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Type 2 diabetes and polycystic ovary syndrome
Type 2 diabetes and polycystic ovary syndrome Richard S. Legro, M.D. Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
Women with polycystic ovary syndrome (PCOS) have multiple factors that contribute to increased diabetes risk, including: insulin resistance, beta-cell dysfunction, obesity, especially centripetal obesity, family history of type 2 diabetes, and personal history of gestational diabetes. Additionally there is some evidence to suggest that polycystic ovaries and chronic anovulation per se are risk factors. Identifying glucose intolerance and treating it are important aspects of the care for women with PCOS. (Fertil Steril威 2006;86(Suppl 1):S16 –7. ©2006 by American Society for Reproductive Medicine.) Key Words: Polycystic ovary syndrome, hyperandrogenism, insulin resistance, diabetes, anovulation
GLUCOSE INTOLERANCE IN PCOS Studies of large cohorts of women with polycystic ovary syndrome (PCOS) in the U.S. have demonstrated that the prevalence rates of glucose intolerance are as high as 40% in PCOS women when the less stringent WHO criteria are used (1–3). These studies are of interest, because they have shown nearly identical rates of impaired glucose tolerance and type 2 diabetes among a diverse cohort, both ethnically and geographically. Undiagnosed diabetes based on 2-h glucose-challenged glucose levels approaches 10% in these cohorts. The majority of affected women are in their third and fourth decade of life, but we have encountered PCOS adolescents with impaired glucose tolerance or type 2 diabetes (4) as well as lean individuals (body mass index ⬍25) with glucose intolerance (2). Based on the prevalence of glucose intolerance in women in the U.S. population, it can be extrapolated that PCOS contributes to approximately 20% of impaired glucose tolerance and 40% of type 2 diabetes in reproductive-aged women. It is important to note that these series report fasting normoglycemia in the majority of women and that, while elevated fasting levels tend to predict elevated 2-h glucose-challenged levels, even women with glucose intolerance tend to have fasting glucose levels below 100 mg/dL. This would suggest that these abnormalities may represent a universal characteristic of women with PCOS, at least those diagnosed on the basis of hyperandrogenic chronic anovulation. However rates of glucose intolerance and diabetes are substantially lower in a thinner European Received March 8, 2006; revised and accepted April 13, 2006. Supported by PHS K24 HD01476, the National Cooperative Program in Infertility Research (NCPIR) U54 HD34449, a GCRC grant MO1 RR 10732, and construction grant C06 RR016499 to Pennsylvania State University. Reprint requests: Richard S. Legro, M.D., Department of Obstetrics and Gynaecology, 500 University Drive, Pennsylvania State University College of Medicine, M.S. Hershey Medical Center, Hershey, PA 17033 (FAX: 717-531-8478; E-mail: [email protected]).
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population with PCOS (5), suggesting again that obesity further exacerbates diabetes risk. PROSPECTIVE STUDIES OF CONVERSION TO DIABETES IN PCOS Natural history supportive of significant worsening of glucose tolerance would support more aggressive identification and treatment of this disorder in PCOS women. In other populations, impaired glucose tolerance (IGT) is a risk factor for the development of type 2 diabetes, with an average conversion rate of 1%–5% per year . There are certainly other groups of women at higher risk for developing type 2 diabetes, such as Latina women with a history of gestational diabetes, whose cumulative conversion rates to diabetes may be as high as 50% over 5 years, or 10% per year (6). To date, there have been several small published studies of conversion rates to diabetes over time in women with PCOS, and rates, while clinically meaningful, do not approach the magnitude found in other high-risk populations, such as women with gestational diabetes. Two studies have noted worsening glucose intolerance over time (1). Body mass index at baseline was an independent significant predictor of conversion risk (7). In a similar-sized but controlled study with an average follow-up of 2.5 years, women with PCOS and IGT had a similar risk, with a net conversion of 6% to type 2 diabetes over approximately 3 years, or 2% per year (8). Although this was less than in the other populations noted above, the effect of PCOS was more pronounced in women with normal glucose tolerance at baseline, with a 40% conversion to IGT (Fig. 1). These small studies all suggest that abnormalities in glucose metabolism tend to increase with age in women with PCOS, and women with PCOS should be rescreened periodically.
Fertility and Sterility姞 Vol. 86, Suppl 1, July 2006 Copyright ©2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/06/$32.00 doi:10.1016/j.fertnstert.2006.04.010
FIGURE 1 Glucose and insulin levels during a 2-h oral glucose tolerance test in control women and women with polycystic ovary syndrome (PCOS) at baseline and follow-up of 2.5 yrs. for PCOS women and 2.9 yrs. for control women. Adapted from Legro et al. (8).
Legro. Type 2 diabetes and PCOS. Fertil Steril 2006.
REFERENCES 1. 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. 2. 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. 3. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:66 –71. 4. 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.
FERTILITY & STERILITY姞
5. Gambineri A, Pelusi C, Manicardi E, Vicennati V, Cacciari M, MorselliLabate AM, et al. Glucose intolerance in a large cohort of mediterranean women with polycystic ovary syndrome: phenotype and associated factors. Diabetes 2004;53:2353– 8. 6. Kjos SL, Peters RK, Xiang A, Henry OA, Montoro M, Buchanan TA. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes 1995; 44:586 –591. 7. Norman RJ, Masters L, Milner CR, Wang JX, Davies MJ. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or noninsulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum Reprod 2001;16:1995– 8. 8. Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab 2005;90:3236 – 42.
