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Horm Metab Res 2013; 45(05): 383-386
DOI: 10.1055/s-0033-1333727
Humans, Clinical
© Georg Thieme Verlag KG Stuttgart · New York

CYP21A2 Mutations in Women with Polycystic Ovary Syndrome (PCOS)

N. Settas
1   First Department of Pediatrics, Unit of Molecular Endocrinology Choremis Research Laboratory, University of Athens, School of Medicine, “Aghia Sophia” Children’s Hospital, Athens, Greece
,
M. Dracopoulou-Vabouli
1   First Department of Pediatrics, Unit of Molecular Endocrinology Choremis Research Laboratory, University of Athens, School of Medicine, “Aghia Sophia” Children’s Hospital, Athens, Greece
,
A. Dastamani
1   First Department of Pediatrics, Unit of Molecular Endocrinology Choremis Research Laboratory, University of Athens, School of Medicine, “Aghia Sophia” Children’s Hospital, Athens, Greece
,
I. Katsikis
2   Second Department of Obstetrics and Gynecology, Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki, Thessaloniki, Greece
,
G. Chrousos
1   First Department of Pediatrics, Unit of Molecular Endocrinology Choremis Research Laboratory, University of Athens, School of Medicine, “Aghia Sophia” Children’s Hospital, Athens, Greece
,
D. Panidis
2   Second Department of Obstetrics and Gynecology, Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki, Thessaloniki, Greece
,
C. Dacou-Voutetakis
1   First Department of Pediatrics, Unit of Molecular Endocrinology Choremis Research Laboratory, University of Athens, School of Medicine, “Aghia Sophia” Children’s Hospital, Athens, Greece
› Author Affiliations
Further Information

Publication History

received 18 May 2012

accepted after second revision 10 January 2013

Publication Date:
05 February 2013 (online)

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Abstract

The question of the contribution of CYP21A2 heterozygosity to the development of polycystic ovary syndrome (PCOS) has repeatedly been raised in the literature. The available data, however, do not offer a satisfactory answer. The discrepancy must be attributed, primarily, to the small number of subjects in the various studies, the type of selected phenotype, and the number of searched mutations. The aim of the study was to define the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS. We searched for 14 molecular defects of the CYP21A2 gene in 197 PCOS women, employing allele specific PCR. Androgen levels were determined at baseline by appropriate methodology in the follicular phase. PCOS women with 17-hydroxyprogesterone (17OHP) basal values >2 ng/ml and/or post-ACTH >10 ng/ml were excluded. Appropriate controls were included. The frequency of the CYP21A2 heterozygous mutations in PCOS women and in controls was 7.6% and 5.9%, respectively [p-value (PCOS vs. controls): 0.663]. Homozygosity for CYP21A2 gene defects was not detected. In conclusion, the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS is not substantiated by our data. Moreover, 17-hydroxyprogesterone values of < 10 ng/ml post-ACTH exclude homozygosity of CYP21A2 mutations.

