Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency: studies on the natural history of the defect and effect of androgens on gender role.
Studies within the Arab population in Israel revealed 25 pseudohermaphrodites due to 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) deficiency. Twenty-three individuals, presently living in the Gaza strip, belong to a very large inbred kinship which extends over 8 generations. All affected subjects (46, XY) were born with mild to moderate degrees of ambiguity of an apparently normal-looking female genitalia and therefore were reared as girls. In childhood, genital abnormalities consisted of a clitoral-like phallus surrounded by a chordee, non-fused labial-scrotal folds and a urogenital sinus. The testes were in the inguinal canals, or rarely, in the labial-scrotal folds. Wolffian structures were normally differentiated while Mullerian structures were absent. At puberty, subjects developed a male body habitus with abundant body hair and beard. Gynecomastia was absent. The phallus and testes enlarged to adult proportions while the prostate remained small. Together with the physical change from girls to boys they developed a male identity having erections and ejaculations, which in 7 cases led to the spontaneous adoption of a male gender role. In adults the hormonal abnormalities consisted of greatly elevated delta 4-androstenedione (delta 4) (350-1267 ng/dl) associated with subnormal testosterone (T) levels (0.9-3.1 ng/ml). Dihydrotestosterone (DHT) levels, with the exception of 1 patient, were relatively low in all cases (27-35 ng/dl). Children had low levels of delta 4, T and DHT, which were normal for age. Although from puberty on there was a significant rise of the 3 androgens, delta 4 always remained extremely elevated and T and DHT relatively low when compared to normal controls. Dexamethasone failed to suppress the androgen pattern while HCG augmented the defect, making the diagnosis possible in 2 prepubertal children. Dehydroepiandrosterone (DHEA) and 17-hydroxyprogesterone (17-OHP) levels were normal or moderately elevated. Estradiol (E2) levels were normal in children and all but 2 adults, who had high levels. LH and FSH levels were very high after puberty, but normal before. However, there was an overresponse to LHRH in all age groups. The contrast between the lack of intrauterine virilization of the external genitalia in fetuses with 17 beta-HSD deficiency versus the marked masculinization that occurs after puberty still remains a puzzling phenomenon. It is conceivable that the postpubertal development of a male phenotype with change of gender identity and role occurs due to the joint effect of delta 4, T and DHT, even though secreted in inadequate proportions. Thus masculinization in these individuals is a slow process requiring a longer period of time than that of normal puberty to be completed.
D015067:17-Hydroxysteroid Dehydrogenases / Q000172:deficiency*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000728:Androgens / Q000097:blood; D002648:Child; D002675:Child, Preschool; D006063:Chorionic Gonadotropin; D012734:Disorders of Sex Development / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005783:Gender Identity; D005836:Genitalia, Female / Q000033:anatomy & histology; D005837:Genitalia, Male / Q000033:anatomy & histology; D006801:Humans; D007223:Infant; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D010375:Pedigree
D000728:Androgens; D006063:Chorionic Gonadotropin; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D015067:17-Hydroxysteroid Dehydrogenases; C032690:3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+))