5α-reductase

**Function and biochemistry** - Enzyme (NADPH-dependent) that reduces the Δ4 double bond of testosterone to form dihydrotestosterone (DHT). - Isoforms: Type 2 (SRD5A2) is the main isoform in prostate, genital skin, and hair follicles. Type 1 (SRD5A1) is found in skin, liver, and scalp. Type 3 is also described. - DHT binds the androgen receptor with higher affinity and a slower dissociation rate than testosterone, so it is about 2-5x more potent.

**Embryology: which tissues depend on testosterone vs DHT** - Testosterone (Wolffian derivatives, "SEVEN UP" mnemonic): Seminal vesicles, Epididymis, Vas deferens, Ejaculatory duct. Testosterone acts on these directly. - DHT: penis, scrotum, prostate (also male-pattern hair, sebaceous gland activity, and acne). - Müllerian-inhibiting factor (AMH) from Sertoli cells is normal, so there are no Müllerian structures (no uterus or fallopian tubes).

**5α-reductase type 2 deficiency (autosomal recessive, 46,XY DSD)** - Karyotype 46,XY with normal testes and normal testosterone production. - Internal Wolffian structures are present and normal. There is no uterus and no fallopian tubes. The vagina ends in a blind pouch. - At birth, external genitalia are ambiguous or female-appearing (severe hypospadias, micropenis or clitoral-like phallus, bifid scrotum). The prostate is hypoplastic. - At puberty, testosterone rises and virilization occurs: voice deepening, muscle mass, phallic growth, and testicular descent. This is sometimes called "penis-at-12" (guevedoces in the Dominican Republic). Individuals may then adopt a male gender identity. - Labs: normal or high testosterone, low DHT, and an elevated testosterone:DHT ratio. LH is normal or high. Facial/body hair is minimal and there is no temporal recession. The prostate remains small. - Contrast with androgen insensitivity syndrome (AIS): AIS has a defective androgen receptor, so testosterone and estrogen are high and LH is high. There is no virilization at puberty, and breast development occurs. 5α-reductase deficiency has a normal receptor and virilizes at puberty.

**Pharmacology: 5α-reductase inhibitors** - Finasteride inhibits type 2. Dutasteride inhibits types 1 and 2. - Uses: BPH (shrinks the prostate over about 6 months, reducing urinary symptoms) and male-pattern baldness (finasteride 1 mg). - Adverse effects: decreased libido, erectile dysfunction, gynecomastia, and reduced ejaculate volume. They are teratogenic: pregnant women should not handle crushed tablets because of the risk of undervirilized male fetal genitalia. - Lab effect: they lower serum PSA by about 50% after 6-12 months, so double the measured PSA when screening for prostate cancer. - Comparison with other BPH agents: α1-blockers (tamsulosin) relieve symptoms quickly but do not shrink the prostate.

**Clinical pearls** - DHT is also implicated in BPH and in androgenetic alopecia. - The classic board question describes a 46,XY phenotypically female child or adolescent with virilization at puberty, testes, no Müllerian structures, and a high testosterone:DHT ratio.