Male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency. Diagnosis, psychological evaluation, and management.

Sixteen subjects (from 10 Brazilian families) with male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency have been evaluated in 1 clinic. The diagnoses were made on the basis of normal plasma testosterone values, normal or low plasma dihydrotestosterone levels and high testosterone/dihydrotestosterone ratios in the basal state in postpubertal subjects or after treatment with either human chorionic gonadotropin or testosterone in prepubertal subjects. The analysis of the ratios of etiocholanolone to androsterone in urine confirmed the diagnosis in all subjects who were tested, and the molecular basis of the underlying mutations was established in 9 of the families. Fourteen of the individuals were evaluated by the same psychologist. All subjects but 1 were given a female sex assignment at birth. Three of the subjects (1 the sibling of an individual who has undergone female to male social behavior) maintain a female social sex; they have been gonadectomized and treated with exogenous estrogens. Ten of 13 subjects of postpubertal age underwent a change of social sex from female to male, had surgical correction of the hypospadias, and were treated with high-dose testosterone esters by parenteral injection and subsequently with dihydrotestosterone cream. These regimens brought serum dihydrotestosterone levels to the normal male range (or above) but resulted only in limited growth of the prostate and penis and, in some, increase in body and facial hair and enhancement of libido and sexual performance. Treatment of the prepubertal boys with testosterone and/or dihydrotestosterone resulted in a doubling of penis size.

Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency.

Autosomal recessive mutations in the 17 beta-hydroxysteroid dehydrogenase 3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with female external genitalia. Such individuals are usually raised as females, but virilize at the time of expected puberty as the result of increases in serum testosterone. Here we describe mutations in 12 additional subjects/families with this disorder. The 14 mutations characterized to date include 10 missense mutations, 3 splice junction abnormalities, and 1 small deletion that results in a frame shift. Three of these mutations have occurred in more than 1 family. Complementary DNAs incorporating 9 of the 10 missense mutations have been constructed and expressed in reporter cells; 8 of the 9 missense mutations cause almost complete loss of enzymatic activity. In 2 subjects with loss of function, missense mutations testosterone levels in testicular venous blood were very low. Considered together, these findings strongly suggest that the common mechanism for testosterone formation in postpubertal subjects with this disorder is the conversion of circulating androstenedione to testosterone by one or more of the unaffected 17 beta-hydroxysteroid dehydrogenase isoenzymes.