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Prevalence of the metabolic syndrome and its components in Brazilian women with polycystic ovary syndrome
Prevalence of the metabolic syndrome and its components in Brazilian women with polycystic ovary syndrome Elvira Maria Mafaldo Soares, M.D.,a George Dantas Azevedo, Ph.D.,b Rafael Goncxalves N obrega Gadelha, M.D.,a Telma Maria Ara ujo Moura Lemos, Ph.D.,c a and T ecia Maria Oliveira Maranh~ ao, Ph.D. a Departamento de Tocoginecologia, Maternidade Escola Januario Cicco; b Departamento de Morfologia, Centro de Bioci^encias; and c Departamento de Analises Clınicas, Centro de Ci^encias da Saude, Programa de Pos-graduac x~ao em Ci^encias da Saude, Universidade Federal do Rio Grande do Norte, Natal-RN, Brazil
Objective: To determine the prevalence of the metabolic syndrome (MetS) and its components in Brazilian women with polycystic ovary syndrome (PCOS). Design: Cross-sectional study. Setting: University Hospital, Federal University of Rio Grande do Norte, Natal-RN, Brazil. Patient(s): 102 women with PCOS by the Rotterdam consensus criteria. Intervention(s): None. Main Outcome Measure(s): Clinical and biochemical parameters for MetS as defined by the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III). Result(s): The prevalence for individual components of MetS were high-density lipoprotein cholesterol level <50 mg/dL in 69.6%, waist circumference R88 cm in 57.9%, triglyceride level R150 mg/dL in 31.7%, blood pressure R130/85 mm Hg in 18.6%, and fasting glucose concentrations R110 mg/dL in 2.9%. Three or more of these individual criteria were present in 29 (28.4%) of the patients. The prevalence of MetS increased with body mass index: 3.2%, 19.2% and 52.3% for normal, overweight, and obese women, respectively. Conclusion(s): These findings indicate that Brazilian women with PCOS have a high prevalence of MetS and its individual components, particularly a decreased high-density lipoprotein cholesterol level. Thus, these women are at increased risk of diabetes mellitus and cardiovascular disease. (Fertil Steril 2008;89:649–55. 2008 by American Society for Reproductive Medicine.) Key Words: Metabolic syndrome, polycystic ovary syndrome, cardiovascular disease
Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women, affecting approximately 5% to 8% of premenopausal women (1–3). This ovarian disfunction syndrome is characterized by chronic anovulation, oligomenorrhea or amenorrhea, hyperandrogenism, infertility, and polycystic ovary morphology (4). Additionally, it is recognized to have a metabolic component consisting of hyperinsulinemic insulin resistance; this finding has led to the correlation of PCOS with increased cardiovascular disease risk, which occurs in both lean and obese women with the disorder (5, 6). The metabolic syndrome (MetS) is another cluster of endocrine disturbances, including insulin resistance, dyslipide-
Received January 2, 2007; revised and accepted March 28, 2007. Supported in part by the Conselho Nacional de Desenvolvimento gico (CNPq), Ministe rio da Sau de do Brasil, and Cientıfico e Tecnolo ~o de Apoio a Pesquisa do Estado do Rio Grande do Norte (FAFundacxa ^nio 0146.00/04-CNPq/FAPERN, projeto: 673.923254). PERN) (Conve Reprint requests: George Dantas Azevedo, Ph.D., Departamento de Mor^ncias, Campus Universita rio, BR 101, Lagoa fologia do Centro de Biocie Nova, Natal-RN, Brasil 59078-970 (FAX: þ55-84-32119207; E-mail: [email protected]).
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.03.081
mia, obesity, central adiposity, and hypertension, (7, 8), that has been associated with a twofold increased risk of cardiovascular disease and a fivefold increased risk of type 2 diabetes (9). Estimates of the prevalence of MetS in women with PCOS have been based mainly on the U.S. population, pointing to a prevalence of approximately 43% to 46% (10–12). Despite this increased prevalence, the exact relationship between insulin resistance and different features of MetS in PCOS patients is not completely understood. There are few data concerning this prevalence in other countries, especially in those where obesity is less frequently found than in the United States. Studies involving Czech and Italian women with PCOS report that MetS and its components were much less frequent in these populations (13, 14), a finding attributed to genetic factors and differences in lifestyle and dietary habits, and, possibly also influenced by the criteria used to diagnose MetS, as well as the criteria used to diagnose PCOS. In the Brazilian population, the prevalence of obesity, increased waist circumference, hypertension, and dyslipidemia is markedly less than observed in the United States (15). Within this context, no data are published on the prevalence
Fertility and Sterility Vol. 89, No. 3, March 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
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of MetS and its components in Brazilian women with PCOS. Our purpose was to estimate this prevalence according to the National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria (16).
