Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications

Evanthia Diamanti-Kandarakis

doi:10.1017/S1462399408000598

Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications

Published online by Cambridge University Press: 30 January 2008

Evanthia Diamanti-Kandarakis

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Evanthia Diamanti-Kandarakis: Affiliation:
University of Athens Medical School, Mikras Asias 75, Goudi 115-27, Athens, Greece. Tel: +30 210 8133318; Fax: +30 210 8130031; E-mail: [email protected]

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Abstract

Polycystic ovarian syndrome (PCOS) is universally recognised as the commonest endocrinopathy of women. The definition and the aetiological hypotheses of PCOS are continuously evolving to accommodate expanding knowledge on the syndrome, which is now known to be more complex than purely a reproductive disorder. Increased androgen synthesis, disrupted folliculogenesis and insulin resistance lie at the pathophysiological core of PCOS. An intriguing concept involves the perpetuation of a vicious circle with endocrine/reproductive and metabolic components. An unfavourable metabolic environment may unmask genetic traits of ovarian dysfunction, and the unfolding endocrine derangement could further aggravate the metabolic disarray. This article reviews the molecular mechanisms known to underlie the ovarian and metabolic abnormalities characterising PCOS. The putative interdependence between reproductive and metabolic aspects of PCOS, and therapeutic implications for the management of PCOS, are also discussed.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e3

DOI: https://doi.org/10.1017/S1462399408000598 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2008

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References

1Diamanti-Kandarakis, E. et al. (1999) A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 84, 4006-4011CrossRef Google Scholar PubMed

2Escobar-Morealle, H. et al. (2000) A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 85, 2434-2438Google Scholar

3Zawadski, J.K. and Dunaif, A.(1992) Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In Polycystic Ovary Syndrome (Dunaif, A. et al. , eds), pp. 377-384, Blackwell Scientific Publications, OxfordGoogle Scholar

4The Rotterdam ESHRE ASRM-sponsored PCOS Consensus Workshop Group(2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81, 19-25Google Scholar

5Franks, S.(2006) Diagnosis of polycystic ovarian syndrome: in defence of the Rotterdam criteria. J Clin Endocrinol Metab 91, 786-789CrossRef Google Scholar PubMed

6Azziz, R.(2006) Diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 91, 781-785CrossRef Google Scholar PubMed

7Azziz, R. et al. (2006) Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 91, 4237-4245CrossRef Google Scholar PubMed

8Chang, W. et al. (2005) Phenotypic spectrum of polycystic ovary syndrome: clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril 83, 1717-23CrossRef Google Scholar PubMed

9Diamanti-Kandarakis, E. and Panidis, D.(2007) Unravelling the phenotypic map of polycystic ovaries syndrome (PCOS): a prospective study of 634 women with PCOS. Clin Endocrinol 67, 735-742CrossRef Google Scholar PubMed

10Barber, T. et al. (2007) Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol 66, 513-517CrossRef Google Scholar PubMed

11Poretsky, L.(1999) The insulin-related ovarian regulatory system in health and disease. Endocr Rev 20, 535-582CrossRef Google Scholar PubMed

12Legro, R.S. et al. (1998) Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A 95, 14956-14960CrossRef Google Scholar PubMed

13Nelson, V.L. et al. (1999) Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol 13, 946-957CrossRef Google Scholar PubMed

14Wood, J.R. et al. (2004) The molecular signature of PCOS theca cells defined by gene expression profiling. J Reprod Immunol 63, 51-60CrossRef Google Scholar PubMed

15Wickenheisser, J.K. et al. (2004) Increased cytochrome P450 17a-hydroxylase promoter function in theca cells isolated from patients with polycystic ovary syndrome involves nuclear factor-1. Mol Endocrinol 18, 588-605CrossRef Google Scholar

16Wickenheisser, J.K., Nelson-Degrave, V.L. and McAllister, J.M.(2006) Human ovarian theca cells in culture. Trends Endocrinol Metab 17, 63-69CrossRef Google Scholar PubMed

