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The importance of insulin resistance in polycystic ovary syndrome
FERTILITY AND STERILITY威 VOL. 80, NO. 2, AUGUST 2003 Copyright ©2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
The importance of insulin resistance in polycystic ovary syndrome Mark O. Goodarzi, M.D., and Stanley G. Korenman, M.D. Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California
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 (1). 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.
Received August 23, 2002; revised and accepted October 23, 2002. Reprint requests: Mark O. Goodarzi, M.D., Division of Endocrinology, Diabetes, and Hypertension, 200 UCLA Medical Plaza, Suite 530, Los Angeles, California 90095-7065 (FAX: 310-267-1899; Email: mgoodarzi@mednet. ucla.edu). 0015-0282/03/$30.00 doi:10.1016/S0015-0282(03) 00734-9
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 (2– 6). More importantly, insulin resistance leads to hypertension, diabetes, and cardiovascular disease, the most significant complications of PCOS.
Detection of Insulin Resistance in 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 (7). 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 (8). We have found the homeostasis model assessment equation (9) 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 (10). 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 (11–14). 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 (15). Obesity, when present, also leads to insulin resistance; however, PCOS confers a risk of insulin resistance beyond that caused by obesity (16, 17).
Insulin Resistance and Increased Risk of Atherosclerosis 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 cor255
onary artery disease. Hyperinsulinemia has been found to correlate with a profile of increased cardiovascular risk factors in PCOS (18). 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 (19). Adolescents with PCOS and impaired glucose tolerance lack the normal nocturnal decline in blood pressure (20). 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 (21, 22). 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 (23), 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 (24). PCOS has also been associated with impaired fibrinolysis (25) and elevated homocysteine levels (26). Elevated levels of plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, were found in women with PCOS and were correlated with insulin levels (27). Endothelin-1, a marker of abnormal endothelial function, has also been found to be elevated in PCOS; treatment of insulin resistance reduced these levels (28). 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 (29 –34). 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 (31–34).
Insulin Resistance and Increased Risk of Diabetes 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 (35). 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 (36). In a study of 254 women with PCOS (17), 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 256
Goodarzi and Korenman
Insulin resistance in PCOS
with PCOS have diabetes or impaired glucose tolerance, often with a family history of diabetes (37). Untreated, impaired glucose tolerance progresses to diabetes at a rate of 11% per year (38). 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 (39).
Insulin Sensitization Therapy in PCOS 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 (3, 4, 40, 41). One long-term study found that metformin-induced improvements lasted up to 26 months (40). Metformin treatment is also associated with increased HDL cholesterol, decreased LDL cholesterol, and decreased triglycerides (42) as well as improved endothelial function (43). In women with PCOS, treatment with metformin has also decreased PAI-1 and Lp(a) levels (44). 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 (41). Most experience with thiazolidinedione insulin sensitizers used troglitazone (2), 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 (38). 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 Vol. 80, No. 2, August 2003
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 (45).
5.
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.
6.
Metformin restores ovulation in a significant proportion of patients with PCOS and has resulted in pregnancy (4, 40, 46). Metformin also increases the efficacy of clomiphene in clomiphene-resistant patients (47, 48). 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 (49 – 51). No teratogenic effects were observed; further trials with similar results will result in an increased use of metformin during pregnancy in women with PCOS.
10.
The Importance of Insulin Resistance in 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.
7. 8. 9.
11. 12. 13. 14. 15.
16.
17.
18. 19.
20.
21. 22.
23.
References 1. Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, Merriam GR, eds. Polycystic ovary syndrome. Cambridge, MA: Blackwell Scientific Publications, 1992:377–84. 2. 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. 3. Nestler JE, Jakubowicz DJ. 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: 4075–9. 4. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin
FERTILITY & STERILITY威
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resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647–54. Arslanian SA, 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;87:1555–9. La 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;72:985–9. 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. Quon MJ. Limitations of the fasting glucose to insulin ratio as an index of insulin sensitivity. J Clin Endocrinol Metab 2001;86:4615–7. 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. Palmert MR, Gordon CM, Kartashov AI, Legro RS, Emans SJ, Dunaif A. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:1017–23. Dunaif A. Insulin action in the polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:341–59. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165–74. Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab 1999;84:1897–9. Lobo RA, Carmina E. The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med 2000;132:989 –93. Pasquali 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;50:517–27. 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. 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. Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril 2000;73:150 –6. Talbott EO, Guzick DS, Sutton-Tyrrell K, McHugh-Pemu KP, Zborowski JV, Remsberg KE, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2000;20:2414 – 21. Arslanian SA, Lewy VD, 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 –71. Dahlgren E, Janson PO. Polycystic ovary syndrome—long-term metabolic consequences. Int J Gynaecol Obstet 1994;44:3–8. 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. Cibula 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;15:785–9. Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM, Sattar N. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001;86:2453–5. Atiomo WU, Bates SA, Condon JE, Shaw S, West JH, Prentice AG. The plasminogen activator system in women with polycystic ovary syndrome. Fertil Steril 1998;69:236 –41. Loverro 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;53:157–62. Sampson M, Kong C, Patel A, Unwin R, Jacobs HS. 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;45:623–9. Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I. Increased endothelin-1 levels in women with polycystic ovary syndrome and the
