Advertisement

Journal of Endocrinological Investigation

, Volume 42, Issue 9, pp 1077–1087 | Cite as

Comprehensive genotyping of Turkish women with hirsutism

  • S. PolatEmail author
  • S. Karaburgu
  • K. Ünlühizarcı
  • M. Dündar
  • Y. Özkul
  • Y. K. Arslan
  • Z. Karaca
  • F. Kelestimur
Original Article
  • 125 Downloads

Abstract

Introduction

Hirsutism is a medical sign rather than a disease affects 5–8% of women of reproductive age. Hirsutism is associated with hyperandrogenemia in most patients excluding those with idiopathic hirsutism (IH). The most common cause of hirsutism is polycystic ovary syndrome (PCOS) followed by IH and idiopathic hyperandrogenemia (IHA); however, the clinical presentation of non-classical congenital adrenal hyperplasia (NCAH) in females is often indistinguishable from other hyperandrogenic disorders with common clinical signs such as hirsutism.

Objective

The primary aim of the study is to examine the physical properties of the three genes and to make a detailed comparison of the mutations with the clinical data to contribute the etiology of hirsutism.

Subjects and Methods

122 women admitted to the Endocrinology Clinic at Erciyes University Hospital with hirsutism were enrolled in the study between 2013-2014. All the participants were clinically evaluated. Protein-encoding exons, exon-intron boundaries of CYP21A2 (including proximal promoter), CYP11B1 and HSD3B2 genes were analyzed via state-of-the-art genetic studies.

Results

DNA sequencing analyses revealed two homozygous and three compound heterozygous 21-hydroxylase deficient (21OHD) NCAH patients. Additionally, three novel CYP21A2 mutations (A89V, M187I and G491S) and two novel CYP11B1 mutations (V188I and G87A) were determined. The frequencies of heterozygous mutations in CYP21A2 (including promoter), CYP11B1 and HSD3B2 genes were determined as 26.5% (15% coding region, 11.5% promoter), 11.5% and 0%, respectively.

Conclusion

21OHD-NCAH prevalence was determined to be ~4%. Unexpectedly, high heterozygous mutation rates were observed in CYP11B1 gene and CYP21A2 promoter region. CYP11B1 and HSD3B2 deficiencies were not prevalent in Turkish women with hirsutism despite the existence of higher heterozygous mutation rate in CYP11B1.

Keywords

PCOS NCAH CYP21A2 CYP11B1 HSD3B2 

Notes

Acknowledgements

We hereby wish to acknowledge biologist Mustafa Akkuş, nurse Nilgün Yıldırım, and graphic designer Şerife Ünel.

Funding

This work was supported by the Scientific Research Projects Coordination Unit of Erciyes University. Grant number: TCD-2014-5098.

Compliance with ethical standards

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 performed according to the Declaration of Helsinki and approval was obtained from the Ethics Committee of the Medical School at Erciyes University.

Informed consent

Informed consent was obtained from all volunteers.

