Insulin resistance and polycystic ovary syndrome through life

Current Pharmaceutical Design

Volumn 18, Issue 34, 2012, Pages 5569-5576

  Diamanti Kandarakis, Evanthia ^a   Spritzer, Poli Mara ^b   Sir Petermann, Teresa ^c   Motta, Alicia Beatriz ^d  

^a UNIVERSITY OF ATHENS MEDICAL SCHOOL   (Greece)

^b FEDERAL UNIVERSITY OF RIO GRANDE DO SUL   (Brazil)

^c UNIVERSITY OF CHILE   (Chile)

^d Centre de Estudios Farmacologicos y Botanicos   (Argentina)

Author keywords

Adolescence; Child; Insulin resistance; Menopause; Polycystic ovary syndrome; Treatments

Indexed keywords

ADVANCED GLYCATION END PRODUCT; CLOMIFENE CITRATE; ENDOCRINE DISRUPTOR; GONADOTROPIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INSULIN SENSITIZING AGENT;

ADOLESCENCE; BODY MASS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHILDHOOD; DIET; HUMAN; INSULIN RESISTANCE; LIFESTYLE MODIFICATION; OVARY POLYCYSTIC DISEASE; OXIDATIVE STRESS; PHYSICAL ACTIVITY; POSTMENOPAUSE; PRIORITY JOURNAL; REVIEW; RISK FACTOR; WEIGHT REDUCTION;

ADOLESCENT; AGE FACTORS; ANIMALS; CHILD; ENDOCRINE DISRUPTORS; FEMALE; HUMANS; INSULIN RESISTANCE; POLYCYSTIC OVARY SYNDROME; POSTMENOPAUSE; RISK FACTORS;

EID: 84867709790     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161212803307590     Document Type: Review

References (123)

1. Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome; towards a rational approach. In: Dunaif A, Givens JR and Haseltine F (eds), Polycystic Ovary Syndrome. Blackwell Scientific, Boston 1992; pp. 377-84.
2. 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. Fert Steril 2003; 81: 19-25.
3. Azziz R, Carmina E, Dewailly D, et al. Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91: 456-88.
4. Consensus on women's health aspects of polycystic ovary syndrome (PCOS). The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Hum Reprod 2012; 27: 14-24.
5. Azziz R, Dumesic DA, Goodarzi MO. Polycystic ovary syndrome: an ancient disorder? Fertil Steril 2011; 95: 1544-8.
6. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997; 18: 774-800.
7. Casals-Casas C, Desvergne B. Endocrine disruptors send the wrong message at the wrong time to the wrong place. Annu Rev Physiol 2011; 73: 135-62.
8. Diamanti-Kandarakis E, Piperi C, Alexandraki K, et al. Short-term effect of orlistat on dietary glycotoxins in healthy women and women with polycystic ovary syndrome. Metabolism 2006; 55: 494-500.
9. Motta AB. Report of the international symposium: polycystic ovary syndrome: first Latin-American consensus. Int J Clin Pract 2010; 64: 544-57.
10. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987; 65: 499-507.
11. Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab 2005; 90: 3236-42.
12. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999; 84: 165-9.
13. Ciaraldi TP, Aroda V, Mudaliar S, Chang RJ, Henry RR. Polycystic ovary syndrome Is associated with tissue-specific differences in insulin resistance. J Clin Endocrinol Metab 2009; 94: 157-63.
14. Svendsen PF, Nilas L, Nørgaard K, Jensen JE, Madsbad S. Obesity, body composition and metabolic disturbances in polycystic ovary syndrome. Hum Reprod 2008; 23: 2113-21.
15. Corbould A. Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women. J Endocrinol 2007; 192: 585-94.
16. Poretsky L, Cataldo N, Rosenwaks Z, Giudice LD. The insulin related ovarian regulatory system in health and disease. Endocr Rev 1999; 20: 535-82.
17. Bremer AA, Miller WL. The serine phosphorylation hypothesis of polycystic ovary syndrome: a unifying mechanism for hyperandrogenemia and insulin resistance. Fertil Steril 2008; 89: 1039-48.
18. Mukherjee S, Maitra A. Molecular & genetic factors contributing to insulin resistance in polycystic ovary syndrome. Indian J Med Res 2010; 131: 743-60.
19. 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; 29: 617-23.
20. Willis D, Franks S. Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 1995; 80: 3788-90.
21. Nestler JE, Jakubowicz DJ. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998; 83: 2001-5.
22. Rice S, Christoforidis N, Gadd C, et al. Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Hum Reprod 2005; 20: 373-81.
23. Doster JA, Purdum MB, Martin LA, Goven AJ, Moorefield R. Gender differences, anger expression, and cardiovascular risk. J Nerv Ment Dis 2009, 197: 552-4.
24. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143-421.
25. Rizzo M, Rini GB, Carmina E. Androgen excess and cardiovascular risk. Minerva Endocrinol 2007; 32: 67-71.
26. Talbott EO, Guzick DS, Sutton-Tyrrell K, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2000; 20: 2414-27.
27. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990; 82: 495-506.
28. Rizzo M, Berneis K. Low-density lipoprotein size and cardiovascular risk assessment. QJM 2006; 99: 1-14.
29. Genctoy G, Ozbek M, Avcu N, Kahraman S, Kirkpantur A. Gingival health status in renal transplant recipients: relationship between systemic inflammation and atherosclerosis. Int J Clin Pract 2007; 61: 577-82.
30. Abbott DH, Dumesic DA, Franks S. Developmental origin of polycystic ovary syndromea hypothesis. J Endocrinol 2002; 174: 1-5.
31. Rizzo M, Berneis K, Hersberger M, Pepe I, Di Fede G. Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype. Hum Reprod 2009; 24: 2286-92.
32. Bayram F, Kocer D, Ozsan M, Muhtaroglu S. Evaluation of endothelial dysfunction, lipid metabolism in women with polycystic ovary syndrome: relationship of paraoxonase 1 activity, malondialdehyde levels, low-density lipoprotein subfractions, and endothelial dysfunction. Gynecol Endocrinol 2012; 28: 497-501.
33. Ibañez L, Di Martino-Nardi J, Potau N, Saenger P. Premature adrenarchenormal variant or forerunner of adult disease? Endocr Rev 2000; 21: 671-96.
34. Ibañez L, de Zegher F, Potau N. Anovulation after precocious pubarche: early markers and time course in adolescence. J Clin Endocrinol Metab 1999; 84: 2691-95.
35. Ibañez L, Ong KO, Potau N, Marcos MV, de Zegher F, Dunger DB. Insulin gene VNTR genotype and the low birthweight, precocious pubarche and hyperinsulinism sequence. J Clin Endocrinol Metab 2001; 86: 5788-93.
