Study of trinucleotide expansions and expression of androgen receptor in infertile men with abnormal spermogram referred to Royan institute.

Androgen receptor (AR) mediates androgen activities such as the growth of accessory sex organs, and initiation and promotion of spermatogenesis. There are two trinucleotide polymorphisms (CAG and GGN repeats) in the first exon of AR gene that their association with infertility is still controversial. The variants of both polymorphic repeats were investigated by PCR-Sequencing in 220 infertile men (80 azoospermic, 60 oligospermic and 80 asthenospermic) and 80 healthy fertile controls. AR Expression level was quantified by RT-qPCR on 30 patients (20 patients with nonobstructive azoospermia (NOA) and 10 obstructive azoospermia patients as controls). Our results demonstrated that the medians of CAG and GGN repeats length in infertile group were significantly higher than fertile men (p < 0.05). AR expression results showed a significant increase in SCOS group compared to control (p < 0.05). Long stretches of tandem repeats of AR gene may negatively affect the function of the gene and consequently lead to male infertility. In patients with SCOS, AR expression increases because of the lack of germ cells. Therefore, with increasing AR expression, the probability of SCOS occurrence is also increased. It can be concluded that increasing AR expression in testes tissue decreases the probability of sperm presence.

Possible role of androgen receptor gene in therapeutic response of infertile men with hypogonadotropic hypogonadism.

Hypogonadotropic hypogonadism (HH) is defined as a dysfunction of hypothalamic-pituitary-gonadal axis, which causes impairments in gametogenesis, pubertal maturation, and/or secretion of the gonadal sex hormones. Human chronic gonadotropin (hCG) stimulates the Leydig cells of the testis to secrete testosterone, which is essential for spermatogenesis. Testosterone replacement therapy is one of the possible options to manage HH treatment. Given the fact that testosterone functions are mediated via androgen receptor (AR), the aim of the present study was to evaluate whether the CAG/GGN triple repeat expansion in AR gene can modulate the response to hCG and testosterone treatment in HH men. Sixty-two men who diagnosed with HH and treated with testosterone and hCG were assessed after treatment. They were classified into two groups, 31 subjects with a positive and 31 subjects with a negative response to replacement therapy within 12-18 months. Androgen receptor CAG and GGN repeat numbers were measured in both groups by hot start polymerase chain reaction (PCR)-sequencing technique. Subjects who reached complete spermatogenesis showed the 20 and 23 as the median numbers of AR CAG/GGN repeats, respectively. In individuals who did not respond to treatment the median length for both CAG/GGN repeats were 23. The average of CAG repeats was statistically lower in patients who had the positive response in comparison to patients who did not respond to hormone therapy (p < 0.05), but the length of GGN repeats were not statistically different between these groups of patients (p > 0.05). The number of CAG repeats are negatively and significantly associated with better hormone therapy response. Our results suggest that the length of CAG repeat polymorphism in AR gene might affect the response to treatment in men suffering from HH, whereas no relationship was found between AR gene GGN repeat polymorphism and testosterone and hCG replacement therapy response. Abbreviations: AR: androgen receptor; FSH: follicle stimulating hormone; Gn: gonadotropins; GnRH: gonadotropin-releasing hormone; hCG: human chronic gonadotropin; HH: hypogonadotropic hypogonadism; LH: luteinizing hormone; PCR: polymerase chain reaction.