References

  1. 1.
    Azziz R, Sanchez LA, Knochenhauer ES, Moran C, Lazenby J, Stephens KC, Taylor K, Boots LR (2004) Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab 89(2):453–462Google Scholar
  2. 2.
    Rosenfield RL (2005) Clinical practice. Hirsutism. N Engl J Med 353(24):2578–2588Google Scholar
  3. 3.
    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):504–509Google Scholar
  4. 4.
    Pasquali R, Gambineri A (2018) New perspectives on the definition and management of polycystic ovary syndrome. J Endocrinol Investig 41(10):1123–1135Google Scholar
  5. 5.
    Atmaca H, Tanriverdi F, Unluhizarci K, Bayram F, Kelestimur F (2006) Investigation of adrenal functions in patients with idiopathic hyperandrogenemia. Eur J Endocrinol Eur Fed Endocr Soc 155(2):307–311Google Scholar
  6. 6.
    Caglayan AO, Dundar M, Tanriverdi F, Baysal NA, Unluhizarci K, Ozkul Y, Borlu M, Batukan C, Kelestimur F (2011) Idiopathic hirsutism: local and peripheral expression of aromatase (CYP19A) and 5alpha-reductase genes (SRD5A1 and SRD5A2). Fertil Steril 96(2):479–482Google Scholar
  7. 7.
    Rouiller DG (2005) Hirsutism. Rev Med Suisse 1(6):420–424Google Scholar
  8. 8.
    Moore A, Magee F, Cunningham S, Culliton M, McKenna TJ (1983) Adrenal abnormalities in idiopathic hirsutism. Clin Endocrinol (Oxf) 18(4):391–399Google Scholar
  9. 9.
    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):902–907Google Scholar
  10. 10.
    Pall M, Azziz R, Beires J, Pignatelli D (2010) The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril 94(2):684–689Google Scholar
  11. 11.
    Unluhizarci K, Karababa Y, Bayram F, Kelestimur F (2004) The investigation of insulin resistance in patients with idiopathic hirsutism. J Clin Endocrinol Metab 89(6):2741–2744Google Scholar
  12. 12.
    Speiser PW, White PC (2003) Congenital adrenal hyperplasia. N Engl J Med 349(8):776–788Google Scholar
  13. 13.
    New MI (2001) Prenatal treatment of congenital adrenal hyperplasia: the United States experience. Endocrinol Metab Clin N Am 30(1):1–13Google Scholar
  14. 14.
    Kelestimur F (2006) Non-classic congenital adrenal hyperplasia. Pediatr Endocrinol Rev 3:451–454Google Scholar
  15. 15.
    Kamel N, Tonyukuk V, Emral R, Corapcioglu D, Bastemir M, Gullu S (2003) The prevalence of late onset congenital adrenal hyperplasia in hirsute women from Central Anatolia. Endocr J 50(6):815–823Google Scholar
  16. 16.
    Romaguera J, Moran C, Diaz-Montes TP, Hines GA, Cruz RI, Azziz R (2000) Prevalence of 21-hydroxylase-deficient nonclassic adrenal hyperplasia and insulin resistance among hirsute women from Puerto Rico. Fertil Steril 74(1):59–62Google Scholar
  17. 17.
    Unluhizarci K, Kula M, Dundar M, Tanriverdi F, Israel S, Colak R, Dokmetas HS, Atmaca H, Bahceci M, Balci MK et al (2010) The prevalence of non-classic adrenal hyperplasia among Turkish women with hyperandrogenism. Gynecol Endocrinol 26(2):139–143Google Scholar
  18. 18.
    Fanta M, Cibula D, Vrbikova J (2008) Prevalence of nonclassic adrenal hyperplasia (NCAH) in hyperandrogenic women. Gynecol Endocrinol 24(3):154–157Google Scholar
  19. 19.
    Escobar-Morreale HF, Sanchon R, San Millan JL (2008) A prospective study of the prevalence of nonclassical congenital adrenal hyperplasia among women presenting with hyperandrogenic symptoms and signs. J Clin Endocrinol Metab 93(2):527–533Google Scholar
  20. 20.
    Hannah-Shmouni F, Morissette R, Sinaii N, Elman M, Prezant TR, Chen W, Pulver A, Merke DP (2017) Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med 19:1276–1279Google Scholar
  21. 21.
    Moran C, Azziz R (2003) 21-Hydroxylase-deficient nonclassic adrenal hyperplasia: the great pretender. Semin Reprod Med. 21(3):295–300Google Scholar
  22. 22.
