BIOSYNTHESIS AND METABOLISM OF ADRENAL CORTICAL HORMONES

Overview of Adrenal Steroids

• Steroids of the Adrenal Cortex
  • Glucocorticoids (cortisol)
  • Mineralocorticoids (aldosterone)
  • Adrenal Androgens (17-ketosteroids, e.g., DHEA, androstenedione)
  • Estrogens
  • Progestogens
• Functional Regulation
  • Zona Fasciculata & Zona Reticularis: Regulated by pituitary corticotropin (ACTH).
  • Zona Glomerulosa: Aldosterone secretion regulated mainly by angiotensin II & potassium, with minor ACTH influence.

ACTH Regulation and Diurnal Rhythm

1. Negative Feedback
   • Decreased blood cortisol → increased CRH & ACTH → raised cortisol levels → inhibitory feedback on CRH & ACTH.
2. Diurnal (Circadian) Variation
   • Maximal ACTH secretion (pulse frequency/amplitude) between 2–8 am.
   • Gradual daytime decrease, lowest in late evening.
   • Dependent on sleep–wake and light–dark cycles; resets over 10–14 days with major time zone changes.
3. Response to Stress
   • Stress (fever, trauma, hypoglycemia, hypotension) overrides feedback, stimulating high ACTH and increased cortisol (up to ~250 mg/day).

Synthesis Pathway of Cortical Steroids

Cholesterol Sources and Modifications

• Cholesterol derived from acetate, stored in adrenal cortex.
• Cyclopentanoperhydrophenanthrene nucleus (3 cyclohexane rings + 1 cyclopentane ring).
• Enzymes introduce hydroxyls or remove hydrogen (oxidation).
• Glucocorticoids: Have α-ketol group & 11-hydroxyl group.
• First Step: Cleavage of cholesterol into pregnenolone (C21 precursor of all steroid hormones) + isocaproaldehyde.
  • Occurs in adrenal cortex, testicular Leydig cells, ovarian theca cells, trophoblasts, some brain cells.
• Steroid Class by Carbon Number
  • C21: Glucocorticoids, progestogens
  • C19: Androgens
  • C18: Estrogens

Key Enzymes and Locations

1. Steroidogenic Acute Regulatory Protein (StAR)
   • Transports cholesterol from outer to inner mitochondrial membrane.
   • Induced by ↑cAMP after ACTH receptor activation.
2. P450scc (Side-Chain Cleavage)
   • Located in mitochondria, converts cholesterol → pregnenolone.
3. Electron Shuttles
   • Adrenodoxin/Adrenodoxin Reductase for mitochondrial P450 enzymes (P450scc, 11β-hydroxylase, aldosterone synthase).
   • P450 oxidoreductase (P450 OR) for endoplasmic reticulum enzymes (17α-hydroxylase, 21-hydroxylase).
   • Cytochrome b5 facilitates 17,20-lyase activity of P450c17.
4. Hydroxysteroid Dehydrogenases
   • E.g., 3β-HSD, convert pregnenolone → progesterone, DHEA → androstenedione, etc.
   • Reactions are often reversible (unlike P450 hydroxylations).

Pathway Details in Adrenal Cortex

1. Zona Glomerulosa
   • Lacks 17α-hydroxylase (P450c17).
   • Produces aldosterone via aldosterone synthase (CYP11B2).
   • Key steps:
     • 21-hydroxylation of progesterone → deoxycorticosterone (DOC), then 11β-hydroxylation → corticosterone, then 18-hydroxylation → aldosterone.
2. Zona Fasciculata
   • Has 17α-hydroxylase → forms 17-hydroxyprogesterone → 21-hydroxylase → 11-deoxycortisol → 11β-hydroxylase → cortisol.
3. Zona Reticularis
   • High 17,20-lyase activity (P450c17 with cytochrome b5).
   • Produces DHEA (dehydroepiandrosterone) + androstenedione.
   • DHEA can be sulfated (DHEA-S) by SULT2A1 or converted to androstenedione by 3β-HSD.
   • Minor testosterone production by 17β-HSD3.