MATERIALS AND METHODS Patients Clinical, anthropometric, biochemical, and hormonal measures were taken of 102 women with PCOS who participated in a cross-sectional study designed to evaluate the association between PCOS and cardiovascular disease. Volunteers were selected at the University Hospital of the Federal University of Rio Grande do Norte, Natal-RN, Brazil, from July 2004 to December 2005. This study was approved by the institutional ethics committee (protocol number 126/04), and all volunteers gave written informed consent. Women aged 20 to 34 years who were R2 years postmenarche were eligible for the study. No classification according to ethnicity was used, as it is very difficult to classify ethnic groups in Brazil where there is abundant racial admixture; the autoreference according to race or color may be not adequate, with significant dissociation of color and genomic ancestry (17, 18). The diagnosis of PCOS was made according to the criteria of the Rotterdam ESHRE-ASRM–sponsored PCOS consensus workshop (4) by the presence of at least two of the following three features: [1] oligo-ovulation and/or anovulation, characterized by oligomenorrhea (intermenstrual intervals of 45 days or more or fewer than eight menses per year), or amenorrhea (intervals >3 months); [2] clinical signs of androgen excess (Ferriman–Gallwey [19] hirsutism score R8 and/or presence of acne), and/or biochemical signs of hyperandrogenism; and [3] ultrasonographic findings of ovarian polycystic morphology (presence of R12 follicles in each ovary measuring 2 to 9 mm in diameter, and/or increased ovarian volume >10 mL) (4). Infertility was defined as the inability to conceive after 1 year of unprotected intercourse. The exclusion of other disorders such as nonclassic congenital adrenal hyperplasia, thyroid dysfunction, and hyperprolactinemia was also considered. Other exclusion criteria for this study were renal or hepatic dysfunction or use of medications known to affect reproductive or metabolic function, such as oral contraceptives, antiandrogen drugs, antidiabetic treatment, statins, or glucocorticoid therapy within 60 days of study entry. Both Rotterdam-PCOS criteria and Ferriman–Gallwey score were assessed by at least two observers. Although many diagnostic criteria for MetS have been proposed, the National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria are the most commonly used for both clinical and research purposes, so these criteria were adopted for our study as well (16). Thus, the MetS was defined by the presence of three or more of the following abnormalities: waist circumference R88 cm; fasting serum glu650
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cose of at least 110 mg/dL; fasting serum triglycerides R150 mg/dL; serum high-density lipoprotein cholesterol (HDL-C) <50 mg/dL; and blood pressure R130/85 mm Hg. Study Protocol All patients underwent a clinical examination where body weight, height, waist and hip circumferences and blood pressure were measured. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m2); overweight was defined as a BMI between 25.0 and 29.9, and obese as 30.0 or higher, according to World Health Organization categories (20). Acanthosis nigricans, a significant marker for insulin resistance (21), was diagnosed by hyperpigmentation of the skin in the posterior region of the neck, axillae, antecubital fossae, and groin. Fasting venous blood samples were collected between 8:00 and 10:00 AM after a 12-hour overnight fast. Serum glucose was measured by the glucose oxidase method. Levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), urea, and creatinine were determined by enzymatic colorimetric assays (BioSystems, Barcelona, Spain). Low-density lipoprotein (LDL) levels were calculated by using Friedewald’s formula.
AM
Blood samples also were obtained at baseline and at 30minute intervals for 2 hours during a 75-g oral glucose tolerance test (OGTT) to measure glucose and insulin. Glucose tolerance was evaluated using the American Diabetes Association’s criteria for the diagnosis and classification of diabetes (22). Insulin sensitivity was evaluated by the quantitative insulin-sensitivity check index (QUICKI): 1/(log insulin [mU/mL] þ log glucose [mg/dL]) (23). Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and insulin were determined by using commercially available diagnostic kits in the IMMULITE 2000 automated chemiluminescence-immunoassay system (Diagnostic Products Corporation, Los Angeles, CA). Total testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone were measured following the manufacturer’s recommendations (Diagnostic Products Corporation, Los Angeles, CA). Exclusion of nonclassic congenital adrenal hyperplasia was based on a basal morning 17-hydroxyprogesterone level less than 200 ng/dL. Statistical Analysis The normality of distribution of all variables was checked by using the Kolmogorov–Smirnov test. The results were expressed as mean standard deviation (SD) unless otherwise indicated. The significance of differences between groups was determined using the unpaired t-test and analysis of variance (ANOVA), as appropriate. Between-group differences were assessed by chi-square testing. For all analyses, twotailed P<.05 was considered statistically significant. Data analysis was performed using SPSS version 13.0 for Windows statistical software (SPSS, Inc., Chicago IL). Vol. 89, No. 3, March 2008
TABLE 1 Age-stratified prevalence of the metabolic syndrome (MetS) in Brazilian women with polycystic ovary syndrome. Age groups (years) 20–24 25–29 30–34 Total
MetS N (%)
No MetS N (%)
Total N (%)
4 (12.1) 13 (31.7) 12 (42.9) 29 (28.4)
29 (87.9) 28 (68.3) 16 (57.1) 73 (71.6)
33 (100.0) 41 (100.0) 28 (100.0) 102 (100.0)
Note: Prevalence of MetS was different across age groups (chi-square test; P¼ .02). Soares. Metabolic syndrome in Brazilian PCOS. Fertil Steril 2008.
