MR

Endocrine Physiology — Adrenal Androgens, Stress Axes, Glucose Homeostasis & Blood-Pressure Hormones

Adrenal Cortex Androgens (Zona Reticularis)

  • Zona reticularis of the adrenal cortex constitutively secretes weak androgens.
    • Output is largely independent of anterior-pituitary control.
    • \text{ACTH} can weakly stimulate secretion, but effect is minimal compared with glucocorticoid control.
    • Production is low, steady and not modified by age or sex.
  • Major products = androstenedione & dehydroepiandrosterone (DHEA).
    • Act as precursors to testosterone (T) ➜ can be converted peripherally if enzymes/receptors present.
    • Reminder: \text{T} \rightarrow \text{estradiol} via aromatase – an extremely small contribution from adrenal pathway.
  • Normal physiologic levels are too low to:
    • Trigger puberty.
    • Cause masculinization of females.
    • Elicit secondary male characteristics in boys.
  • Androgenital (congenital adrenal) syndrome
    • Tumor or enzymatic defect ➜ overproduction of adrenal androgens.
    • Consequences
    • Females: virilization, hirsutism, clitoral hypertrophy.
    • Pre-pubertal males: precocious puberty.
    • Excess T escapes gonadal negative feedback → ↓\text{GnRH}, ↓\text{FSH/LH}, impaired spermatogenesis.
    • Treatment: surgical removal of hyper-secreting adrenal tissue.
  • Anecdote: MLB slugger publicly seen with “andro” supplement – illustrates how even a precursor can fuel androgen scandals despite weak intrinsic potency.

Stress Response Systems

  • Hypothalamus orchestrates two parallel stress axes:
    1. Sympatho-Adreno-Medullary (SAM)
    • "Short-term" – milliseconds to seconds.
    • Preganglionic sympathetic fiber ➜ chromaffin cells of adrenal medulla.
    • Catecholamines released into blood behave as hormones (not synaptic transmitters).
      • Lag in onset, but prolonged action because clearance is slow.
    1. Hypothalamo-Pituitary-Adrenal (HPA)
    • "Long-term" – minutes to hours.
    • \text{CRH} \rightarrow \text{ACTH} \rightarrow \text{cortisol}.

Catecholamine (Epi/Norepi) Targets & Actions

  • Cardiovascular: ↑HR, ↑contractility, generalized vasoconstriction except to heart & working skeletal muscle.
  • Respiratory: β₂-mediated bronchodilation (basis for rescue inhalers in asthma).
  • Metabolic
    • Hepatocytes + skeletal muscle: glycogenolysis ➜ ↑blood glucose.
    • Adipocytes: lipolysis ➜ ↑free fatty acids (FFA) (glucose-sparing for brain).
    • Overall ↑metabolic rate & body temperature.
  • GI: ↓motility & secretions.
  • Exercise/exam anxiety examples: catecholamines mobilize glucose & fatty acids for muscle/brain.

Hyper-catecholaminemia (Pheochromocytoma)

  • Tumor of adrenal medulla ➜ chronically high Epi/NE.
  • Signs: sustained HTN, tachycardia, sweating, weight loss, heat intolerance, elevated BMR.

Blood Glucose Regulation (Primary Hormones)

  • Humoral control via pancreatic islets keeps plasma glucose in 85\text{–}100\;\text{mg·dL}^{-1} (book simplifies to 90\;\text{mg·dL}^{-1}).

Glucagon (α-cells)

  • Peptide (29 aa). Stimulus = low glucose.
  • Major targets
    • Liver: glycogenolysis, gluconeogenesis ➜ ↑glucose output.
    • Adipose: lipolysis ➜ glycerol (gluconeogenic substrate) + FFA (fuel).
  • Net effect: ↑blood glucose; gluconeogenic substrates spare glucose for CNS.
  • Negative feedback: rising glucose suppresses α-cells.

Insulin (β-cells)

  • Large protein (pre-pro-insulin ➜ pro-insulin ➜ insulin + C-peptide).
  • Stimulus = high glucose; also parasympathetic activity, incretins, certain amino acids.
  • All nucleated cells carry insulin receptors (RTK type).
    • Binding ➜ insertion of \text{GLUT4} vesicles (muscle & adipose) or activation of \text{GLUT2} (liver) ➜ glucose uptake.
    • Liver & muscle: glycogenesis.
  • Negative feedback: falling glucose terminates secretion.
  • Insulin & glucagon = antagonistic pair.

Other “glucose-raising” hormones (not primary regulators)

  • Cortisol, Epi/NE, Growth Hormone (GH).
    • Elevation driven by stress/growth – not by plasma glucose itself.