17Wickenheisser, J.K. et al. (2005) Retinoids and retinol differentially regulate steroid biosynthesis in ovarian theca cells isolated from normal cycling women and women with polycystic ovary syndrome. J Clin Endocrinol Metab 90, 4858-4865CrossRef Google Scholar PubMed

18Oksjoki, S. et al. (2005) Molecular profiling of polycystic ovaries for markers of cell invasion and matrix turnover. Fertil Steril 83 937-944CrossRef Google Scholar PubMed

19Wickenheisser, J.K. et al. (2005) Dysregulation of cytochrome P450 17alpha-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome. J Clin Endocrinol Metab 90, 1720-1727CrossRef Google Scholar PubMed

20Wood, J.R. et al. (2003) The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem 278, 26380-26390CrossRef Google Scholar PubMed

21Pandey, A.V. and Miller, W.L.(2005) Regulation of 17,20 lyase activity by cytochrome b5 and by serine phosphorylation of P450c17. J Biol Chem 280, 13265-13271CrossRef Google Scholar PubMed

22Zhang, L. et al. (1995) Serine phosphorylation of human P450c17 increases 17,20 lyase activity: implications for adrenarche and for the polycystic ovary syndrome. Proc Natl Acad Sci U S A 92, 10619-10623CrossRef Google Scholar PubMed

23Akhtar, M., Kelly, S. and Kaderbhai, M.(2005) Cytochrome b5 modulation of 17{alpha} hydroxylase and 17-20 lyase (CYP17)activities in steroidogenesis. J Endocrinol 187, 267-274CrossRef Google Scholar PubMed

24Pandey, A.V., Mellon, S.H. and Miller, W.L.(2003) Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17. J Biol Chem 278, 2837-2844CrossRef Google Scholar PubMed

25Nelson-Degrave, V.L. et al. (2005) Alterations in MAPK kinase and ERK signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome. Mol Endocrinol 19, 379-390CrossRef Google Scholar

26Jonard, S. and Dewailly, D.(2004) The follicular excess in polycystic ovaries, due to intraovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update 10, 107-117CrossRef Google Scholar PubMed

27Baillargeon, J.P. and Carpentier, A.(2007) Role of insulin in the hyperandrogenemia of lean women with polycystic ovary syndrome and normal insulin sensitivity. Fertil Steril 88, 886-893CrossRef Google Scholar PubMed

28Munir, I. et al. (2004) Insulin augmentation of 17a-hydroxylase activity is mediated by phosphatidyl inositol 3-kinase but not extracellular signall-regulated kinase-1/2 in human ovarian theca cells. Endocrinology 145, 175-183CrossRef Google Scholar

29Nestler, J.E. et al. (1998) 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 signall transduction system. J Clin Endocrinol Metab 83, 2001-2005Google Scholar

30Knight, P.G. and Glister, C.(2006) TGF-β superfamily members and ovarian follicle development. Reproduction 121, 503-512Google Scholar PubMed

31Ingraham, H.A. et al. (2000) Autocrine and paracrine Műllerian inhibiting substance hormone signallling in reproduction. Recent Prog Horm Res 55, 53-67Google Scholar

32Pigny, P. et al. (2003) Elevated serum level of Anti-müllerian hormone (AMH) in polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metab 88, 5957-5962CrossRef Google Scholar

33McConell, L.A. et al. (2002) The distribution of betaglycan protein and mRNA in rat brain, pituitary, and gonads: implications for a role for betaglycan in inhibin-mediated reproductive functions. Endocrinology 143, 1066-1075CrossRef Google Scholar

34Pigny, P. et al. (2000) Serum levels of inhibins are differentially altered in patients with polycystic ovary syndrome: effects of being overweight and relevance to hyperandrogenism. Fertil Steril 73, 972-7CrossRef Google Scholar PubMed

