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Are women with polycystic ovary syndrome at increased risk of cardiovascular disease? Too early to be sure, but not too early to act!
Are Women with Polycystic Ovary Syndrome at Increased Risk of Cardiovascular Disease? Too Early to Be Sure, but Not too Early to Act! Stephen Franks, MD
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olycystic ovary syndrome is now acknowledged by many to be the most common endocrine disorder among women of reproductive age and the major cause of anovulatory infertility (1). Its reproductive consequences have been recognized for several decades, but in the last 20 years, there has been an increasing number of studies demonstrating an association between the syndrome and a characteristic metabolic disorder. That, in turn, has led to concern about the effect of polycystic ovary syndrome on long-term health, particularly with regard to diabetes and coronary heart disease. The central features of the metabolic disturbance are peripheral insulin resistance and hyperinsulinemia (2), the mechanisms of which are not certain but there is evidence of abnormalities in both insulin action and pancreatic -cell function (2). There is also an important association between polycystic ovaries and body weight, so that whereas lean women with polycystic ovary syndrome often have normal insulin levels and sensitivity, the majority of women whose body mass index is greater than 30 have reduced insulin sensitivity compared with weight-matched controls (3). It is not surprising, therefore, that there is a high prevalence of impaired glucose tolerance among obese young women with polycystic ovary syndrome—and indeed some may have frank diabetes (2)—suggesting that women with polycystic ovary syndrome have a substantially higher risk of developing type 2 diabetes in later life. As yet, there have been few long-term follow-up studies, but in a recent epidemiologic analysis by Wild et al. (4), the relative risk of type 2 diabetes in a large cohort of middle-aged women with polycystic ovary syndrome was found to be three times that of the reference population. Abnormalities in lipid and lipoprotein levels have also been widely reported in women with polycystic ovary syndrome. These metabolic features, together with centripetal fat distribution, constitute a cluster of risk factors for cardiovascular disease and have been a major concern in considering the long-term management of patients with polycystic ovary syndrome. However, interpreting the
Am J Med. 2001;111:665– 666. From the Department of Reproductive Science and Medicine, Faculty of Medicine, Imperial College, London, United Kingdom. Requests for reprints should be addressed to Stephen Franks, MD, Department of Reproductive Science and Medicine, Imperial College, Institute of Reproductive and Developmental Biology, Hammersmith Hospital, London W12 0NN, United Kingdom. 䉷2001 by Excerpta Medica, Inc. All rights reserved.
relevance of these abnormalities in terms of cardiovascular risk is not easy. First, there are inconsistencies among studies in the features of the dyslipidemia. Second, it is not yet clear how the combined risk factors translate into a real risk of developing cardiovascular disease. The article by Legro et al. (5) in this issue of the Journal draws attention to the debate surrounding the interpretation of lipid metabolism disorders that have been described in polycystic ovary syndrome. For example, some, but by no means all, studies have described elevated total cholesterol concentrations, although previous investigators (including Legro et al.) have been fairly consistent in their reports of hypertriglyceridemia (5–9). Some groups have demonstrated significantly lower levels of high-density lipoprotein (HDL) cholesterol (thought to be the strongest metabolic predictor of coronary heart disease) in women with polycystic ovary syndrome compared with weight-matched controls (6,7). In contrast, Legro et al. described HDL cholesterol levels that were higher than normal, although this difference was not significant after adjusting for other variables such as body mass index and fasting insulin. The predominant abnormality observed in this study was an elevation of low-density lipoprotein (LDL) cholesterol levels in both lean and obese women with polycystic ovary syndrome, an observation that has some resonance in other recent reports of abnormalities in LDL cholesterol levels and particle size (8 –10). The advantage of the study is that it comprised an impressively large number of patients with polycystic ovary syndrome (n ⫽ 195) and a reasonably large control population (n ⫽ 62). The finding of disturbances in lipid and lipoprotein metabolism is therefore fairly common. Reported differences concerning the nature of the dyslipidemia may be explained by inherent differences among the populations studied. Importantly, as Legro et al. point out, polycystic ovary syndrome and the associated changes in insulin secretion or action account for no more than about 25% of the variance in lipoprotein levels. Similarly, Robinson et al. (7) found that, with respect to HDL cholesterol levels, insulin sensitivity accounted for 22% of the variance, while body mass index accounted for 54%. The remaining uncertainties surrounding the reports of dyslipidemia in polycystic ovary syndrome emphasize the need for caution when pronouncing the implications for cardiovascular health in polycystic ovary disease. While there is little doubt that polycystic ovary syn0002-9343/01/$–see front matter 665 PII S0002-9343(01)01038-5
Polycystic Ovary Syndrome/Franks
drome, independent of obesity, constitutes a significant risk factor for type 2 diabetes, there is, at present, no direct evidence of increased morbidity or mortality from coronary heart disease. Endothelial dysfunction (11) and ultrasonographic evidence of carotid intima-medial abnormalities (12) have been described in young and middle-aged women, but these must still be regarded as surrogate indexes of cardiovascular disease. Although some studies, such as the one by Wild et al., report no increase in morbidity or mortality from coronary heart disease (4), it would nevertheless be unwise to be complacent about the long-term management of patients with polycystic ovary syndrome. It is quite conceivable that the incidence of coronary heart disease will diverge from normal with age. As Legro et al. conclude in their paper, more long-term follow-up studies are required before a definitive relation can be established. It has already been demonstrated that lifestyle changes (especially in diet) can markedly improve the metabolic profile of obese women with polycystic ovary syndrome, and at the very least can be expected to reduce the chance of type 2 diabetes developing (13,14). The new generation of insulin-sensitizing agents may also limit the effect of the metabolic complications of polycystic ovary syndrome (5). Certainly, it is difficult to argue against the view that calorie restriction and increased exercise for obese young women with polycystic ovary syndrome is eminently sensible, not just to improve reproductive function (which it clearly does) (13) but also as an investment in a healthy future.