RESULTS Clinical Characteristics of Patients For the entire cohort, the mean age at baseline evaluation was 26.4 5.3 years and mean BMI was 29.4 6.7 kg/m2. The overall prevalence of women who were overweight or obese was 25.5% (26 out of 102) and 43.1% (44 out of 102), respectively. The prevalence rates of oligomenorrhea, hirsutism, and infertility were 56.9%, 41.2%, and 64.7%, respectively. Prevalence of the Metabolic Syndrome and Glucose Intolerance The prevalence of MetS in this cohort of 102 women with PCOS was 28.4% (n ¼ 29 patients). A considerable proportion (30.4%) of these women fulfilled two criteria, and 26.5% fulfilled one criteria for MetS. Only 14.7% of them had no MetS factors. Table 1 shows the age-stratified prevalence of MetS, where the increasing prevalence according to age group can be seen. The prevalence of MetS was also statistically significantly associated with BMI (Table 2). Overweight and obese women had a sixfold and 16-fold increased risk for MetS, respectively, when compared with
the normal BMI group. High waist circumference and high blood pressure were also more prevalent in the overweight and obese groups (P<.0001). Based on the 2-hour glucose level during OGTT, glucose tolerance was found to be normal in 80 (78.4%) of the 102 women; 20 (19.6%) had impaired glucose tolerance, and two (2.0%) had noninsulin-dependent diabetes mellitus at the time of baseline evaluation. When we analyzed fasting glucose levels according to the recommendations of the Expert Committee of the American Diabetes Association (22), we found that 99 (97.1%) women had normal fasting glucose (<110 mg/dL), and three (2.9%) had impaired fasting glucose (R110 and <126 mg/dL). The clinical and metabolic characteristics of subgroups with and without MetS are presented in Table 3. Compared with women without MetS, the patients with MetS had higher BMI, waist circumference, and systolic and diastolic blood pressure as well as higher levels of total cholesterol, triglycerides, fasting glucose, fasting insulin, creatinine, and gammaglutamyltransferase and a lower QUICKI index.
TABLE 2 Prevalence of the metabolic syndrome and individual abnormalities in Brazilian women with polycystic ovary syndrome stratified by body mass index group. Body mass index (kg/m2)
Metabolic syndrome High waist circumference Hypertriglyceridemia Low HDL-C High blood pressure High fasting glucose Impaired glucose tolerance NIDDM
<25 (n [ 32)
25 – 29 (n [ 26)
R30 (n [ 44)
P valuea
01 (3.2%) 02 (6.3%) 06 (19.4%) 18 (62.1%) — — 04 (12.5%) —
05 (19.2%) 14 (53.8%) 08 (30.8%) 19 (76.0%) 03 (11.5%) 01 (3.8%) 04 (15.4%) —
23 (52.3%) 43 (97.7%) 18 (40.9%) 34 (85.0%) 16 (36.4%) 02 (4.5%) 12 (27.3%) 2 (4.5%)
< .0001 < .0001 .14 .09 < .0001 .48 .19 .19
Note: HDL-C, high-density lipoprotein cholesterol; NIDDM, noninsulin-dependent diabetes mellitus. a Chi-square test. Soares. Metabolic syndrome in Brazilian PCOS. Fertil Steril 2008.