Normal Secretion Rates

• Cortisol: 10–20 mg/day
• Aldosterone: 0.1–0.15 mg/day
• DHEA: ~4 mg/day, DHEA-S: 10 mg/day, Androstenedione: 1.5 mg/day, Testosterone: 0.05 mg/day.
• Adrenal androgens have lower potency vs. gonadal testosterone.

Metabolism of Cortisol and Aldosterone

Cortisol Binding and Interconversion

• 90% Bound in plasma (CBG > albumin).
  • CBG↑ with oral estrogen, pregnancy, active hepatitis.
  • CBG↓ with cirrhosis, nephrotic syndrome, multiple myeloma, hyperthyroidism.
• Half-Life: ~60–120 minutes.
• 11β-Hydroxysteroid Dehydrogenase (11β-HSD) Isozymes
  • Type 1 (11β-HSD1): Liver, converts cortisone → cortisol (activating).
  • Type 2 (11β-HSD2): Kidney, inactivates cortisol → cortisone to protect mineralocorticoid receptor (MR).
• Apparent Mineralocorticoid Excess (AME)
  • Deficient or inhibited 11β-HSD2 → cortisol excess at MR → hypertension, hypokalemia, low renin, low aldosterone.
  • May be hereditary or due to inhibition by glycyrrhizic acid (licorice).
• Further Metabolism
  • Cortisol/cortisone → reduced to tetrahydrometabolites (tetrahydrocortisol, tetrahydrocortisone), conjugated with glucuronic acid → excreted in urine.

Aldosterone Metabolism

• Liver: Aldosterone → tetrahydroaldosterone → excreted as 3-glucuronide conjugates (20–30 μg/day in urine).
• Small fraction appears in free form (1–5 μg/day).

BIOLOGIC ACTIONS OF CORTISOL

Carbohydrate, Protein, and Lipid Metabolism

1. Hyperglycemic Effects
   • ↑Glycogen deposition (liver).
   • ↑Gluconeogenesis enzymes (glucose-6-phosphatase, phosphoenolpyruvate carboxykinase).
   • ↑Lipolysis (adipose) → ↑free fatty acids.
   • Facilitates insulin resistance (synergistic with glucagon, catecholamines).
   • Excess → Diabetogenic, central adiposity.

Skin, Muscle, and Connective Tissues

• Catabolic in excess: diverts AAs from muscle → liver.
• Muscle wasting, proximal muscle weakness.
• Decreased collagen synthesis, inhibited epidermal cell division → thin skin, poor wound healing.

Bone and Calcium Metabolism

• Osteopenia/Osteoporosis from ↓osteoblast function, ↑bone resorption.
• Risk of osteonecrosis (avascular necrosis), especially femoral head.
• ↓Intestinal Ca²⁺ absorption, ↑Renal Ca²⁺ excretion → negative calcium balance.

Blood Pressure Control

• ↑GFR, ↑Proximal tubular Na⁺ reabsorption, ↑free water clearance.
• Mineralocorticoid Receptor Overload if 11β-HSD2 is overwhelmed, leading to salt retention, hypokalemia.
• Enhances vascular reactivity to catecholamines, angiotensin II.
• Increases angiotensinogen synthesis.

Anti-Inflammatory and Immunosuppressive Actions

• ↓Blood lymphocytes (redistribution to lymph nodes, spleen).
• ↓Immunoglobulin synthesis, ↓Cytokine production, ↑Lymphocyte apoptosis.
• ↑Neutrophils, ↓Eosinophils.
• ↓Monocyte → Macrophage differentiation.
• ↓Local inflammatory mediators (histamine, plasminogen activators, prostaglandins).
• Mild polycythemia in patients on high-dose glucocorticoids.

Central Nervous System and Eyes

• Behavioral Changes: Depression, euphoria, psychosis, apathy, lethargy possible with either deficiency or excess.
• Insomnia from increased neuroexcitability.
• Glaucoma Risk: ↑Intraocular pressure by ↑aqueous humor production, ↓drainage (matrix deposition in trabecular meshwork).

Gastrointestinal Tract

• ↑Peptic ulcer risk from ↑acid, ↑pepsin, ↓mucus in stomach.

Endocrine Effects

• Thyroid: ↓TSH secretion, inhibits T4 → T3 (5′ deiodinase).
• Gonadal: ↓GnRH pulsatility, ↓LH/FSH release → potential hypogonadism.