Infertility affects 15% of married couples in the U.S. and a male factor(s) contributes to as many as 50% of the infertility problems. Since normal spermatogenesis requires gonadotropins and androgens, abnormalities in the hypothalamic-pituitary-testicular axis would be expected to be the major cause of oligo- or azoospermia. However, endocrine abnormalities are relatively rare and """"""""idiopathic"""""""" forms of infertility comprise 25% or more of the cases. In addition, cryptorchidism is a common disorder which is frequently associated with infertility. Normal descent of the testes also requires gonadotropin and androgen action. Our working hypothesis is that end-organ insensitivity to androgen action may be the molecular basis for inadequate spermatogenesis in certain subjects with otherwise unexplained infertility and in a few patients within the heterogenous group with testicular maldescent. Males with """"""""idiopathic"""""""" infertility will be evaluated to determine the frequency of androgen insensitivity among them. Patients will be ascertained on the basis of history, physical examination, blood hormone levels, and semen analysis (including the zonapellucida free hamster egg penetration test where appropriate). Scrotal skin biopsies will be obtained and cultured skin fibroblasts will be assayed for quantitative and qualitative defects in androgen receptors related to receptor number (Bmax), binding affinity (Kd), nuclear uptake, temperature lability, stability on sucrose density gradients, up-regulation, dissociation rates, and where indicated DNA-cellulose, gel filtration and ion-exchange chromatography and isoelectric focusing. The effectiveness of a therapeutic trial regimen intended to decrease estrogen levels and thereby alter the effective androgen/estrogen ratio will be evaluated in infertile males with an identifiable abnormality of androgen receptor function. Our study of androgen receptor function and infertility will be extended to children with bilateral cryptorchidism. Patients who achieve normal levels of plasma androgens following 6-weeks hCG stimulation but who do not have testicular descent will be evaluated for androgen receptor abnormalities using genital skin fibroblasts. The long term objectives are 1) to relate the possible spectrum of abnormalities at the molecular level of androgen action to the pathophysiology of male infertility, 2) to further define the role of androgens in testicular descent and 3) to test certain therapeutic modalities which may improve fertility in men with diminished sensitivity to androgens.
