Skip to main content

Advertisement

SpringerLink
Log in

The role of androgen receptor CAG repeat polymorphism in androgen excess disorder and idiopathic hirsutism

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

The study aimed to investigate whether repeat number in the androgen receptor (AR) gene has any contribution to phenotypes of the disease of androgen excess (polycystic ovary syndrome (PCOS), idiopathic hyperandrogenemia (IHA) and idiopathic hirsutism (IH) in a cohort of Turkish women.

Methods

Three hundred and fifty-four voluntary premenopausal women (172 healthy controls and 182 patients with androgen excess disorders and idiopathic hirsutism) 18–45 years of age seen at an outpatient endocrine clinic at Erciyes University Hospital between January 2013 and December 2014 were included. All volunteers have undergone physical examination and biochemical evaluation. The polymorphic (CAG)n repeat of the human AR was determined by fragment analyses.

Results

Detailed clinical analyses of the patients ended up with 137 PCOS, 24 IHA, and 21 IH. Pairwise comparisons revealed the CAG repeat number differences between the PCOS and controls (p = 0.005) and IH and controls (p = 0.020). Women with CAG repeat length ≤ 17 had a significantly increased twofold risk for PCOS than those women with > 17 CAG repeats OR: 2.0 (95% CI 1.2–3.3, p = 0.005). Women with CAG repeat length ≤ 17 had a significantly increased threefold risk for IH than those women with > 17 CAG repeats OR: 2.9 (95% CI 1.2–7.3, p = 0.020). When correlation analysis was performed, a weak negative correlation was detected between the short allele and FGS score (r = − 0.131, p = 0.013) and a positive relationship between total testosterone and longer allele in the IHA group (r = 0.425, p = 0.039). Median repeat length of the shorter allele between oligomenorrhea and woman with normal menstrual cycle was found to be statistically significant (p = 0.017).

Conclusion

This study indicated that the risk of PCOS and IH is associated with the inheritance of ARs with shorter CAG repeats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF (2009) The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 91 (2):456–488. https://doi.org/10.1016/j.fertnstert.2008.06.035

    Article  PubMed  Google Scholar 

  2. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R (2011) Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 7 (4):219–231. https://doi.org/10.1038/nrendo.2010.217

    Article  CAS  PubMed  Google Scholar 

  3. Barber TM, Franks S (2013) Genetics of polycystic ovary syndrome. Polycyst Ovary Syndr Novel Insight Causes Ther 40:28–39

    CAS  Google Scholar 

  4. Panda PK, Rane R, Ravichandran R, Singh S, Panchal H (2016) Genetics of PCOS: a systematic bioinformatics approach to unveil the proteins responsible for PCOS. Genom Data 8:52–60. https://doi.org/10.1016/j.gdata.2016.03.008

    Article  PubMed  PubMed Central  Google Scholar 

  5. Azziz R, Carmina E, Sawaya ME (2000) Idiopathic hirsutism 1. Endocr Rev 21 (4):347–362

    CAS  PubMed  Google Scholar 

  6. Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C (1997) Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist? Metabolism 46 (8):902–907

    CAS  PubMed  Google Scholar 

  7. Escobar-Morreale H, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, Pugeat M, Qiao J, Wijeyaratne C, Witchel S (2012) Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 18 (2):146–170

    CAS  PubMed  Google Scholar 

  8. Unluhizarci K, Gokce C, Atmaca H, Bayram F, Kelestimur F (2004) A detailed investigation of hirsutism in a Turkish population: idiopathic hyperandrogenemia as a perplexing issue. Exp Clin Endocrinol Diabetes 112 (9):504–509. https://doi.org/10.1055/s-2004-821307

    Article  CAS  PubMed  Google Scholar 

  9. Carmina E (2006) The spectrum of androgen excess disorders. Fertil Steril 85 (6):1582–1585. https://doi.org/10.1016/j.fertnstert.2006.02.069

    Article  CAS  PubMed  Google Scholar 

  10. Brown CJ, Goss SJ, Lubahn DB, Joseph DR, Wilson EM, French FS, Willard HF (1989) Androgen receptor locus on the human X-chromosome—regional localization to Xq11-12 and description of a DNA polymorphism. Am J Hum Genet 44 (2):264–269

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Carson-Jurica MA, Schrader WT, O'Malley BW (1990) Steroid receptor family: structure and functions. Endocr Rev 11 (2):201–220. https://doi.org/10.1210/edrv-11-2-201

    Article  CAS  PubMed  Google Scholar 

  12. Chamberlain NL, Driver ED, Miesfeld RL (1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22 (15):3181–3186

    CAS  PubMed  PubMed Central  Google Scholar 

  13. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352 (6330):77–79. https://doi.org/10.1038/352077a0