36. Ibañez L, Valls C, Potau N, Marcos MV, de Zegher F. Polycystic ovary syndrome after precocious pubarche: ontogeny of the lowbirth-weight effect. Clin Endocrinol 2001; 55: 667-72.
37. Ibáñez L, Ferrer A, Ong K, Amin R, Dunger D, de Zegher F. Insulin sensitization early after menarche prevents progression from precocious pubarche to polycystic ovary syndrome. J Pediatr 2004; 144: 23-9.
38. Neville KA. Walker JL. Precocious pubarche is associated with SGA, prematurity, weight gain and obesity. Arch Dis Child 2005; 90: 258-61.
39. Ibañez L, Potau N, Zampolli M, Rique S, Saenger P, Carrascosa A. Hyperinsulinemia and decreased insulin-like growth factor binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab 1997; 82: 2283-8.
40. Ibañez 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: 3558-662.
41. Ibañez L, Potau N, Chacon P, Pascual C, Carrascosa A. Hyperinsulinemia, dyslipemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia 1998; 41: 1057-63.
42. Santos BR, Mascarenhas LP, Satler F, Boguszewski MC, Spritzer PM. Vitamin D receptor gene polymorphisms and sex steroid secretion in girls with precocious pubarche in Southern Brazil: a pilot study. J Endocrinol Invest. 2011; in press.
43. Ibáñez L, López-Bermejo A, Díaz M, Marcos MV, de Zegher F. Early metformin therapy (age 8-12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess, and oligomenorrhea in adolescence. J Clin Endocrinol Metab 2011; 96: 262-7.
44. Lázaro I, Díaz M, Cabré A, Masana L, Ibáñez L. Fatty acid-binding protein-4 plasma levels are associated to metabolic abnormalities and response to therapy in girls and young women with androgen excess. Gynecol Endocrinol 2011; 27: 935-9.
45. Ibáñez L, Lopez-Bermejo A, Diaz M, Marcos MV, de Zegher F. Early metformin therapy to delay menarche and augment height in girls with precocious pubarche. Fertil Steril 2011; 95: 727-30.
46. Petry CJ, Ong KK, Wingate DL, de Zegher F, Ibáñez L, Dunger DB. Lack of association between common polymorphisms in the 17beta-hydroxysteroid dehydrogenase type V gene (HSD17B5) and precocious pubarche. J Steroid Biochem Mol Biol 2007; 105: 176-80.
47. de Zegher F, Ibáñez L. Prenatal growth restraint followed by catchup of weight: a hyperinsulinemic pathway to polycystic ovary syndrome. Fertil Steril 2006; 86: 4-5.
48. Rosenfield RL. Clinical review: Identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab. 2007; 92: 787-96.
49. Sir-Petermann T, Codner E, Maliqueo M, et al. Increased antiMüllerian hormone serum concentrations in prepubertal daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91: 3105-9.
50. Crisosto N, Codner E, Maliqueo M, et al. Anti-Müllerian hormone levels in peripubertal daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92: 2739-43.
51. Sir-Petermann T, Codner E, Pérez V, et al. Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2009; 94: 1923-30.
52. Hickey M. Clinical, ultrasound and biochemical features of polycystic ovary syndrome in adolescents: implications for diagnosis. Hum Reprod 2011; 26: 1469-77.
53. Villarroel C, Merino PM, López P, et al. Polycystic ovarian morphology in adolescents with regular menstrual cycles is associated with elevated anti-Mullerian hormone. Hum Reprod 2011; 26: 2861-8.
54. Bronstein J, Tawdekar S, Liu Y, Pawelczak M, David R, Shah B. Age of onset of polycystic ovarian syndrome in girls may be earlier than previously thought. J Pediatr Adolesc Gynecol 2011; 24: 15-20.
55. Doster JA, Purdum MB, Martin LA, Goven AJ, Moorefield R. Gender differences, anger expression, and cardiovascular risk. J Nerv Ment Dis 2009, 197: 552-4.
56. Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005; 90: 3847-53.
57. Oppermann K, Fuchs SC, Spritzer PM. Ovarian volume in preand perimenopausal women: a population-based study. Menopause 2003; 10: 209-13.
58. Donato GB, Fuchs SC, Oppermann K, Bastos C, Spritzer PM. Association between menopause status and central adiposity measured at different cutoffs of waist circumference and waist-to-hip ratio. Menopause 2006; 13: 280-5.
59. Maturana MA, Spritzer PM. Association between hyperinsulinemia and endogenous androgen levels in periand postmenopausal women. Metabolism 2002; 51: 238-43.
60. Krentz AJ, von Mühlen D, Barrett-Connor E. Searching for polycystic ovary syndrome in postmenopausal women: evidence of a dose-effect association with prevalent cardiovascular disease. Menopause 2007; 14: 284-92.
61. Maturana MA, Breda V, Lhullier F, Spritzer PM. Relationship between endogenous testosterone and cardiovascular risk in early postmenopausal women. Metabolism 2008; 57: 961-5.
62. de Groot PC, Dekkers OM, Romijn JA, Dieben SW, Helmerhorst FM. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Hum Reprod Update 2011; 17: 495-500.
