Length of Androgen Receptor—CAG Repeats in Fertile and Infertile Egyptian Men

Abstract

Androgens play key roles in spermatogenesis, and they exert their effect via the androgen receptor (AR). The AR gene has a repetitive DNA sequence in exon 1 that encodes a polyglutamine tract. Instability in the glutamine (CAG) repeat unit length is polymorphic across ethnic groups. Previous studies of the relationship between the repeat unit length and male infertility have been contradictory. To establish the range of wild-type alleles in Egyptian men, we determined the range of repeat lengths in a population of normally fertile, ethnically selected Egyptian men. We also investigated the association between trinucleotide repeat length within the AR gene and male factor infertility in a population of ethnically selected Egyptian infertile men, who were compared with fertile, ethnic group-matched and age-matched controls. The study included 129 clinically selected infertile Egyptian men who were scheduled for intracytoplasmic sperm injection and 52 ethnically matched fertile controls. The experimental population was grouped according to sperm counts ranging from nonobstructive azoospermia to normozoospermia. The CAG repeat N-terminal domain region of the AR gene was amplified in peripheral blood DNA, and allele size was determined by fragment analysis. Allele size and single-nucleotide polymorphism and mutation rates were determined by sequencing individual amplified alleles. The mean CAG repeat length in the azoospermia group was 18.55 6 2.0; in the severe oligozoospermia group it was 18.21 6 3.42; in the oligozoospermia group it was 18.27 6 2.93; and in the infertile with normal sperm count group it was 17.72 6 2.0. In the control group, the mean CAG repeat length was 18.18 6 3.63. No significant correlation was found between CAG repeat length and the risk of male factor infertility in an ethnically defined population of Egyptian men. However, a significant and positive correlation between CAG repeat length and serum testosterone concentration was demonstrated. This suggests the involvement of epigenetic regulation linked to this region.

Cytogenetic and molecular analysis of infertile Chinese men: karyotypic abnormalities, Y-chromosome microdeletions, and CAG and GGN repeat polymorphisms in the androgen receptor gene

“…These results were consistent with other studies in which no association was found (Dadze et al, 2000;Sasagawa et al, 2001;Van Golde et al, 2002;Rajpert-De Meyts et al, 2002;Lund et al, 2003;Martinez-Garza et al, 2008;Badran et al, 2009), but discordant with other studies that did find associations (Tut et al, 1997;Komori et al, 1999;Dowsing et al, 1999;Yoshida et al, 1999;Mifsud et al, 2001;Patrizio et al, 2001;Wallerand et al, 2001;Mengual et al, 2003;Katagiri et al, 2006). However, for CAG repeats >23, risks of >1.2-fold and >1.8-fold were found in azoospermia and severe oligospermia compared to the controls, although CAG repeat length was not significantly correlated with sperm counts in azoospermia and severe oligospermia.…”

“…Previous studies on CAG repeats in infertile men have reported conflicting results. Some suggested no expansion (Dadze et al, 2000;Sasagawa et al, 2001;Van Golde et al, 2002;Rajpert-De Meyts et al, 2002;Lund et al, 2003;MartinezGarza et al, 2008;Badran et al, 2009), while others reported increased length (but still within the normal range) with respect to controls (Tut et al, 1997;Dowsing et al, 1999;Yoshida et al, 1999;Mifsud et al, 2001;Patrizio et al, 2001;Wallerand et al, 2001;Mengual et al, 2003;Katagiri et al, 2006). Only one study indicated that reduced CAG repeats are closely associated with impaired spermatogenesis in infertile men (Komori et al, 1999).…”

Androgen insensitivity syndrome

“…The AR uniquely contains an extended N-terminal domain which includes polymorphic polyglutamine (CAG) and poly-glycine (GGN) repeats which are known to influence AR activity [2,3]. In clinical studies, the CAG repeat length has an association with genital abnormalities [3], a positive correlation with serum testosterone concentrations but not with male infertility [4]. A shorter CAG repeat polymorphism may increase the risk of prostate cancer [5].…”

Evaluation of CAG repeat length of androgen receptor expressing cells in human testes showing different pictures of spermatogenic impairment

“…Current studies investigating the correlation between CAG length, fertility and impaired sperm production do (Tut et al 1997;Dowsing et al 1999;Mifsud et al 2001;von Eckardstein et al 2001;Claessens et al 2005) or do not (Dadze et al 2000;Rajpert-De Meyts et al 2002;Westerveld et al 2008;Badran et al 2009) find a connection. Davis-Dao et al (2007) identified a mild association of AR-CAG length on male idiopathic infertility by comparing 33 reports in a meta-analysis.…”