Infertility occurs in 10-15% of couples, male factor infertility representing about 50% of the cases [1]. It is now evident that a significant proportion of male infertility is associated with a variety of genetic abnormalities. Genetic defects associated with male infertility include chromosomal aberrations, Y chromosome microdeletions involving one or more azoospermia factor (AZF) regions, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and mutations in the androgen receptor (AR) gene.

Androgens are essential for male sexual development and for fertility. They act through the AR, which is a transcriptional factor that contains functional domains for DNA binding, ligand binding and transcriptional regulation. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that codes for a polyglutamine tract. The number of CAG repeats in the normal population varies between 10 and 36. Expansion of the polyglutamine tract to >38 repeats in males leads to Kennedy disease [spinal bulbar muscular atrophy (SBMA)] [2]. In addition to neurological symptoms, SBMA patients show signs of hypogonadism, such as gynecomastia, impotence, testicular atrophy and reduced fertility.

In vitro studies have demonstrated a negative correlation between CAG repeat size and AR function [3]. Short AR CAG repeat tracts have been associated with prostate cancer [4] and polycystic ovary syndrome [5], while long CAG repeat tracts have been associated with moderate-to-severe undermasculinization [6], breast cancer [7] and male subfertility [8]. The possible association of a long CAG repeat with male infertility in Asian populations was suggested because of a four-fold increase in the risk of impaired spermatogenesis in males who had >28 CAG repeats [8]. Since then, the association of the long CAG repeat number in the AR gene and male infertility has been controversial. This study aims to evaluate the possible effect of long CAG repeat tracts in the AR on infertility among Macedonian men.