Genetic variants associated with insulin signaling and glucose homeostasis in the pathogenesis of insulin resistance in polycystic ovary syndrome: A systematic review

Journal of Assisted Reproduction and Genetics

Volumn 30, Issue 7, 2013, Pages 883-895

  Lakkakula, Bhaskar Venkata Kameswara Subrahmanya ^a   Thangavelu, Maheswari ^a   Godla, Usha Rani ^a  

^a SRI RAMACHANDRA UNIVERSITY   (India)

Author keywords

Genetics; Insulin resistance; PCOS; SNP

Indexed keywords

ADENYLATE KINASE; CALPAIN 10; GLUCOSE; GLUCOSE TRANSPORTER 4; INSULIN; INSULIN RECEPTOR; INSULIN RECEPTOR SUBSTRATE 1; INSULIN RECEPTOR SUBSTRATE 2; MESSENGER RNA; METFORMIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE; PLACENTA PROTEIN 14; PREPROINSULIN; PROGESTERONE; PROTEIN KINASE B; SEX HORMONE BINDING GLOBULIN; SOMATOMEDIN B; SOMATOMEDIN C; STEROID 21 MONOOXYGENASE; TESTOSTERONE;

ALLELE; DNA SEQUENCE; ENVIRONMENTAL FACTOR; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE; GLUCOSE HOMEOSTASIS; HAPLOTYPE; HUMAN; INSULIN METABOLISM; INSULIN RELEASE; INSULIN RESISTANCE; INSULIN SENSITIVITY; MEDLINE; OVARY HYPERSTIMULATION; OVARY POLYCYSTIC DISEASE; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTEMATIC REVIEW;

FEMALE; GENETIC PREDISPOSITION TO DISEASE; GENETIC VARIATION; GLUCOSE; HOMEOSTASIS; HUMANS; INSULIN; INSULIN RESISTANCE; POLYCYSTIC OVARY SYNDROME; POLYMORPHISM, SINGLE NUCLEOTIDE; SIGNAL TRANSDUCTION;

EID: 84881151005     PISSN: 10580468     EISSN: 15737330     Source Type: Journal    
DOI: 10.1007/s10815-013-0030-1     Document Type: Review

References (181)

1. Abbott DH, Dumesic DA, Franks S. Developmental origin of polycystic ovary syndrome - a hypothesis. J Endocrinol. 2002;174(1):1-5.
2. Ablooglu AJ, Frankel M, Rusinova E, Ross JB, Kohanski RA. Multiple activation loop conformations and their regulatory properties in the insulin receptor's kinase domain. J Biol Chem. 2001;276(50):46933-40.
3. Adair LS, Prentice AM. A critical evaluation of the fetal origins hypothesis and its implications for developing countries. J Nutr. 2004;134(1):191-3.
4. Adams JM, Taylor AE, Crowley Jr WF, Hall JE. Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome. J Clin Endocrinol Metab. 2004;89(9):4343-50.
5. Almind K, Frederiksen SK, Bernal D, Hansen T, Ambye L, Urhammer S, et al. Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity. Diabetologia. 1999;42(10):1244-9.
6. Almind K, Inoue G, Pedersen O, Kahn CR. A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. J Clin Invest. 1996;97(11):2569-75.
7. Antoine HJ, Pall M, Trader BC, Chen YD, Azziz R, Goodarzi MO. Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome. Fertil Steril. 2007;87(4):862-9.
8. Araki E, Lipes MA, Patti ME, Bruning JC, Haag 3rd B, Johnson RS, et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994;372(6502):186-90.
9. Araki E, Sun XJ, Haag 3rd BL, Chuang LM, Zhang Y, Yang-Feng TL, et al. Human skeletal muscle insulin receptor substrate-1. Characterization of the cDNA, gene, and chromosomal localization. Diabetes. 1993;42(7):1041-54.
10. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab. 2000;85(7):2434-8.
11. Azziz R. PCOS: a diagnostic challenge. Reprod Biomed Online. 2004;8(6):644-8.
12. Azziz R, Farah LA, Moran C, Knochenhauer ES, Potter HD, Boots LR. Early adrenarche in normal prepubertal girls: a prospective longitudinal study. J Pediatr Endocrinol Metab. 2004;17(9):1231-7.
13. 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(6):2745-9.
14. Baba T, Endo T, Sata F, Honnma H, Kitajima Y, Hayashi T, et al. Polycystic ovary syndrome is associated with genetic polymorphism in the insulin signaling gene IRS-1 but not ENPP1 in a Japanese population. Life Sci. 2007;81(10):850-4.