    Article  PubMed  Google Scholar 

  14. Zhang T, Liang W, Fang M, Yu J, Ni Y, Li Z (2013) Association of the CAG repeat polymorphisms in androgen receptor gene with polycystic ovary syndrome: a systemic review and meta-analysis. Gene 524 (2):161–167. https://doi.org/10.1016/j.gene.2013.04.040

    Article  CAS  PubMed  Google Scholar 

  15. Schuring AN, Welp A, Gromoll J, Zitzmann M, Sonntag B, Nieschlag E, Greb RR, Kiesel L (2012) Role of the CAG repeat polymorphism of the androgen receptor gene in polycystic ovary syndrome (PCOS). Exp Clin Endocrinol Diabetes 120 (2):73–79. https://doi.org/10.1055/s-0031-1291343

    Article  CAS  PubMed  Google Scholar 

  16. Calvo RM, Asuncion M, Sancho J, San Millan JL, Escobar-Morreale HF (2000) The role of the CAG repeat polymorphism in the androgen receptor gene and of skewed X-chromosome inactivation, in the pathogenesis of hirsutism. J Clin Endocrinol Metab 85 (4):1735–1740. https://doi.org/10.1210/jcem.85.4.6561

    Article  CAS  PubMed  Google Scholar 

  17. Wang R, Goodarzi MO, Xiong T, Wang D, Azziz R, Zhang H (2012) Negative association between androgen receptor gene CAG repeat polymorphism and polycystic ovary syndrome? A systematic review and meta-analysis. Mol Hum Reprod 18 (10):498–509. https://doi.org/10.1093/molehr/gas024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Legro RS, Shahbahrami B, Lobo RA, Kovacs BW (1994) Size polymorphisms of the androgen receptor among female Hispanics and correlation with androgenic characteristics. Obstet Gynecol 83 (5 Pt 1):701–706

    CAS  PubMed  Google Scholar 

  19. Skrgatic L, Baldani DP, Cerne JZ, Ferk P, Gersak K (2012) CAG repeat polymorphism in androgen receptor gene is not directly associated with polycystic ovary syndrome but influences serum testosterone levels. J Steroid Biochem Mol Biol 128 (3–5):107–112. https://doi.org/10.1016/j.jsbmb.2011.11.006

    Article  CAS  PubMed  Google Scholar 

  20. Ferriman D, Gallwey J (1961) Clinical assessment of body hair growth in women. J Clin Endocrinol Metabol 21 (11):1440–1447

    CAS  Google Scholar 

  21. Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E, American Association of Clinical E, American College of E, Androgen E, Society P (2015) American Association of Clinical Endocrinologists, American College of Endocrinology, and androgen excess and Pcos Society Disease State Clinical Review: Guide to the Best Practices in the Evaluation and Treatment of Polycystic Ovary Syndrome-Part 1. Endocr Pract 21 (11):1291–1300. https://doi.org/10.4158/EP15748.DSC

    Article  Google Scholar 

  22. Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E, American Association of Clinical E, American College of E, Androgen E, Society P (2015) American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and Pcos Society Disease State Clinical Review: Guide to the Best Practices in the Evaluation and Treatment of Polycystic Ovary Syndrome—Part 2. Endocr Pract 21 (12):1415–1426. https://doi.org/10.4158/EP15748.DSCPT2

    Article  Google Scholar 

  23. Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C (1997) Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist? Metab Clin Exp 46 (8):902–907

    CAS  PubMed  Google Scholar 

  24. Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, Monauni T, Muggeo M (2000) Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 23 (1):57–63

    CAS  PubMed  Google Scholar 

  25. Naiki Y, Kawamoto T, Mitsuuchi Y, Miyahara K, Toda K, Orii T, Imura H, Shizuta Y (1993) A nonsense mutation (TGG [Trp116]–%3eTAG [Stop]) in CYP11B1 causes steroid 11 beta-hydroxylase deficiency. J Clin Endocrinol Metabol 77 (6):1677–1682. https://doi.org/10.1210/jcem.77.6.7903314

    Article  CAS  Google Scholar 

  26. Wedell A, Thilen A, Ritzen EM, Stengler B, Luthman H (1994) Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metabol 78 (5):1145–1152. https://doi.org/10.1210/jcem.78.5.8175971

    Article  CAS  Google Scholar 

  27. Chang YT, Kappy MS, Iwamoto K, Wang J, Yang X, Pang S (1993) Mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene in a patient with classic salt-wasting 3 beta-hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia. Pediatr Res 34 (5):698–700. https://doi.org/10.1203/00006450-199311000-00026

    Article  CAS  PubMed  Google Scholar 

  28. Araujo RS, Mendonca BB, Barbosa AS, Lin CJ, Marcondes JA, Billerbeck AE, Bachega TA (2007) Microconversion between CYP21A2 and CYP21A1P promoter regions causes the nonclassical form of 21-hydroxylase deficiency. J Clin Endocrinol Metabol 92 (10):4028–4034. https://doi.org/10.1210/jc.2006-2163