Key words

CYP21A2 gene - PCOS - hyperandrogenemia - CAH - molecular defects
 

  • References

  • 1 Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC, Spina GG, Zapanti ED, Bartzis MI. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999; 84: 4006-4011
    CrossrefPubMedGoogle Scholar
  • 2 Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004; 89: 2745-2749
    CrossrefPubMedGoogle Scholar
  • 3 The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19-25
    PubMedGoogle Scholar
  • 4 Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome. In: Dunaif A, Givens JR, Haseltin FP, Merriam GE. (eds.) Polycystic ovary syndrome. USA: Blackwell Scientific Boston, Mass; 1992: 377-384
    Google Scholar
  • 5 Diamanti-Kandarakis E, Piperi C, Spina J, Argyrakopoulou G, Papanastasiou L, Bergiele A, Panidis D. Polycystic ovary syndrome: the influence of environmental and genetic factors. Hormones 2006; 5: 17-34
    CrossrefPubMedGoogle Scholar
  • 6 Dunaif A, Segal KR, Futterfeit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity in polycystic ovary syndrome. Diabetes 1989; 38: 1165-1174
    CrossrefPubMedGoogle Scholar
  • 7 Michelmore K, Ong K, Mason S, Bennett S, Perry L, Vessey M, Balen A, Dunger D. Clinical features in women with polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR and birth weight. Clin Endocrinol (Oxf) 2001; 55: 439-446
    CrossrefPubMedGoogle Scholar
  • 8 Jones MR, Wilson SG, Mullin BH, Mead R, Watts GF, Stuckey BG. Polymorphism of the follistatin gene in polycystic ovary syndrome. Mol Hum Reprod 2007; 13: 237-241
    CrossrefPubMedGoogle Scholar
  • 9 Hague WM, Adams J, Rodda C, Brook CG, de Bruyn R, Grant DB, Jacobs HS. The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives. Clin Endocrinol (Oxf) 1990; 33: 501-510
    CrossrefPubMedGoogle Scholar
  • 10 White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21: 245-291
    CrossrefPubMedGoogle Scholar
  • 11 Bidet M, Bellanné-Chantelot C, Galand-Portier MB, Tardy V, Billaud L, Laborde K, Coussieu C, Morel Y, Vaury C, Golmard JL, Claustre A, Mornet E, Chakhtoura Z, Mowszowicz I, Bachelot A, Touraine P, Kuttenn F. Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. J Clin Endocrinol Metab 2009; 94: 1570-1578
    CrossrefPubMedGoogle Scholar
  • 12 Bidet M, Bellanné-Chantelot C, Galand-Portier MB, Golmard JL, Tardy V, Morel Y, Clauin S, Coussieu C, Boudou P, Mowzowicz I, Bachelot A, Touraine P, Kuttenn F. Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Metab 2010; 95: 1182-1190
    CrossrefPubMedGoogle Scholar
  • 13 Pall M, Azziz R, Beires J, Pignatelli D. The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase deficient nonclassic adrenal hyperplasia. Fertil Steril 2010; 94: 684-689
    CrossrefPubMedGoogle Scholar
  • 14 Moran C, Azziz R. 21-hydroxylase-deficient nonclassic adrenal hyperplasia: the great pretender. Semin Reprod Med 2003; 21: 295-300
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Dacou-Voutetakis C, Dracopoulou M. Non-classical congenital adrenal hyperplasia. Pediatr Endocrinol Rev 2006; 1: 195-197
    PubMedGoogle Scholar
  • 16 Bachega TA, Brenlha EM, Billerbeck AE, Marcondes JA, Madureira G, Arnhold IJ, Mendonca BB. Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations. J Clin Endocrinol Metab 2002; 87: 786-790
    CrossrefPubMedGoogle Scholar
  • 17 Witchel SF, Lee PA. Identification of heterozygotic carriers of 21-hydroxylase deficiency: sensitivity of ACTH stimulation tests. Am J Med Genet 1998; 76: 337-342
    CrossrefPubMedGoogle Scholar
  • 18 Dacou-Voutetakis C, Dracopoulou M. High incidence of molecular defects of the CYP21A2 gene in patients with premature adrenarche. J Clin Endocrinol Metab 1999; 84: 1570-1574
    CrossrefPubMedGoogle Scholar
  • 19 Paris F, Tardy V, Chalançon A, Picoy MC, Morel Y, Sultan C. Premature pubarce in Mediterranean girls: high prevalence of heterozygous CYP21 mutation carriers. Gynecol Endocrinol 2010; 26: 319-324
    CrossrefPubMedGoogle Scholar
  • 20 Ibáñez L, Valis C, Potau N, Marcos MV, de Zegher F. Polycystic ovary syndrome after precocious pubarche: ontogeny of the low-birthweight effect. Clin Endocrinol (Oxf) 2001; 55: 667-672
    CrossrefPubMedGoogle Scholar
  • 21 Dracopoulou-Vabouli M, Maniati-Christidi M, Dacou-Voutetakis C. The spectrum of molecular defects of the CYP21 gene in the Hellenic population: variable concordance between genotype and phenotype in the different forms of congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86: 2845-2848
    CrossrefPubMedGoogle Scholar
  • 22 Piouka A, Farmakiotis D, Katsikis I, Macut D, Gerou S, Panidis D. Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels. Am J Physiol Endocrinol Metab 2009; 296: 238-243
    PubMedGoogle Scholar
  • 23 Witchel SF, Kahsar-Miller M, Aston CE, White C, Azziz R. Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess. Fertil Steril 2005; 83: 371-375
    CrossrefPubMedGoogle Scholar
  • 24 Witchel SF, Lee PA, Suda-Hartman M, Hoffman EP. Hyperandrogenism and manifesting heterozygotes for 21-hydroxylase deficiency. Biochem Mol Med 1997; 62: 151-158
    CrossrefPubMedGoogle Scholar
  • 25 Escobar-Morreale HF, San Millán JL, Smith RR, Sancho J, Witchel SF. The presence of the 21-hydroxylase deficiency carrier status in hirsute women: phenotype-genotype correlations. Fertil Steril 1999; 72: 629-638
    CrossrefPubMedGoogle Scholar
  • 26 Ghanaati Z, Peters H, Müller S, Ventz M, Pfüller B, Enchshargal ZA, Rohde W, Dörner G. Endocrinological and genetic studies in patients with Polycystic Ovary Syndrome (PCOS). Neuro Endocrinol Lett 1999; 20: 323-327
    PubMedGoogle Scholar
  • 27 Witchel SF, Aston CE. The role of heterozygosity for CYP21 in the polycystic ovary syndrome. J Pediatr Endocrinol Metab 2000; 13: 1315-1317
    PubMedGoogle Scholar
  • 28 Glintborg D, Hermann AP, Brusgaard K, Hangaard J, Hagen C, Andersen M. Significantly higher adrenocorticotropin-stimulated cortisol and 17-hydroxyprogesterone levels in 337 consecutive, premenopausal, caucasian, hirsute patients compared with healthy controls. J Clin Endocrinol Metab 2005; 90: 1347-1353
    CrossrefPubMedGoogle Scholar