CAG Expansion in Androgen Receptor Gene of Infertile Men in Erbil Governorate
https://doi.org/10.24017/Science.2022.2.9
Abstract views: 398 / PDF downloads: 157Abstract
Spermatogenesis and male phenotypic development during puberty are mainly done by androgen and their function is regulated by the androgen receptor (AR) gene. This gene has a polymorphism site in Exon1 which encode androgen receptor and have various length of CAG trinucleotide repeat which causes the production of polyglutamine chain in different length of the N-terminal domain of AR protein which reduces producing sperm by disrupting spermatogenesis.
The aim is to determine the relation of infertility in male with the increased frequency of CAG repeats in the AR gene, and the correlation between CAG repetition and hormonal changes.
The case-control research was carried out in the Immunogene center and IVF center in the maternity teaching hospital Erbil-Kurdistan region-Iraq. The convenience sample included 50 men, 30 infertile and 20 fertile over one year starting from March 2021 to March 2022.
Men with infertility had CAG repeats in their AR gene, ranging from (17-26) repeats, with a mean (21.3 ±0.16). In infertile men, CAG expansion was longer than the fertile men. The motility and normal morphology of sperm in infertile men have negative relation while sperm count and concentration have a positive relation with CAG expansion. The relation of hormones (Testosterone, LH, and FSH) with CAG repetition was statistically not significant.
In conclusion, CAG expansion was longer in infertile (case) men compared with fertile (control) men. Polyglutamine effect on increasing sperm abnormal morphology and immotility which is the reason for infertility but statistically not significant and it will not affect hormonal assay in infertile men.
Keywords:
Male infertility, AR gene, and CAG expansion
References
[1] T. Miyamoto, A. Tsujimura, Y. Miyagawa, E. Koh, M. Namiki, and K. Sengoku, "Male infertility and its causes in human," Advances in urology, vol. 2012, 2011.
https://doi.org/10.1155/2012/384520
[2] M. Vander Borght and C. Wyns, "Fertility and infertility: Definition and epidemiology," Clinical biochemistry, vol. 62, pp. 2-10, 2018.
https://doi.org/10.1016/j.clinbiochem.2018.03.012
[3] M. C. Inhorn and P. Patrizio, "Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century," Human reproduction update, vol. 21, pp. 411-426,2015.
https://doi.org/10.1093/humupd/dmv016
[4] R. J. Hart, "Physiological aspects of female fertility: role of the environment, modern lifestyle, and genetics," Physiological reviews, vol. 96, pp. 873-909, 2016.
https://doi.org/10.1152/physrev.00023.2015
[5] A. Agarwal and D. A. Kumar, "Viscoelastic Assisted Bubble Formation in Pre Descemet's Endothelial Keratoplasty (PDEK)," The Official Scientific Journal of Delhi Ophthalmological Society, vol. 26, pp. 37-39, 2015.
https://doi.org/10.7869/djo.133
[6] K.-W. Shih, P.-Y. Shen, C.-C. Wu, and Y.-N. Kang, "Testicular versus percutaneous epididymal sperm aspiration for patients with obstructive azoospermia: a systematic review and meta-analysis," Translational andrology and urology, vol. 8, p. 631, 2019.
https://doi.org/10.21037/tau.2019.11.20
[7] R. Zhou, J. Wu, B. Liu, Y. Jiang, W. Chen, J. Li, et al., "The roles and mechanisms of Leydig cells and myoid cells in regulating spermatogenesis," Cellular and molecular life sciences, vol. 76, pp. 2681-2695, 2019.
https://doi.org/10.1007/s00018-019-03101-9
[8] M. C. Louie and M. B. Sevigny, "Steroid hormone receptors as prognostic markers in breast cancer," American journal of cancer research, vol. 7, p. 1617, 2017.