Diabetes Mellitus

  • “Diabetes” = "overflow"; "mellitus" = "sweet" (glycosuria). Contrast with diabetes insipidus (tasteless urine, ADH problem).

Type I (IDDM, Juvenile)

  • Autoimmune destruction of β-cells (viral trigger + genetics) ➜ no insulin.
  • Without treatment (exogenous insulin)
    • Starvation in the land of plenty: cells cannot uptake glucose ➜ gluconeogenesis from amino acids (proteolysis) & lipolysis.
    • Severe hyperglycemia (≥600\;\text{mg·dL}^{-1}), osmotic diuresis ➜ polyuria, dehydration, polydipsia.
    • Polyphagia (hunger) despite weight loss.
    • FFA ➜ hepatic ketone bodies ➜ ketoacidosis (↓pH) ➜ Kussmaul respirations, fruity/acetone breath, electrolyte loss, CNS depression ➜ coma ➜ death within ~1 week if untreated.

Type II (NIDDM, Adult/Insulin-Resistant)

  • Insulin present, but receptor signaling ↓.
  • Initially compensated by hyperinsulinemia; chronic demand kills β-cells ➜ may evolve to absolute deficiency.
  • Multifactorial (genetics + lifestyle). High prevalence in U.S. Southeast (SC ≈ #48, MS worst).
  • Chronic complications: HTN, premature atherosclerosis, retinopathy ➜ blindness, nephropathy ➜ renal failure, autonomic & peripheral neuropathies ➜ ulcers, amputations.
  • Management: diet, exercise, metformin, GLP-1 analogs, ± exogenous insulin.

Gestational Diabetes

  • Type II-like insulin resistance during pregnancy.
  • Typically resolves postpartum, especially with breastfeeding, yet predicts high risk of future Type II DM in mother.

Shared Clinical Clues

  • Polyuria, polydipsia, unexplained fatigue, slow-healing wounds, recurrent infections.
  • Type I unique: rapid onset, ketoacidosis; Type II: insidious, often asymptomatic for years.

Renin–Angiotensin–Aldosterone System (RAAS)

  • Purpose: restore low blood pressure/volume.
  • Unusual architecture – active hormone generated in circulation:
    • Liver continuously secretes angiotensinogen.
    • Kidney juxtaglomerular cells detect ↓BP/↓Na⁺/↑SNS ➜ release renin (enzyme).
    • \text{Angiotensinogen} \xrightarrow{\text{Renin}} \text{Ang I} \xrightarrow{\text{ACE}} \text{Ang II}.
  • Angiotensin II effects
    1. Potent systemic vasoconstriction ➜ ↑TPR, ↑BP.
    2. ↑Sympathetic activity (central & peripheral).
    3. Direct Na⁺ reabsorption in proximal tubule (mimics weak aldosterone).
    4. Stimulates aldosterone release (zona glomerulosa) ➜ distal nephron Na⁺/water reabsorption.
    5. Stimulates ADH release (posterior pituitary) + hypothalamic thirst.
  • All five raise blood volume/pressure ➜ negative feedback shuts renin release.

Pharmacologic Modulation of RAAS

  • ACE inhibitors (e.g., lisinopril)
    • Block Ang I ➜ Ang II conversion.
    • Lower BP, renal protective, cheap generics; main SE = dry cough, dry mouth.
  • Ang II receptor blockers (ARBs) (e.g., losartan)
    • Block AT₁ receptors when ACEi insufficient/intolerant.

Atrial Natriuretic Peptide (ANP)

  • Peptide hormone from atrial cardiomyocytes.
    • Stimulus: stretch due to ↑venous return / ↑blood volume / ↑atrial pressure.
  • Key mnemonic: “ANP makes you pee.”
  • Actions (antagonistic to aldosterone/RAAS)
    • Kidneys: ↓Na⁺ reabsorption (natriuresis) ➜ ↓water reabsorption ➜ ↑urine output.
    • Direct vasodilation.
    • Inhibits renin release ➜ ↓Ang II & ↓aldosterone.
  • Net: ↓blood volume & ↓BP, protecting heart from chronic volume overload.

Integrative & Clinical Pearls

  • Goldilocks principle: endocrine system generally strives for “just-right” levels, not excess/deficit (exceptions: oxytocin, prolactin).
  • Exercise: transient renal hypoperfusion can stimulate renin; catecholamine surge mobilizes fuels; cortisol arrives later to sustain supply.
  • Weight-class & competitive-eating athletes preload water; ANP response prevents fatal hyponatremia.
  • High-fructose vs. glucose debate: fructose absorption bypasses normal hepatic regulation → associated with NAFLD & insulin resistance.
  • Public-health messaging skewed lay understanding: most now equate diabetes solely with hyperglycemia, forgetting diabetes insipidus (ADH insufficiency).