REFERENCES 1. Franks S. Medical progress article: polycystic ovary syndrome. N Engl J Med. 1995;333:853–861.
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December 1, 2001
THE AMERICAN JOURNAL OF MEDICINE威
2. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism of action and implications for pathogenesis. Endocr Rev. 1996;18:774 –800. 3. Holte J. Disturbances in insulin secretion and sensitivity in women with the polycystic ovary syndrome. Baillieres Clin Endocrinol Metab. 1996;10:221–247. 4. Wild S, Pierpoint T, McKeigue P, Jacobs HS. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol. 2000;52: 595–600. 5. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med. 2001;111:607– 613. 6. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease in lean and obese women with polycystic ovary syndrome. Clin Endocrinol. 1992;37:119 –125. 7. Robinson S, Henderson AD, Gelding SV, et al. Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol. 1996;44:277–284. 8. Talbott E, Clerici A, Berga SL, et al. Adverse lipid and coronary heart risk profiles in young women with polycystic ovary syndrome: results of a case-control study. J Clin Epidemiol. 1998;51:415–422. 9. Pirwany IR, Fleming R, Greer IA, et al. Lipids and lipoprotein subfractions in women with PCOS: relationship to metabolic and endocrine parameters. Clin Endocrinol. 2001;54:447–453. 10. Dejager S, Pichard C, Giral P, et al. Smaller LDL particle size in women with polycystic ovary syndrome compared to controls. Clin Endocrinol. 2001;54:455–462. 11. Paradisi G, Steinberg HO, Hempfling A, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation. 2001;103:1410 –1415. 12. Talbott EO, Guzick DS, Sutton-Tyrrell K, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol. 2000;20:2414 –2421. 13. Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol. 1992;36: 105–111. 14. Clark AM, Ledger W, Galletly C, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod. 1995;10:2705–2712.
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olycystic ovary syndrome is now acknowledged by many to be the most common endocrine disorder among women of reproductive age and the major cause of anovulatory infertility (1). Its reproductive consequences have been recognized for several decades, but in the last 20 years, there has been an increasing number of studies demonstrating an association between the syndrome and a characteristic metabolic disorder. That, in turn, has led to concern about the effect of polycystic ovary syndrome on long-term health, particularly with regard to diabetes and coronary heart disease. The central features of the metabolic disturbance are peripheral insulin resistance and hyperinsulinemia (2), the mechanisms of which are not certain but there is evidence of abnormalities in both insulin action and pancreatic -cell function (2). There is also an important association between polycystic ovaries and body weight, so that whereas lean women with polycystic ovary syndrome often have normal insulin levels and sensitivity, the majority of women whose body mass index is greater than 30 have reduced insulin sensitivity compared with weight-matched controls (3). It is not surprising, therefore, that there is a high prevalence of impaired glucose tolerance among obese young women with polycystic ovary syndrome—and indeed some may have frank diabetes (2)—suggesting that women with polycystic ovary syndrome have a substantially higher risk of developing type 2 diabetes in later life. As yet, there have been few long-term follow-up studies, but in a recent epidemiologic analysis by Wild et al. (4), the relative risk of type 2 diabetes in a large cohort of middle-aged women with polycystic ovary syndrome was found to be three times that of the reference population. Abnormalities in lipid and lipoprotein levels have also been widely reported in women with polycystic ovary syndrome. These metabolic features, together with centripetal fat distribution, constitute a cluster of risk factors for cardiovascular disease and have been a major concern in considering the long-term management of patients with polycystic ovary syndrome. However, interpreting the
Am J Med. 2001;111:665– 666. From the Department of Reproductive Science and Medicine, Faculty of Medicine, Imperial College, London, United Kingdom. Requests for reprints should be addressed to Stephen Franks, MD, Department of Reproductive Science and Medicine, Imperial College, Institute of Reproductive and Developmental Biology, Hammersmith Hospital, London W12 0NN, United Kingdom. 䉷2001 by Excerpta Medica, Inc. All rights reserved.