15. Baier LJ, Permana PA, Yang X, Pratley RE, Hanson RL, Shen GQ, et al. A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest. 2000;106(7):R69-73.
16. Bennett ST, Lucassen AM, Gough SC, Powell EE, Undlien DE, Pritchard LE, et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet. 1995;9(3):284-92.
17. Bidzinska-Speichert B, Lenarcik A, Tworowska-Bardzinska U, Slezak R, Bednarek-Tupikowska G, Milewicz A. Pro12Ala PPAR gamma2 gene polymorphism in PCOS women: the role of compounds regulating satiety. Gynecol Endocrinol. 2012;28(3):195-8.
18. Bidzinska-Speichert B, Lenarcik A, Tworowska-Bardzinska U, Slezak R, Bednarek-Tupikowska G, Milewicz A, et al. Pro12Ala PPAR gamma2 gene polymorphism in women with polycystic ovary syndrome. Ginekol Pol. 2011;82(6):426-9.
19. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12(6):673-83.
20. Calvo RM, Telleria D, Sancho J, San Millan JL, Escobar-Morreale HF. Insulin gene variable number of tandem repeats regulatory polymorphism is not associated with hyperandrogenism in Spanish women. Fertil Steril. 2002;77(4):666-8.
21. Carlsson E, Poulsen P, Storgaard H, Almgren P, Ling C, Jensen CB, et al. Genetic and nongenetic regulation of CAPN10 mRNA expression in skeletal muscle. Diabetes. 2005;54(10):3015-20.
22. Carmina E, Orio F, Palomba S, Longo RA, Cascella T, Colao A, et al. Endothelial dysfunction in PCOS: role of obesity and adipose hormones. Am J Med. 2006;119(4):356 e1-6.
23. Chae SJ, Kim JJ, Choi YM, Kim JM, Cho YM, Moon SY. Peroxisome proliferator-activated receptor-gamma and its coactivator-1alpha gene polymorphisms in Korean women with polycystic ovary syndrome. Gynecol Obstet Invest. 2010;70(1):1-7.
24. Chakraborty C. Biochemical and molecular basis of insulin resistance. Curr Protein Pept Sci. 2006;7(2):113-21.
25. Chang L, Chiang SH, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med. 2004;10(7-12):65-71.
26. Chen ZJ, Shi YH, Zhao YR, Li Y, Tang R, Zhao LX, et al. Correlation between single nucleotide polymorphism of insulin receptor gene with polycystic ovary syndrome. Zhonghua Fu Chan Ke Za Zhi. 2004;39(9):582-5.
27. Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Li Z, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet. 2011;43(1):55-9.
28. Christopoulos P, Mastorakos G, Gazouli M, Deligeoroglou E, Katsikis I, Diamanti-Kandarakis E, et al. Peroxisome proliferator-activated receptor-gamma and -delta polymorphisms in women with polycystic ovary syndrome. Ann N Y Acad Sci. 2010;1205:185-91.
29. Christopoulos P, Mastorakos G, Gazouli M, Deligeoroglou E, Katsikis I, Diamanti-Kandarakis E, et al. Study of association of IRS-1 and IRS-2 genes polymorphisms with clinical and metabolic features in women with polycystic ovary syndrome. Is there an impact? Gynecol Endocrinol. 2010;26(9):698-703.
30. Ciaraldi TP. Molecular defects of insulin action in the polycystic ovary syndrome: possible tissue specificity. J Pediatr Endocrinol Metab. 2000;13 Suppl 5:1291-3.
31. Colilla S, Cox NJ, Ehrmann DA. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. J Clin Endocrinol Metab. 2001;86(5):2027-31.
32. Conway GS, Avey C, Rumsby G. The tyrosine kinase domain of the insulin receptor gene is normal in women with hyperinsulinaemia and polycystic ovary syndrome. Hum Reprod. 1994;9(9):1681-3.
33. Costello MF, Chapman M, Conway U. A systematic review and meta-analysis of randomized controlled trials on metformin co-administration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod. 2006;21(6):1387-99.
34. Dasgupta S, Sirisha PV, Neelaveni K, Anuradha K, Reddy BM. Association of CAPN10 SNPs and haplotypes with polycystic ovary syndrome among South Indian Women. PLoS One. 2012;7(2):e32192.
35. Dasgupta S, Sirisha P, Neelaveni K, Anuradha K, Sudhakar G, Reddy BM. Polymorphisms in the IRS-1 and PPAR-gamma genes and their association with polycystic ovary syndrome among South Indian women. Gene. 2012;503(1):140-6.