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TABLE 3 Comparison of clinical and endocrine characteristics of Brazilian women with polycystic ovary syndrome women with and without the metabolic syndrome (MetS). Variables Weight (kg) Body mass index (kg/m2) Waist circumference Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Prolactin (ng/mL) TSH (mU/mL) Serum total testosterone (ng/dL) DHEAS (ng/dL) Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Triglycerides (mg/dL) Fasting glucose (mg/dL) Fasting insulin (mU/mL) QUICKI Aspartate aminotransferase (mg/dL) Alanine aminotransferase (mg/dL) Gamma-glutamyltransferase (mg/dL) Urea (mg/dL) Creatinine (mg/dL)
MetS (n [ 29)
No MetS (n [ 73)
84.3 15.0 34.2 5.3 101.2 12.3 125.8 13.5 81.0 10.5 13.2 1.5 1.67 0.14 114.4 35.0 73.3 23.0 200.6 39.6 37.6 8.0 123.7 39.5 196.2 71.4 88.3 14.1 15.8 9.2 0.33 0.02 27.5 9.4 28.0 12.4 29.2 20.9 22.2 5.2 1.01 0.16
67.4 17.1a 27.5 6.2a 86.8 15.6a 109.7 10.3a 68.9 9.1a 15.5 1.8 1.62 0.21 105.6 11.8 97.4 16.5 182.5 41.7a 42.3 11.9 119.2 40.5 103.3 50.6a 82.2 10.7a 10.2 6.5a 0.35 0.04a 26.0 9.8 24.6 17.7 20.3 8.1a 22.1 6.0 0.89 0.14a
Note: Data presented as mean standard deviation. DHEAS, dehydroepiandrosterone sulfate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; QUICKI, quantitative insulin-sensitivity check index; TSH, thyroid-stimulating hormone. a Student’s-t test, P< .001. Soares. Metabolic syndrome in Brazilian PCOS. Fertil Steril 2008.
The Metabolic Syndrome Abnormalities The most prevalent isolated MetS abnormality in women with PCOS was high-density lipoprotein cholesterol levels below 50 mg/dL, present in 69.6% (71 out of 102). Other abnormalities were increased waist circumference in 57.9% (59/102), increased serum triglycerides in 31.4% (32 out of 102), hypertension in 18.6% (19 out of 102), and high fasting glucose concentrations in 2.9% (3 out of 102). Analysis of the prevalence of other PCOS clinical features according to the presence of MetS showed a statistically significant association with the presence of acanthosis nigricans; the condition was more frequent in women with MetS than in women without MetS (Table 4).
DISCUSSION In this study, the prevalence of MetS in Brazilian women with PCOS was 28.4%. There are no published references about age-adjusted prevalence of MetS by sex in the general Brazilian population (24). Limited information can be obtained from a recent study involving a specific sample of a rural population from Bahia, Brazil, which showed a 7% prevalence of MetS for the 25- to 34-year age group, 652
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with higher frequency in women than in men (25). This limitation led us to compare our results with those reported by Ford et al. for the general U.S. population (26). Despite the higher prevalence of obesity in the U.S. population, we found a statistically significant higher prevalence of MetS in our sample of Brazilian women with PCOS than that of U.S. women aged 25 to 34 years. Several studies have been conducted to evaluate the prevalence of MetS in women with PCOS. Glueck et al. (10) and Apridonidze et al. (11) observed that the prevalence of MetS in U.S. women with PCOS was 46% and 43%, respectively, much higher than that observed in our study. Conversely, Vrbıkova et al. (13) did not find a higher prevalence of MetS in Czech women with PCOS, even though those women had higher BMI and waist circumference, higher systolic and diastolic blood pressure, and lower HDL-cholesterol levels than women without PCOS. In Italian women, Carmina et al. (14) observed that MetS was more frequent in women with PCOS than in the general population; however, this prevalence was much lower than in the United States. These differences could be attributed to genetic factors or lifestyle characteristics and dietary habits, such as the higher incidence of obesity in the U.S. population. Vol. 89, No. 3, March 2008
TABLE 4 Prevalence of clinical characteristics in Brazilian women with polycystic ovary syndrome with and without the metabolic syndrome (MetS). Prevalence [N (%)] Variables
MetS (N [ 29)
No MetS (N [ 73)
P valuea
21 (72.4) 18 (62.1) 14 (48.3) 21 (72.4) 21 (72.4) 12 (41.4) 24 (82.8)
58 (79.5) 48 (65.8) 29 (39.7) 29 (39.7) 56 (76.7) 34 (46.6) 50 (68.5)
.44 .72 .62 .005 .89 .44 .34
15 (51.7) 21 (72.4) 13 (44.8)
31 (42.5) 46 (63.0) 24 (32.9)
.62 .51 .28
Amenorrhea Infertility Hirsutism Acanthosis Polycystic ovary morphology FH cardiovascular disease FH systemic arterial hypertension FH obesity FH NIDDM FH dyslipidemia
Note: FH, family history; NIDDM, noninsulin-dependent diabetes mellitus. a Chi-square test. Soares. Metabolic syndrome in Brazilian PCOS. Fertil Steril 2008.
