Metabolc aspects of polycystic ovary syndrome
Abstract
Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies, characterised by hyperandrogenism and chronic anovulation. Over the last twenty years, it has been widely recognized that in addition to endocrine and reproductive abnormalities, most women with PCOS demonstrate metabolic disturbances. This is not a surprising finding, since insulin resistance (IR) followed by compensatory hyperinsulinemia has been recognized as the central pathogenetic feature of the syndrome. Consequently, the PCOS women have higher rate and degree of impaired glucose tolerance, type 2 diabetes, central obesity, atherogenic dyslipidemia, arterial hypertension and even subclinical signs of atherosclerosis compared to age and weight matched controls. They often have an adverse cardiovascular risk profile, characteristic of the metabolic syndrome.
Conclusions: The knowledge about the association between IR and PCOS has been recently incorporated into the framework of PCOS treatment. There is increasing evidence that application of insulin sensitizing drugs, metformin and PPAR gamma agonists thiazolidinediones (TZDs), has favorable endocrine, reproductive and metabolic effects in PCOS. Recent developments and findings of the cardiometabolic abnormalities in patients with PCOS are reviewed here and the effects of insulin sensitizing drugs in this disorder are summarised, as well.
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References
Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853–61.
Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004; 89: 2745–9.
Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980; 50: 113–6.
Legro RS, Chiu P, Kunselman AR. Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype. J Clin Endocrinol Metab 2005; 90: 2571–9.
Venkatesan AM, Dunaif A, Corbould A. Insulin resistance in polycystic ovary syndrome: progress and paradoxes. Recent Prog Horm Res 2001; 56: 295–308.
Shoupe D, Kumar DD, Lobo RA. Insulin resistance in polycystic ovary syndrome. Am J Obstet Gynecol 1983; 174: 588–92.
Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic
ovary syndrome. Diabetes 1989; 38: 1165–74.
Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997; 18: 774–800.
Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 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.
Kauffman RP, Baker VM, Dimarino P, Gimpel T, Castracane VD. Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: a comparison of two distinct populations. Am J Obstet Gynecol 2002; 187: 1362–9.
Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004; 59: 141–54.
Nestler JE. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome , and its clinical implications. Semin Reprod Endocrinol 1997; 15: 111–22.
El Tabbakh GH, Lofty I, Azab I. Correlation of the ultrasonic appearance of the ovaries in polycystic ovarian disease and the clinical, hormonal, and laparoscopic findings. Am J Obstet Gynecol 1986; 154: 892.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19–25.
Cussons AJ, Stuckey BG, Walsh JP, Burke V, Norman RJ. Polycystic ovarian syndrome: marked differences between endocrinologists and gynaecologists in diagnosis and management. Clin Endocrinol 2005; 62: 289–95.
Carmina E, Napoli N, Longo RA, Rini GB, Lobo RA. Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis of PCOS. Eur J Endocrinol 2006; 154: 141–5.
Azziz R. PCOS: a diagnostic challenge. Reprod Biomed Online 2004; 8: 644–8.
Moller DE, Flier JS. Insulin resistance-mechanisms, syndromes, and implications. N Engl J Med 1991; 325: 938–48.
Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992; 41: 1257–66.
Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and In skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995; 96: 801–10.
Li M, Youngren JF, Dunaif A, Goldfine ID, Maddux BA, Zhang BB, et al. Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators. J Clin Endocrinol Metab 2002; 87: 4088–93.
Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, et al. Insulin resistance in the skeletal muscle of women with PCOS
involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 2005; 288: 1047–54.
Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA 1995; 92: 10619–23.
Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 1993; 264: 197–202.
Alberti KGMM. Introduction to the metabolic syndrome. Eu Heart J 2005; 7 Suppl D: D3–D5.
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365:1415–28.
Meirow D, Yossepowitch O, Rosler A, Brzezinski A, Schenker JG, Laufer N, et al. Insulin resistant and non-resistant polycystic ovary syndrome represent two clinical and endocrinological subgroups. Hum Reprod 1995; 10: 1951–6.
Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 1992; 41: 715–22.