63. Ramos RB, Casanova GK, Maturana MA, Spritzer PM. Variations in the fat mass and obesity-associated (FTO) gene are related to glucose levels and higher lipid accumulation product in postmenopausal women from southern. Brazil Fertil Steril 2011; 96: 974-9.
64. Uribarri J, Tuttle KR. Advanced glycation end products and nephrotoxicity of high-protein diets. Clin J Am Soc Nephrol 2006; 1: 1293-9.
65. Diamanti-Kandarakis E, Katsikis I, Piperi C, et al. Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2008; 69: 634-41.
66. Diamanti-Kandarakis E, Piouka A, Livadas S, et al. Anti-mullerian hormone is associated with advanced glycosylated end products in lean women with polycystic ovary syndrome. Eur J Endocrinol 2009; 160: 847-53.
67. Jinno M, Takeuchi M, Watanabe A, et al. Advanced glycation endproducts accumulation compromises embryonic development and achievement of pregnancy by assisted reproductive technology. Hum Reprod 2011; 26: 604-10.
68. Fernández 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: 1217-22.
69. Masuno H, Kidani T, Sekiya K, et al. Bisphenol A in combination with insulin can accelerate the conversion of 3T3-L1 fibroblasts to adipocytes. J Lipid Res 2002; 43: 676-84.
70. Kandaraki E, Chatzigeorgiou A, Livadas S, 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: 480-4.
71. Zhou W, Liu J, Liao L, Han S, Liu J. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol Cell Endocrinol 2008; 13: 12-8.
72. Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. Obesity and reproductive disorders in women. Hum Reprod Update 2003; 9: 359-72.
73. Froen JF, Arnestad M, Frey K, Vege A, Saugstad OD, Stray-Pedersen B. Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986-1995. Am J Obstet Gynecol 2001; 184: 694-702.
74. 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: 673-83.
75. Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1999; 84: 1617-22.
76. Imani B, Eijkemans MJ, de Jong FH, et al. Free androgen index and leptin are the most prominent endocrine predictors of ovarian response during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 2000; 85: 676-82.
77. Imani B, Eijkemans MJ, de Velde ER, Habbema JD, Fauser BC. A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. Fertil Steril 2002; 77: 91-7.
78. Mulders AG, Laven JS, Eijkemans MJ, Hughes EG, Fauser BC. Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis. Hum Reprod Update 2003; 9: 429-49.
79. Balen AH, Platteau P, Andersen AN, et al. The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group II anovulatory infertility. BJOG 2006; 113: 1195-202.
80. Moran LJ, Brinkworth G, Noakes M, Norman RJ. Effects of lifestyle modification in polycystic ovarian syndrome. Reprod Biomed Online 2006; 12: 569-78.
81. Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992; 36: 105-11.
82. Spritzer PM, Wiltgen D. Prevalence of metabolic syndrome in patients of south of Brazil with polycystic ovary syndrome (PCOS). Arq Bras Endocrinol Metabol 2007; 51: 146-7.
83. Toscani M, Migliavacca R, Sisson de Castro JÁ, Spritzer PM. Estimation of truncal adiposity using waist circumference or the sum of trunk skinfolds: a pilot study for insulin resistance screening in hirsute patients with or without polycystic ovary syndrome. Metabolism 2007; 56: 992-7.
84. Wiltgen D, Benedetto IG, Mastella LS, Spritzer PM. Lipid accumulation product index: a reliable marker of cardiovascular risk in polycystic ovary syndrome. Hum Reprod 2009; 24: 1726-31.
85. Xiang S, Hua F, Tang Y, Jiang X, Zhuang Q, Qian F. Relationship between Serum Lipoprotein Ratios and Insulin Resistance in Polycystic Ovary Syndrome. Int J Endocrinol 2012; doi: 10.1155/2012/173281.
86. Wiltgen D, Spritzer PM. Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes. Fertil Steril 2010; 94: 2493-6.
87. Carmina E, Legro RS, Stamets K, Lowell J, Lobo RA. Difference in body weight between American and Italian women with polycystic ovary syndrome: influence of the diet. Hum Reprod 2003; 18: 2289-93.
88. Toscani MK, Mario FM, Radavelli-Bagatini S, Spritzer PM. Insulin resistance is not strictly associated with energy intake or dietary macronutrient composition in women with polycystic ovary syndrome. Nutr Res 2011; 31: 97-103.
89. Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2011; 7: CD007506.
90. Moran LJ, Pasquali R, Teede HJ et al. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 2009; 92: 1966-82.
91. Hutchison SK, Stepto NK, Harrison CL, Moran LJ, Strauss BJ, Teede HJ. Effects of exercise on insulin resistance and body composition in overweight and obese women with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2011; 96: 48-56.
92. Harrison CL, Lombard CB, Moran LJ, Teede HJ. Exercise therapy in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2011; 17: 171-83.
93. Palomba S, Falbo A, Giallauria F, et al. Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial. Hum Reprod 2010; 25: 2783-91.