[9] B. Pan, R. Li, Y. Chen, Q. Tang, W. Wu, L. Chen, et al., "Genetic association between androgen receptor gene CAG repeat length polymorphism and male infertility: a meta-analysis," Medicine, vol. 95, 2016.
https://doi.org/10.1097/MD.0000000000002878
[10] K. Bogefors, Y. L. Giwercman, J. Eberhard, O. Stahl, E. Cavallin-Stahl, G. Cohn-Cedermark, et al., "Androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment," Asian Journal of Andrology, vol. 19, p. 538, 2017.
https://doi.org/10.4103/1008-682X.191126
[11] S. Sharestani, S. M. Kalantar, N. Ghasemi, and E. F. Yazd, "CAG repeat polymorphism in androgen receptor and infertility: A case-control study," International Journal of Reproductive BioMedicine, vol. 19, p. 845, 2021.
https://doi.org/10.18502/ijrm.v19i9.9717
[12] G. Tirabassi, A. Cignarelli, S. Perrini, G. Furlani, M. Gallo, F. Pallotti, et al., "Influence of CAG repeat polymorphism on the targets of testosterone action," International journal of endocrinology, vol. 2015, 2015.
https://doi.org/10.1155/2015/298107
[13] N. Delli Muti, A. Agarwal, E. Buldreghini, A. Gioia, A. Lenzi, M. Boscaro, et al., "Have androgen receptor gene CAG and GGC repeat polymorphisms an effect on sperm motility in infertile men?," Andrologia, vol. 46, pp. 564-569, 2014.
https://doi.org/10.1111/and.12119
[14] R. Menkveld, "Clinical significance of the low normal sperm morphology value as proposed in the fifth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen," Asian journal of andrology, vol. 12, p. 47, 2010.
https://doi.org/10.1038/aja.2009.14
[15] C. J. Cortes and A. R. L. Spada, "X-linked spinal and bulbar muscular atrophy: from clinical genetic features and molecular pathology to mechanisms underlying disease toxicity," Polyglutamine Disorders, pp. 103-133, 2018.
https://doi.org/10.1007/978-3-319-71779-1_5
[16] F. Xiao, A. Lan, Z. Lin, J. Song, Y. Zhang, J. Li, et al., "Impact of CAG repeat length in the androgen receptor gene on male infertility-a meta-analysis," Reproductive biomedicine online, vol. 33, pp. 39-49, 2016.
https://doi.org/10.1016/j.rbmo.2016.03.012
[17] N. Mobasseri, F. Babaei, M. Karimian, and H. Nikzad, "Androgen receptor (AR)-CAG trinucleotide repeat length and idiopathic male infertility: A case-control trial and a meta-analysis," EXCLI journal, vol. 17, p.1167, 2018.
[18] T. Mostafa, L. El?Shahid, A. El Azeem, O. Shaker, H. Gomaa, and H. Abd El Hamid, "Androgen receptor?CAG repeats in infertile Egyptian men," Andrologia, vol. 44, pp. 147-151, 2012.
https://doi.org/10.1111/j.1439-0272.2010.01125.x
[19] Y. Mosaad, D. Shahin, A. A. M. Elkholy, A. Mosbah, and W. Badawy, "CAG repeat length in androgen receptor gene and male infertility in Egyptian patients," Andrologia, vol. 44, pp. 26-33, 2012.
https://doi.org/10.1111/j.1439-0272.2010.01100.x
[20] M. S. Al Zoubi, H. Bataineh, M. Rashed, B. Al?Trad, A. A. Aljabali, R. M. Al?Zoubi, et al., "CAG repeats in the androgen receptor gene is associated with oligozoospermia and teratozoospermia in infertile men in Jordan," Andrologia, vol. 52, p. e13728, 2020.
https://doi.org/10.1111/and.13728
[21] D. Milatiner, D. Halle, M. Huerta, E. J. Margalioth, Y. Cohen, A. Ben?Chetrit, et al., "Associations between androgen receptor CAG repeat length and sperm morphology," Human Reproduction, vol. 19, pp. 1426- 1430, 2004.
https://doi.org/10.1093/humrep/deh251
[22] H. Wallerand, A. Rémy-Martin, E. Chabannes, L. Bermont, G.-L. Adessi, and H. Bittard, "Relationship between expansion of the CAG repeat in exon 1 of the androgen receptor gene and idiopathic male infertility," Fertility and sterility, vol. 76, pp. 769-774, 2001.
https://doi.org/10.1016/S0015-0282(01)01987-2
[23] S. R. Khatami, H. Galehdari, A. Rasekh, H. Mombeini, and E. Konar, "Assessment of correlation between androgen receptor CAG repeat length and infertility in infertile men living in khuzestan, Iran," International Journal of Fertility & Sterility, vol. 9, p. 189, 2015.