The occurrence of low HDL-C was the most frequent individual MetS component in Brazilian women with PCOS, followed by increased waist circumference and increased serum triglycerides. Other studies have reported similar results and point to the fact that dyslipidemia is the most common metabolic abnormality in PCOS, with a prevalence of up to 70% according to NCEP criteria (6, 11, 27). Furthermore, it is important to observe that the majority of our patients (85.3%) had at least one MetS abnormality, a finding similar to that found by Apridonidze et al. (11). A very consistent finding is that the prevalence of MetS is highly age and BMI dependent (28, 29). In our study, the prevalence of MetS in women with PCOS aged 20 to 24 years was 12.1%, with a progressive increase to 31.7% in the 25- to 29-year group and 42.9% in the 30- to 34-year group. A previous case-control study involving 86 women with PCOS aged between 18 and 22 years found a MetS prevalence of 11%, supporting the idea that the prevalence of MetS in women with PCOS is high in all age groups (30). Many women with PCOS (between 38% and 88%) are overweight or obese, and there is no doubt that adiposity plays a crucial role in the development and maintenance of PCOS and strongly influences the severity of both its clinical and endocrine features in many women (31). Obesity seems to contribute as an independent factor for MetS abnormalities (32, 33), and our results are in accordance with this idea, given that increased waist circumference and hypertension showed an increasing prevalence with BMI. Nevertheless, the rates of dyslipidemia and impaired glucose tolerance showed no statistically significant difference among the BMI groups, an important finding corroborating the releFertility and Sterility
vance of screening for MetS and other cardiovascular risk factors in all women with PCOS, regardless of obesity. Insulin resistance is associated with MetS, and is considered a common denominator of metabolic alterations that characterize the syndrome (34, 35). Our data support this hypothesis, with the finding of a statistically significant lower QUICKI index in women with PCOS and MetS when compared with those without MetS. Corroborating this finding, we also observed that acanthosis nigricans was more prevalent in women with PCOS and MetS. Recently, several clinical, epidemiological, and biochemical studies have supported the concept that insulin resistance is accompanied by many other alterations that are not included in the diagnostic criteria for MetS. These conditions include nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis, obstructive sleep apnea, and increased levels of prothrombotic factors, homocysteine, and proinflammatory cytokines (8). Results of our observations in women with PCOS show higher gamma-glutamyltransferase serum levels in women with MetS than in women without MetS, which is in accordance with published data on the subject. Whitfield et al. (36) showed that changes in enzyme gamma-glutamyltransferase and alanine-aminotransferase are associated with cardiovascular risk factors. In the Brazilian population, Araujo et al. (37) found that gamma-glutamyltransferase activity was associated with the number of MetS abnormalities in obese women. Additionally, Setji et al. (38) observed that abnormal aminotransferase activity is common in women with PCOS (about 15%), and is significantly associated to dyslipidemia and hyperinsulinemia. Taken together, these data suggest that women with PCOS may have an increased risk of developing 653
many of the consequences of MetS, including nonalcoholic steatohepatitis. Despite these relevant findings, it is important to point out the limitations of our study. We included only cross-sectional measures; prospective data from this cohort study will be available in the future to determine conclusively the association between PCOS and cardiovascular disease in Brazilian women. Other limitations include the relatively small sample size and the fact that only one diagnostic criteria for MetS were considered. Additionally, the results may be influenced by the way in which PCOS and MetS were diagnosed. The findings of this study confirm that the prevalence of MetS and its individual components, particularly a decreased high-density lipoprotein cholesterol level, is substantially higher in women with PCOS than in the general population. However, the prevalence of MetS in Brazilian women with PCOS appears to be much lower than that found in the U.S. population, as previously reported in other non-U.S. studies. Thus, these women are at increased risk of diabetes mellitus and cardiovascular disease; it is therefore important to screen all women with PCOS for cardiovascular risk factors. Identification and clinical management of this highrisk group is an important aspect of coronary heart disease prevention, and better understanding of these issues is critical to preventing mortality from cardiovascular disease in these patients.
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36. Whitfield JB, Zhu G, Nestler JE, Heath AC, Martin NG. Genetic covariation between serum gamma-glutamyl-transferase activity and cardiovascular risk factors. Clin Chem 2002;48:1426–31. 37. Araujo LM, Lima DS, Daltro C. Association of gamma-glutamyl transferase and the metabolic syndrome in obese women. Arq Bras Endocrinol Metab 2005;49:557–62. 38. Setji TL, Holland ND, Sanders LL, Pereira KC, Diehl AM, Brown AJ. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:1741–7.
