Natural potent androgens: Lessons from human genetic models

Abstract

Male pseudohermaphroditism due to 17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3) deficiency and 5α-reductase-2 (5α-RD-2) deficiency provides natural human genetic models to elucidate androgen actions. To date, five 17β-HSD isozymes have been cloned that catalyse the oxidoreduction of androstenedione and testosterone and dihydrotestosterone (DHT), oestrone and oestradiol. Mutations in the isozyme 17β-HSD-3 gene are responsible for male pseudohermaphroditism due to 17β-HSD deficiency. The type 3 isozyme preferentially catalyses the reduction of androstenedione to testosterone and is primarily expressed in the testes. Fourteen mutations in the 17β-HSD-3 gene have been identified from different ethnic groups. Affected males with the 17β-HSD-3 gene defect have normal wolffian structures but ambiguous external genitalia at birth. Many are raised as girls but virilize at the time of puberty and adopt a male gender role. Some develop gynaecomastia at puberty, which appears to be related to the testosterone/oestradiol ratio.

Two 5α-reductase (5α-RD) isozymes, types 1 and 2, have been identified, which convert testosterone to the more potent androgen DHT. Mutations in the 5α-RD-2 gene cause male pseudohermaphroditism, and 31 mutations in the 5α-RD-2 gene have been reported from various ethnic groups. Such individuals also have normal wolffian structure but ambiguous external genitalia at birth and are raised as girls. Virilization occurs at puberty, often with a gender role change. The prostate remains infantile and facial hair is decreased. Balding has not been reported.

The coexistence of both 17β-HSD-3 and 5α-RD-2 gene defects has been identified in a Turkish community. The studies of inherited enzymatic defects involving androgen biosynthesis and action highlight the importance of testosterone and DHT in male sexual differentiation and male physiology.