36. de Franca Neto AH, Rogatto S, Do Amorim MM, Tamanaha S, Aoki T, Aldrighi JM. Oncological repercussions of polycystic ovary syndrome. Gynecol Endocrinol. 2010;26(10):708-11.
37. De Leo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril. 1999;72(2):282-5.
38. DeClue TJ, Shah SC, Marchese M, Malone JI. Insulin resistance and hyperinsulinemia induce hyperandrogenism in a young type B insulin-resistant female. J Clin Endocrinol Metab. 1991;72(6):1308-11.
39. DeUgarte CM, Bartolucci AA, Azziz R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril. 2005;83(5):1454-60.
40. Dilek S, Ertunc D, Tok EC, Erdal EM, Aktas A. Association of Gly972Arg variant of insulin receptor substrate-1 with metabolic features in women with polycystic ovary syndrome. Fertil Steril. 2005;84(2):407-12.
41. Dragojevič J, Marc J, Mlinar B. Association between Pro12Ala and His477His polymorphisms in PPARG gene and insulin resistance in patients with polycystic ovary syndrome. Biochemia Medica. 2008;18(3):342-50.
42. Dravecka I, Lazurova I, Habalova V. The prevalence of Gly972Arg and C825T polymorphisms in Slovak women with polycystic ovary syndrome and their relation to the metabolic syndrome. Gynecol Endocrinol. 2010;26(5):356-60.
43. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18(6):774-800.
44. Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest. 1989;83(1):23-9.
45. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81(9):3299-306.
46. Dunaif A, Thomas A. Current concepts in the polycystic ovary syndrome. Annu Rev Med. 2001;52:401-19.
47. Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, et al. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985;40(4):747-58.
48. Ehrmann DA, Schwarz PE, Hara M, Tang X, Horikawa Y, Imperial J, et al. Relationship of calpain-10 genotype to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(4):1669-73.
49. Ehrmann DA, Tang X, Yoshiuchi I, Cox NJ, Bell GI. Relationship of insulin receptor substrate-1 and -2 genotypes to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(9):4297-300.
50. El Mkadem SA, Lautier C, Macari F, Molinari N, Lefebvre P, Renard E, et al. Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. Diabetes. 2001;50(9):2164-8.
51. Emori Y, Kawasaki H, Imajoh S, Kawashima S, Suzuki K. Isolation and sequence analysis of cDNA clones for the small subunit of rabbit calcium-dependent protease. J Biol Chem. 1986;261(20):9472-6.
52. Ertunc D, Tok EC, Aktas A, Erdal EM, Dilek S. The importance of IRS-1 Gly972Arg polymorphism in evaluating the response to metformin treatment in polycystic ovary syndrome. Hum Reprod. 2005;20(5):1207-12.
53. Escobar-Morreale HF, Peral B, Villuendas G, Calvo RM, Sancho J, San Millan JL. Common single nucleotide polymorphisms in intron 3 of the calpain-10 gene influence hirsutism. Fertil Steril. 2002;77(3):581-7.
54. Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R, et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem. 1997;272(30):18779-89.
55. Farah-Eways L, Reyna R, Knochenhauer ES, Bartolucci AA, Azziz R. Glucose action and adrenocortical biosynthesis in women with polycystic ovary syndrome. Fertil Steril. 2004;81(1):120-5.
56. Ferk P, Perme MP, Gersak K. Insulin gene polymorphism in women with polycystic ovary syndrome. J Int Med Res. 2008;36(6):1180-7.
57. Fernandez M, Bourguignon N, Lux-Lantos V, Libertun C. Neonatal exposure to bisphenol a and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats. Environ Health Perspect. 2010;118(9):1217-22.
58. Georgia S, Bhushan A. p27 Regulates the transition of beta-cells from quiescence to proliferation. Diabetes. 2006;55(11):2950-6.
59. Giallauria F, Orio F, Palomba S, Lombardi G, Colao A, Vigorito C. Cardiovascular risk in women with polycystic ovary syndrome. J Cardiovasc Med (Hagerstown). 2008;9(10):987-92.
60. Glazener CM, Kelly NJ, Hull MG. Borderline hyperprolactinemia in infertile women: evaluation of the prolactin response to thyrotropin releasing hormone and double-blind placebo-controlled treatment with bromocriptine. Gynecol Endocrinol. 1987;1(4):373-8.
61. Gonzalez A, Abril E, Roca A, Aragon MJ, Figueroa MJ, Velarde P, et al. Comment: CAPN10 alleles are associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(8):3971-6.
62. Gonzalez A, Abril E, Roca A, Aragon MJ, Figueroa MJ, Velarde P, et al. Specific CAPN10 gene haplotypes influence the clinical profile of polycystic ovary patients. J Clin Endocrinol Metab. 2003;88(11):5529-36.
