Adrenal cortex + gonad pathway converting cholesterol to glucocorticoids / mineralocorticoids / androgens / estrogens. Rate-limiting: cholesterol side-chain cleavage by CYP11A1 (P450scc; StAR-mediated cholesterol import) → pregnenolone. Branch points: 17α-hydroxylase (CYP17A1) — glucocorticoid + androgen path; aldosterone synthase (CYP11B2) — mineralocorticoid path; aromatase (CYP19A1) — androgen → estrogen. Drug targets: ketoconazole + abiraterone block CYP17A1 (high-dose ketoconazole and abiraterone for castration-resistant prostate cancer); aromatase inhibitors (anastrozole / letrozole / exemestane) block CYP19A1 for ER+ breast cancer; metyrapone blocks 11β-hydroxylase (Cushing diagnostic). 21-hydroxylase deficiency (CYP21A2) is most common congenital adrenal hyperplasia.
Organ Systems
endocrine
reproductive
Pathway Steps
cholesterol → pregnenolone — via CYP11A1 (P450scc) — RATE-LIMITING; mitochondrial; StAR-mediated import. The rate-limiting step is StAR-mediated delivery of cholesterol to the inner mitochondrial membrane, then CYP11A1 (side-chain cleavage) makes pregnenolone — the common precursor of all steroid hormones. ACTH/LH acutely drive StAR; StAR or CYP11A1 defects cause lipoid adrenal hyperplasia.
pregnenolone → progesterone — via 3β-HSD. 3β-HSD converts Δ5 steroids to Δ4 and sits on every branch, so its deficiency impairs cortisol, aldosterone, and sex steroids together — a form of congenital adrenal hyperplasia.
progesterone → cortisol — via 21-hydroxylase (CYP21A2) + 11β-hydroxylase (CYP11B1). The glucocorticoid arm runs via 21-hydroxylase (CYP21A2) then 11β-hydroxylase. CYP21A2 deficiency is the commonest congenital adrenal hyperplasia (~90%): blocked cortisol shunts precursors to androgens (virilization) and loses aldosterone (salt-wasting).
pregnenolone → testosterone — via CYP17A1 (17α-hydroxylase + 17,20-lyase) — KETOCONAZOLE + ABIRATERONE TARGET. CYP17A1 has dual 17α-hydroxylase + 17,20-lyase activities gating the androgen/sex-steroid branch; the lyase step commits toward DHEA/androgens. It is the target of abiraterone (prostate cancer) and is inhibited off-target by ketoconazole.
testosterone → estradiol — via aromatase (CYP19A1) — AROMATASE-INHIBITOR TARGET. Aromatase irreversibly converts androgens to estrogens in gonads, adipose, brain, and bone — the basis of aromatase inhibitors (anastrozole/letrozole) in ER-positive breast cancer, and why adipose is a major peripheral estrogen source.
Known Modulators
ketoconazole (inhibitor) — CYP17A1 (at high dose, off-target for prostate Ca historically)
spironolactone (inhibitor) — 17α-hydroxylase / 17,20-lyase (off-target; basis for gynecomastia)