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The importance of insulin resistance in polycystic ovary syndrome

2003; Elsevier BV; Volume: 80; Issue: 2 Linguagem: Inglês

10.1016/s0015-0282(03)00734-9

1556-5653

Mark O. Goodarzi, Stanley G. Korenman,

Growth Hormone and Insulin-like Growth Factors

The most widely accepted criteria for the diagnosis of polycystic ovary syndrome (PCOS) are hyperandrogenism and/or hyperandrogenemia and oligo-ovulation, with the exclusion of other hyperandrogenic disorders (1Zawadzki J.K. Dunaif A. Diagnostic criteria for polycystic ovary syndrome towards a rational approach.in: Dunaif A. Givens J.R. Haseltine F. Merriam G.R. Polycystic ovary syndrome. Blackwell Scientific Publications, Cambridge, MA1992: 377-384Google Scholar). Thus, androgen elevation defines the syndrome. This definition permits a wide range of presentations and clinical appearances, that is, a continuum of patients with PCOS. Androgen excess, of ovarian and often also adrenal origin, underlies the symptoms of hirsutism, acne, alopecia, and seborrhea, and treatment with anti-androgens is the most effective method of reducing these complaints. Hyperandrogenemia may also be responsible for the weight gain present in about 50% of cases. What has been increasingly recognized is that PCOS is associated with insulin resistance and compensatory hyperinsulinemia. While not required for the diagnosis of PCOS, insulin resistance appears to cause or exacerbate hyperandrogenemia in many patients, as evidenced by the reduction in ovarian and adrenal androgen levels with insulin-sensitizing therapy (2Ehrmann D.A. Schneider D.J. Sobel B.E. Cavaghan M.K. Imperial J. Rosenfield R.L. 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: 2108-2116Crossref PubMed Scopus (492) Google Scholar, 3Nestler J.E. Jakubowicz D.J. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens.J Clin Endocrinol Metab. 1997; 82: 4075-4079Crossref PubMed Google Scholar, 4Velazquez E.M. Mendoza S. Hamer T. Sosa F. Glueck C.J. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.Metabolism. 1994; 43: 647-654Abstract Full Text PDF PubMed Scopus (773) Google Scholar, 5Arslanian S.A. Lewy V. Danadian K. Saad R. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance.J Clin Endocrinol Metab. 2002; 87: 1555-1559Crossref PubMed Scopus (210) Google Scholar, 6La Marca A. Morgante G. Paglia T. Ciotta L. Cianci A. De Leo V. Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome.Fertil Steril. 1999; 72: 985-989Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). More importantly, insulin resistance leads to hypertension, diabetes, and cardiovascular disease, the most significant complications of PCOS. Exactly what proportion of women with PCOS actually have insulin resistance depends on the method of measurement. The gold standard, the euglycemic clamp technique, is invasive and used only as a research tool. Other methods, such as the frequently sampled IV glucose tolerance test, are also impractical. Most popular in clinical settings is the fasting glucose-to-insulin ratio (7Legro R.S. 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: 2694-2698Crossref PubMed Scopus (671) Google Scholar). Unfortunately, this only gives information about one moment in time and may fail to detect insulin-resistant subjects. In addition, the ratio is not valid if beta cell function has deteriorated and glucose intolerance is already present (8Quon M.J. Limitations of the fasting glucose to insulin ratio as an index of insulin sensitivity.J Clin Endocrinol Metab. 2001; 86: 4615-4617Crossref PubMed Scopus (94) Google Scholar). We have found the homeostasis model assessment equation (9Matthews D.R. Hosker J.P. Rudenski A.S. Naylor B.A. Treacher D.F. Turner R.C. Homeostasis model assessment insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia. 1985; 28: 412-419Crossref PubMed Scopus (24799) Google Scholar) to be a useful tool; however, this is also based on a single fasting measurement of glucose and insulin. A recent study suggested that oral glucose tolerance testing is more sensitive than the glucose-to-insulin ratio in the detection of impaired glucose tolerance in adolescents with PCOS (10Palmert M.R. Gordon C.M. Kartashov A.I. Legro R.S. Emans S.J. Dunaif A. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome.J Clin Endocrinol Metab. 2002; 87: 1017-1023Crossref PubMed Scopus (268) Google Scholar). The oral glucose tolerance test may be the test that gives the most information with the least patient burden. In any case, estimates of the prevalence of insulin resistance in PCOS range from a minority to the vast majority, with higher detection rates when using more sensitive methods (11Dunaif A. Insulin action in the polycystic ovary syndrome.Endocrinol Metab Clin North Am. 1999; 28: 341-359Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 12Dunaif A. Segal K.R. Futterweit W. Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.Diabetes. 1989; 38: 1165-1174Crossref PubMed Google Scholar, 13Carmina E. Lobo R.A. Polycystic ovary syndrome (PCOS) arguably the most common endocrinopathy is associated with significant morbidity in women.J Clin Endocrinol Metab. 1999; 84: 1897-1899Crossref PubMed Google Scholar, 14Lobo R.A. Carmina E. The importance of diagnosing the polycystic ovary syndrome.Ann Intern Med. 2000; 132: 989-993Crossref PubMed Scopus (244) Google Scholar). Also, a woman with PCOS may test negative for insulin resistance when young and thin but develop it with time. Hyperinsulinemia appears to worsen spontaneously with age in adult women with PCOS without worsening of hyperandrogenemia (15Pasquali R. Gambineri A. Anconetani B. Vicennati V. Colitta D. Caramelli E. et al.The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment.Clin Endocrinol (Oxf). 1999; 50: 517-527Crossref PubMed Scopus (124) Google Scholar). Obesity, when present, also leads to insulin resistance; however, PCOS confers a risk of insulin resistance beyond that caused by obesity (16Dunaif 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: 499-507Crossref PubMed Scopus (537) Google Scholar, 17Legro R.S. Kunselman A.R. Dodson W.C. 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: 165-169Crossref PubMed Scopus (1516) Google Scholar). Much more important than how many patients with PCOS have insulin resistance is the fact that these women are at increased risk of having the metabolic syndrome (syndrome X). This is characterized by dyslipidemia, central obesity, hypercoagulability, impaired fibrinolysis, and an increased risk of development of hypertension, type 2 diabetes mellitus, and coronary artery disease. Hyperinsulinemia has been found to correlate with a profile of increased cardiovascular risk factors in PCOS (18Mather K.J. Kwan F. Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity.Fertil Steril. 2000; 73: 150-156Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). Older women with PCOS have been found to have a greater burden of atherosclerosis than normal women as measured by carotid intima-medial thickness on ultrasound (19Talbott E.O. Guzick D.S. Sutton-Tyrrell K. McHugh-Pemu K.P. Zborowski J.V. Remsberg K.E. et al.Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women.Arterioscler Thromb Vasc Biol. 2000; 20: 2414-2421Crossref PubMed Scopus (447) Google Scholar). Adolescents with PCOS and impaired glucose tolerance lack the normal nocturnal decline in blood pressure (20Arslanian S.A. Lewy V.D. Danadian K. Glucose intolerance in obese adolescents with polycystic ovary syndrome roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease.J Clin Endocrinol Metab. 2001; 86: 66-71Crossref PubMed Scopus (261) Google Scholar). As women with PCOS reach their fourth and fifth decades, the risk of hypertension is increased three-fold and of myocardial infarction up to seven-fold (21Dahlgren E. Janson P.O. Polycystic ovary syndrome—long-term metabolic consequences.Int J Gynaecol Obstet. 1994; 44: 3-8Abstract Full Text PDF PubMed Scopus (27) Google Scholar, 22Dahlgren E. Janson P.O. 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: 599-604Crossref PubMed Scopus (491) Google Scholar). By their fifth and sixth decades, women with and without PCOS appear to have similar cardiovascular risk factor profiles, but those with PCOS have a higher prevalence of diabetes and coronary artery disease (23Cibula D. Cifkova R. Fanta M. Poledne R. Zivny J. Skibova J. Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome.Hum Reprod. 2000; 15: 785-789Crossref PubMed Scopus (224) Google Scholar), suggesting that they developed adverse risk factors at an earlier age, leading to increased long-term risk. Chronic inflammation, a predisposing factor to coronary heart disease, is increased in PCOS, as evidenced by elevated C-reactive protein levels that correlate with insulin resistance and obesity, not androgen levels (24Kelly C.C. Lyall H. Petrie J.R. Gould G.W. Connell J.M. Sattar N. Low grade chronic inflammation in women with polycystic ovarian syndrome.J Clin Endocrinol Metab. 2001; 86: 2453-2455Crossref PubMed Scopus (389) Google Scholar). PCOS has also been associated with impaired fibrinolysis (25Atiomo W.U. Bates S.A. Condon J.E. Shaw S. West J.H. Prentice A.G. The plasminogen activator system in women with polycystic ovary syndrome.Fertil Steril. 1998; 69: 236-241Abstract Full Text PDF PubMed Scopus (127) Google Scholar) and elevated homocysteine levels (26Loverro G. Lorusso F. Mei L. Depalo R. Cormio G. Selvaggi L. The plasma homocysteine levels are increased in polycystic ovary syndrome.Gynecol Obstet Invest. 