63. Goodarzi MO, Erickson S, Port SC, Jennrich RI, Korenman SG. beta-Cell function: a key pathological determinant in polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(1):310-5.
64. Goodarzi MA, Firoozabadi A. Reliability and validity of the Padua inventory in an Iranian population. Behav Res Ther. 2005;43(1):43-54.
65. Goodarzi MO, Louwers YV, Taylor KD, Jones MR, Cui J, Kwon S, Chen YD, Guo X, Stolk L, Uitterlinden AG, Laven JS, Azziz R. Replication of association of a novel insulin receptor gene polymorphism with polycystic ovary syndrome. Fertil Steril. 2011; 95(5):1736-1741 e1731-1711.
66. Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, et al. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. 1995;4(4-5):281-99.
67. Gu BH, Baek KH. Pro12Ala and His447His polymorphisms of PPAR-gamma are associated with polycystic ovary syndrome. Reprod Biomed Online. 2009;18(5):644-50.
68. Guzman N, Erices L, Valdes P, Salzar L. A common 34C > G variant at the peroxisome proliferator-activated receptor γ2- gene in Chilean women with polycystic ovary syndrome and controls. Int J Morphol. 2007;25(4):867-73.
69. Haap M, Machicao F, Stefan N, Thamer C, Tschritter O, Schnuck F, et al. Genetic determinants of insulin action in polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2005;113(5):275-81.
70. Haddad L, Evans JC, Gharani N, Robertson C, Rush K, Wiltshire S, et al. Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(6):2606-10.
71. Hahn S, Fingerhut A, Khomtsiv U, Khomtsiv L, Tan S, Quadbeck B, et al. The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 2005;62(5):573-9.
72. Haller K, Laisk T, Peters M, Talving E, Karits P, Karro H, et al. VNTR I/I genotype of insulin gene is associated with the increase of follicle number independent from polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2007;86(6):726-32.
73. Hara M, Alcoser SY, Qaadir A, Beiswenger KK, Cox NJ, Ehrmann DA. Insulin resistance is attenuated in women with polycystic ovary syndrome with the Pro(12)Ala polymorphism in the PPARgamma gene. J Clin Endocrinol Metab. 2002;87(2):772-5.
74. Harper ME, Ullrich A, Saunders GF. Localization of the human insulin gene to the distal end of the short arm of chromosome 11. Proc Natl Acad Sci U S A. 1981;78(7):4458-60.
75. He J, Wang L, Liu J, Liu F, Li X. A meta-analysis on the association between PPAR-gamma Pro12Ala polymorphism and polycystic ovary syndrome. J Assist Reprod Genet. 2012;29(7):669-77.
76. Huang WJ, Liu JY, Li LN. Analysis of environmental factors and polycystic ovary syndrome. Zhonghua Fu Chan Ke Za Zhi. 2007;42(5):302-4.
77. Huang M, Xiao J, Zhao X, Liu C, Chen Q. Four polymorphisms of the CAPN 10 gene and their relationship to polycystic ovary syndrome susceptibility: a meta-analysis. Clin Endocrinol (Oxf). 2012;76(3):431-8.
78. Hull MG. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol. 1987;1(3):235-45.
79. Ibanez L, Potau N, Francois I, de Zegher F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab. 1998;83(10):3558-62.
80. Ioannidis A, Ikonomi E, Dimou NL, Douma L, Bagos PG. Polymorphisms of the insulin receptor and the insulin receptor substrates genes in polycystic ovary syndrome: a Mendelian randomization meta-analysis. Mol Genet Metab. 2010;99(2):174-83.
81. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347(6294):645-50.
82. Jakubowicz DJ, Seppala M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H, et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86(3):1126-33.
83. Jin L, Zhu XM, Luo Q, Qian Y, Jin F, Huang HF. A novel SNP at exon 17 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS. Mol Hum Reprod. 2006;12(3):151-5.
84. Junien C, van Heyningen V. Report of the committee on the genetic constitution of chromosome 11. Cytogenet Cell Genet. 1990;55(1-4):153-69.
85. Kahsar-Miller M, Boots LR, Bartolucci A, Azziz R. Role of a CYP17 polymorphism in the regulation of circulating dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome. Fertil Steril. 2004;82(4):973-5.
86. Kalidas K, Wasson J, Glaser B, Meyer JM, Duprat LJ, White MF, et al. Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role. Diabetologia. 1998;41(11):1389-91.