Barbieri RL, Hornstein MD. Hyperinsulinemia and ovarian hyperandrogenism. Cause and effect: a review. Endocrinol Metab Clin North Am 1988; 17: 685–703.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance
and beta cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–9.
Hedblad B, Nilsson P, Janzon L, Berglund G. Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmo, Sweden. Diabet Med 2000; 17: 299–307.
Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ, de la Luz Sierra M, et al. Mutations in the insulin receptor gene. Endocr Rev 1992; 13: 566–95.
Dunaif A, Hoffman AR. Insulin resistance and hyperandrogenism: clinical syndromes and possible mechanisms. In: Pancheri P, Zichella L, eds. Biorhythms and stress in the physiopathology of reproduction. Washington: Hemisphere Publishing Co.;: 1988. p. 293–317.
Dunaif A. Insulin resistance and ovarian hyperandrogenism. The Endocrinologist 1992; 2: 248–60. 35. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, et al. The syndromes of insulin resistance and achantosis nigricans. N Engl J Med 1976; 294: 739–45.
Nestler JE, Jacubowitcz. 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: 617–23.
Nestler JE. Insulin regulation of human ovarian androgens. Hum Reprod 1997; 12 Suppl 1: 53–62.
Melrose P, Gross L. Steroid effects on the secretory modalities of gonadotropin-releasing hormone release. Endocrinology 1987; 121: 190–9.
Yen SCC, Laughlin GA, Morales AJ. Interface between extra- and intraovarian factors in polycystic ovarian syndrome. Ann NY Acad Sci 1993; 687: 98–111.
Magoffin DA, Weitsman SR. Differentiation of ovarian thecainterstitial cells in vitro: regulation of 17 alpha-hydroxylase messenger
ribonucleic acid expression by luteinizing hormone and insulin-like growth factor-I. Endocrinology 1993; 132: 1945–51.
Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16: 3–34.
Lanzone A, Fulghesu AM, Guido M, Fortini A, Caruso A, Mancuso S. Differential androgen response to adrenocorticotropic hormone stimulation in polycystic ovarian syndrome: relationship with insulin secretion. Fertil Steril 1992; 58: 296–301.
Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991; 72: 83–9.
Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999; 22: 141–6.
Dahlgren E, Janson PO. Polycystic ovary syndrome-long-term metabolic consequences. Int J Gynaecol Obstet 1994; 44: 3–8.
Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of women with polycystic ovary syndrome at long-term follow- up. J Clin Epidemiol 1998; 51: 581–6.
Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998; 83: 2694–8.
Silfen ME, Denburg MR, Manibo AM, Lobo RA, Jaffe R, Ferin M, et al. Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents. J Clin Endocrinol Metab 2003; 88: 4682–8.
DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–94.
Wild S, Pierpoint T, McKeige P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow up: a retrospective cohort study. Clin Endocrinol 2000; 52: 595–604.
Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol 1992; 37: 119–25.
Zimmerman S, Phillips RA, Wikenfeld C. Polycystic ovary syndrome: Lack of hypertension despite insulin resistance. J Clin Endocrinol Metab 1992; 75: 508–13.
Orbetzova MM, Shigarminova RG, Genchev GG, Milcheva BA, Lozanov LB, Genov NS, et al. Role of 24-hour monitoring in assessing blood pressure changes in polycystic ovary syndrome. Folia Med 2003; 45: 21–5.
Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 2001; 111: 607–13.
Robinson S, Henderson AD, Gelding SV, Kiddy D, Niththyananthan R, Bush A, et al. Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol 1996; 44: 277–84.
Wild RA, Alaupovic P, Parker IJ. Lipid and apolipoprotein abnormalities in hirsute women. I. The association with insulin resistance. Am J Obstet Gynecol 1992; 166: 1191–6.
Wild RA, Alaupovic P, Givens JR, Parker IJ. Lipoprotein abnormalities in hirsute women. II. Compensatory responses of insulin resistance and dehydroepiandrosterone sulfate with obesity. Am J Obstet Gynecol 1992; 167: 1813–8.
Wild RA, Bartholomew M, Applebaum-Bowden D, Demers LM, Hazzard W, Santen RJ. Evidence of heterogeneous mechanisms in lipoprotein lipid alterations in hyperandrogenic women. Am J Obstet Gynecol 1990; 163: 1998–2005.
Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN; PCOS/Troglitazone Study Group. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91: 48–53.
Guzick DS, Talbott EO, Sutton-Tyrrell K, Herzog HC, Kuller LH, Wolfson SK Jr. Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am J Obstet Gynecol 1996; 174: 1224–9.
Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard MK, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 2000; 103: 1410–5.
Bickerton AS, Clark N, Meeking D, Shaw KM, Crook M, Lumb P, et al. Cardiovascular risk in women with polycystic ovarian syndrome (PCOS). J Clin Pathol 2005; 58: 151–4.
Wild RA, Grubb B, Hartz A, Van Nort JJ, Bachman W, Bartholomew M. Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil Steril 1990; 54: 255–9.
Rebora A. Baldness and coronary artery disease: the dermatologic point of view of a controversial issue. Arch Dermatol 2001; 137: 943–7.
Gorgels WJ, v d Graaf Y, Blankenstein MA, Collette HJ, Erkelens DW, Banga JD. Urinary sex hormone excretions in premenopausal women and coronary heart disease risk: a nested casereferent study in the DOM-cohort. J Clin Epidemiol 1997; 50: 275–81.
Price JF, Lee AJ, Fowkes FG. Steroid sex hormones and peripheral arterial disease in the Edinburgh Artery Study. Steroids 1997; 62: 789–94.
Barrett-Connor E, Goodman-Gruen D. Prospective study of endogenous sex hormones and fatal cardiovascular disease in postmenopausal women. BMJ 1995; 311: 1193–6.
Birdsall MA, Farquhar CM. Polycystic ovaries in pre and postmenopausal women. Clin Endocrinol 1996; 44: 269–76.
Dahlgren E, Janson PO, Johansson S, Lapidus L, Oden A. Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand 1992; 71: 599– 604.
Lakhani K, Constantinovici N, Purcell WM, Fernando R, Hardiman P. Internal carotid artery haemodynamics in women with polycystic ovaries. Clin Sci 2000; 98: 661–5.
Solomon CG, Hu FB, Dunaif A, Rich-Edwards JE, Stampfer MJ, Willett WC, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 2002; 87: 2013– 7.
Solomon CG, Hu FB, Dunaif A, Rich-Edwards J, Willett WC, Hunter DJ, et al. Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA 2001; 286: 2421–6.
Cussons AJ, Stuckey BG, Watts GF. Cardiovascular disease in the polycystic ovary syndrome: New insights and perspectives. Atherosclerosis 2006; 185: 227–39.
Crosignani PG, Colombo M, Vegetti W, Somigliana E, Gessati A, Ragni G. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet. Hum Reprod 2003; 18: 1928–32.
Harborne L, Fleming R, Lyall H, Norman J, Sattar N. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003; 361: 1894–901.
Lord JM, Flinght IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003; 327: 951–3.
Costello MF, Eden JA. A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril 2003; 79: 1–3.
Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Colitta D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000; 85: 2767–74.
Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 2001; 86: 1626–32.
Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y, Kurabayashi T, Tanaka K. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril 1999; 71: 323–7.
Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosenfield RL, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 2108–16.
Stout DL, Fugate SE. Thiazolidinediones for treatment of polycystic ovary syndrome. Review. Pharmacotherapy 2005; 25: 244– 52.
Sepilian V, Nagamani M. Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance. J Clin Endocrinol Metab 2005; 90: 60–5.
Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke RW. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 2003; 79: 562–6.
Cataldo NA, Abbasi F, McLaughlin TL, Lamendola C, Reaven GM. Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone. Fertil Steril 2001; 76: 1057–9.
Cataldo NA, Abbasi F, McLaughlin TL, Basina M, Fechner PY, Giudice LC, et al. Metabolic and ovarian effects of rosiglitazone treatment for 12 weeks in insulin-resistant women with polycystic ovary syndrome. Hum Reprod 2006; 21: 109–20.
Shobokshi A, Shaarawy M. Correction of insulin resistance and hyperandrogenism in polycystic ovary syndrome by combined rosiglitazone and clomiphene citrate therapy. J Soc Gynecol Investig 2003; 10: 99–104.
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