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Women with polycystic ovary syndrome (PCOS) have multiple factors that contribute to increased diabetes risk, including: insulin resistance, beta-cell dysfunction, obesity, especially centripetal obesity, family history of type 2 diabetes, and personal history of gestational diabetes. Additionally there is some evidence to suggest that polycystic ovaries and chronic anovulation per se are risk factors. Identifying glucose intolerance and treating it are important aspects of the care for women with PCOS. (Fertil Steril威 2006;86(Suppl 1):S16 –7. ©2006 by American Society for Reproductive Medicine.) Key Words: Polycystic ovary syndrome, hyperandrogenism, insulin resistance, diabetes, anovulation
GLUCOSE INTOLERANCE IN PCOS Studies of large cohorts of women with polycystic ovary syndrome (PCOS) in the U.S. have demonstrated that the prevalence rates of glucose intolerance are as high as 40% in PCOS women when the less stringent WHO criteria are used (1–3). These studies are of interest, because they have shown nearly identical rates of impaired glucose tolerance and type 2 diabetes among a diverse cohort, both ethnically and geographically. Undiagnosed diabetes based on 2-h glucose-challenged glucose levels approaches 10% in these cohorts. The majority of affected women are in their third and fourth decade of life, but we have encountered PCOS adolescents with impaired glucose tolerance or type 2 diabetes (4) as well as lean individuals (body mass index ⬍25) with glucose intolerance (2). Based on the prevalence of glucose intolerance in women in the U.S. population, it can be extrapolated that PCOS contributes to approximately 20% of impaired glucose tolerance and 40% of type 2 diabetes in reproductive-aged women. It is important to note that these series report fasting normoglycemia in the majority of women and that, while elevated fasting levels tend to predict elevated 2-h glucose-challenged levels, even women with glucose intolerance tend to have fasting glucose levels below 100 mg/dL. This would suggest that these abnormalities may represent a universal characteristic of women with PCOS, at least those diagnosed on the basis of hyperandrogenic chronic anovulation. However rates of glucose intolerance and diabetes are substantially lower in a thinner European Received March 8, 2006; revised and accepted April 13, 2006. Supported by PHS K24 HD01476, the National Cooperative Program in Infertility Research (NCPIR) U54 HD34449, a GCRC grant MO1 RR 10732, and construction grant C06 RR016499 to Pennsylvania State University. Reprint requests: Richard S. Legro, M.D., Department of Obstetrics and Gynaecology, 500 University Drive, Pennsylvania State University College of Medicine, M.S. Hershey Medical Center, Hershey, PA 17033 (FAX: 717-531-8478; E-mail: [email protected]).
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population with PCOS (5), suggesting again that obesity further exacerbates diabetes risk. PROSPECTIVE STUDIES OF CONVERSION TO DIABETES IN PCOS Natural history supportive of significant worsening of glucose tolerance would support more aggressive identification and treatment of this disorder in PCOS women. In other populations, impaired glucose tolerance (IGT) is a risk factor for the development of type 2 diabetes, with an average conversion rate of 1%–5% per year . There are certainly other groups of women at higher risk for developing type 2 diabetes, such as Latina women with a history of gestational diabetes, whose cumulative conversion rates to diabetes may be as high as 50% over 5 years, or 10% per year (6). To date, there have been several small published studies of conversion rates to diabetes over time in women with PCOS, and rates, while clinically meaningful, do not approach the magnitude found in other high-risk populations, such as women with gestational diabetes. Two studies have noted worsening glucose intolerance over time (1). Body mass index at baseline was an independent significant predictor of conversion risk (7). In a similar-sized but controlled study with an average follow-up of 2.5 years, women with PCOS and IGT had a similar risk, with a net conversion of 6% to type 2 diabetes over approximately 3 years, or 2% per year (8). Although this was less than in the other populations noted above, the effect of PCOS was more pronounced in women with normal glucose tolerance at baseline, with a 40% conversion to IGT (Fig. 1). These small studies all suggest that abnormalities in glucose metabolism tend to increase with age in women with PCOS, and women with PCOS should be rescreened periodically.
Fertility and Sterility姞 Vol. 86, Suppl 1, July 2006 Copyright ©2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/06/$32.00 doi:10.1016/j.fertnstert.2006.04.010
FIGURE 1 Glucose and insulin levels during a 2-h oral glucose tolerance test in control women and women with polycystic ovary syndrome (PCOS) at baseline and follow-up of 2.5 yrs. for PCOS women and 2.9 yrs. for control women. Adapted from Legro et al. (8).
Legro. Type 2 diabetes and PCOS. Fertil Steril 2006.
REFERENCES 1. 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. 2. 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. 3. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:66 –71. 4. 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.
FERTILITY & STERILITY姞
5. Gambineri A, Pelusi C, Manicardi E, Vicennati V, Cacciari M, MorselliLabate AM, et al. Glucose intolerance in a large cohort of mediterranean women with polycystic ovary syndrome: phenotype and associated factors. Diabetes 2004;53:2353– 8. 6. Kjos SL, Peters RK, Xiang A, Henry OA, Montoro M, Buchanan TA. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes 1995; 44:586 –591. 7. Norman RJ, Masters L, Milner CR, Wang JX, Davies MJ. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or noninsulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum Reprod 2001;16:1995– 8. 8. Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab 2005;90:3236 – 42.
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