5-alpha reductase

**Function / Biochemistry** - Enzyme (NADPH-dependent) that reduces the Δ4,5 double bond of testosterone to form dihydrotestosterone (DHT). - Three isoenzymes: Type 1 (skin, liver, scalp), Type 2 (prostate, genital skin, hair follicles, seminal vesicles; the clinically key form for male sexual differentiation), Type 3 (widely expressed; roles in glycosylation). - DHT binds the androgen receptor with higher affinity and dissociates more slowly than testosterone, so it is a much more potent androgen.

**Testosterone vs DHT (classic board distinction)** - Testosterone (Wolffian duct derivatives, in utero): epididymis, vas deferens, seminal vesicles (internal structures). Also drives muscle mass, libido, spermatogenesis, deepening of the voice, and the pubertal growth spurt. - DHT: male external genitalia (penis, scrotum), prostate. Also drives male-pattern baldness, sebaceous gland activity/acne, and facial/body hair growth. Mnemonic: "SEVSTEROID", where seminal vesicles, epididymis, and vas deferens come from testosterone; DHT makes the penis, scrotum, and prostate ("Dihydrotestosterone = Dick, Scrotum, Prostate" in some mnemonics).

**5-alpha reductase 2 deficiency (autosomal recessive; SRD5A2 mutation)** - 46,XY with normal testes, normal Müllerian-inhibiting factor (MIF/AMH) action, and normal testosterone production. Wolffian structures develop normally, and Müllerian structures regress (no uterus or fallopian tubes). - Impaired DHT leads to ambiguous or female-appearing external genitalia at birth (undervirilized, often a clitoris-like phallus, bifid scrotum, blind-ending vaginal pouch, hypospadias), and a small or absent prostate. - At puberty, the surge in testosterone causes virilization (deepening of voice, muscle growth, phallic growth, testicular descent), sometimes called "penis at 12". Individuals raised as girls may transition to a male gender identity. Reported in clusters in the Dominican Republic (guevedoces) and Papua New Guinea. - Labs: normal or high testosterone, low DHT, elevated testosterone:DHT ratio (>10-20:1), normal to high LH. The phenotype contrasts with androgen insensitivity syndrome, in which testosterone and DHT are both normal or high but the receptor is defective, and no pubertal virilization occurs. - Other features: minimal facial hair, acne, or temporal balding; small prostate; no gynecomastia (versus AIS), since estrogen conversion is normal.

**Differential (46,XY DSD)** - Androgen insensitivity (complete): female phenotype, blind vagina, no uterus, undescended testes, breast development at puberty, scant pubic/axillary hair, elevated testosterone, LH, and estrogen. - 5-alpha reductase deficiency: ambiguous genitalia at birth, virilization at puberty, low DHT, normal testosterone. - 17α-hydroxylase and 17,20-lyase deficiencies, 17β-hydroxysteroid dehydrogenase deficiency, and Leydig cell hypoplasia are other causes. Note that 17β-HSD deficiency (impaired androstenedione-to-testosterone conversion) can also virilize at puberty.

**Pharmacology: 5-alpha reductase inhibitors** - Finasteride: selective type 2 inhibitor. Used for BPH (shrinks prostate, improves urinary flow over months) and androgenetic alopecia (1 mg dose). - Dutasteride: inhibits types 1 and 2 (and 3), so it lowers DHT more completely. Used for BPH. - Adverse effects: decreased libido, erectile dysfunction, ejaculatory dysfunction, gynecomastia, and depression. - Teratogenic: pregnant women should not handle crushed or broken tablets because of the risk of feminization of a male fetus (ambiguous genitalia). - Lower PSA by about 50% after 6-12 months, so double the measured PSA when screening for prostate cancer. - Reduce the risk of low-grade prostate cancer but may be associated with a relative increase in high-grade tumors. - The PCPT (Prostate Cancer Prevention Trial) evaluated finasteride for prevention. - BPH treatment contrasts: alpha-1 blockers (tamsulosin) act in days by relaxing smooth muscle, whereas 5-ARIs act over months by shrinking the gland. They are often combined in large prostates.

**Other clinical associations** - BPH: DHT is the primary driver of prostatic growth, particularly in the periurethral transition zone. - Male-pattern baldness: DHT shortens the anagen phase and miniaturizes scalp follicles. - Hirsutism/PCOS: increased 5-alpha reductase activity in skin raises local DHT. Treatments include antiandrogens (spironolactone, flutamide), and finasteride is sometimes used off-label. - Steroid physiology: 5-alpha reductase also acts on progesterone, cortisol, and aldosterone, producing neuroactive metabolites (e.g., allopregnanolone).

**High-yield takeaways** - Testosterone → DHT via 5-alpha reductase; testosterone → estradiol via aromatase. - DHT builds external male genitalia and the prostate in utero, while testosterone builds the internal Wolffian structures. - 5-alpha reductase deficiency: 46,XY, ambiguous genitalia, virilization at puberty, normal MIF (no Müllerian structures), and a high testosterone:DHT ratio. - Finasteride treats BPH and baldness, lowers PSA, and is teratogenic.