine from tyrosine, thyroid hormones T3/T4) - tyrosine derivatives. Catecholamines act on membrane receptors; thyroid hormones act on nuclear receptors like steroids.

• Endocrine - hormone travels via blood to distant targets
• Paracrine - acts on neighboring cells
• Autocrine - acts on the secreting cell itself
• Juxtacrine - cell-to-cell contact signaling

16.2 - Hormone Synthesis and Secretion

• Peptide hormones are synthesized on ribosomes as preprohormones (signal peptide + prohormone). The signal peptide is cleaved in the ER, giving a prohormone (e.g., proinsulin), which is then processed in the Golgi/secretory granules to the active hormone (e.g., insulin). Cleavage can generate multiple bioactive peptides from one precursor (e.g., POMC gives ACTH, β-MSH, β-endorphin, β-lipotropin).
• Steroid hormones are not stored - they are synthesized on demand from cholesterol via a series of enzymatic steps in the mitochondria and ER of adrenal cortex, gonads, and placenta.
• Thyroid hormones are unique - they are synthesized and stored extracellularly in thyroid follicle colloid as thyroglobulin, then cleaved and released when needed.
• Secretion patterns: Some hormones are secreted in a pulsatile/episodic manner (e.g., GH, LH), others in a diurnal rhythm (e.g., cortisol - peaks at dawn), and others more continuously. The pattern of secretion matters as much as the absolute level.

16.3 - Hormone Transport and Plasma Binding Proteins

• Most steroid and thyroid hormones circulate bound to specific plasma carrier proteins:
  • Thyroid hormones: thyroxine-binding globulin (TBG), transthyretin (TTR), albumin
  • Cortisol: cortisol-binding globulin (transcortin/CBG)
  • Sex hormones: sex hormone-binding globulin (SHBG)
• Only the free (unbound) fraction can enter cells, bind receptors, and exert biologic effects. However, the bound fraction serves as a large reservoir that buffers rapid fluctuations.
• Binding proteins also prolong hormone half-life by protecting from hepatic degradation and renal filtration.
• Peptide hormones generally do not have specific binding proteins (except IGF-1 and GH), so they have short half-lives (minutes).
• A rise in TBG (e.g., during pregnancy, estrogen therapy) increases total T4 but free T4 stays normal - the person is still euthyroid. This is a key clinical concept.

16.4 - Hormone Receptors and Mechanisms of Action

• G protein-coupled receptors (GPCRs): Linked to Gs (activates adenylyl cyclase → ↑cAMP → PKA), Gi (inhibits cAMP), or Gq (activates PLC → IP3 + DAG → PKC + Ca²+)
• Receptor tyrosine kinases (RTKs): e.g., insulin receptor - autophosphorylation on tyrosine residues → activates downstream signaling (PI3K, MAPK)
• JAK-STAT pathway: used by cytokines and growth hormone - receptor-associated JAK kinases phosphorylate STAT proteins that translocate to the nucleus

• Steroid hormone receptors are typically in the cytoplasm (and translocate to nucleus on binding) or already in the nucleus
• Thyroid hormone receptors are constitutively nuclear
• Hormone-receptor complex acts as a transcription factor, binding hormone response elements (HREs) in DNA to activate or repress gene transcription
• Effects are slow (hours) but prolonged

• Down-regulation: chronic high hormone levels reduce receptor number (e.g., insulin resistance in type 2 diabetes)
• Desensitization: receptor uncouples from signaling even if still present (e.g., β-adrenergic receptor phosphorylation by GRK)
• Up-regulation: low hormone levels can increase receptor number

16.5 - Feedback Control of Hormone Secretion and Endocrine Disease

• In a classic hypothalamic-pituitary-target gland axis (e.g., HPT axis): hypothalamus releases TRH → pituitary releases TSH → thyroid releases T3/T4 → T3/T4 feeds back to inhibit both TRH and TSH secretion.
• This "long-loop" feedback maintains hormone levels within a narrow range.
• "Short-loop" feedback: anterior pituitary hormone feeds back on the hypothalamus.
• "Ultra-short-loop": hypothalamic hormone feeds back on the hypothalamus itself.

• Hormone deficiency (hyposecretion): Primary (gland failure - e.g., Hashimoto's hypothyroidism), Secondary (pituitary failure), or Tertiary (hypothalamic failure). In primary failure, the pituitary hormone (e.g., TSH) is elevated due to loss of feedback inhibition.
• Hormone excess (hypersecretion): Often due to endocrine tumors that secrete autonomously and are not subject to normal feedback regulation (e.g., pheochromocytoma, Cushing's disease).
• Hormone resistance: Normal or elevated hormone levels but inadequate cellular response, due to defective receptors or signaling (e.g., type 2 diabetes mellitus - insulin resistance; pseudohypoparathyroidism - PTH resistance).
• Iatrogenic: Exogenous glucocorticoids suppress the HPA axis; sudden withdrawal can cause adrenal crisis.

Source: Ganong's Review of Medical Physiology, 26th Edition, Chapter 16