Androgen receptor polymorphisms and mutations in male infertility

Normal spermatogenesis depends on a sequential cascade of genetic events tr iggered by factors encoded by sex chromosomes. To determine the contributio n of genetic aberrations to male infertility, the X-linked androgen recepto r (AR) gene was examined for mutations and polymorphisms in a large cohort of infertile men. Genetic screening of over 400 patients and controls showe d that defects in the AR gene lead to the production of dysfunctional recep tor protein in up to 10% of males with abnormally low sperm production and male infertility. The dozens of mutations and polymorphisms uncovered were associated with subtly reduced intrinsic AR activity, and are of two main c ategories: polymorphic changes in length of a trinucleotide CAG tract in th e N-terminal transactivation domain, and missense mutations in the C-termin al ligand-binding domain. These polymorphisms and mutations are associated with reduced AR function due to defective intermolecular protein-protein in teractions with coactivator molecules. Genetic screening for AR mutations a nd polymorphism should be offered to severely oligospermic and azoospermic patients. These traits can be transmitted to progeny, and counseling can be offered to affected families. Clarification of the molecular mechanisms of pathogenesis has led to rational hormonal therapy. (J. Endocrinol. Invest. 23: 573-577, 2000) (C) 2000, Editrice Kurtis.