CAG repeat polymorphism in androgen receptor and infertility: A case-control study
Background: Androgens play a role in the development of male phenotype and spermatogenesis during puberty, the function of which is regulated by the androgen receptor (AR) gene. There is a polymorphism site in exon 1 of the gene encoding this receptor that can have different frequencies of CAG trinucleotide repeats and leads to the formation of polyglutamine chains of different lengths in the N-terminal domain of the AR protein and reduced sperm production by affecting spermatogenesis.
Objective: To investigate whether the cause of a group of unexplained infertilities could be the increased frequency of CAG repeats in the AR gene of patients with oligozoospermia and azoospermia.
Materials and Methods: In this case-control study, 84 men including 42 with unexplained infertility As a case group and 42 fertile men as a control group were selected. The frequency of CAG repeats was determined by the polymerase chain reaction method and then the difference in the frequency of these repeats was determined based on the difference in band size on the agarose gel.
Results: The mean CAG repeat length in the azoospermia and oligozoospermia group was 17.5 ± 0.63 and in the fertile group it was 16.11 ± 0.75 (p = 0.46). In addition, most men (88.1% in the case group and 71.41% in the control group) had 13-23 repeats.
Conclusion: No significant correlation was found between CAG repeat length and the risk of male factor infertility in an ethnically defined population of Iranian men. The role of regulatory factors and epigenetic changes should be taken into account too.
Key words: Infertility, Azoospermia, Androgens, X chromosome, Spermatogenesis.
 Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, et al. International committee for monitoring assisted reproductive technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril 2009; 92: 1520– 1524.
 Saito H, Hara K, Tanemura K. Prenatal and postnatal exposure to low levels of permethrin exerts reproductive effects in male mice. Reprod Toxicol 2017; 74: 108–115.
 Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel Sh, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: A systematic analysis of 277 health surveys. PLoS Med 2012; 9: e1001356.
 Louie MC, Sevigny MB. Steroid hormone receptors as prognostic markers in breast cancer. Am J Cancer Res 2017; 7: 1617–1636.
 Bogefors K, Giwercman YL, Eberhard J, Stahl O, Cavallin-Stahl E, Cohn-Cedermark G, et al. Androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment. Asian J Androl 2017; 19: 538–542.
 Mobasseri N, Babaei F, Karimian M, Nikzad H. Androgen receptor (AR)-CAG trinucleotide repeat length and idiopathic male infertility: A case-control trial and a meta-analysis. EXCLI J 2018; 17: 1167–1179.
 Andersen ML, Guindalini C, Santos-Silva R, Bittencourt LRA, Tufik S. Androgen receptor CAG repeat polymorphism is not associated with erectile dysfunction complaints, gonadal steroids, and sleep parameters: Data from a population-based survey. J Androl 2011; 32: 524–529.
 Mosaad YM, Shahin D, Elkholy AAM, Mosbah A, Badawy W. CAG repeat length in androgen receptor gene and male IF in Egyptian patients. Andrologia 2012; 44: 26–33.
 Delli Muti N, Agarwal A, Buldreghini E, Gioia A, Lenzi A, Boscaro M, et al. Have androgen receptor gene CAG and GGC repeat polymorphisms an effect on sperm motility in infertile men? Andrologia 2014; 46: 564–569.
 Pan XF. Mechanism of trinucleotide repeats instabilities: The necessities of repeat non-B secondary structure formation and the roles of cellular trans-acting factors. Yi Chuan Xue Bao 2006; 33: 1–11.
 Yong EL, Ghadessy F, Wang Q, Mifsud A, Ng SC. Androgen receptor transactivation domain and control of spermatogenesis. Rev Reprod 1998; 3: 141–144.
 Dowsing AT, Yong EL, Clark M, McLachlan RI, de Kretser DM, Trounson AO. Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet 1999; 354: 640– 643.
 Dadze S, Wieland C, Jakubiczka S, Funke K, Schröder E, Royer-Pokora B, et al. The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin. Mol Hum Reprod 2000; 6: 207–214.
 Grigorova M, Punab M, Kahre T, Ivandi M, Tõnisson N, Poolamets O, et al. The number of CAG and GGN triplet repeats in the androgen receptor gene exert combinatorial effect on hormonal and sperm parameters in young men. Andrology 2017; 5: 495– 504.
 Guo D, Li Sh, Behr B, Eisenberg ML. Hypertension and male fertility. World J Men’s Health 2017; 35: 59– 64.
 Xiong DK, Chen HH, Ding XP, Zhang ShH, Zhang JH. Association of polymorphisms in glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) with idiopathic azoospermia or oligospermia in Sichuan, China. Asian J Androl 2015; 17: 481–486.
 Chan AL, La HM, Legrand J, Makela JA, Eichenlaub M, De Seram M, et al. Germline stem cell activity is sustained by SALL4-Dependent silencing of distinct tumor suppressor genes. Stem Cell Reports 2017; 9: 956–971.