3alpha-Hydroxysteroid dehydrogenase type III deficiency: a novel mechanism for hirsutism.

Context: Dihydrotestosterone (DHT), the primary active androgen in peripheral target tissues, is metabolized by 3 alpha-hydroxysteroid dehydrogenase type III (3 alpha-HSD), encoded by the AKR1C2 gene, forming 5 alpha-androstane-3 alpha, 17 alpha-diol (3 alpha-diol). 3 alpha-HSD may play a role in the pathogenesis of hirsutism. Objectives: Our objective was to evaluate the role of 3 alpha-HSD in hirsutism by comparing 1) tissue levels of active androgens, 2) relative gene expression of AKR1C2, and 3) activity of 3 alpha-HSD in genital skin from normal and hirsute women. Design: Genital skin was obtained from normal and hirsute women. After homogenization, testosterone (T) and DHT levels were quantified by conventional RIA. From isolated RNA, relative expression of AKR1C2 was determined by real-time PCR. In addition, minced genital skin was incubated with [H-3] DHT, and the product, [H-3]3 alpha-diol, was quantified by radio-HPLC. Setting: The study took place at an inner-city hospital. Patients: Patients included women undergoing posterior colporrhaphy. Main Outcome Measures: We assessed 1) tissue levels of T, DHT, and 3 alpha-diol; 2) relative expression of AKR1C2; and 3) conversion ratio of [H-3]3 alpha-diol to [H-3] DHT. Results: In genital skin, tissue DHT and T concentrations in hirsute women were 1.90-fold and 1.84-fold higher than in normal women (P = 0.002 and 0.03), and relative expression of AKR1C2 mRNA was reduced approximately 7-fold (P = 0.04). Genital skin from hirsute women showed less metabolism of [H-3] DHT to [H-3]3 alpha-diol (conversion ratio, 0.24 +/- 0.19 vs. 0.85 +/- 0.55, P = 0.01). Conclusions: In genital skin of hirsute women, reduced AKR1C2 gene expression and 3 alpha-HSD activity results in decreased DHT metabolism and elevated tissue levels of DHT. Diminished DHT metabolism may play an important role in the pathogenesis of hirsutism.