[24] C. P. Ryan, T. W. McDade, L. T. Gettler, D. T. Eisenberg, M. Rzhetskaya, M. G. Hayes, et al., "Androgen receptor CAG repeat polymorphism and hypothalamic?pituitary?gonadal function in Filipino young adult males," American Journal of Human Biology, vol. 29, p. e22897, 2017.
https://doi.org/10.1002/ajhb.22897
[25] Y.-M. Ma, K.-J. Wu, L. Ning, J. Zeng, B. Kou, H.-J. Xie, et al., "Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China: a cross-sectional study," Asian Journal of Andrology, vol. 16, p. 478, 2014.
https://doi.org/10.4103/1008-682X.124560
[26] M. Grigorova, M. Punab, T. Kahre, M. Ivandi, N. Tõnisson, O. Poolamets, 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, vol. 5, pp. 495-504, 2017.
https://doi.org/10.1111/andr.12344
https://doi.org/10.1155/2012/384520
[2] M. Vander Borght and C. Wyns, "Fertility and infertility: Definition and epidemiology," Clinical biochemistry, vol. 62, pp. 2-10, 2018.
https://doi.org/10.1016/j.clinbiochem.2018.03.012
[3] M. C. Inhorn and P. Patrizio, "Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century," Human reproduction update, vol. 21, pp. 411-426,2015.
https://doi.org/10.1093/humupd/dmv016
[4] R. J. Hart, "Physiological aspects of female fertility: role of the environment, modern lifestyle, and genetics," Physiological reviews, vol. 96, pp. 873-909, 2016.
https://doi.org/10.1152/physrev.00023.2015
[5] A. Agarwal and D. A. Kumar, "Viscoelastic Assisted Bubble Formation in Pre Descemet's Endothelial Keratoplasty (PDEK)," The Official Scientific Journal of Delhi Ophthalmological Society, vol. 26, pp. 37-39, 2015.
https://doi.org/10.7869/djo.133
[6] K.-W. Shih, P.-Y. Shen, C.-C. Wu, and Y.-N. Kang, "Testicular versus percutaneous epididymal sperm aspiration for patients with obstructive azoospermia: a systematic review and meta-analysis," Translational andrology and urology, vol. 8, p. 631, 2019.
https://doi.org/10.21037/tau.2019.11.20
[7] R. Zhou, J. Wu, B. Liu, Y. Jiang, W. Chen, J. Li, et al., "The roles and mechanisms of Leydig cells and myoid cells in regulating spermatogenesis," Cellular and molecular life sciences, vol. 76, pp. 2681-2695, 2019.
https://doi.org/10.1007/s00018-019-03101-9
[8] M. C. Louie and M. B. Sevigny, "Steroid hormone receptors as prognostic markers in breast cancer," American journal of cancer research, vol. 7, p. 1617, 2017.
[9] B. Pan, R. Li, Y. Chen, Q. Tang, W. Wu, L. Chen, et al., "Genetic association between androgen receptor gene CAG repeat length polymorphism and male infertility: a meta-analysis," Medicine, vol. 95, 2016.
https://doi.org/10.1097/MD.0000000000002878
[10] K. Bogefors, Y. L. Giwercman, J. Eberhard, O. Stahl, E. Cavallin-Stahl, G. Cohn-Cedermark, et al., "Androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment," Asian Journal of Andrology, vol. 19, p. 538, 2017.
https://doi.org/10.4103/1008-682X.191126
[11] S. Sharestani, S. M. Kalantar, N. Ghasemi, and E. F. Yazd, "CAG repeat polymorphism in androgen receptor and infertility: A case-control study," International Journal of Reproductive BioMedicine, vol. 19, p. 845, 2021.
https://doi.org/10.18502/ijrm.v19i9.9717
[12] G. Tirabassi, A. Cignarelli, S. Perrini, G. Furlani, M. Gallo, F. Pallotti, et al., "Influence of CAG repeat polymorphism on the targets of testosterone action," International journal of endocrinology, vol. 2015, 2015.
https://doi.org/10.1155/2015/298107
[13] N. Delli Muti, A. Agarwal, E. Buldreghini, A. Gioia, A. Lenzi, M. Boscaro, et al., "Have androgen receptor gene CAG and GGC repeat polymorphisms an effect on sperm motility in infertile men?," Andrologia, vol. 46, pp. 564-569, 2014.
https://doi.org/10.1111/and.12119
[14] R. Menkveld, "Clinical significance of the low normal sperm morphology value as proposed in the fifth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen," Asian journal of andrology, vol. 12, p. 47, 2010.
