The nature of the defect in familial male pseudohermaphroditism in Arabs of Gaza

Studies in six Arab individuals from Gaza with familial male pseudohermaphroditism (MPH) due to 17-ketoreductase deficiency revealed several metabolic aberrations associated with the disorder. Plasma LH, FSH, testosterone, and androstenedione concentrations were low in the two prepubertal patients. After hCG administration plasma androstenedione increased markedly. The four postpubertal MPH patients had very high plasma gonadotropin and androstenedione concentrations, the latter increasing further after hCG administration. Plasma testosterone concentrations in all six patients were moderately low or normal for age and increased little after hCG administration. Spermatic venous testosterone concentrations, measured in three adults, were within the normal range in two and low in one, while androstenedione concentrations were markedly elevated (15- to 32-fold) in all three patients. Kinetic analyses of progesterone and androstenedione metabolism were performed in testicular tissue of these patients and compared to the results in two control subjects. While testicular tissue from the two prepubertal patients metabolized progesterone only to androstenedione, and that to a limited extent, the tissue from the four postpubertal patients metabolized progesterone to 16 alpha- and 16 beta-hydroxyprogesterone, 17 alpha-hydroxyprogesterone, androstenedione, and testosterone and metabolized androstenedione to testosterone. The Michaelis constants of these reactions were similar in the tissue from the MPH and the control subjects. The production of 16 alpha- plus 16 beta-hydroxyprogesterone was 5.4- to 10.3-fold greater, and 17-hydroxylase activity was 5.8- to 8.1-fold lower in the testes of the postpubertal MPH patients compared to values in the control subjects. The preference of androstenedione production through the delta 4- or delta 5-pathways was examined in the testes of two adult MPH patients using an equimolar concentration of 14C]progesterone and 3H]pregnenolone as substrates. While the flow of substrates in the control testes was equal or slightly greater through the delta 4-pathway, the delta 5-pathway predominated in the testes of the MPH patients. A large amount of dehydroepiandrosterone accumulated when NAD, the cofactor for 3 beta-hydroxysteroid dehydrogenase-isomerase, was omitted, supporting the contention that androstenedione was produced in the testes of the MPH patients mainly through the delta 5-pathway. Additional support for this suggestion was the finding that the 3H/14C ratio in androstenedione and testosterone produced from both substrates was 8 times higher in the testes from MPH patients than in those from the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)