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Objective: To determine the prevalence of the metabolic syndrome (MetS) and its components in Brazilian women with polycystic ovary syndrome (PCOS). Design: Cross-sectional study. Setting: University Hospital, Federal University of Rio Grande do Norte, Natal-RN, Brazil. Patient(s): 102 women with PCOS by the Rotterdam consensus criteria. Intervention(s): None. Main Outcome Measure(s): Clinical and biochemical parameters for MetS as defined by the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III). Result(s): The prevalence for individual components of MetS were high-density lipoprotein cholesterol level <50 mg/dL in 69.6%, waist circumference R88 cm in 57.9%, triglyceride level R150 mg/dL in 31.7%, blood pressure R130/85 mm Hg in 18.6%, and fasting glucose concentrations R110 mg/dL in 2.9%. Three or more of these individual criteria were present in 29 (28.4%) of the patients. The prevalence of MetS increased with body mass index: 3.2%, 19.2% and 52.3% for normal, overweight, and obese women, respectively. Conclusion(s): These findings indicate that Brazilian women with PCOS have a high prevalence of MetS and its individual components, particularly a decreased high-density lipoprotein cholesterol level. Thus, these women are at increased risk of diabetes mellitus and cardiovascular disease. (Fertil Steril 2008;89:649–55. 2008 by American Society for Reproductive Medicine.) Key Words: Metabolic syndrome, polycystic ovary syndrome, cardiovascular disease
Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women, affecting approximately 5% to 8% of premenopausal women (1–3). This ovarian disfunction syndrome is characterized by chronic anovulation, oligomenorrhea or amenorrhea, hyperandrogenism, infertility, and polycystic ovary morphology (4). Additionally, it is recognized to have a metabolic component consisting of hyperinsulinemic insulin resistance; this finding has led to the correlation of PCOS with increased cardiovascular disease risk, which occurs in both lean and obese women with the disorder (5, 6). The metabolic syndrome (MetS) is another cluster of endocrine disturbances, including insulin resistance, dyslipide-
Received January 2, 2007; revised and accepted March 28, 2007. Supported in part by the Conselho Nacional de Desenvolvimento gico (CNPq), Ministe rio da Sau de do Brasil, and Cientıfico e Tecnolo ~o de Apoio a Pesquisa do Estado do Rio Grande do Norte (FAFundacxa ^nio 0146.00/04-CNPq/FAPERN, projeto: 673.923254). PERN) (Conve Reprint requests: George Dantas Azevedo, Ph.D., Departamento de Mor^ncias, Campus Universita rio, BR 101, Lagoa fologia do Centro de Biocie Nova, Natal-RN, Brasil 59078-970 (FAX: þ55-84-32119207; E-mail: [email protected]).
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.03.081
mia, obesity, central adiposity, and hypertension, (7, 8), that has been associated with a twofold increased risk of cardiovascular disease and a fivefold increased risk of type 2 diabetes (9). Estimates of the prevalence of MetS in women with PCOS have been based mainly on the U.S. population, pointing to a prevalence of approximately 43% to 46% (10–12). Despite this increased prevalence, the exact relationship between insulin resistance and different features of MetS in PCOS patients is not completely understood. There are few data concerning this prevalence in other countries, especially in those where obesity is less frequently found than in the United States. Studies involving Czech and Italian women with PCOS report that MetS and its components were much less frequent in these populations (13, 14), a finding attributed to genetic factors and differences in lifestyle and dietary habits, and, possibly also influenced by the criteria used to diagnose MetS, as well as the criteria used to diagnose PCOS. In the Brazilian population, the prevalence of obesity, increased waist circumference, hypertension, and dyslipidemia is markedly less than observed in the United States (15). Within this context, no data are published on the prevalence
Fertility and Sterility Vol. 89, No. 3, March 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
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of MetS and its components in Brazilian women with PCOS. Our purpose was to estimate this prevalence according to the National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria (16).