    Article  CAS  Google Scholar 

  29. Bharaj BS, Vassilikos EJ, Diamandis EP (1999) Rapid and accurate determination of (CAG)n repeats in the androgen receptor gene using polymerase chain reaction and automated fragment analysis. Clin Biochem 32 (5):327–332

    CAS  PubMed  Google Scholar 

  30. Shah NA, Antoine HJ, Pall M, Taylor KD, Azziz R, Goodarzi MO (2008) Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome. J Clin Endocrinol Metabol 93 (5):1939–1945. https://doi.org/10.1210/jc.2008-0038

    Article  CAS  Google Scholar 

  31. Ferk P, Perme MP, Teran N, Gersak K (2008) Androgen receptor gene (CAG)n polymorphism in patients with polycystic ovary syndrome. Fertil Steril 90 (3):860–863. https://doi.org/10.1016/j.fertnstert.2007.07.1291

    Article  CAS  PubMed  Google Scholar 

  32. Laisk T, Haller-Kikkatalo K, Laanpere M, Jakovlev U, Peters M, Karro H, Salumets A (2010) Androgen receptor epigenetic variations influence early follicular phase gonadotropin levels. Acta Obstet Gynecol Scand 89 (12):1557–1563. https://doi.org/10.3109/00016349.2010.526182

    Article  CAS  PubMed  Google Scholar 

  33. Xita N, Georgiou I, Lazaros L, Psofaki V, Kolios G, Tsatsoulis A (2008) The role of sex hormone-binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome. Hum Reprod 23 (3):693–698. https://doi.org/10.1093/humrep/dem382

    Article  CAS  PubMed  Google Scholar 

  34. Xia Y, Che Y, Zhang X, Zhang C, Cao Y, Wang W, Xu P, Wu X, Yi L, Gao Q, Wang Y (2012) Polymorphic CAG repeat in the androgen receptor gene in polycystic ovary syndrome patients. Mol Med Rep 5 (5):1330–1334. https://doi.org/10.3892/mmr.2012.789

    Article  CAS  PubMed  Google Scholar 

  35. Ibanez L, Ong KK, Mongan N, Jaaskelainen J, Marcos MV, Hughes IA, De Zegher F, Dunger DB (2003) Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism. J Clin Endocrinol Metabol 88 (7):3333–3338. https://doi.org/10.1210/jc.2002-021791

    Article  CAS  Google Scholar 

  36. Hickey T, Chandy A, Norman RJ (2002) The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J Clin Endocrinol Metabol 87 (1):161–165. https://doi.org/10.1210/jcem.87.1.8137

    Article  CAS  Google Scholar 

  37. Rajender S, Carlus SJ, Bansal SK, Negi MP, Sadasivam N, Sadasivam MN, Thangaraj K (2013) Androgen receptor CAG repeats length polymorphism and the risk of polycystic ovarian syndrome (PCOS). PLoS ONE 8 (10):e75709. https://doi.org/10.1371/journal.pone.0075709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim JJ, Choung SH, Choi YM, Yoon SH, Kim SH, Moon SY (2008) Androgen receptor gene CAG repeat polymorphism in women with polycystic ovary syndrome. Fertil Steril 90 (6):2318–2323. https://doi.org/10.1016/j.fertnstert.2007.10.030

    Article  CAS  PubMed  Google Scholar 

  39. Liu Q, Hong J, Cui B, Zhang Y, Gu W, Chi Z, Su Y, Ning G (2008) Androgen receptor gene CAG (n) trinucleotide repeats polymorphism in Chinese women with polycystic ovary syndrome. Endocrine 33 (2):165–170. https://doi.org/10.1007/s12020-008-9069-7

    Article  CAS  PubMed  Google Scholar 

  40. Dasgupta S, Sirisha PV, Neelaveni K, Anuradha K, Reddy AG, Thangaraj K, Reddy BM (2010) Androgen receptor CAG repeat polymorphism and epigenetic influence among the south Indian women with polycystic ovary syndrome. PLoS ONE 5 (8):e12401. https://doi.org/10.1371/journal.pone.0012401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jaaskelainen J, Korhonen S, Voutilainen R, Hippelainen M, Heinonen S (2005) Androgen receptor gene CAG length polymorphism in women with polycystic ovary syndrome. Fertil Steril 83 (6):1724–1728. https://doi.org/10.1016/j.fertnstert.2004.11.080