87. Kandaraki E, Chatzigeorgiou A, Livadas S, Palioura E, Economou F, Koutsilieris M, et al. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011;96(3):E480-4.
88. Knebel B, Janssen OE, Hahn S, Jacob S, Gleich J, Kotzka J, et al. Increased low grade inflammatory serum markers in patients with Polycystic ovary syndrome (PCOS) and their relationship to PPARgamma gene variants. Exp Clin Endocrinol Diabetes. 2008;116(8):481-6.
89. Knebel B, Janssen OE, Hahn S, Nitzgen U, Jacob S, Haas J, et al. Combined analyses of paraoxonase-1 and IGF-2 polymorphism in polycystic ovary syndrome. Dtsch Med Wochenschr. 2009;134(20):1040-6.
90. Koika V, Marioli DJ, Saltamavros AD, Vervita V, Koufogiannis KD, Adonakis G, et al. Association of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma2 with decreased basic metabolic rate in women with polycystic ovary syndrome. Eur J Endocrinol. 2009;161(2):317-22.
91. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril. 2000;73(6):1149-54.
92. Korhonen S, Heinonen S, Hiltunen M, Helisalmi S, Hippelainen M, Koivunen R, et al. Polymorphism in the peroxisome proliferator-activated receptor-gamma gene in women with polycystic ovary syndrome. Hum Reprod. 2003;18(3):540-3.
93. Lee JY, Lee WJ, Hur SE, Lee CM, Sung YA, Chung HW. 111/121 diplotype of Calpain-10 is associated with the risk of polycystic ovary syndrome in Korean women. Fertil Steril. 2009;92(2):830-3.
94. Lee EJ, Oh B, Lee JY, Kimm K, Lee SH, Baek KH. A novel single nucleotide polymorphism of INSR gene for polycystic ovary syndrome. Fertil Steril. 2008;89(5):1213-20.
95. Leng Y, Karlsson HK, Zierath JR. Insulin signaling defects in type 2 diabetes. Rev Endocr Metab Disord. 2004;5(2):111-7.
96. Li AC, Glass CK. PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res. 2004;45(12):2161-73.
97. Lin TC, Yen JM, Gong KB, Kuo TC, Ku DC, Liang SF, et al. Abnormal glucose tolerance and insulin resistance in polycystic ovary syndrome amongst the Taiwanese population- not correlated with insulin receptor substrate-1 Gly972Arg/Ala513Pro polymorphism. BMC Med Genet. 2006;7:36.
98. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327(7421):951-3.
99. Lucassen AM, Julier C, Beressi JP, Boitard C, Froguel P, Lathrop M, et al. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat Genet. 1993;4(3):305-10.
100. Ludvigsson J. Why diabetes incidence increases - a unifying theory. Ann N Y Acad Sci. 2006;1079:374-82.
101. Marioli DJ, Koika V, Adonakis GL, Saltamavros AD, Karela A, Armeni AK, et al. No association of the G972S polymorphism of the insulin receptor substrate-1 gene with polycystic ovary syndrome in lean PCOS women with biochemical hyperandrogenemia. Arch Gynecol Obstet. 2010;281(6):1045-9.
102. Marquez JL, Pacheco A, Valdes P, Salazar LA. Association between CAPN10 UCSNP-43 gene polymorphism and polycystic ovary syndrome in Chilean women. Clin Chim Acta. 2008;398(1-2):5-9.
103. Meenakumari KJ, Agarwal S, Krishna A, Pandey LK. Effects of metformin treatment on luteal phase progesterone concentration in polycystic ovary syndrome. Braz J Med Biol Res. 2004;37(11):1637-44.
104. Michelmore KF, Balen AH, Dunger DB, Vessey MP. Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol (Oxf). 1999;51(6):779-86.
105. Michelmore K, Ong K, Mason S, Bennett S, Perry L, Vessey M, et al. Clinical features in women with polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR and birth weight. Clin Endocrinol (Oxf). 2001;55(4):439-46.
106. Miles RA, Cassidenti DL, Carmina E, Gentzschein E, Stanczyk FZ, Lobo RA. Cutaneous application of an androstenedione gel as an in vivo test of 5 alpha-reductase activity in women. Fertil Steril. 1992;58(4):708-12.
107. Moran C, Reyna R, Boots LS, Azziz R. Adrenocortical hyperresponsiveness to corticotropin in polycystic ovary syndrome patients with adrenal androgen excess. Fertil Steril. 2004;81(1):126-31.
108. Moran L, Teede H. Metabolic features of the reproductive phenotypes of polycystic ovary syndrome. Hum Reprod Update. 2009;15(4):477-88.