    Mathieson J, Couzinet B, Wekstein-Noel S, Nahoul K, Turpin G, Schaison G (1992) The incidence of late-onset congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency among hirsute women. Clin Endocrinol (Oxf) 36(4):383–388Google Scholar
  23. 23.
    Kelestimur F, Sahin Y, Ayata D, Tutus A (1996) The prevalence of non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency among hirsute women in a Turkish population. Clin Endocrinol (Oxf) 45(4):381–384Google Scholar
  24. 24.
    Sahin Y, Kelestimur F (1997) The frequency of late-onset 21-hydroxylase and 11 beta-hydroxylase deficiency in women with polycystic ovary syndrome. Eur J Endocrinol Eur Fed Endocr Soc 137(6):670–674Google Scholar
  25. 25.
    Carbunaru G, Prasad P, Scoccia B, Shea P, Hopwood N, Ziai F, Chang YT, Myers SE, Mason JI, Pang S (2004) The hormonal phenotype of nonclassic 3 beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab 89(2):783–794Google Scholar
  26. 26.
    Akinci A, Yordam N, Ersoy F, Ulusahin N, Oguz H (1992) The incidence of non-classical 21-hydroxylase deficiency in hirsute adolescent girls. Gynecol Endocrinol 6(2):99–106Google Scholar
  27. 27.
    Hatch R, Rosenfield RL, Kim MH, Tredway D (1981) Hirsutism: implications, etiology, and management. Am J Obstet Gynecol 140(7):815–830Google Scholar
  28. 28.
    Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ, International PN (2018) Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Clin Endocrinol (Oxf) 89(3):251–268Google Scholar
  29. 29.
    Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE et al (2009) The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 91(2):456–488Google Scholar
  30. 30.
    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):902–907Google Scholar
  31. 31.
    New MI, Lorenzen F, Lerner AJ, Kohn B, Oberfield SE, Pollack MS, Dupont B, Stoner E, Levy DJ, Pang S et al (1983) Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 57(2):320–326Google Scholar
  32. 32.
    Azziz R, Rafi A, Smith BR, Bradley EL Jr, Zacur HA (1990) On the origin of the elevated 17-hydroxyprogesterone levels after adrenal stimulation in hyperandrogenism. J Clin Endocrinol Metab 70(2):431–436Google Scholar
  33. 33.
    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):57–63Google Scholar
  34. 34.
    Naiki Y, Kawamoto T, Mitsuuchi Y, Miyahara K, Toda K, Orii T, Imura H, Shizuta Y (1993) A nonsense mutation (TGG [Trp116]→TAG [Stop]) in CYP11B1 causes steroid 11 beta-hydroxylase deficiency. J Clin Endocrinol Metab 77(6):1677–1682Google Scholar
  35. 35.
    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 Metab 78(5):1145–1152Google Scholar
  36. 36.
    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):698–700Google Scholar
  37. 37.
    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 Metab 92(10):4028–4034Google Scholar
  38. 38.
    Barr M (2006) MRC Blood Pressure Group. Glasgow Cardiovascular Research Centre. University of Glasgow, UK, pp 1–296Google Scholar
  39. 39.
    Dolzan V, Prezelj J, Vidan-Jeras B, Breskvar K (1999) Adrenal 21-hydroxylase gene mutations in Slovenian hyperandrogenic women: evaluation of corticotrophin stimulation and HLA polymorphisms in screening for carrier status. Eur J Endocrinol 141(2):132–139Google Scholar
  40. 40.
    Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI (1985) High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 37(4):650–667Google Scholar
  41. 41.
    Dumic M, Brkljacic L, Speiser PW, Wood E, Crawford C, Plavsic V, Baniceviac M, Radmanovic S, Radica A, Kastelan A et al (1990) An update on the frequency of nonclassic deficiency of adrenal 21-hydroxylase in the Yugoslav population. Acta Endocrinol (Copenh). 122(6):703–710Google Scholar
  42. 42.
    Trakakis E, Rizos D, Loghis C, Chryssikopoulos A, Spyropoulou M, Salamalekis E, Simeonides G, Vagopoulos V, Salamalekis G, Kassanos D (2008) The prevalence of non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Greek women with hirsutism and polycystic ovary syndrome. Endocr J 55(1):33–39Google Scholar
