CAG repeat length in the androgen receptor gene affects the risk of male infertility

Abstract

During recent years several studies have suggested that a slight increase in the number of CAG repeat sequences in exon 1 of the androgen receptor gene causes idiopathic oligozoospermia. We tested whether CAG repeats are more numerous in men with idiopathic infertility compared to those with known causes of oligozoospermia. CAG repeats were analysed in a consecutive sample of 217 infertile men covering a wide range of diagnoses and sperm counts. Data were compared with those of a control group of 131 normozoospermic men including 62 fathers. CAG repeats (x +/- SD) did not differ between idiopathically (21.4 +/- 2.9) and non-idiopathically infertile men (21.6 +/- 2.8) or normozoospermic men of unproven fertility (20.6 +/- 3.0). Only fathers had significantly fewer repeats (19.4 +/- 3.1; p < 0.001). Different from controls, no correlation between CAG repeats and any semen parameter existed in patients. Comparison of our and published studies showed that odds ratios for infertility in men with CAG repeat length in the upper quartile of the normal range increased when the controls were selected by proven fertility. We conclude that more numerous CAG repeats do not directly cause oligozoospermia and propose that men with longer CAG repeats might be more prone to develop infertility in response to any pathogen/epigenetic factors.

Gene polymorphisms/mutations relevant to abnormal spermatogenesis

“…Despite promising in-vitro data, the initial observations of a significant association between relatively long CAG repeats and Symposium -Mutations and spermatogenesis -F Nuti & C Krausz impaired sperm production (Dowsing et al, 1999) have not been confirmed by subsequent studies (for review see Asatiani et al, 2003). Similarly, it is still under question whether the (GGC) n repeat has a pathogenic role in abnormal spermatogenesis (see Krausz and Giachini, 2007).…”

The role of the polyglutamine tract in androgen receptor

“…male infertility, hypogonadism, gynecomastia, cryptorchidism, etc.). For example, some studies have shown the presence of larger CAG repeat size in the AR gene of infertile men with extremely severe oligozoospermia [34] and azoospermia [35]; other studies failed to demonstrated a direct correlation between long CAG triplet repeats and semen parameter found abnormal in oligozoospermia, but it has been proposed that the CAG repeats might allow the development of infertility in response to any pathogen/epigenetic factors [36]. Some other studies have associated the increased CAG triplet repeat size in AR with fat-free mass in men [37], while contrasting results have been obtained on the link with depression in middle-aged [38] or elderly [39] men.…”

CAG repeat length in an infertile male population of Irish origin

“…However, the Chinese study found an association between CAG repeat length and depressed spermatogenesis in an azoospermic subgroup only but not in a severely oligozoospermic group of patients. The most recent CAG expansion publications have reported no link between CAG repeat polymorphisms and male infertility in Israeli, German, Indian, Finnish, and Italian populations (Asatiani et al, 2003;Dhillon & Husain, 2003;Lund et al, 2003;Ferlin et al, 2004;Milatiner et al, 2004). The Israeli study did, however, demonstrate an association between CAG repeat length and a teratozoospermic (<30% with normal forms) subgroup.…”