https://doi.org/10.1038/aja.2009.14
[15] C. J. Cortes and A. R. L. Spada, "X-linked spinal and bulbar muscular atrophy: from clinical genetic features and molecular pathology to mechanisms underlying disease toxicity," Polyglutamine Disorders, pp. 103-133, 2018.
https://doi.org/10.1007/978-3-319-71779-1_5
[16] F. Xiao, A. Lan, Z. Lin, J. Song, Y. Zhang, J. Li, et al., "Impact of CAG repeat length in the androgen receptor gene on male infertility-a meta-analysis," Reproductive biomedicine online, vol. 33, pp. 39-49, 2016.
https://doi.org/10.1016/j.rbmo.2016.03.012
[17] N. Mobasseri, F. Babaei, M. Karimian, and H. Nikzad, "Androgen receptor (AR)-CAG trinucleotide repeat length and idiopathic male infertility: A case-control trial and a meta-analysis," EXCLI journal, vol. 17, p.1167, 2018.
[18] T. Mostafa, L. El?Shahid, A. El Azeem, O. Shaker, H. Gomaa, and H. Abd El Hamid, "Androgen receptor?CAG repeats in infertile Egyptian men," Andrologia, vol. 44, pp. 147-151, 2012.
https://doi.org/10.1111/j.1439-0272.2010.01125.x
[19] Y. Mosaad, D. Shahin, A. A. M. Elkholy, A. Mosbah, and W. Badawy, "CAG repeat length in androgen receptor gene and male infertility in Egyptian patients," Andrologia, vol. 44, pp. 26-33, 2012.
https://doi.org/10.1111/j.1439-0272.2010.01100.x
[20] M. S. Al Zoubi, H. Bataineh, M. Rashed, B. Al?Trad, A. A. Aljabali, R. M. Al?Zoubi, et al., "CAG repeats in the androgen receptor gene is associated with oligozoospermia and teratozoospermia in infertile men in Jordan," Andrologia, vol. 52, p. e13728, 2020.
https://doi.org/10.1111/and.13728
[21] D. Milatiner, D. Halle, M. Huerta, E. J. Margalioth, Y. Cohen, A. Ben?Chetrit, et al., "Associations between androgen receptor CAG repeat length and sperm morphology," Human Reproduction, vol. 19, pp. 1426- 1430, 2004.
https://doi.org/10.1093/humrep/deh251
[22] H. Wallerand, A. Rémy-Martin, E. Chabannes, L. Bermont, G.-L. Adessi, and H. Bittard, "Relationship between expansion of the CAG repeat in exon 1 of the androgen receptor gene and idiopathic male infertility," Fertility and sterility, vol. 76, pp. 769-774, 2001.
https://doi.org/10.1016/S0015-0282(01)01987-2
[23] S. R. Khatami, H. Galehdari, A. Rasekh, H. Mombeini, and E. Konar, "Assessment of correlation between androgen receptor CAG repeat length and infertility in infertile men living in khuzestan, Iran," International Journal of Fertility & Sterility, vol. 9, p. 189, 2015.
[24] C. P. Ryan, T. W. McDade, L. T. Gettler, D. T. Eisenberg, M. Rzhetskaya, M. G. Hayes, et al., "Androgen receptor CAG repeat polymorphism and hypothalamic?pituitary?gonadal function in Filipino young adult males," American Journal of Human Biology, vol. 29, p. e22897, 2017.
https://doi.org/10.1002/ajhb.22897
[25] Y.-M. Ma, K.-J. Wu, L. Ning, J. Zeng, B. Kou, H.-J. Xie, et al., "Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China: a cross-sectional study," Asian Journal of Andrology, vol. 16, p. 478, 2014.
https://doi.org/10.4103/1008-682X.124560
[26] M. Grigorova, M. Punab, T. Kahre, M. Ivandi, N. Tõnisson, O. Poolamets, 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, vol. 5, pp. 495-504, 2017.
https://doi.org/10.1111/andr.12344
Downloads
How to Cite
[1]
D. A. Salih and K. J. Karim, “CAG Expansion in Androgen Receptor Gene of Infertile Men in Erbil Governorate”, KJAR, vol. 7, no. 2, pp. 107–114, Jan. 2023, doi: 10.24017/Science.2022.2.9.
Article Metrics
Published
09-01-2023
Issue
Section
Pure and Applied Science
License
Copyright (c) 2023 Dashne Abdulla Salih, Karim Jalal Karim
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
