[Androgen receptor and male infertility]

The androgen receptor (AR) mediates androgen action determining male sexual phenotypes and promotion of spermatogenesis. Mutations in the AR cause various degrees of androgen resistance resulting in a range of androgen insensitivity syndromes. A single copy gene in the X chromosome encodes the AR. The gene contains a polymorphic triple repeat sequence [(CAG)n] with 9-36 repeats in the normal population, and displays ethnic dependence. In vitro, there is an inverse correlation between CAG repeat length and AR function. Associations exist between short alleles and prostate cancer in men or clinical hyperandrogenism in women. Expansion of the CAG tract > 40 repeats leads to spinal bulbar muscular atrophy (SBMA, Kennedy disease), an adult onset neurodegenerative disease that also presents with low virilization and spermatogenetic defects. The disease may show evidence of anticipation (increasing severity with succeeding generations accompanying further expansion of repeat length). Twelve studies involving Singaporean, Australian, North American and Japanese men reported a relationship between AR CAG repeat length and male infertility, whereas 10 studies, most of them European, found no association. Differences in hereditary or acquired factors in these populations may explain the equivocality. However, statistical methods, sample sizes, study definition and control populations, in addition to laboratory methods vary widely within the published papers, and could affect the results and conclusions. Current data is insufficient to conclude whether IVF patients who display AR CAG expansion may transfer infertility or premutation of neurodegenerative disease to their descendants. We recommend screening of AR CAG repeat length, at least in those populations where an association between repeat length and infertility could be found.