Androgen receptor gene and male infertility

Abstract

Androgens are critical steroid hormones that determine the expression of the male phenotype. Their actions are mediated by a single androgen receptor (AR) which, upon ligand binding, translocates to the nucleus to regulate the expression of androgen-responsive genes. Mutations that disrupt AR function totally result in the complete feminization of 46 XY individuals and the complete androgen insensitivity syndrome. Studies have revealed that AR mutations that do not lead to complete abrogation of its activity can cause a wide spectrum of milder androgen insensitivity syndromes, from ambiguous genitalia in newborn infants to 'idiopathic' male infertility. Recent studies indicate that missense amino-acid substitutions in the ligand-binding domain of the AR result in infertility through a novel mechanism that involves defective protein-protein interactions between receptor domains and coactivator proteins. Independent of missense mutations, studies involving Singaporean, Australian, North American and Japanese subjects indicate that increases in length of a trinucleotide repeat (CAG) tract, encoding a polyglutamine stretch in the transactivation domain of the AR, are associated with increased risk of defective spermatogenesis and undermasculinization. This association was however not observed in European populations, suggesting that the genetic background may play a significant role in the expression of the AR defects.

No Association of Androgen Receptor GGN Repeat Length Polymorphism With Infertility in Indian Men

“…Thus the majority of infertile cases remain unexplained. Mutations in the AR gene, including variation in the number of CAG repeats, have been found to be associated with male infertility in some populations but not others (Yong et al, 2003). AR-GGN repeat length polymorphism has been less studied in male infertility.…”

“…The CAG repeat has been well studied in a variety of medical conditions in addition to male infertility (Hickey et al, 2002;Sasaki et al, 2003;Yong et al, 2003). Expansion of the CAG repeat above the normal range has been found to be associated with adult onset of spinal and bulbar muscular atrophy (La Spada et al, 1991), characterized by undermasculinization and progressive neuromuscular degeneration.…”

Impaired expression of testicular androgen receptor and collagen fibers in the testis of diabetic rats under HAART: the role of Hypoxis hemerocallidea

“…Androgen and estrogen exert their cellular effects via steroid receptors (ARs and ERs, respectively) of the nuclear receptor superfamily and act as ligand-dependent transcription factors [26]. After the binding of androgens, ARs undergo a conformational change, dimerization, translocation to the cell nucleus and binding to specific DNA sequence, thus modulating expression of target genes [27].…”

The association between androgen receptor gene CAG polymorphism and polycystic ovary syndrome: a case-control study and meta-analysis

“…Previous studies in vitro have demonstrated that CAG repeat number shows an inverse correlation with AR activity [9][10][11][12][13][14]. Hence, it's not difficult to understand that shorter CAG repeats, increasing AR activity, are associated with prostate cancer [15,16], hirsutism [17] and hyperandrogenism in ovary [18,19], while longer CAG repeats, decreasing AR activity, are related to hypoandrogenicity [20] and male infertility due to impaired sperm production [10,21]. CAG tracts beyond the normal range (>40 CAG repeats) leads to Kennedy's syndrome, a fatal neuromuscular disease [22].…”