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beneficial effect of metformin therapy. J Clin Endocrinol Metab 2001; 86:4666 –73. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 2001;111:607–13. Talbott E, Clerici A, Berga SL, 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;51:415–22. Pirwany IR, Fleming R, Greer IA, Packard CJ, Sattar N. Lipids and lipoprotein subfractions in women with PCOS: relationship to metabolic and endocrine parameters. Clin Endocrinol (Oxf) 2001;54:447– 53. 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 (Oxf) 1996;44:277– 84. 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 (Oxf) 1992;37:119 –25. 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. Hsueh WA, Law RE. Cardiovascular risk continuum: implications of insulin resistance and diabetes. Am J Med 1998;105:4S–14S. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Charles MA, Bennett PH. A two-step model for development of non–insulin-dependent diabetes. Am J Med 1991;90:229 –35. Ehrmann DA. Relation of functional ovarian hyperandrogenism to non-insulin dependent diabetes mellitus. Baillieres Clin Obstet Gynaecol 1997;11:335–47. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403. 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. Moghetti 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 random-
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ized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139 – 46. Oberfield SE. Metabolic lessons from the study of young adolescents with polycystic ovary syndrome—is insulin, indeed, the culprit? J Clin Endocrinol Metab 2000;85:3520 –5. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281–303. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 2001;37: 1344 –50. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. 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 –7. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854 –65. Batukan C, Baysal B. Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome. Arch Gynecol Obstet 2001;265:124 –7. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. 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 –5. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876 –80. Glueck CJ, 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 –52. Glueck CJ, 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 –5. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524 –9.
Vol. 80, No. 2, August 2003
The importance of insulin resistance in polycystic ovary syndrome Mark O. Goodarzi, M.D., and Stanley G. Korenman, M.D. Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California
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 (1). 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.
Received August 23, 2002; revised and accepted October 23, 2002. Reprint requests: Mark O. Goodarzi, M.D., Division of Endocrinology, Diabetes, and Hypertension, 200 UCLA Medical Plaza, Suite 530, Los Angeles, California 90095-7065 (FAX: 310-267-1899; Email: mgoodarzi@mednet. ucla.edu). 0015-0282/03/$30.00 doi:10.1016/S0015-0282(03) 00734-9
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 (2– 6). More importantly, insulin resistance leads to hypertension, diabetes, and cardiovascular disease, the most significant complications of PCOS.
Detection of Insulin Resistance in 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 (7). 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 (8). We have found the homeostasis model assessment equation (9) 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 (10). 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 (11–14). 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 (15). Obesity, when present, also leads to insulin resistance; however, PCOS confers a risk of insulin resistance beyond that caused by obesity (16, 17).
Insulin Resistance and Increased Risk of Atherosclerosis 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 cor255
onary artery disease. Hyperinsulinemia has been found to correlate with a profile of increased cardiovascular risk factors in PCOS (18). 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 (19). Adolescents with PCOS and impaired glucose tolerance lack the normal nocturnal decline in blood pressure (20). 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 (21, 22). 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 (23), 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 (24). PCOS has also been associated with impaired fibrinolysis (25) and elevated homocysteine levels (26). Elevated levels of plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, were found in women with PCOS and were correlated with insulin levels (27). Endothelin-1, a marker of abnormal endothelial function, has also been found to be elevated in PCOS; treatment of insulin resistance reduced these levels (28). 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 (29 –34). 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 (31–34).
Insulin Resistance and Increased Risk of Diabetes 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 (35). 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 (36). In a study of 254 women with PCOS (17), 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 256
Goodarzi and Korenman
Insulin resistance in PCOS
with PCOS have diabetes or impaired glucose tolerance, often with a family history of diabetes (37). Untreated, impaired glucose tolerance progresses to diabetes at a rate of 11% per year (38). 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 (39).
Insulin Sensitization Therapy in PCOS 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 (3, 4, 40, 41). One long-term study found that metformin-induced improvements lasted up to 26 months (40). Metformin treatment is also associated with increased HDL cholesterol, decreased LDL cholesterol, and decreased triglycerides (42) as well as improved endothelial function (43). In women with PCOS, treatment with metformin has also decreased PAI-1 and Lp(a) levels (44). 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 (41). Most experience with thiazolidinedione insulin sensitizers used troglitazone (2), 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 (38). 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 Vol. 80, No. 2, August 2003
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 (45).
5.
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.
6.
Metformin restores ovulation in a significant proportion of patients with PCOS and has resulted in pregnancy (4, 40, 46). Metformin also increases the efficacy of clomiphene in clomiphene-resistant patients (47, 48). 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 (49 – 51). No teratogenic effects were observed; further trials with similar results will result in an increased use of metformin during pregnancy in women with PCOS.
10.
The Importance of Insulin Resistance in 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.
7. 8. 9.
11. 12. 13. 14. 15.
16.
17.
18. 19.
20.
21. 22.
23.
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Vol. 80, No. 2, August 2003