AJ

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.