35Welt, C. et al. (2002) Serum inhibin B in polycystic ovary syndrome: regulation by insulin and luteinizing hormone. J Clin Endocrinol Metab 87, 5559-5565CrossRef Google Scholar PubMed

36Goodarzi, M. et al. (2007) Correlation of adrenocorticotropin steroid levels between women with polycystic ovary syndrome and their sisters. Am J Obstet Gynecol 196, 398.e1-398.e6CrossRef Google Scholar PubMed

37Yildiz, B. et al. (2004) Stability of adrenocortical steroidogenesis over time in healthy women and women with polycystic ovary syndrome. J Clin Endocrinol Metab 89, 5558-5562CrossRef Google Scholar PubMed

38Tsilchorozidou, T., Honour, J. and Conway, G.(2003) Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5a-reduction but not the elevated adrenal steroid production rates. J Clin Endocrinol Metab 88, 5907-5913CrossRef Google Scholar

39Rosenfield, R.(1999) Ovarian and adrenal function in PCOS. Endocrinol Metab Clin North Amer 28, 265-293CrossRef Google Scholar

40Broekmans, F.J. et al. (2006) PCOS according to the Rotterdam consensus criteria: change in prevalence among WHO-II anovulation and association with metabolic factors. BJOG 113, 1210-1217CrossRef Google Scholar

41Webber, L.J. et al. (2003) Formation and early development of follicles in the polycystic ovary. Lancet 362, 1017-1021CrossRef Google Scholar PubMed

42Webber, L.J. et al. (2007) Prolonged survival in culture of preantral follicles from polycystic ovaries. J Clin Endocrinol Metab 92, 1975-1978CrossRef Google Scholar PubMed

43Nikolaou, D. and Gilling-Smith, C.(2004) Early ovarian ageing: Are women with polycystic ovaries protected. Hum Reprod 19, 2175-2179CrossRef Google Scholar PubMed

44Jakimiuk, A.J. et al. (2001) Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab 86, 1318-1323Google Scholar PubMed

45Willis, D. et al. (1998) Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation. J Clin Endocrinol Metab 83, 3984-3991Google Scholar PubMed

46Zeleznik, J., Little-Ihrig, L. and Ramasawamy, S.(2004) Administration of dihydrotestosterone to rhesus monkeys inhibits gonadotropin-stimulated ovarian steroidogenesis. J Clin Endocrinol Metab 89, 860-866CrossRef Google Scholar PubMed

47Loumaye, E. et al. (2003) Clinical evidence for an LH ‘ceiling’ effect induced by administration of recombinant human LH during the late follicular phase of stimulated cycles in World Health Organization type I and type II anovulation. Hum Reprod 18, 314-322CrossRef Google Scholar

48Coffler, M.S. et al. (2003) Evidence for abnormal granulosa cell responsiveness to FSH in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88, 1742-1747CrossRef Google Scholar PubMed

49Tao, Z. and Yan, L.(2005) Luteinizing hormone and insulin inducing earlier and excess expression of luteinizing hormone receptor messenger ribonucleic acids in granulosa cells of polycystic ovary syndrome. Fertil Steril 84, S426-S427CrossRef Google Scholar

50Poretsky, L.(2006) Commentary: polycystic ovary syndrome – increased or preserved ovarian sensitivity to insulin? J Clin Endocrinol Metab 91, 2859-2860CrossRef Google Scholar PubMed

51Phy, J. et al. (2004) Insulin and messenger ribonucleic acid expression of insulin receptor isoforms in ovarian follicles from nonhirsute ovulatory women and polycystic ovary syndrome patients. J Clin Endocrinol Metab 89, 3561-3566CrossRef Google Scholar PubMed

52Poretsky, L. et al. (2001) Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary. J Clin Endocrinol Metab 86, 3115-3119Google Scholar PubMed

53Seto-Young, D. et al. (2003) The role of mitogen-activated protein kinase in insulin and insulin-like growth factor I (IGF-I) signalling cascades for progesterone and IGF-binding protein-1 production in human granulosa cells. J Clin Endocrinol Metab 88, 3385-3391CrossRef Google Scholar PubMed

