Adrenal Steroidogenesis, CAH & Mineralocorticoid Excess

Adrenal zones, embryology and regulation

Three cortical zones. From the capsule inward, the zona glomerulosa makes mineralocorticoids (aldosterone), the zona fasciculata makes glucocorticoids (cortisol), and the zona reticularis makes adrenal androgens (DHEA, DHEA-S, androstenedione): salt, sugar and sex. The cortex develops from mesoderm, whereas the chromaffin cells of the medulla derive from neural crest. Cortisol-rich blood drains from the cortex through the medulla and induces PNMT, the enzyme that converts norepinephrine to epinephrine.

Regulators. Aldosterone secretion is driven mainly by angiotensin II and by a rise in serum potassium, which depolarizes glomerulosa cells; ACTH has only a minor, transient effect. Cortisol and adrenal androgens are driven by ACTH acting on the melanocortin-2 receptor (MC2R), which signals through Gs and cAMP. Because the glomerulosa does not depend on ACTH, pituitary (secondary) adrenal insufficiency spares aldosterone, and hyperkalemia is a feature only of primary adrenal failure.

Zonal enzymes. Only the glomerulosa expresses aldosterone synthase (CYP11B2), and it lacks 17α-hydroxylase, so it cannot make cortisol or androgens. The fasciculata and reticularis express 17α-hydroxylase and 11β-hydroxylase (CYP11B1); the reticularis adds strong 17,20-lyase activity and sulfates DHEA to DHEA-S, a marker of adrenal androgen output.

The steroidogenic pathway

Reading the map. Mineralocorticoids come from the branch that skips 17α-hydroxylation; cortisol needs 17α-, 21- and 11β-hydroxylation in turn; androgens leave at the 17,20-lyase step and need neither 21- nor 11β-hydroxylase. DOC is itself a potent mineralocorticoid, and corticosterone has real glucocorticoid activity, two facts that explain several enzyme defects. Peripheral tissues convert the weak adrenal androgens to testosterone, dihydrotestosterone and, via aromatase, estrogens.

Drug sites: ketoconazole inhibits CYP11A1 and 17,20-lyase (and 11β-hydroxylase), lowering all adrenal steroids; metyrapone, osilodrostat and IV etomidate block 11β-hydroxylase, so 11-deoxycortisol and DOC accumulate; abiraterone blocks CYP17 in prostate cancer and is given with prednisone to prevent ACTH-driven DOC excess. When metyrapone lowers cortisol, an intact pituitary raises ACTH and 11-deoxycortisol climbs, which is the metyrapone test of ACTH reserve.

Congenital adrenal hyperplasia

The common logic. Every form of CAH is autosomal recessive. A block in cortisol synthesis removes negative feedback, ACTH rises, both adrenals become hyperplastic, and precursors pile up behind the block and spill into whichever branches remain open. Three questions predict the phenotype: is aldosterone made (sodium, potassium, renin), is DOC in excess (hypertension, hypokalemia), and are androgens excessive or absent (genitalia, puberty)?

21-hydroxylase deficiency. Over 90% of CAH. CYP21A2 lies within the HLA region on chromosome 6, beside a pseudogene that drives gene conversion. 17-OH progesterone accumulates and is the newborn screening marker. About three quarters of classic cases are salt-wasting: cortisol and aldosterone are both deficient, and at 1–3 weeks of life vomiting, hypotension, hyponatremia, hyperkalemia and hypoglycemia appear with high renin. Simple virilizers keep enough aldosterone to avoid crisis. Girls have virilized external genitalia (clitoromegaly, labial fusion) with normal ovaries and uterus; boys look normal at birth and present with salt crisis or later with early pubic hair and rapid growth. Excess androgen speeds growth but fuses the epiphyses early: tall children, short adults. In poorly controlled males, chronic ACTH drive can grow benign testicular adrenal rest tumors that impair fertility.

Nonclassic 21-hydroxylase deficiency. Milder enzyme loss spares cortisol and aldosterone but produces androgen excess later: premature pubarche in children and hirsutism, acne, oligomenorrhea and infertility in young women that mimic polycystic ovary syndrome. An exaggerated 17-OH progesterone rise after cosyntropin (ACTH) confirms it.