relevance of these abnormalities in terms of cardiovascular risk is not easy. First, there are inconsistencies among studies in the features of the dyslipidemia. Second, it is not yet clear how the combined risk factors translate into a real risk of developing cardiovascular disease. The article by Legro et al. (5) in this issue of the Journal draws attention to the debate surrounding the interpretation of lipid metabolism disorders that have been described in polycystic ovary syndrome. For example, some, but by no means all, studies have described elevated total cholesterol concentrations, although previous investigators (including Legro et al.) have been fairly consistent in their reports of hypertriglyceridemia (5–9). Some groups have demonstrated significantly lower levels of high-density lipoprotein (HDL) cholesterol (thought to be the strongest metabolic predictor of coronary heart disease) in women with polycystic ovary syndrome compared with weight-matched controls (6,7). In contrast, Legro et al. described HDL cholesterol levels that were higher than normal, although this difference was not significant after adjusting for other variables such as body mass index and fasting insulin. The predominant abnormality observed in this study was an elevation of low-density lipoprotein (LDL) cholesterol levels in both lean and obese women with polycystic ovary syndrome, an observation that has some resonance in other recent reports of abnormalities in LDL cholesterol levels and particle size (8 –10). The advantage of the study is that it comprised an impressively large number of patients with polycystic ovary syndrome (n ⫽ 195) and a reasonably large control population (n ⫽ 62). The finding of disturbances in lipid and lipoprotein metabolism is therefore fairly common. Reported differences concerning the nature of the dyslipidemia may be explained by inherent differences among the populations studied. Importantly, as Legro et al. point out, polycystic ovary syndrome and the associated changes in insulin secretion or action account for no more than about 25% of the variance in lipoprotein levels. Similarly, Robinson et al. (7) found that, with respect to HDL cholesterol levels, insulin sensitivity accounted for 22% of the variance, while body mass index accounted for 54%. The remaining uncertainties surrounding the reports of dyslipidemia in polycystic ovary syndrome emphasize the need for caution when pronouncing the implications for cardiovascular health in polycystic ovary disease. While there is little doubt that polycystic ovary syn0002-9343/01/$–see front matter 665 PII S0002-9343(01)01038-5
Polycystic Ovary Syndrome/Franks
drome, independent of obesity, constitutes a significant risk factor for type 2 diabetes, there is, at present, no direct evidence of increased morbidity or mortality from coronary heart disease. Endothelial dysfunction (11) and ultrasonographic evidence of carotid intima-medial abnormalities (12) have been described in young and middle-aged women, but these must still be regarded as surrogate indexes of cardiovascular disease. Although some studies, such as the one by Wild et al., report no increase in morbidity or mortality from coronary heart disease (4), it would nevertheless be unwise to be complacent about the long-term management of patients with polycystic ovary syndrome. It is quite conceivable that the incidence of coronary heart disease will diverge from normal with age. As Legro et al. conclude in their paper, more long-term follow-up studies are required before a definitive relation can be established. It has already been demonstrated that lifestyle changes (especially in diet) can markedly improve the metabolic profile of obese women with polycystic ovary syndrome, and at the very least can be expected to reduce the chance of type 2 diabetes developing (13,14). The new generation of insulin-sensitizing agents may also limit the effect of the metabolic complications of polycystic ovary syndrome (5). Certainly, it is difficult to argue against the view that calorie restriction and increased exercise for obese young women with polycystic ovary syndrome is eminently sensible, not just to improve reproductive function (which it clearly does) (13) but also as an investment in a healthy future.
REFERENCES 1. Franks S. Medical progress article: polycystic ovary syndrome. N Engl J Med. 1995;333:853–861.
666
December 1, 2001
THE AMERICAN JOURNAL OF MEDICINE威
2. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism of action and implications for pathogenesis. Endocr Rev. 1996;18:774 –800. 3. Holte J. Disturbances in insulin secretion and sensitivity in women with the polycystic ovary syndrome. Baillieres Clin Endocrinol Metab. 1996;10:221–247. 4. Wild S, Pierpoint T, McKeigue P, Jacobs HS. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol. 2000;52: 595–600. 5. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med. 2001;111:607– 613. 6. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease in lean and obese women with polycystic ovary syndrome. Clin Endocrinol. 1992;37:119 –125. 7. Robinson S, Henderson AD, Gelding SV, et al. Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol. 1996;44:277–284. 8. Talbott E, Clerici A, Berga SL, et al. Adverse lipid and coronary heart risk profiles in young women with polycystic ovary syndrome: results of a case-control study. J Clin Epidemiol. 1998;51:415–422. 9. Pirwany IR, Fleming R, Greer IA, et al. Lipids and lipoprotein subfractions in women with PCOS: relationship to metabolic and endocrine parameters. Clin Endocrinol. 2001;54:447–453. 10. Dejager S, Pichard C, Giral P, et al. Smaller LDL particle size in women with polycystic ovary syndrome compared to controls. Clin Endocrinol. 2001;54:455–462. 11. Paradisi G, Steinberg HO, Hempfling A, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation. 2001;103:1410 –1415. 12. Talbott EO, Guzick DS, Sutton-Tyrrell K, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol. 2000;20:2414 –2421. 13. Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol. 1992;36: 105–111. 14. Clark AM, Ledger W, Galletly C, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod. 1995;10:2705–2712.
Volume 111