Oestrogen formation in genital and non-genital skin fibroblasts cultured from patients with hypospadias.

Abstract

Hypospadias is the most common birth defect in males. In most cases the aetiology is unknown. Since penile development is androgen dependent and oestrogen can modify androgen action, we compared the formation of oestrogen in penile tissue from patients with hypospadias to those with normal penile development. Oestrogen formation was assessed in fibroblast monolayers grown from biopsies of genital and non-genital skin from 11 males with normal genital development (controls) and 18 males with severe hypospadias utilizing the incorporation of tritium into H2O resulting from the aromatization of 1 beta-3H-androstenedione. In paired fibroblast strains from genital and non-genital skin of nine males with hypospadias, oestrogen formation was significantly (P < 0.025) lower in non-genital skin. Rates of oestrogen formation were also higher in a subset of foreskins from subjects with hypospadias than in normal controls and the remaining hypospadias subjects. In addition, oestrogen formation in this subset of fibroblast strains from patients with hypospadias was markedly enhanced by incubation of intact monolayers with either cholera toxin or forskolin, agents known to stimulate cAMP formation. Oestrogen formation in the remaining cell strains (controls and hypospadias) was also enhanced in most instances by cholera toxin and forskolin, although to a much lower degree. Thus, we identified in the hypospadias group a subgroup of fibroblast strains in which unstimulated and stimulated oestrogen formation was markedly higher than in other strains examined. Since oestrogen can modify certain androgen effects within cells and since formation of the male genitalia during embryogenesis is mediated by androgens, elevated oestrogen formation in male genital tissue might be a causative factor of hypospadias in some instances.