Steroid 17β-hydroxysteroid dehydrogenase deficiency in man: an inherited form of male pseudohermaphroditism

Abstract

Sixty-eight males with testicular 17β-hydroxysteroid dehydrogenase deficiency (17β-HSD) were identified among a highly inbred Arab population in Israel, and 45 studied over the last 15 years. The founders of this defect originated in the mountainous region of present Lebanon and Syria, but most of the families now live in Jerusalem, Hebron, the Tel-Aviv area, and in particular Gaza, where the frequency of affected males is estimated at 1 in 100 to 150. Affected individuals (46,XY) are born with ambiguity of the genitalia and reared as females until puberty. Thereafter marked virilization occurs, leading in many cases to the spontaneous adoption of a male gender role. Adults develop a male habitus with abundant body hair and beard, and the phallus and testes enlarge to adult proportions. Gender reassignment was possible only when enough erectile tissue was present at birth and developed into a normal size penis with systemic testosterone. male genitoplasty was performed in 15 children and 8 post-pubertal patients, and female genitoplasty in 2 children and 4 post-pubertal patients. In adults the defect is characterized by markedly increased concentrations of 4-androstendione (4-A) with borderline low to normal testosterone (T) levels, and a high 4-A/T ratio. Dihydrotestosterone (DHT) concentrations were either moderately decreased, normal, or high, and dehydroepiandrosterone levels were high. The estrogen pathway was also impaired, even though both estrone and estradiol-17β levels were elevated. Children had low basal levels of all androgens, but the defect could be demonstrated after prolonged stimulation with human chorionic gonadotropin. LH and FSH levels were very high after puberty, and normal in childhood. However, an over-response to gonadotropin-releasing hormone was found at all ages. Studies in testicular tissue revealed various abnormalities in steroid metabolism. Tissue from pre-pubertal patients metabolized progesterone (P) only to 4-A, while tissue from post-pubertal patients metabolized P to 16α- and 16β-hydroxyprogesterone (5.4- to 10.3-fold greater production), 17α-hydroxyprogesterone (5.4- to 8-fold smaller production), 4-A and T. 4-A was also metabolized to T, indicating that 17β-HSD was no longer deficient. Flow studies with equimolar concentrations of [¹⁴C]P and [³H]pregnenolone showed that the 5-ene pathway was the preferential one for androgen biosynthesis. Both in vivo and in vitro studies indicate that the severity of testicular 17β-HSD deficiency changes with age. Whereas the enzyme activity is absent in childhood, there is a progressive restoration after puberty. Androgen production increases progressively to normal so that T and DHT concentrations are sufficiently high to gradually induce somatic and genital virilization, thus enabling an adequate male gender function.