109. Mounier C, Posner BI. Transcriptional regulation by insulin: from the receptor to the gene. Can J Physiol Pharmacol. 2006;84(7):713-24.
110. Mukherjee S, Shaikh N, Khavale S, Shinde G, Meherji P, Shah N, et al. Genetic variation in exon 17 of INSR is associated with insulin resistance and hyperandrogenemia among lean Indian women with polycystic ovary syndrome. Eur J Endocrinol. 2009;160(5):855-62.
111. Navaratnarajah R, Pillay OC, Hardiman P. Polycystic ovary syndrome and endometrial cancer. Semin Reprod Med. 2008;26(1):62-71.
112. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996;335(9):617-23.
113. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338(26):1876-80.
114. Ng EH, Wat NM, Ho PC. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Hum Reprod. 2001;16(8):1625-31.
115. O'Dell SD, Day IN. Insulin-like growth factor II (IGF-II). Int J Biochem Cell Biol. 1998;30(7):767-71.
116. O'Meara NM, Blackman JD, Ehrmann DA, Barnes RB, Jaspan JB, Rosenfield RL, et al. Defects in beta-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab. 1993;76(5):1241-7.
117. Orio F, Cascella T, Giallauria F, Palomba S, De Lorenzo A, Lucci R, et al. Polycystic ovary syndrome: an example of obesity-related cardiovascular complication affecting young women. Monaldi Arch Chest Dis. 2006;66(1):48-53.
118. Orio Jr F, Matarese G, Di Biase S, Palomba S, Labella D, Sanna V, et al. Exon 6 and 2 peroxisome proliferator-activated receptor-gamma polymorphisms in polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(12):5887-92.
119. Orio Jr F, Palomba S, Cascella T, Di Biase S, Labella D, Russo T, et al. Lack of an association between peroxisome proliferator-activated receptor-gamma gene Pro12Ala polymorphism and adiponectin levels in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89(10):5110-5.
120. Pappalardo MA, Russo GT, Pedone A, Pizzo A, Borrielli I, Stabile G, et al. Very high frequency of the polymorphism for the insulin receptor substrate 1 (IRS-1) at codon 972 (glycine972arginine) in Southern Italian women with polycystic ovary syndrome. Horm Metab Res. 2010;42(8):575-84.
121. Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C. The INS 5′ variable number of tandem repeats is associated with IGF2 expression in humans. J Biol Chem. 1998;273(23):14158-64.
122. Pasquali R, Stener-Victorin E, Yildiz BO, Duleba AJ, Hoeger K, Mason H, et al. PCOS Forum: research in polycystic ovary syndrome today and tomorrow. Clin Endocrinol (Oxf). 2011;74(4):424-33.
123. Pihlajamaki J, Salmenniemi U, Vanttinen M, Ruotsalainen E, Kuusisto J, Vauhkonen I, et al. Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes. Diabetologia. 2006;49(7):1560-6.
124. Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. 2006;116(7):1761-6.
125. Powell BL, Haddad L, Bennett A, Gharani N, Sovio U, Groves CJ, et al. Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits. J Clin Endocrinol Metab. 2005;90(5):2988-93.
126. Ramos Cirilo PD, Rosa FE, Moreira Ferraz MF, Rainho CA, Pontes A, Rogatto SR. Genetic polymorphisms associated with steroids metabolism and insulin action in polycystic ovary syndrome. Gynecol Endocrinol. 2012;28(3):190-4.
127. Rashidi B, Azizy L, Najmeddin F, Azizi E. Prevalence of the insulin receptor substrate-1(IRS-1) Gly972Arg and the insulin receptor substrate-2(IRS-2) Gly1057Asp polymorphisms in PCOS patients and non-diabetic healthy women. J Assist Reprod Genet. 2012;29(2):195-201.
128. Rique S, Ibanez L, Marcos MV, Carrascosa A, Potau N. Effects of metformin on androgens and insulin concentrations in type A insulin resistance syndrome. Diabetologia. 2000;43(3):385-6.
129. Robinson JE, Forsdike RA, Taylor JA. In utero exposure of female lambs to testosterone reduces the sensitivity of the gonadotropin-releasing hormone neuronal network to inhibition by progesterone. Endocrinology. 1999;140(12):5797-805.
130. Rosenfield RL, Bordini B. Evidence that obesity and androgens have independent and opposing effects on gonadotropin production from puberty to maturity. Brain Res. 2010;1364:186-97.
131. Ruan Y, Ma J, Xie X. Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis. Endocr J. 2012;59(7):601-9.
132. Saez ME, Gonzalez-Sanchez JL, Ramirez-Lorca R, Martinez-Larrad MT, Zabena C, Gonzalez A, et al. The CAPN10 gene is associated with insulin resistance phenotypes in the Spanish population. PLoS One. 2008;3(8):e2953.
133. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799-806.
134. San Millan 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(6):2640-6.
135. Sawathiparnich P, Weerakulwattana L, Santiprabhob J, Likitmaskul S. Obese adolescent girls with polycystic ovary syndrome (PCOS) have more severe insulin resistance measured by HOMA-IR score than obese girls without PCOS. J Med Assoc Thai. 2005;88 Suppl 8:S33-7.
136. Seino S, Seino M, Nishi S, Bell GI. Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci U S A. 1989;86(1):114-8.
137. Seto-Young D, Paliou M, Schlosser J, Avtanski D, Park A, Patel P, et al. Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production. J Clin Endocrinol Metab. 2005;90(11):6099-105.
138. Siegel S, Futterweit W, Davies TF, Concepcion ES, Greenberg DA, Villanueva R, et al. A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome. Fertil Steril. 2002;78(6):1240-3.
139. Sir-Petermann T, Angel B, Maliqueo M, Santos JL, Riesco MV, Toloza H, et al. Insulin secretion in women who have polycystic ovary syndrome and carry the Gly972Arg variant of insulin receptor substrate-1 in response to a high-glycemic or low-glycemic carbohydrate load. Nutrition. 2004;20(10):905-10.
140. Sir-Petermann T, Perez-Bravo F, Angel B, Maliqueo M, Calvillan M, Palomino A. G972R polymorphism of IRS-1 in women with polycystic ovary syndrome. Diabetologia. 2001;44(9):1200-1.
141. Skov V, Glintborg D, Knudsen S, Jensen T, Kruse TA, Tan Q, et al. Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome. Diabetes. 2007;56(9):2349-55.
142. Sorbara LR, Tang Z, Cama A, Xia J, Schenker E, Kohanski RA, et al. Absence of insulin receptor gene mutations in three insulin-resistant women with the polycystic ovary syndrome. Metabolism. 1994;43(12):1568-74.
143. Stead JD, Jeffreys AJ. Structural analysis of insulin minisatellite alleles reveals unusually large differences in diversity between Africans and non-Africans. Am J Hum Genet. 2002;71(6):1273-84.
144. Steiner DF, Oyer PE. The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma. Proc Natl Acad Sci U S A. 1967;57(2):473-80.
145. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991;352(6330):73-7.
146. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers Jr MG, Glasheen E, et al. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995;377(6545):173-7.
147. Takeuchi K, Kato T, Taniyama Y, Tsunoda K, Takahashi N, Ikeda Y, et al. Three cases of Gitelman's syndrome possibly caused by different mutations in the thiazide-sensitive Na-Cl cotransporter. Intern Med. 1997;36(8):582-5.
148. Talbot JA, Bicknell EJ, Rajkhowa M, Krook A, O'Rahilly S, Clayton RN. Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 1996;81(5):1979-83.
149. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994;372(6502):182-6.
150. Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR, Randeva HS. Upregulation of adiponectin receptor 1 and 2 mRNA and protein in adipose tissue and adipocytes in insulin-resistant women with polycystic ovary syndrome. Diabetologia. 2006;49(11):2723-8.
151. Tang ST, Wang CJ, Tang HQ, Peng WJ, Wang YM, Zhang Q. Association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma with polycystic ovary syndrome: a meta-analysis. Mol Biol Rep. 2012;39(10):9649-60.
152. Taylor SI, Kadowaki T, Kadowaki H, Accili D, Cama A, McKeon C. Mutations in insulin-receptor gene in insulin-resistant patients. Diabetes Care. 1990;13(3):257-79.
153. 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)-gamma2 Pro12Ala genotype. Hum Reprod. 2005;20(6):1590-5.
154. Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, et al. Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women. Eur J Endocrinol. 2011;164(2):197-203.
155. Tucci S, Futterweit W, Concepcion ES, Greenberg DA, Villanueva R, Davies TF, et al. Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor gene locus. J Clin Endocrinol Metab. 2001;86(1):446-9.
156. Unsal T, Konac E, Yesilkaya E, Yilmaz A, Bideci A, Ilke Onen H, et al. Genetic polymorphisms of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes in adolescent girls with polycystic ovary syndrome. J Assist Reprod Genet. 2009;26(4):205-16.
157. Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, et al. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A. 1999;96(15):8573-8.
158. Valdes P, Cerda A, Barrenechea C, Kehr M, Soto C, Salazar LA. No association between common Gly972Arg variant of the insulin receptor substrate-1 and polycystic ovary syndrome in Southern Chilean women. Clin Chim Acta. 2008;390(1-2):63-6.