MATERIALS AND METHODS Patients Clinical, anthropometric, biochemical, and hormonal measures were taken of 102 women with PCOS who participated in a cross-sectional study designed to evaluate the association between PCOS and cardiovascular disease. Volunteers were selected at the University Hospital of the Federal University of Rio Grande do Norte, Natal-RN, Brazil, from July 2004 to December 2005. This study was approved by the institutional ethics committee (protocol number 126/04), and all volunteers gave written informed consent. Women aged 20 to 34 years who were R2 years postmenarche were eligible for the study. No classification according to ethnicity was used, as it is very difficult to classify ethnic groups in Brazil where there is abundant racial admixture; the autoreference according to race or color may be not adequate, with significant dissociation of color and genomic ancestry (17, 18). The diagnosis of PCOS was made according to the criteria of the Rotterdam ESHRE-ASRM–sponsored PCOS consensus workshop (4) by the presence of at least two of the following three features: [1] oligo-ovulation and/or anovulation, characterized by oligomenorrhea (intermenstrual intervals of 45 days or more or fewer than eight menses per year), or amenorrhea (intervals >3 months); [2] clinical signs of androgen excess (Ferriman–Gallwey [19] hirsutism score R8 and/or presence of acne), and/or biochemical signs of hyperandrogenism; and [3] ultrasonographic findings of ovarian polycystic morphology (presence of R12 follicles in each ovary measuring 2 to 9 mm in diameter, and/or increased ovarian volume >10 mL) (4). Infertility was defined as the inability to conceive after 1 year of unprotected intercourse. The exclusion of other disorders such as nonclassic congenital adrenal hyperplasia, thyroid dysfunction, and hyperprolactinemia was also considered. Other exclusion criteria for this study were renal or hepatic dysfunction or use of medications known to affect reproductive or metabolic function, such as oral contraceptives, antiandrogen drugs, antidiabetic treatment, statins, or glucocorticoid therapy within 60 days of study entry. Both Rotterdam-PCOS criteria and Ferriman–Gallwey score were assessed by at least two observers. Although many diagnostic criteria for MetS have been proposed, the National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria are the most commonly used for both clinical and research purposes, so these criteria were adopted for our study as well (16). Thus, the MetS was defined by the presence of three or more of the following abnormalities: waist circumference R88 cm; fasting serum glu650
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cose of at least 110 mg/dL; fasting serum triglycerides R150 mg/dL; serum high-density lipoprotein cholesterol (HDL-C) <50 mg/dL; and blood pressure R130/85 mm Hg. Study Protocol All patients underwent a clinical examination where body weight, height, waist and hip circumferences and blood pressure were measured. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m2); overweight was defined as a BMI between 25.0 and 29.9, and obese as 30.0 or higher, according to World Health Organization categories (20). Acanthosis nigricans, a significant marker for insulin resistance (21), was diagnosed by hyperpigmentation of the skin in the posterior region of the neck, axillae, antecubital fossae, and groin. Fasting venous blood samples were collected between 8:00 and 10:00 AM after a 12-hour overnight fast. Serum glucose was measured by the glucose oxidase method. Levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), urea, and creatinine were determined by enzymatic colorimetric assays (BioSystems, Barcelona, Spain). Low-density lipoprotein (LDL) levels were calculated by using Friedewald’s formula.
AM
Blood samples also were obtained at baseline and at 30minute intervals for 2 hours during a 75-g oral glucose tolerance test (OGTT) to measure glucose and insulin. Glucose tolerance was evaluated using the American Diabetes Association’s criteria for the diagnosis and classification of diabetes (22). Insulin sensitivity was evaluated by the quantitative insulin-sensitivity check index (QUICKI): 1/(log insulin [mU/mL] þ log glucose [mg/dL]) (23). Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and insulin were determined by using commercially available diagnostic kits in the IMMULITE 2000 automated chemiluminescence-immunoassay system (Diagnostic Products Corporation, Los Angeles, CA). Total testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone were measured following the manufacturer’s recommendations (Diagnostic Products Corporation, Los Angeles, CA). Exclusion of nonclassic congenital adrenal hyperplasia was based on a basal morning 17-hydroxyprogesterone level less than 200 ng/dL. Statistical Analysis The normality of distribution of all variables was checked by using the Kolmogorov–Smirnov test. The results were expressed as mean standard deviation (SD) unless otherwise indicated. The significance of differences between groups was determined using the unpaired t-test and analysis of variance (ANOVA), as appropriate. Between-group differences were assessed by chi-square testing. For all analyses, twotailed P<.05 was considered statistically significant. Data analysis was performed using SPSS version 13.0 for Windows statistical software (SPSS, Inc., Chicago IL). Vol. 89, No. 3, March 2008
TABLE 1 Age-stratified prevalence of the metabolic syndrome (MetS) in Brazilian women with polycystic ovary syndrome. Age groups (years) 20–24 25–29 30–34 Total
MetS N (%)
No MetS N (%)
Total N (%)
4 (12.1) 13 (31.7) 12 (42.9) 29 (28.4)
29 (87.9) 28 (68.3) 16 (57.1) 73 (71.6)
33 (100.0) 41 (100.0) 28 (100.0) 102 (100.0)
Note: Prevalence of MetS was different across age groups (chi-square test; P¼ .02). Soares. Metabolic syndrome in Brazilian PCOS. Fertil Steril 2008.
