Skip to content

Physiology of the Adrenal Gland

4 min read

Peer reviewed Updated
Cite this article
AMA
MD A.. Physiology of the Adrenal Gland. My Endo Consult. Published January 11, 2025. Accessed October 4, 2026. https://myendoconsult.com/learn/topics/physiology-of-the-adrenal-gland/
APA
MD A. (2025). Physiology of the Adrenal Gland. My Endo Consult. https://myendoconsult.com/learn/topics/physiology-of-the-adrenal-gland/
Vancouver
MD A.. Physiology of the Adrenal Gland [Internet]. My Endo Consult; January 11, 2025 [cited October 4, 2026]. Available from: https://myendoconsult.com/learn/topics/physiology-of-the-adrenal-gland/
BibTeX
@online{myendoconsult4422384,
  author = {Akuffo Quarde, MD},
  title  = {Physiology of the Adrenal Gland},
  organization = {My Endo Consult},
  year   = {2025},
  url    = {https://myendoconsult.com/learn/topics/physiology-of-the-adrenal-gland/},
  urldate = {October 4, 2026}
}

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).
Normal Circadian Rhythm

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
Adrenal Steroidogenesis

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.

Related reading