2002; 53: 157-162Crossref PubMed Scopus (110) Google Scholar). Elevated levels of plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, were found in women with PCOS and were correlated with insulin levels (27Sampson M. Kong C. Patel A. Unwin R. Jacobs H.S. Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome.Clin Endocrinol (Oxf). 1996; 45: 623-629Crossref PubMed Scopus (169) Google Scholar). Endothelin-1, a marker of abnormal endothelial function, has also been found to be elevated in PCOS; treatment of insulin resistance reduced these levels (28Diamanti-Kandarakis E. Spina G. Kouli C. Migdalis I. Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy.J Clin Endocrinol Metab. 2001; 86: 4666-4673Crossref PubMed Scopus (180) Google Scholar). Lipid abnormalities characteristic of the metabolic syndrome, depressed HDL cholesterol levels and elevated triglyceride levels, as well as elevated LDL cholesterol levels, have also been found in women with PCOS (29Legro R.S. Kunselman A.R. Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome.Am J Med. 2001; 111: 607-613Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 30Talbott E. Clerici A. Berga S.L. Kuller L. Guzick D. Detre K. et al.Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome results of a case-control study.J Clin Epidemiol. 1998; 51: 415-422Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 31Pirwany I.R. Fleming R. Greer I.A. Packard C.J. Sattar N. Lipids and lipoprotein subfractions in women with PCOS relationship to metabolic and endocrine parameters.Clin Endocrinol (Oxf). 2001; 54: 447-453Crossref PubMed Scopus (142) Google Scholar, 32Robinson S. Henderson A.D. Gelding S.V. Kiddy D. Niththyananthan R. Bush A. et al.Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries.Clin Endocrinol (Oxf). 1996; 44: 277-284Crossref PubMed Scopus (158) Google Scholar, 33Conway G.S. Agrawal R. Betteridge D.J. Jacobs H.S. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome.Clin Endocrinol (Oxf). 1992; 37: 119-125Crossref PubMed Scopus (391) Google Scholar, 34Wild R.A. Alaupovic P. Parker I.J. Lipid and apolipoprotein abnormalities in hirsute women. I. The association with insulin resistance.Am J Obstet Gynecol. 1992; 166: 1191-1196Abstract Full Text PDF PubMed Scopus (96) Google Scholar). Insulin resistance/hyperinsulinemia, as opposed to hyperandrogenemia, often appears to be the main predictor of these lipid abnormalities as well as elevated levels of atherogenic small, dense LDL cholesterol in PCOS (31Pirwany I.R. Fleming R. Greer I.A. Packard C.J. Sattar N. Lipids and lipoprotein subfractions in women with PCOS relationship to metabolic and endocrine parameters.Clin Endocrinol (Oxf). 2001; 54: 447-453Crossref PubMed Scopus (142) Google Scholar, 32Robinson S. Henderson A.D. Gelding S.V. Kiddy D. Niththyananthan R. Bush A. et al.Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries.Clin Endocrinol (Oxf). 1996; 44: 277-284Crossref PubMed Scopus (158) Google Scholar, 33Conway G.S. Agrawal R. Betteridge D.J. Jacobs H.S. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome.Clin Endocrinol (Oxf). 1992; 37: 119-125Crossref PubMed Scopus (391) Google Scholar, 34Wild R.A. Alaupovic P. Parker I.J. Lipid and apolipoprotein abnormalities in hirsute women. I. The association with insulin resistance.Am J Obstet Gynecol. 1992; 166: 1191-1196Abstract Full Text PDF PubMed Scopus (96) Google Scholar). PCOS is a powerful risk factor for impaired glucose tolerance and type 2 diabetes mellitus. In one model of the pathogenesis of type 2 diabetes, insulin resistance is the primary defect and diabetes occurs once the pancreatic beta cells become unable to compensate (35Hsueh W.A. Law R.E. Cardiovascular risk continuum implications of insulin resistance and diabetes.Am J Med. 1998; 105: 4S-14SAbstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Insulin-resistant patients with PCOS maintain normal glucose levels by insulin hypersecretion. These patients are likely to be at an increased risk of beta cell exhaustion and development of type 2 diabetes mellitus (36Saad M.F. Knowler W.C. Pettitt D.J. Nelson R.G. Charles M.A. Bennett P.H. A two-step model for development of non–insulin-dependent diabetes.Am J Med. 1991; 90: 229-235PubMed Google Scholar). In a study of 254 women with PCOS (17Legro R.S. Kunselman A.R. Dodson W.C. 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: 165-169Crossref PubMed Scopus (1516) Google Scholar), 31% had impaired glucose tolerance, and 7.5% had type 2 diabetes. This represents a huge increase over population expectations. In the nonobese patients with PCOS, 10.3% had impaired glucose tolerance and 1.5% had diabetes, rates almost three times that of normal women. Up to 40% of patients with PCOS have diabetes or impaired glucose tolerance, often with a family history of diabetes (37Ehrmann D.A. Relation of functional ovarian hyperandrogenism to non-insulin dependent diabetes mellitus.Baillieres Clin Obstet Gynaecol. 