159. Vankova M, Vrbikova J, Hill M, Cinek O, Bendlova B. Association of insulin gene VNTR polymorphism with polycystic ovary syndrome. Ann N Y Acad Sci. 2002;967:558-65.
160. Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90(3):392-5.
161. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994;43(5):647-54.
162. Vigouroux C. What have we learned form monogenic forms of severe insulin resistance associated with PCOS/HAIRAN? Ann Endocrinol (Paris). 2010;71(3):222-4.
163. Villuendas G, Botella-Carretero JI, Roldan B, Sancho J, Escobar-Morreale HF, San Millan JL. Polymorphisms in the insulin receptor substrate-1 (IRS-1) gene and the insulin receptor substrate-2 (IRS-2) gene influence glucose homeostasis and body mass index in women with polycystic ovary syndrome and non-hyperandrogenic controls. Hum Reprod. 2005;20(11):3184-91.
164. Villuendas G, Escobar-Morreale HF, Tosi F, Sancho J, Moghetti P, San Millan JL. Association between the D19S884 marker at the insulin receptor gene locus and polycystic ovary syndrome. Fertil Steril. 2003;79(1):219-20.
165. Vollmert C, Hahn S, Lamina C, Huth C, Kolz M, Schopfer-Wendels A, et al. Calpain-10 variants and haplotypes are associated with polycystic ovary syndrome in Caucasians. Am J Physiol Endocrinol Metab. 2007;292(3):E836-44.
166. Wang Y, Wu X, Cao Y, Yi L, Fan H, Chen J. Polymorphisms of the peroxisome proliferator-activated receptor-gamma and its coactivator-1alpha genes in Chinese women with polycystic ovary syndrome. Fertil Steril. 2006;85(5):1536-40.
167. Wardle PG, McLaughlin E, Sykes JA, Hull MG. Intrauterine insemination. Lancet. 1987;1(8527):270.
168. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, et al. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet. 1997;349(9057):986-90.
169. Wijeyaratne CN, Balen AH, Barth JH, Belchetz PE. Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference? Clin Endocrinol (Oxf). 2002;57(3):343-50.
170. Wiltgen D, Furtado L, Kohek MB, Spritzer PM. CAPN10 UCSNP-43, UCSNP-19 and UCSNP-63 polymorphisms and metabolic syndrome in polycystic ovary syndrome. Gynecol Endocrinol. 2007;23(3):173-8.
171. 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(2):371-5.
172. Witchel SF, Smith R, Tomboc M, Aston CE. Candidate gene analysis in premature pubarche and adolescent hyperandrogenism. Fertil Steril. 2001;75(4):724-30.
173. Wu XK, Zhou SY, Liu JX, Pollanen P, Sallinen K, Makinen M, et al. Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome. Fertil Steril. 2003;80(4):954-65.
174. Xita N, Lazaros L, Georgiou I, Tsatsoulis A. The Pro12Ala polymorphism of the PPAR-gamma gene is not associated with the polycystic ovary syndrome. Hormones (Athens). 2009;8(4):267-72.
175. Xu Y, Wei Z, Zhang Z, Xing Q, Hu P, Zhang X, et al. No association of the insulin gene VNTR polymorphism with polycystic ovary syndrome in a Han Chinese population. Reprod Biol Endocrinol. 2009;7:141.
176. Yilmaz M, Ergun MA, Karakoc A, Yurtcu E, Cakir N, Arslan M. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma gene in women with polycystic ovary syndrome. Gynecol Endocrinol. 2006;22(6):336-42.
177. Yilmaz M, Yurtcu E, Demirci H, Ergun MA, Ersoy R, Karakoc A, et al. Calpain 10 gene single-nucleotide 44 polymorphism may have an influence on clinical and metabolic features in patients with polycystic ovary syndrome. J Endocrinol Invest. 2009;32(1):13-7.
178. Yun JH, Gu BH, Kang YB, Choi BC, Song S, Baek KH. Association between INS-VNTR polymorphism and polycystic ovary syndrome in a Korean population. Gynecol Endocrinol. 2012;28(7):525-8.
179. Zhang H, Bi Y, Hu C, Lu W, Zhu D. Association between the Pro12Ala polymorphism of PPAR-gamma gene and the polycystic ovary syndrome: a meta-analysis of case-control studies. Gene. 2012;503(1):12-7.
180. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-74.
181. Zusterzeel PL, Peters WH, Visser W, Hermsen KJ, Roelofs HM, Steegers EA. A polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia. J Med Genet. 2001;38(4):234-7.