A mutation of the androgen receptor associated with partial androgen resistance, familial gynecomastia, and fertility

A family is described in which gynecomastia and undervirilization in five men (four of whom have fathered children) were inherited in a manner compatible with an X-linked defect. Three members from whom blood could be obtained had supranormal serum testosterone and normal LH and FSH levels. One man had severe oligospermia with decreased motility, and one had normal sperm density and motility. In fibroblasts cultured from genital skin biopsies from two of the men, the levels of androgen receptor and affinity of binding of receptor to dihydrotestosterone were normal. However, androgen binding i n fibroblast monolayers was thermolabile, up-regulation of receptor levels did not occur after prolonged incubation of mono-layers with dihydrotestosterone or methyltrienolone, and dissociation rates at 37 C were increased with the synthetic androgen mibolerone. In addition, in cytosol preparations the androgen receptor protein was unstable. This disorder probably represents the most subtle functional abnormality of androgen receptor characterized to date, since it is compatible with normal male phenotypic development and in some affected men with fertility. It follows that infertility is not an invariable feature of androgen resistance as we previously suggested.