Endocrine System – Comprehensive Exam Review

Hormone Classifications

• General idea

  • Hormones are chemical messengers secreted into the blood to regulate physiology and behavior.
  • Four broad structural classes, each dictating solubility, receptor location, transport, half-life, and mechanism of action.

• Amines

  • Water-soluble (except thyroid hormones which behave more like steroids)
  • Synthesized from a single amino acid (either tyrosine or tryptophan)
  • Receptors are on the cell surface → activation of second-messenger pathways
  • Examples: norepinephrine (NE), epinephrine (Epi), thyroxine T4, triiodothyronine T3
  • Significance
  • Rapid onset, short half-life (mins) for catecholamines (Epi, NE).
  • Thyroid hormones are unique: transported bound to plasma proteins, cross membrane to nuclear receptors, act as transcription factors → longer latency and duration.

• Peptides / Proteins

  • Water-soluble chains of 3 → 100+ amino acids.
  • Cannot cross lipid bilayer, therefore rely on cell-surface receptors + second messengers.
  • Examples: insulin, antidiuretic hormone (ADH/vasopressin), growth hormone (GH), oxytocin.
  • Clinical note: can be administered intravenously or subcutaneously but are destroyed in the GI tract (no oral form).

• Glycoproteins

  • Water-soluble hormones consisting of a protein backbone with carbohydrate side chains.
  • Cell-surface receptors → primarily cAMP pathway.
  • Examples: luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH).
  • Importance: share a common α-subunit but have unique β-subunits that confer receptor specificity—a frequent NBME test point.

• Steroids

  • Lipid-soluble, synthesized from cholesterol via enzymatic steps in smooth ER/mitochondria.
  • Receptor location: cytoplasm (glucocorticoid, mineralocorticoid) or nucleus (estrogen, androgen, vitamin D).
  • Examples: cortisol, aldosterone, testosterone, estradiol.
  • Mechanism
  • Hormone diffuses through membrane → binds intracellular receptor → hormone-receptor complex binds DNA at hormone-response elements (HREs) → altered transcription/translation.
  • Slow onset (hours) but sustained effect (days).

Second-Messenger Systems (Water-Soluble Hormones)

• Rationale: Because membranes are impermeable to hydrophilic hormones, signaling information must be relayed inside via “second messengers.”

• cAMP (classic Gs pathway)

  • Utilized by most polypeptides/glycoproteins (e.g., ACTH, FSH, LH, TSH, glucagon).
  • Sequence
  1. Hormone binds receptor → conformational change.
  2. Gsα exchanges GDP for GTP → activates adenylate cyclase.
  3. Adenylate cyclase converts ATP → cAMP.
  4. cAMP activates protein kinase A (PKA).
  5. PKA phosphorylates target proteins → physiological response.
  • Termination: cAMP degraded by phosphodiesterase (PDE); GTP hydrolyzed to GDP.

• IP3 / DAG + Ca^{2+} (Gq pathway)

  • Seen with some peptide hormones (e.g., oxytocin, ADH V1 receptor, α1-adrenergic receptors).
  • Steps
  1. Hormone → receptor → Gq protein.
  2. Activates phospholipase C (PLC).
  3. PLC cleaves PIP2 → inositol trisphosphate (IP3) + diacylglycerol (DAG).
  4. IP3 releases Ca^{2+} from ER → Ca^{2+} binds calmodulin → enzyme activation.
  5. DAG + Ca^{2+} activate protein kinase C (PKC) → downstream effects.

• Receptor Tyrosine Kinase (RTK)

  • Used by insulin, many growth factors (EGF, PDGF, IGF-1).
  • Mechanism
  1. Hormone binds two receptor monomers → dimerization.
  2. Autophosphorylation of intracellular tyrosine residues.
  3. Docking proteins/adapter molecules trigger MAP-kinase or PI3K-Akt cascades.
  • Unique property: The receptor itself is the enzyme (no G-protein intermediary), allowing rapid and versatile signal amplification.

Receptor Locations & Functional Consequences

• Water-soluble hormones

  • Receptors anchored in plasma membrane; signal via second messengers.
  • Fast (milliseconds to minutes), transient effects (e.g., glycogen breakdown, ion channel opening).

• Lipid-soluble hormones

  • Receptors in cytoplasm or nucleus → act as transcription factors.
  • Slow onset but long-lasting (gene expression, developmental pathways).