    Article  CAS  PubMed  Google Scholar 

  42. Nenonen H, Bjork C, Skjaerpe PA, Giwercman A, Rylander L, Svartberg J, Giwercman YL (2010) CAG repeat number is not inversely associated with androgen receptor activity in vitro. Mol Hum Reprod 16 (3):153–157. https://doi.org/10.1093/molehr/gap097

    Article  CAS  PubMed  Google Scholar 

  43. Sawaya ME, Shalita AR (1998) Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg 3 (1):9–15. https://doi.org/10.1177/120347549800300103

    Article  CAS  PubMed  Google Scholar 

  44. Weintrob N, Eyal O, Slakman M, Becker AS, Israeli G, Kalter-Leibovici O, Ben-Shachar S (2018) The effect of CAG repeats length on differences in hirsutism among healthy Israeli women of different ethnicities. PLoS ONE. https://doi.org/10.1371/journal.pone.0195046

    Article  PubMed  PubMed Central  Google Scholar 

  45. Brum IS, Spritzer PM, Paris F, Maturana MA, Audran F, Sultan C (2005) Association between androgen receptor gene CAG repeat polymorphism and plasma testosterone levels in postmenopausal women. J Soc Gynecol Invest 12 (2):135–141. https://doi.org/10.1016/j.jsgi.2004.11.003

    Article  CAS  Google Scholar 

  46. Mifsud A, Ramirez S, Yong EL (2000) Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metabol 85 (9):3484–3488. https://doi.org/10.1210/jcem.85.9.6832

    Article  CAS  Google Scholar 

  47. Yamazaki M, Sato A, Toyoshima KE, Kojima Y, Okada T, Ishii Y, Kurata S, Yoshizato K, Tsuboi R (2011) Polymorphic CAG repeat numbers in the androgen receptor gene of female pattern hair loss patients. J Dermatol 38 (7):680–684. https://doi.org/10.1111/j.1346-8138.2010.01060.x

    Article  PubMed  Google Scholar 

  48. Tong D, Deng J, Sun H, Chen L, Wu X (2010) The relationship between CAG repeat length polymorphism and infertility in Southern Chinese Han women. J Endocrinol Invest 33 (8):559–563. https://doi.org/10.1007/BF03346648

    Article  CAS  PubMed  Google Scholar 

  49. Wang Q, Udayakumar TS, Vasaitis TS, Brodie AM, Fondell JD (2004) Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells. J Biol Chem 279 (17):17319–17328. https://doi.org/10.1074/jbc.M400970200

    Article  CAS  PubMed  Google Scholar 

  50. Lyon MF (1972) X-chromosome inactivation and developmental patterns in mammals. Biol Rev Camb Philos Soc 47 (1):1–35

    CAS  PubMed  Google Scholar 

  51. Sharp A, Robinson D, Jacobs P (2000) Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 107 (4):343–349. https://doi.org/10.1007/s004390000382

    Article  CAS  PubMed  Google Scholar 

  52. Liu PY, Death AK, Handelsman DJ (2003) Androgens and cardiovascular disease. Endocr Rev 24 (3):313–340. https://doi.org/10.1210/er.2003-0005

    Article  CAS  PubMed  Google Scholar 

  53. Rytinki MM, Kaikkonen S, Sutinen P, Palvimo JJ (2011) Analysis of androgen receptor SUMOylation. Methods Mol Biol 776:183–197. https://doi.org/10.1007/978-1-61779-243-4_12

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Scientific Research Projects Coordination Unit of Erciyes University. Grand Number: TDK-2014–5099.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Medical Faculty, Erzincan University, Basbaglar Mah, 24100, Erzincan, Merkez, Turkey

    S. Polat

  2. Department of Endocrinology, Medical Faculty, Erciyes University, Kayseri, Turkey

    S. Karaburgu, K. Unluhizarci, Z. Karaca & F. Kelestimur

  3. Department of Medical Genetics, Medical Faculty, Erciyes University, Kayseri, Turkey

    M. Dündar & Y. Özkul

  4. Department of Biostatistics, Medical Faculty, Erzincan University, Erzincan, Turkey

    Y. K. Arslan

  5. Department of Endocrinology, Medical Faculty, Yeditepe University, İstanbul, Turkey

    F. Kelestimur

Authors
  1. S. Polat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Karaburgu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Unluhizarci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Dündar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. Özkul
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. K. Arslan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z. Karaca
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Kelestimur
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Polat.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest relevant to the subject matter or materials included in this work.

Ethical approval

The study was approved by the Ethics Committee of Medical School at Erciyes University. All procedures performed in studies involving human participants and/or animals were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Polat, S., Karaburgu, S., Unluhizarci, K. et al. The role of androgen receptor CAG repeat polymorphism in androgen excess disorder and idiopathic hirsutism. J Endocrinol Invest 43, 1271–1281 (2020). https://doi.org/10.1007/s40618-020-01215-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-020-01215-7

Keywords

Search

Navigation