Abstract
Background
Polycystic ovary syndrome (PCOS) is a common endocrine disease affecting 5~10% of women with reproductive age. Familial aggregation suggests the evidence supporting a genetic basis for PCOS. The mode of inheritance of PCOS is not yet clear, however, probably polygenic and might be related to insulin resistance. Polymorphism of peroxisome proliferator-activated receptor (PPAR)-γ gene is a susceptible gene for the development of obesity and diabetes. In this study, we examined the frequency and genetic effect of PPAR-γ polymorphism on insulin resistance or hyperandrogenemia in Korean women with PCOS.
Methods
One-hundred twenty five Korean women with PCOS were evaluated for their metabolic and reproductive hormonal status. PPAR-γ polymorphism was analyzed.
Results
Genetic frequency of PPAR-γ was not significantly different between women with PCOS (n = 125) and those with regular menstrual cycles (n = 344). PCOS with Pro12Ala polymorphism had significantly higher levels of waist circumference and subcutaneous fat area compared with those with Pro12Pro genotype. They also had tendency of higher levels of fasting glucose concentration, body mass index (BMI) and visceral fat area. After BMI adjustment, this polymorphism was related to lower fasting insulin and higher insulin sensitivity index, and higher sex hormone binding globulin and lower free testosterone levels.
Conclusion
Pro12Ala polymorphism of PPAR-γ gene might be associated with obesity. However, after BMI adjustment, it may have favorable effect on insulin resistance and hyperandrogenemia. Because this study has limitations to conclude the genetic causality, further study is needed to support these findings.
References
1. Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab. 1999. 84:1897–1899.
2. Dunaif A, Givens JR, Haseltine FP, Merriam GR. Current issues in endocrinology and metabolism: polycystic ovary syndrome. 1992. Boston: Blackwell.
3. Legro RS. The genetics of polycystic ovary syndrome. Am J Med. 1995. 98:9S–16S.
4. Givens JR. Familial polycystic ovarian disease. Endocrinol Metabol Clin North Am. 1988. 17:771–783.
5. Gharani N, Waterworth DM, Batty S, White D, Gilling-Smith C, Conway GS, McCarthy M, Franks S, Williamson R. Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hypernadrogenism. Hum Mol Genet. 1997. 6:397–402.
6. Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P, Franks S, Williamson R. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet. 1994. 3:1873–1876.
7. Franks S. Polycystic ovary syndrome. N Eng J Med. 1995. 333:853–861.
8. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992. 41:1257–1266.
9. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995. 96:801–810.
10. Ciaraldi TP, el_Roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SS. Cellular mechanisms of insulin resistance in polycystic ovary syndrome. J Clin Endocrinol Metab. 1992. 75:577–583.
11. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks S. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol. 1992. 36:105–111.
12. Deeb SS, Fajas L, Nemoto M, Pihlamajaki J, Mykkanen L, Kuusisto J, Lakkso M, Fujimoto W, Auwerx JA. A Pro12Ala substitution in PPAR-γ2 is associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1988. 20:284–287.
13. Altshuler D, Hirschhorn JN, Klannermark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C. The common PPAR-γ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000. 26:76–80.
14. Lei H, Chen M, Yang W, Chiu M, Chen M, Tai T, Chuang L. Peroxisome proliferator-activated receptor PPAR-γ2 Pro12Ala gene variant is strongly associated with larger body mass in the Taiwanese. Metabolism. 2000. 49:1267–1270.
15. valve R, Sivenius K, Miettinen R, Pihlajamaki J, Rissanen A, Deeb S, Auwerx J, Unsitupa M, Laakso M. Two polymorphisms in the peroxisome proliferator-activated receptor γ gene are associated with severe overweight among obese women. J Clin endocrinol Metab. 1999. 84:3708–3712.
16. Mancini F, Vaccaro O, Sabatino L, Tufano A, Rivellese A, Riccardi G, Colantuoni V. Pro12Ala subsitution in the peroxisome proliferator-activated receptor-γ2 is not associated with type 2 diabetes. Diabetes. 1999. 48:1466–1468.
17. Hara M, Alcoser SY, Qaadir A, Beiswenger KK, Cox NJ, Ehrman DA. Insulin resistance is attenuated in women with polycystic ovary syndrome with the Pro12Ala polymorphism in the PPARγ gene. J Clin Endocrinol Metab. 2002. 87:772–775.
18. San Millian JL, Corton M, Villuendas G, Sancho J, Peral B, Escobar-Morreale HF. Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. J Clin Endocrinol Metab. 2004. 89:2640–2646.
19. Orio Fr Jr, Matarese G, Di Biase S, Palomba S, Labella D, Sana V, Savastano S, Zullo F, Colao A, Lombardi G. Exon 6 and 2 peroxisone proliferator-activated receptor-γ polymorphisms in polycystic ovary syndrome. J Clin Endocrinol Metab. 2003. 88:887–892.
20. Orio F Jr, Palomba S, Casella T, Di Biase S, Labella D, Russo T, Savastano S, Zullo F, Colao A, Vettor R. Lack of an association between peroxisone proliferator-activated receptor-γ gene Pro12Ala polymorphism and adiponetin levels in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2004. 89:5110–5115.
21. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long health risks related to polycystic ovary syndrome. Hum Reprod. 2004. 19:41–47.
22. Zawadeski JK, Dunaif A. Dunaif A, editor. Diagnostic criteria for PCOS: towards a more rational approach. PCOS. 1992. Boston: Blackwell Scientific;377–384.
23. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999. 84:3666–3672.
24. De Fronzo RA, Tobin JD, Andres R. Glucose clamp technique: A method for quantifying insulin secretion and resistance. Am J Physiol. 1979. 237:E214.
25. Yilmaz M, Ergun MA, Karakoc A, Yurtcu E, Yetkin I, Ayvaz G, Cakir N, Arslan M. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ gene in first-degree relatives of subjects with polycystic ovary syndrome. Gynecol Endocrinol. 2005. 21:206–210.
26. Tok EC, Aktas A, Ertunc D, Erdal EM, Dilek S. Evaluation of glucose metabolism and reproductive hormones in polycystic ovary syndrome on the basis of peroxisome proliferator-activated receptor (PPAR)-γ2 Pro12Ala genotype. Hum Reprod. 2005. 20:1590–1595.
27. Debril MB, Renaud JP, Fajas L, Auwerx J. The pleiotropic functions of peroxisome proliferator-activated receptor gamma. J Mol Med. 2001. 79:30–47.
28. Komar CM, Braissant O, Wahli W, Curry TE Jr. Expression and localization of PPARs in the rat ovary during follicular development and the periovulatory period. Endocrinology. 2001. 142:4831–4838.
29. Hahn S, Fingerhut A, Khomtsiv L, Tan S, Quadbeck S, Herrmann BL, Knebel B, Muller-Wieland D, Mann K. The peroxisome proliferator-activated receptor γ Pro12Ala polymorphism is associated with a lower hirsutism sore and increased insulin sensitivity in women with polycystic ovary syndrome. Clin Endocrinol. 2005. 62:573–579.