54Rice, S. et al. (2005) Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Hum Reprod 20, 373-381CrossRef Google Scholar PubMed

55Wu, X.K. et al. (2003) Selective ovary resistance to insulin signalling in women with polycystic ovary syndrome. Fertil Steril 80, 954-965CrossRef Google Scholar PubMed

56Foong, S. et al. (2006) Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapy for in vitro fertilization. J Clin Endocrinol Metab 91, 2327-2333CrossRef Google Scholar PubMed

57Coffler, M. et al. (2003) Enhanced granulosa cell responsiveness to follicle-stimulating hormone during insulin infusion in women with polycystic ovary syndrome treated with pioglitazone. J Clin Endocrinol Metab 88, 5624-5631CrossRef Google Scholar PubMed

58Bhatia, B. and Price, C.(2001) Insulin alters the effects of follicle stimulating hormone on aromatase in bovine granulosa cells in vitro. Steroids 66, 511-519CrossRef Google Scholar PubMed

59Maciel, G. et al. (2004) Stockpiling of transitional and classic primary follicles in ovaries of women with polycystic ovary syndrome. J Clin Endocrinol Metab 89, 5321-5327CrossRef Google Scholar PubMed

60Rice, S. et al. (2007) Stage-specific expression of androgen receptor, follicle-stimulating hormone receptor, and antimullerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries. J Clin Endocrinol Metab 92, 1034-1040CrossRef Google Scholar PubMed

61Vendola, K. et al. (1999) Androgens promote insulin-like growth factor-I and insulin-like growth factor-I receptor gene expression in the primate ovary. Hum Reprod 14, 2328-2332CrossRef Google Scholar PubMed

62Luo, W. and Wiltbank, M.C.(2006) Distinct regulation by steroids of messenger RNAs for FSHR and CYP19A1 in bovine granulosa cells. Biol Reprod 75, 217-225CrossRef Google Scholar PubMed

63Weil, S. et al. (1999) Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab 84, 2951-2956CrossRef Google Scholar PubMed

64Pradeep, P.K. et al. (2002) Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase. Endocrinology 143, 2930-2935CrossRef Google Scholar PubMed

65Hickey, T.E. et al. (2005) Androgens augment the mitogenic effects of oocyte secreted factors and growth differentiation factor 9 on porcine granulosa cells. Biol Reprod 73, 825-832CrossRef Google Scholar PubMed

66Greisen, S., Ledet, T. and Ovesen, P.(2001) Effects of androstenedione, insulin and LH on steroidogenesis in human granulosa luteal cells. Hum Reprod 16, 2061-2065CrossRef Google Scholar PubMed

67Dumesic, D. et al. (2003) Reduced intrafollicular androstenedione and estradiol levels in early-treated prenatally androgenized female rhesus monkeys receiving FSH therapy for in vitro fertilization. Biol Reprod 69, 1213-1219CrossRef Google Scholar PubMed

68Jakimiuk, A.J., Weitsman, S.R. and Magoffin, D.A.(1999) 5alpha-Reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 84, 2414-2418Google Scholar PubMed

69Weenen, C. et al. (2004) AntiMullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 10, 77-83CrossRef Google Scholar PubMed

70Cook, C.L. et al. (2002) Relationship between serum mullerian-inhibiting substance and other reproductive hormones in untreated women with polycystic ovary syndrome and normal women. Fertil Steril 77, 141-146CrossRef Google Scholar PubMed

71Pellatt, L. et al. (2007) Granulosa cell production of antimullerian hormone is increased in polycystic ovaries. J Clin Endocrinol Metab 92, 240-245CrossRef Google Scholar PubMed

72Pigny, P. et al. (2006) Serum antiMullerian hormone as a surrogate for antral follicle count for definition of the polycystic ovary syndrome. J Clin Endocrinol Metab 91, 941-945CrossRef Google Scholar PubMed