Hormonal Interactions (Integration of Signals)

• Synergistic

  • Definition: Combined effect of two hormones exceeds additive effects.
  • Example: Epinephrine + norepinephrine each increase heart rate; together produce a larger tachycardia.
  • Physiology: Often converge on same second-messenger pathway or amplify each other’s receptors.

• Permissive

  • One hormone must be present for another to exert full effect.
  • Classic example: Estrogen upregulates progesterone receptors in uterus → progesterone then stimulates secretory changes of endometrium.
  • Concept extends to cortisol permissive role for glucagon/epinephrine in gluconeogenesis.

• Antagonistic

  • Two hormones produce opposite effects on same target.
  • Canonical pair: insulin (↓ blood glucose) vs glucagon (↑ blood glucose).
  • Regulatory advantage: precise titration of physiological variables.

Hypothalamic–Pituitary Axis (HPA)

• Functional anatomy

  • Hypothalamus integrates neural inputs and releases hormones that control the pituitary.

• Posterior pituitary (neurohypophysis)

  • Not a true endocrine gland—acts as storage & release site for hypothalamic peptides.
  • Hormones
  • ADH (vasopressin): water reabsorption in kidneys, vasoconstriction via V1 receptors.
  • Oxytocin: uterine contraction, milk ejection (let-down).
  • Transport: Synthesized in paraventricular/supraoptic nuclei → down axons through infundibulum → released into systemic circulation.

• Anterior pituitary (adenohypophysis)

  • True endocrine tissue; regulated by hypothalamic releasing/inhibiting hormones delivered via hypophyseal portal veins.
  • Major tropic hormones: ACTH, TSH, LH, FSH, GH, prolactin.

• Negative feedback loops

  • Target-gland hormones (e.g., cortisol, T3/T4) inhibit secretion of both pituitary tropic hormones and hypothalamic releasing hormones.
  • Example feedback equation: \text{↑ cortisol} \Rightarrow \text{↓ CRH} \; (hypothalamus), \; \text{↓ ACTH} \; (anterior\,pituitary).
  • Pathophysiology tie-in: Cushing disease vs ectopic ACTH vs adrenal tumor can be distinguished by feedback testing.

Adrenal Gland Organization

• Cortex (outer 80–90 %)

  • Three concentric zones “GFR” (glomerulosa, fasciculata, reticularis)
  1. Zona glomerulosa → mineralocorticoids (aldosterone)
  2. Zona fasciculata → glucocorticoids (cortisol)
  3. Zona reticularis → adrenal androgens (DHEA, androstenedione)
  • Regulation: ACTH controls cortisol/androgens, whereas aldosterone is primarily regulated by \text{RAAS} and K^{+}; ACTH has permissive role.

• Medulla (inner 10–20 %)

  • Chromaffin cells derived from neural crest = modified postganglionic sympathetic neurons.
  • Secretion: 80 % epinephrine, 20 % norepinephrine.
  • Stimulated by preganglionic sympathetic fibers releasing ACh.
  • Stress response: rapid mobilization of glucose, lipolysis, increased cardiac output, bronchodilation ("fight or flight").

Ethical, Clinical & Real-World Connections

• Pharmacology

  • Synthetic steroids (e.g., prednisone) exploit transcription-factor action but risk iatrogenic Cushing syndrome via negative feedback suppression of ACTH.
  • β-adrenergic agonists/antagonists modulate catecholamine effects (synergistic vs antagonistic clinical parallels).

• Endocrine testing logic

  • Because of feedback loops, measuring a tropic hormone alone is insufficient—must pair with target-gland hormone (e.g., ACTH + cortisol, TSH + T4).

• Environmental / Stress implications

  • Chronic stress → prolonged cortisol elevation → immunosuppression, metabolic syndrome—illustrates long-acting steroid mechanism.

• Evolutionary perspective

  • Permissive hormone actions (e.g., thyroid hormone on catecholamine receptors) fine-tune metabolic rate to environmental temperature and caloric intake.

Formula & Numerical References

• Fractional secretion in adrenal medulla: Epi:NE = 80:20
• Second-messenger amplification: One activated adenylate cyclase can produce \sim 1000 cAMP molecules per second.
• Protein kinase cascades can generate 10^{6} – 10^{8} phosphorylated substrates from a single hormone–receptor interaction, underlying concept of signal amplification.