1997; 11: 335-347Abstract Full Text PDF PubMed Scopus (20) Google Scholar). Untreated, impaired glucose tolerance progresses to diabetes at a rate of 11% per year (38Knowler W.C. Barrett-Connor E. Fowler S.E. Hamman R.F. Lachin J.M. Walker E.A. et al.Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.N Engl J Med. 2002; 346: 393-403Crossref PubMed Scopus (14207) Google Scholar). In the Nurses' Health Study, the risk of development of diabetes was increased two-fold among women with long or irregular menstrual cycles, including the nonobese women (39Solomon C.G. Hu F.B. Dunaif A. Rich-Edwards J. Willett W.C. Hunter D.J. et al.Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus.JAMA. 2001; 286: 2421-2426Crossref PubMed Scopus (275) Google Scholar). Since the complications associated with insulin resistance, particularly development of diabetes and atherosclerosis, are potentially deadly, in our patient care we emphasize the detection and treatment of insulin resistance. The most studied agent to treat insulin resistance in PCOS is metformin. Metformin has repeatedly been found to lower T levels, increase sex hormone–binding globulin (thus reducing bioavailable T levels), improve menstrual frequency, decrease weight, and facilitate pregnancy (3Nestler J.E. Jakubowicz D.J. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens.J Clin Endocrinol Metab. 1997; 82: 4075-4079Crossref PubMed Google Scholar, 4Velazquez E.M. Mendoza S. Hamer T. Sosa F. Glueck C.J. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.Metabolism. 1994; 43: 647-654Abstract Full Text PDF PubMed Scopus (773) Google Scholar, 40Moghetti P. Castello R. Negri C. Tosi F. Perrone F. Caputo M. et al.Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.J Clin Endocrinol Metab. 2000; 85: 139-146Crossref PubMed Scopus (667) Google Scholar, 41Oberfield S.E. Metabolic lessons from the study of young adolescents with polycystic ovary syndrome—is insulin, indeed, the culprit?.J Clin Endocrinol Metab. 2000; 85: 3520-3525Crossref PubMed Google Scholar). One long-term study found that metformin-induced improvements lasted up to 26 months (40Moghetti P. Castello R. Negri C. Tosi F. Perrone F. Caputo M. et al.Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.J Clin Endocrinol Metab. 2000; 85: 139-146Crossref PubMed Scopus (667) Google Scholar). Metformin treatment is also associated with increased HDL cholesterol, decreased LDL cholesterol, and decreased triglycerides (42DeFronzo R.A. Pharmacologic therapy for type 2 diabetes mellitus.Ann Intern Med. 1999; 131: 281-303Crossref PubMed Scopus (1003) Google Scholar) as well as improved endothelial function (43Mather K.J. Verma S. Anderson T.J. Improved endothelial function with metformin in type 2 diabetes mellitus.J Am Coll Cardiol. 2001; 37: 1344-1350Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar). In women with PCOS, treatment with metformin has also decreased PAI-1 and Lp(a) levels (44Velazquez E.M. Mendoza S.G. Wang P. Glueck C.J. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome.Metabolism. 1997; 46: 454-457Abstract Full Text PDF PubMed Scopus (245) Google Scholar). The most commonly studied and used target doses in PCOS are 500 mg three times a day or 850 mg twice a day. The main drawback of metformin use is gastrointestinal intolerance, which often can be avoided by starting with a low dose and titrating to the goal dose over a few weeks. An overview of several trials involving the use of metformin in PCOS (over 360 patients in total) revealed no cases of lactic acidosis in these young women with normal renal function (41Oberfield S.E. Metabolic lessons from the study of young adolescents with polycystic ovary syndrome—is insulin, indeed, the culprit?.J Clin Endocrinol Metab. 2000; 85: 3520-3525Crossref PubMed Google Scholar). Most experience with thiazolidinedione insulin sensitizers used troglitazone (2Ehrmann D.A. Schneider D.J. Sobel B.E. Cavaghan M.K. Imperial J. Rosenfield R.L. 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: 2108-2116Crossref PubMed Scopus (492) Google Scholar), which has been removed from the market because of hepatotoxicity. Since thiazolidinediones tend to cause weight gain and fluid retention and have been studied less in PCOS, metformin is the insulin sensitizer of choice at this time. Regarding the long-term effects of treating insulin resistance in PCOS, studies are needed to demonstrate the reduction in rates of diabetes and coronary artery disease with insulin-sensitizing therapy. Large trials in other populations, however, suggest that long-term insulin sensitization may be beneficial. In the Diabetes Prevention Program, subjects with impaired glucose tolerance who were treated with metformin (850 mg twice daily) experienced a 31% reduction in the incidence of diabetes (38Knowler W.C. Barrett-Connor E. Fowler S.E. Hamman R.F. Lachin J.M. Walker E.A. et al.Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.N Engl J Med. 2002; 346: 393-403Crossref PubMed Scopus (14207) Google Scholar). Of note, in this trial, an intensive program of diet and exercise, also expected to ameliorate insulin resistance, reduced the incidence of diabetes by 58%. In the United Kingdom Prospective Diabetes Study, overweight type 2 diabetics treated with metformin experienced a decreased myocardial infarction and stroke rate compared with those on conventional therapy and a decreased all-cause mortality, total diabetes-related endpoints, and incidence of stroke compared with those treated with insulin or sulfonylurea therapy (45UK Prospective Diabetes Study (UKPDS) GroupEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7358) Google Scholar). Until proven by randomized, controlled trials of metformin use in PCOS, we assume that the prevention of diabetes and cardiovascular events and improved survival attributed to metformin in these studies will apply to women with PCOS. Given the increased risk of atherosclerosis in women with PCOS, blood pressure control, smoking cessation, lipid lowering, diet modification, and exercise are needed in addition to insulin sensitization. Metformin restores ovulation in a significant proportion of patients with PCOS and has resulted in pregnancy (4Velazquez E.M. Mendoza S. Hamer T. Sosa F. Glueck C.J. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.Metabolism. 1994; 43: 647-654Abstract Full Text PDF PubMed Scopus (773) Google Scholar, 40Moghetti P. Castello R. Negri C. Tosi F. Perrone F. Caputo M. et al.Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.J Clin Endocrinol Metab. 2000; 85: 139-146Crossref PubMed Scopus (667) Google Scholar, 46Batukan C. Baysal B. Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome.Arch Gynecol Obstet. 2001; 265: 124-127Crossref PubMed Scopus (41) Google Scholar). Metformin also increases the efficacy of clomiphene in clomiphene-resistant patients (47Vandermolen D.T. Ratts V.S. Evans W.S. Stovall D.W. Kauma S.W. Nestler J.E. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone.Fertil Steril. 2001; 75: 310-315Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 48Nestler J.E. Jakubowicz D.J. Evans W.S. Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.N Engl J Med. 1998; 338: 1876-1880Crossref PubMed Scopus (716) Google Scholar). Recent small studies also suggest that metformin continued during pregnancy reduces the high rates of gestational diabetes and first-trimester spontaneous abortion characteristic of PCOS (49Glueck C.J. Phillips H. Cameron D. Sieve-Smith L. Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion a pilot study.Fertil Steril. 2001; 75: 46-52Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 50Glueck C.J. Wang P. Kobayashi S. Phillips H. Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome.Fertil Steril. 2002; 77: 520-525Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 51Jakubowicz D.J. Iuorno M.J. Jakubowicz S. Roberts K.A. Nestler J.E. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.J Clin Endocrinol Metab. 2002; 87: 524-529Crossref PubMed Scopus (388) Google Scholar). No teratogenic effects were observed; further trials with similar results will result in an increased use of metformin during pregnancy in women with PCOS. While it is true that not all women with insulin resistance have PCOS, those who do have PCOS are more likely to come to the attention of the medical community. This opportunity to diagnose and treat insulin resistance and possibly reduce long-term morbidity and mortality in these women is critical and must not be overlooked while attention is being focused on their fertility and cosmetic problems. While hyperandrogenemia and concomitant hirsutism, acne, or infertility are certainly troublesome to a woman, an increased risk of developing diabetes and atherosclerosis has the potential to shorten her lifespan. Thus, we recommend an investigation to detect insulin resistance in every hirsute woman. Treating insulin resistance, when present, with metformin may improve fertility, facilitate weight loss, improve the lipid profile, reduce the incidence of diabetes, and prevent atherosclerosis, myocardial infarction, and stroke. Clinical trials verifying these benefits in patients with PCOS are urgently needed.