  43. 43.
    Donohoue PA, van Dop C, McLean RH, White PC, Jospe N, Migeon CJ (1986) Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein. J Clin Endocrinol Metab 62(5):995–1002Google Scholar
  44. 44.
    L’Allemand D, Tardy V, Gruters A, Schnabel D, Krude H, Morel Y (2000) How a patient homozygous for a 30-kb deletion of the C4-CYP 21 genomic region can have a nonclassic form of 21-hydroxylase deficiency. J Clin Endocrinol Metab 85(12):4562–4567Google Scholar
  45. 45.
    Binay C, Simsek E, Cilingir O, Yuksel Z, Kutlay O, Artan S (2014) Prevalence of nonclassic congenital adrenal hyperplasia in Turkish children presenting with premature pubarche, hirsutism, or oligomenorrhoea. Int J Endocrinol 2014:768506Google Scholar
  46. 46.
    Solyom J, Halasz Z, Hosszu E, Glaz E, Vihko R, Orava M, Homoki J, Wudy SA, Teller WM (1995) Serum and urinary steroids in girls with precocious pubarche and/or hirsutism due to mild 3-beta-hydroxysteroid dehydrogenase deficiency. Horm Res 44(3):133–141Google Scholar
  47. 47.
    Meer A, Duprey J, Fiet J, Boudou P, Ducornet B, Sultan M, Lifchitz E (1994) Late onset hyperandrogenism caused by 3-beta-hydroxysteroid dehydrogenase deficiency. Presse Med 23(29):1339–1343Google Scholar
  48. 48.
    Sawaya ME, Shalita AR (1998) Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg 3(1):9–15Google Scholar
  49. 49.
    Colak R, Kelestimur F, Unluhizarci K, Bayram F, Sahin Y, Tutus A (2002) A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome. Eur J Endocrinol 147(4):473–477Google Scholar
  50. 50.
    Unluhizarci K, Kelestimur F, Guven M, Bayram F, Colak R (2002) The value of low dose (1 microg) ACTH stimulation test in the investigation of non-classic adrenal hyperplasia due to 11beta-hydroxylase deficiency. Exp Clin Endocrinol Diabetes 110(8):381–385Google Scholar
  51. 51.
    Strott CA, Lipsett MB (1968) Measurement of 17-hydroxyprogesterone in human plasma. J Clin Endocrinol Metab 28(10):1426–1430Google Scholar
  52. 52.
    Barnes ND, Atherden SM (1972) Diagnosis of congenital adrenal hyperplasia by measurement of plasma 17-hydroxyprogesterone. Arch Dis Child 47(251):62–65Google Scholar
  53. 53.
    Kelestimur F, Everest H, Dundar M, Tanriverdi F, White C, Witchel SF (2009) The frequency of CYP 21 gene mutations in Turkish women with hyperandrogenism. Exp Clin Endocrinol Diabetes 117(5):205–208Google Scholar
  54. 54.
    Koppens PF, Hoogenboezem T, Degenhart HJ (2002) Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes. Hum Genet 111(4–5):405–410Google Scholar
  55. 55.
    Kharrat M, Riahi A, Maazoul F, M’Rad R, Chaabouni H (2011) Detection of a frequent duplicated CYP21A2 gene carrying a Q318X mutation in a general population with quantitative PCR methods. Diagn Mol Pathol Am J Surg Pathol Part B 20(2):123–127Google Scholar
  56. 56.
    Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y (2006) Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin Endocrinol (Oxf) 64(6):645–651Google Scholar
  57. 57.
    Alper OM, Erengin H, Manguoglu AE, Bilgen T, Cetin Z, Dedeoglu N, Luleci G (2004) Consanguineous marriages in the province of Antalya, Turkey. Annales de genetique 47(2):129–138Google Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  1. 1.Department of Medical Genetics, Medical FacultyErzincan UniversityErzincanTurkey
  2. 2.Department of Endocrinology, Medical FacultyErciyes UniversityKayseriTurkey
  3. 3.Department of Medical Genetics, Medical FacultyErciyes UniversityKayseriTurkey
  4. 4.Department of Biostatistics, Medical FacultyErzincan UniversityErzincanTurkey
  5. 5.Department of Endocrinology, Medical FacultyYeditepe UniversityIstanbulTurkey

Personalised recommendations