Hypertensive forms. In 11β-hydroxylase deficiency (about 5–8% of CAH), 11-deoxycortisol and DOC accumulate; DOC causes hypertension and hypokalemia and suppresses renin and aldosterone, while androgen shunting virilizes girls as in 21-hydroxylase deficiency. In 17α-hydroxylase deficiency neither cortisol nor sex steroids can be made, but DOC and corticosterone accumulate: hypertension and hypokalemia with low renin, and no adrenal crisis because corticosterone supplies glucocorticoid activity. Genetic males have female-appearing or ambiguous external genitalia, no uterus (their testes still secrete antimüllerian hormone) and undescended testes; genetic females are normal at birth but have absent puberty and primary amenorrhea.

3β-HSD deficiency and lipoid CAH. 3β-HSD2 deficiency blocks every Δ5 → Δ4 conversion, so aldosterone, cortisol and testosterone are low while DHEA and 17-OH pregnenolone rise; a high Δ5:Δ4 ratio is diagnostic. Infants waste salt, boys are undervirilized, and girls are mildly virilized because peripheral 3β-HSD1 converts the excess DHEA. In lipoid CAH, loss of StAR traps cholesterol outside the mitochondria: no steroids are made, the adrenals swell with cholesterol esters, infants have an early salt-losing crisis, and every 46,XY infant has female external genitalia.

Treatment. Glucocorticoid replacement (hydrocortisone in children, to limit growth suppression) replaces cortisol and suppresses the ACTH drive, shutting down androgen and DOC excess and lowering blood pressure in the hypertensive forms. Salt-wasters also need fludrocortisone and sodium chloride, and all patients need stress dosing during illness.

Low-renin mineralocorticoid excess

The final common pathway. Overactivity at the mineralocorticoid receptor (MR) of collecting-duct principal cells increases ENaC-mediated sodium reabsorption and potassium and hydrogen ion secretion: hypertension, hypokalemia and metabolic alkalosis, with renin suppressed by volume expansion and no edema because of aldosterone escape. Measuring renin and aldosterone together sorts the cause.

Glucocorticoid-remediable aldosteronism (GRA). Unequal crossing over between the neighboring CYP11B1 and CYP11B2 genes fuses the ACTH-responsive regulatory region of CYP11B1 to the coding sequence of CYP11B2. Aldosterone synthase is then expressed in the fasciculata under ACTH control, and hybrid steroids (18-hydroxycortisol, 18-oxocortisol) appear in excess. Inheritance is autosomal dominant, hypertension begins in childhood or youth with low renin, hypokalemia is often mild, and families have early hemorrhagic strokes from ruptured intracranial aneurysms. Dexamethasone suppresses ACTH and aldosterone; long-term therapy is a low-dose glucocorticoid or an MR antagonist, and adrenalectomy does not help because both glands carry the chimera.

Apparent mineralocorticoid excess (AME). The MR binds cortisol and aldosterone with equal affinity, and cortisol circulates at 100–1000 times the concentration of aldosterone. In the kidney, colon and salivary glands, 11β-HSD2 oxidizes cortisol to inactive cortisone and keeps the receptor free for aldosterone (11β-HSD1 in liver and fat does the reverse). Autosomal recessive loss of HSD11B2 lets cortisol activate the MR: severe childhood hypertension, hypokalemia, low renin and low aldosterone, often with low birth weight and failure to thrive. Treatment is spironolactone or eplerenone, often plus dexamethasone to suppress endogenous cortisol.

Licorice and severe Cushing. Glycyrrhetinic acid, the active metabolite of glycyrrhizin in real licorice, inhibits 11β-HSD2 and produces an acquired AME that resolves after exposure stops; licorice-flavored chewing tobacco and licorice-root teas do the same. Very high cortisol, especially from ectopic ACTH secretion such as small cell lung cancer, saturates 11β-HSD2 and causes marked hypokalemic alkalosis and hypertension with low renin and aldosterone.

Liddle syndrome. Autosomal dominant gain-of-function mutations of the β or γ subunit of ENaC delete the PY motif that the ubiquitin ligase Nedd4-2 recognizes, so channels are not removed from the apical membrane and sodium reabsorption runs unchecked. Hypertension, hypokalemia and metabolic alkalosis occur with low renin and low aldosterone. Spironolactone fails because aldosterone is not the driver; amiloride or triamterene, which block ENaC directly, plus salt restriction, control it.