Defects of the testosterone biosynthetic pathway in boys with hypospadias

We determined the incidence of defects in 3 enzymes, namely 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase and 17,20-lyase, on the testosterone biosynthetic pathway in boys with hypospadias.

We evaluated 30 boys with a 46,XY karyotype, fully descended testes and penoscrotal or proximal shaft hypospadias. Serum concentrations of the metabolites mediated by these enzymes were measured, from which the precursor-to-product ratios were calculated. Seven patients underwent adrenocorticotropic hormone stimulation. Findings were compared to previously published data on age matched normal boys.

A total of 11 boys had evidence of impaired function of 3beta-hydroxysteroid dehydrogenase alone or in combination with impaired 17,20-lyase or 17alpha-hydroxylase activity. An additional 4 boys had evidence of isolated 17,20-lyase deficiency. Thus, of the 30 boys studied 15 (50%) had evidence of a testosterone biosynthetic defect. The effect of adrenocorticotropic hormone stimulation varied with widening of the precursor-to-product ratios in some boys and narrowing in others.

A high incidence of 3beta-hydroxysteroid dehydrogenase and 17,20-lyase deficiency was found in boys with proximal hypospadias. The response to adrenocorticotropic hormone stimulation suggests that enzymes in the adrenal glands and testes may be affected independently. Our findings support the hypothesis that hypospadias is the result of fetal endocrinopathy.