73McNatty, K.P. et al. (2004) The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology Reproduction 128, 379-386CrossRef Google Scholar

74Teixeira Filho, F.L. et al. (2002) Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J Clin Endocrinol Metab 87, 1337-1344CrossRef Google Scholar PubMed

75Gambineri, A.R. et al. (2002) Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord 26, 883-896CrossRef Google Scholar PubMed

76Azziz, R. et al. (2004) The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89, 2745-2749CrossRef Google Scholar

77Alvarez-Blasco, F. et al. (2006) Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med 166, 2081-2086CrossRef Google Scholar PubMed

78Ciaraldi, T.P. et al. (1992) Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 75, 577-583Google Scholar PubMed

79Dunaif, A. et al. (1992) Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41, 1257-1266CrossRef Google Scholar PubMed

80Lystedt, E. et al. (2005) Subcutaneous adipocytes from obese hyperinsulinemic women with polycystic ovary syndrome exhibit normal insulin sensitivity but reduced maximal insulin responsiveness. Eur J Endocrinol 153, 831-835CrossRef Google Scholar PubMed

81Mor, E. et al. (2004) The insulin resistant subphenotype of polycystic ovary syndrome: clinical parameters and pathogenesis. Am J Obstet Gynecol 190, 1654-1660CrossRef Google Scholar PubMed

82Diamanti-Kandarakis, E. and Papavasiliou, A.(2006) Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Trends Mol Med 12, 324-332CrossRef Google Scholar PubMed

83Goodarzi, M. et al. (2007) Preliminary evidence of glycogen synthase kinase 3 beta as a genetic determinant of the polycystic ovary syndrome. Fertil Steril 87, 1473-1476CrossRef Google Scholar PubMed

84Rosenbaum, D., Haber, R.S. and Dunaif, A.(1993) Insulin resistance in PCOS: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 264, E197-202Google Scholar PubMed

85Seow, K.M. et al. (2007) Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery. Hum Reprod 22, 1003-1010CrossRef Google Scholar PubMed

86Corton, M. et al. (2007) Differential gene expression profile in omental adipose tissue in women with polycystic ovary syndrome. J Clin Endocrinol Metab 92, 328-337CrossRef Google Scholar PubMed

87Dunaif, A. et al. (1995) 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 96, 801-810CrossRef Google Scholar PubMed

88Dunaif, A. et al. (2001) Defects in insulin receptor signalling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab 281, E392-E399CrossRef Google Scholar PubMed

89Corbould, A. et al. (2005) Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signalling. Am J Physiol Endocrinol Metab 288, E1047-E1054CrossRef Google Scholar

90Corbould, A. et al. (2006) Enhanced mitogenic signalling in skeletal muscle of women with polycystic ovary syndrome. Diabetes 55, 751-759CrossRef Google Scholar PubMed

91Abbott, D., Dumesic, D. and Franks, S.(2002) Developmental origin of polycystic ovary syndrome - a hypothesis. J Endocrinol 174, 1-5CrossRef Google Scholar PubMed

92Ibanez, L. et al. (2003) Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinemia and androgenemia from pre-puberty to postmenarche. Clin Endocrinol (Oxf) 58, 372-379CrossRef Google Scholar

93Ibanez, L. and de Zegher, F.(2003) Flutamide-metformin therapy to reduce fat mass in hyperinsulinemic ovarian hyperandrogenism: effects in adolescents and in women on third-generation oral contraception. J Clin Endocrinol Metab 88, 4720-4724CrossRef Google Scholar PubMed

94Rodriguez-Cuenca, S. et al. (2005) Depot differences in steroid receptor expression in adipose tissue: possible role of the local steroid milieu. Am J Physiol Endocrinol Metab 288, E200-E207CrossRef Google Scholar PubMed