94. Homburg R. Clomiphene citrate-end of an era? A mini-review. Hum Reprod 2005; 20: 2043-51.
95. Legro RS, Barnhart HX, Schlaff WD, et al. Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356: 551-66.
96. Palomino WA, Fuentes A, González RR, et al. Differential expression of endometrial integrins and progesterone receptor during the window of implantation in normo-ovulatory women treated with clomiphene citrate. Fertil Steril 2005; 83: 587-93.
97. Moghetti PR, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: A randomized, double-blind, placebocontrolled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metabol 2000; 85: 139-46.
98. Glueck CJ, Fontaine RN, Wang P, et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism 2001; 50: 856-61.
99. Jakubowicz DJ, Sépala M, Jakubowicz S, 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 he polycystic ovary syndrome. J Clin Endocrinol Metabol 2001; 86: 1126-33.
100. Faure P, Rossini E, Wiernsperger N. An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. Diabetes 1999; 48: 353-7.
101. Ceriello, A. Oxidative stress and glycemic regulation. Metabolism 2000; 49: 27-9.
102. Srividhya S, Ravichandran MK, Anuradha CV. Metformin attenuates blood lipid peroxidation and potentiates antioxidant defense in high fructose-fed rats. J Biochem Mol Biol Bioph 2000; 6: 379-85.
103. Bonnefont-Rousselot D, Raji B, Walrand M, et al. An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. Metabolism 2003; 52: 586-9.
104. Elia E, Sander V, Luchetti CG, et al. The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice. Mol Hum Reprod 2006; 12: 475-81.
105. Sander V, Luchetti CG, Solano ME, et al. Role of the N,Ń- dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone. Reproduction 2006; 131: 591-602.
106. Solano ME, Elia E, Luchetti CG, et al. Metformin prevents embryonic resorption induced by hyperandrogenization with dehydroepiandrosterone in mice. Reprod Fert Dev 2006; 18: 533-44.
107. Zhou G, Myers R, Li Y, et al. Role of AMP- activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167-74.
108. Musi N, Hirshman MF, Nygren J, et al. Metformin increases AMP- activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002; 51: 2074-81.
109. Zou MH, Kirkpatrick SS, Davis BJ, et al. Activation of the AMP- activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species.J Biolog Chem 2004; 279: 43940-51.
110. Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol 2010; 162: 193-212.
111. Crisosto N, Echiburú B, Maliqueo M, et al. Improvement of hyperandrogenism and hyperinsulinemia during pregnancy in women with polycystic ovary syndrome: possible effect in the ovarian follicular mass of their daughters. Fertil Steril 2012; 97: 218-24.
112. Brown JB. Pituitary control of ovarian function-concepts derived from gonadotrophin therapy. Aust N Z J Obstet Gynaecol 1978; 18: 46-54.
113. Baird DT. A model for follicular selection and ovulation: lessons from superovulation. J Steroid Biochem 1987; 27: 15-23.
114. Dale O, Tanbo T, Lunde O, Abyholm T. Ovulation induction with low-dose follicle-stimulating hormone in women with the polycystic ovary syndrome. Acta Obstet Gynecol Scand 1993; 72: 43-6.
115. Fauser BC, Van Heusden AM. Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr Rev 1997; 18: 71-106.
116. Balasch J, Fabregues F, Creus M, Puerto B, Penarrubia J, Vanrell JA. Follicular development and hormone concentrations following recombinant FSH administration for anovulation associated with polycystic ovarian syndrome: prospective, randomized comparison between low-dose step-up and modified step-down regimens. Hum Reprod 2001; 16: 652-6.
117. Christin-Maitre S, Hugues JN. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum Reprod 2003; 18: 1626-31.
118. van Santbrink EJ, Donderwinkel PF, van Dessel TJ, Fauser BC. Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients. Hum Reprod 1995; 10: 1048-53.
119. Hugues JN, Cedrin-Durnerin I, Howles CM, et al. The use of a decremental dose regimen in patients treated with a chronic lowdose step-up protocol for WHO Group II anovulation: a prospective randomized multicentre study. Hum Reprod 2006; 21: 2817-22.
120. Banaszewska B, Pawelczyk L, Spaczynski RZ, Dziura J, Duleba AJ. Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial. J Clin Endocrinol Metab 2007; 92: 456-61.
121. Rizzo M, Berneis K, Carmina E, Rini GB. How should we manage atherogenic dyslipidemia in women with polycystic ovary syndrome? Am J Obstet Gynecol 2008; 198: 1-5.
122. Gao L, Zhao FL, Li SC. Statin is a Reasonable Treatment Option for Patients with Polycystic Ovary Syndrome: a Meta-analysis of Randomized Controlled Trials. Exp Clin Endocrinol Diabetes 2012; 120: 367-95.
123. Sokalska A, Cress A, Kaylon L, et al. Simvastatin decreases invasiveness of human endometrial stromal cells. Biol Reprod 2012; 87: 2-9.