NATURAL POTENT ANDROGENS - LESSONS FROM HUMAN GENETIC MODELS

Male pseudohermaphroditism clue to 17 beta-hydroxysteroid dehydrogenas e-3 (17 beta-HSD-3) deficiency and 5 alpha-reductase-2 (5 alpha-RD-2) deficiency provides natural human genetic models to elucidate androgen actions. To date, five 17 beta-HSD isozymes have been cloned that cat alyse the oxidoreduction of androstenedione and testosterone and dihyd rotestosterone (DHT), oestrone and oestradiol. Mutations in the isozym e 17 beta-BSD-3 gene are responsible for male pseudohermaphroditism du e to 17 beta-HSD deficiency. The type 3 isozyme preferentially catalys es the reduction of androstenedione to testosterone and is primarily e xpressed in the testes. Fourteen mutations in the 17 beta-HSD-3 gene h ave been identified from different ethnic groups. Affected males with the 17 beta-HSD-3 gene defect have normal wolffian structures but ambi guous external genitalia at birth. Many are raised as girls but virili ze at the time of puberty and adopt a male gender role. Some develop g ynaecomastia at puberty, which appears to be related to the testostero ne/oestradiol ratio. Two 5 alpha-reductase (5 alpha-RD) isozymes, type s I and 2, have been identified, which convert testosterone to the mor e potent androgen DHT. Mutations in the 5 alpha-RD-2 gene cause male p seudohermaphroditism, and 31 mutations in the 5 alpha-RD-2 gene have b een reported from various ethnic groups. Such individuals also have no rmal wolffian structure but ambiguous external genitalia at birth and are raised as girls. Virilization occurs at puberty, often with a gend er role change. The prostate remains infantile and facial hair is decr eased. Balding has not been reported. The coexistence of both 17 beta- HSD-3 and 5 alpha-RD-2 gene defects has been identified in a Turkish c ommunity. The studies of inherited enzymatic defects involving androge n biosynthesis and action highlight the importance of testosterone and DHT in male sexual differentiation and male physiology.