95De Pergola, G.(2000) The adipose tissue metabolism: role of testosterone and dehydroepiandrosterone. Int J Obes Relat Metab Disord 24 (Suppl 2), S59-S63CrossRef Google Scholar PubMed

96Corbould, A.(2007) Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women. J Endocrinol 192, 585-594CrossRef Google Scholar PubMed

97Polderman, K. et al. (1994) Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79, 265-271Google Scholar

98Elbers, J. et al. (2003) Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects Clin Endocrinol 58, 562-571CrossRef Google Scholar PubMed

99Allemand, M. et al. (2005) An in vitro model for PCOS related insulin resistance: the effects of testosterone on phosphorylation of intracellular insulin signalling proteins in rat skeletal muscle primary culture. Fertil Steril Abstracts 84 (Suppl 1), S30-31CrossRef Google Scholar

100Puder, J. et al. (2005) Central fat excess in polycystic ovary syndrome: relation to low-grade inflammation and insulin resistance J Clin Endocrinol Metab 90, 6014-6021CrossRef Google Scholar PubMed

101Sayin, N.C. et al. (2003) Elevated serum TNF-a levels in normal-weight women with polycystic ovaries or the polycystic ovary syndrome. J Reprod Med 48, 165-170Google Scholar PubMed

102González, F. et al. (2006) In vitro evidence that hyperglycemia stimulates TNF- α release in obese women with polycystic ovary syndrome. J Endocrinol 188, 521-529CrossRef Google Scholar PubMed

103Vlassara, H.(2005) Advanced glycation in health and disease: role of the modern environment. Ann N Y Acad Sci 1043, 452-460CrossRef Google Scholar PubMed

104Diamanti-Kandarakis, E. et al. (2005) Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin Endocrinol 62, 37-43CrossRef Google Scholar PubMed

105Miele, C. et al. (2003) Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin eceptor substrate (IRS) signalling through a protein kinase C-α mediated mechanism. J Biol Chem 278, 47376-47387CrossRef Google Scholar

106Diamanti-Kandarakis, E. et al. (2007) Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol 127, 581-589CrossRef Google Scholar PubMed

107Diamanti-Kandarakis, E. et al. (2007) Accumulation of dietary glycotoxins in the reproductive system of normal female rats. J Mol Med 85, 1413-1420CrossRef Google Scholar PubMed

108Margolin, E. et al. (2005) Polycystic ovary syndrome in post-menopausal women—marker of the metabolic syndrome. Maturitas 50, 331-336CrossRef Google Scholar PubMed

109Krentz, A., von Mühlen, D. and Barrett-Connor, E.(2007) Searching for polycystic ovary syndrome in postmenopausal women: evidence of a dose-effect association with prevalent cardiovascular disease. Menopause 14, 284-292CrossRef Google Scholar PubMed

110Diamanti-Kandarakis, E. et al. (2006) Polycystic ovary syndrome: the influence of environmental and genetic factors. Hormones (Athens) 5, 17-34CrossRef Google Scholar PubMed

111Mlinar, B. et al. (2007) Molecular mechanisms of insulin resistance and associated diseases. Clin Chim Acta 375, 20-35CrossRef Google Scholar PubMed

112Mai, K. et al. (2006) Free fatty acids increase androgen precursors in vivo. J Clin Endocrinol Metab 91, 1501-1507CrossRef Google Scholar PubMed

113Kelly, C. et al. (2001) Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 86, 2453-2455CrossRef Google Scholar PubMed

114Diamanti-Kandarakis, E. et al. (2006) Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin. Hum Reprod 21, 1426-1431CrossRef Google Scholar PubMed

115Spaczynski, R.Z., Arici, A. and Duleba, A.J.(1999) Tumor necrosis factor-a stimulates proliferation of rat ovarian theca interstitial cells. Biol Reprod 61, 993-998CrossRef Google Scholar

116Kwintkiewicz, J. et al. (2006) Insulin and oxidative stress modulate proliferation of rat ovarian theca-interstitial cells through diverse signal transduction pathways. Biol Reprod 74, 1034-1040CrossRef Google Scholar PubMed

117Panidis, D. et al. (2004) Serum resistin levels in women with polycystic ovary syndrome. Fertil Steril 81, 361-366CrossRef Google Scholar PubMed

118Munir, I. et al. (2005) Resistin stimulation of 17alpha-hydroxylase activity in ovarian theca cells in vitro: relevance to polycystic ovary syndrome. J Clin Endocrinol Metab 90, 4852-4857CrossRef Google Scholar PubMed

119Escobar-Morreale, H.F., Villuendas, G. and Botella-Carretero, J.I.(2006) Adiponectin and resistin in PCOS: a clinical, biochemical and molecular genetic study. Hum Reprod 121, 2257-2265CrossRef Google Scholar

120Seow, K., Juan, C. and Ho, L.(2007) Adipocyte resistin mRNA levels are down-regulated by laparoscopic ovarian electrocautery in both obese and lean women with polycystic ovary syndrome. Hum Reprod 22, 1100-1106CrossRef Google Scholar PubMed

121Moran, L.J. et al. (2003) Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 88, 812-819CrossRef Google Scholar PubMed

122Hoeger, K.M. et al. (2004) A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril 82, 421-429CrossRef Google Scholar PubMed

123Marsh, K. and Brand-Miller, J.(2005) The optimal diet for women with polycystic ovary syndrome? B J Nutr 94, 154-165CrossRef Google Scholar PubMed

124Nestler, J.(2002) Should patients with polycystic ovarian syndrome be treated with metformin? An enthusiastic endorsement. Hum Reprod. 17, 1950-1953CrossRef Google Scholar PubMed

125Diamanti-Kandarakis, E.(2007) Insulin resistance and polycystic ovarian syndrome: pathogenesis, evaluation and treatment. In Pharmaceutical Intervention in Metabolic and Cardiovascular Risk Factors in Polycystic Ovary Syndrome (Diamanti-Kandarakis, E. et al. , eds), pp. 367-385, Humana PressGoogle Scholar

126Kolodziejczyk, B. et al. (2000) Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril 73, 1149-1154CrossRef Google Scholar PubMed

127Lord, J.M., Flight, I.H. and Norman, R.J.(2003) Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 327, 951-953CrossRef Google Scholar PubMed

128Jakubowicz, D.J. et al. (2002) Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 87, 524-529CrossRef Google Scholar PubMed

129Morin Papunen, L. et al. (2003) Metformin reduces serum C-Reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88, 4649-4654CrossRef Google Scholar PubMed

130Diamanti-Kandarakis, E. et al. (2005) Metformin administration improves endothelial function in women with polycystic ovary syndrome. Eur J Endocrinol 152, 749-56CrossRef Google Scholar PubMed

131Diamanti-Kandarakis, E. et al. (2007) Effect of metformin administration on plasma advanced glycation end product levels in women with polycystic ovary syndrome. Metabolism 56, 129-134CrossRef Google Scholar PubMed

132Genazzani, A. et al. (2007) Metformin administration is more effective when non- obese patients with polycystic ovary syndrome show both hyperandrogenism and hyperinsulinemia. Gynecol Endocrinol 23, 146-152CrossRef Google Scholar PubMed

133Genazzani, A. et al. (2004) Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril 81, 114-119CrossRef Google Scholar PubMed

134Attia, G.R. et al. (2001) Metformin directly inhibits androgen production in human thecal cells. Fertil Steril 76, 517-524CrossRef Google Scholar PubMed

135Costello, M. et al. (2007) Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. Hum Reprod 22, 1200-1209CrossRef Google Scholar PubMed

136Legro, R. et al. (2007) Clomiphene, metformin or both for infertility in the polycystic ovary syndrome. N Engl J Med 356, 551-566CrossRef Google Scholar PubMed

137Palomba, S. et al. (2005) Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 90, 4068-4074CrossRef Google Scholar PubMed

138Romualdi, D. et al. (2003) Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome. Hum Reprod 18, 1210-1218CrossRef Google Scholar PubMed

139Brettenthaler, N. et al. (2004) Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J Clin Endocrinol Metab 89, 3835-3840CrossRef Google Scholar PubMed

140Sepilian, V. and Nagamani, M.(2005) Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance. J Clin Endocrinol Metab 90, 60-65CrossRef Google Scholar PubMed

141Seto-Young, D. et al. (2005) 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 90, 6099-6105CrossRef Google Scholar PubMed

142Ortega-Gonzalez, C. et al. (2005) Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab 90, 1360-1365CrossRef Google Scholar PubMed

143Glueck, C.J. et al. (2003) Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Hum Reprod 18, 1618-1625CrossRef Google Scholar

144Kilicdag, E.B. et al. (2005) Homocysteine levels in women with polycystic ovary syndrome. Hum Reprod 20, 894-899CrossRef Google Scholar PubMed

145Baillargeon, J.P. et al. (2004) Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril 82, 893-902CrossRef Google Scholar PubMed

146Legro, R.S. et al. (2003) Minimal response of circulating lipids in women with polycystic ovary syndrome to improvement in insulin sensitivity with troglitazone. J Clin Endocrinol Metab 88, 5137-5144CrossRef Google Scholar PubMed

147Diamanti-Kandarakis, E. et al. (1995) Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome. Metabolism 44, 525-531CrossRef Google Scholar PubMed

148Moghetti, P. et al. (1996) The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 81, 952-960Google Scholar PubMed

149Sahin, I. et al. (2004) Metformin versus flutamide in the treatment of metabolic consequences of non-obese young women with polycystic ovary syndrome: a randomized prospective study. Gynecol Endocrinol 19, 115-124CrossRef Google Scholar PubMed

150Diamanti-Kandarakis, E. et al. (1998) The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome. J Clin Endocrinol Metab 83, 2699-2705CrossRef Google Scholar PubMed

151Vrbikova, J. et al. (2004) Flutamide suppresses adrenal steroidogenesis but has no effect on insulin resistance and secretion and lipid levels in overweight women with polycystic ovary syndrome. Gynecol Obstet Invest 58, 36-41CrossRef Google Scholar PubMed

152Nader, S. et al. (1997) The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women. J Clin Endocrinol Metab 82, 3074-3077Google Scholar PubMed

153Diamanti-Kandarakis, E. et al. (2003) A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. J Clin Endocrinol Metab 88, 1927-1932CrossRef Google Scholar PubMed

154Mastorakos, G. et al. (2006) Effects of two forms of combined oral contraceptives on carbohydrate metabolism in adolescents with polycystic ovary syndrome. Fertil Steril 85, 420-427CrossRef Google Scholar PubMed

155Charitidou, C. et al. (2007) The administration of estrogens, combined with antiandrogens, has beneficial effects on the hormonal features and asymmetric dimethylarginine levels in women with polycystic ovary syndrome. Atherosclerosis, Apr 5; [Epub ahead of print]Google Scholar

156Morin-Papunen, L.C. et al. (2000) Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 85, 3161-3168Google Scholar PubMed

157Luque Ramirez, M. et al. (2007) Comparison of ethinyl-estradiol plus cyproterone acetate versus metformin effects on classic metabolic cardiovascular risk factors in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 92, 2453-2461CrossRef Google Scholar PubMed

158Banaszewska, B. et al. (2007) Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial. J Clin Endocrinol Metab 92, 456-461CrossRef Google Scholar PubMed

159Kwintkiewicz, J.(2006) Mevastatin inhibits proliferation of rat ovarian theca-interstitial cells by blocking the mitogen activated protein kinase pathway. Fertil Steril 86 (Suppl 3), 1053-1058CrossRef Google Scholar PubMed

160Edison, R.J. and Muenke, M.(2004) Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet 131, 287-298CrossRef Google Scholar PubMed

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Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications

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Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications

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