RESULTS Clinical Characteristics of Patients For the entire cohort, the mean age at baseline evaluation was 26.4 5.3 years and mean BMI was 29.4 6.7 kg/m2. The overall prevalence of women who were overweight or obese was 25.5% (26 out of 102) and 43.1% (44 out of 102), respectively. The prevalence rates of oligomenorrhea, hirsutism, and infertility were 56.9%, 41.2%, and 64.7%, respectively. Prevalence of the Metabolic Syndrome and Glucose Intolerance The prevalence of MetS in this cohort of 102 women with PCOS was 28.4% (n ¼ 29 patients). A considerable proportion (30.4%) of these women fulfilled two criteria, and 26.5% fulfilled one criteria for MetS. Only 14.7% of them had no MetS factors. Table 1 shows the age-stratified prevalence of MetS, where the increasing prevalence according to age group can be seen. The prevalence of MetS was also statistically significantly associated with BMI (Table 2). Overweight and obese women had a sixfold and 16-fold increased risk for MetS, respectively, when compared with
the normal BMI group. High waist circumference and high blood pressure were also more prevalent in the overweight and obese groups (P<.0001). Based on the 2-hour glucose level during OGTT, glucose tolerance was found to be normal in 80 (78.4%) of the 102 women; 20 (19.6%) had impaired glucose tolerance, and two (2.0%) had noninsulin-dependent diabetes mellitus at the time of baseline evaluation. When we analyzed fasting glucose levels according to the recommendations of the Expert Committee of the American Diabetes Association (22), we found that 99 (97.1%) women had normal fasting glucose (<110 mg/dL), and three (2.9%) had impaired fasting glucose (R110 and <126 mg/dL). The clinical and metabolic characteristics of subgroups with and without MetS are presented in Table 3. Compared with women without MetS, the patients with MetS had higher BMI, waist circumference, and systolic and diastolic blood pressure as well as higher levels of total cholesterol, triglycerides, fasting glucose, fasting insulin, creatinine, and gammaglutamyltransferase and a lower QUICKI index.
TABLE 2 Prevalence of the metabolic syndrome and individual abnormalities in Brazilian women with polycystic ovary syndrome stratified by body mass index group. Body mass index (kg/m2)
Metabolic syndrome High waist circumference Hypertriglyceridemia Low HDL-C High blood pressure High fasting glucose Impaired glucose tolerance NIDDM
<25 (n [ 32)
25 – 29 (n [ 26)
R30 (n [ 44)
P valuea
01 (3.2%) 02 (6.3%) 06 (19.4%) 18 (62.1%) — — 04 (12.5%) —
05 (19.2%) 14 (53.8%) 08 (30.8%) 19 (76.0%) 03 (11.5%) 01 (3.8%) 04 (15.4%) —
23 (52.3%) 43 (97.7%) 18 (40.9%) 34 (85.0%) 16 (36.4%) 02 (4.5%) 12 (27.3%) 2 (4.5%)
< .0001 < .0001 .14 .09 < .0001 .48 .19 .19
Note: HDL-C, high-density lipoprotein cholesterol; NIDDM, noninsulin-dependent diabetes mellitus. a Chi-square test. Soares. Metabolic syndrome in Brazilian PCOS. Fertil Steril 2008.
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TABLE 3 Comparison of clinical and endocrine characteristics of Brazilian women with polycystic ovary syndrome women with and without the metabolic syndrome (MetS). Variables Weight (kg) Body mass index (kg/m2) Waist circumference Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Prolactin (ng/mL) TSH (mU/mL) Serum total testosterone (ng/dL) DHEAS (ng/dL) Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Triglycerides (mg/dL) Fasting glucose (mg/dL) Fasting insulin (mU/mL) QUICKI Aspartate aminotransferase (mg/dL) Alanine aminotransferase (mg/dL) Gamma-glutamyltransferase (mg/dL) Urea (mg/dL) Creatinine (mg/dL)
MetS (n [ 29)
No MetS (n [ 73)
84.3 15.0 34.2 5.3 101.2 12.3 125.8 13.5 81.0 10.5 13.2 1.5 1.67 0.14 114.4 35.0 73.3 23.0 200.6 39.6 37.6 8.0 123.7 39.5 196.2 71.4 88.3 14.1 15.8 9.2 0.33 0.02 27.5 9.4 28.0 12.4 29.2 20.9 22.2 5.2 1.01 0.16
67.4 17.1a 27.5 6.2a 86.8 15.6a 109.7 10.3a 68.9 9.1a 15.5 1.8 1.62 0.21 105.6 11.8 97.4 16.5 182.5 41.7a 42.3 11.9 119.2 40.5 103.3 50.6a 82.2 10.7a 10.2 6.5a 0.35 0.04a 26.0 9.8 24.6 17.7 20.3 8.1a 22.1 6.0 0.89 0.14a
Note: Data presented as mean standard deviation. DHEAS, dehydroepiandrosterone sulfate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; QUICKI, quantitative insulin-sensitivity check index; TSH, thyroid-stimulating hormone. a Student’s-t test, P< .001. Soares. Metabolic syndrome in Brazilian PCOS. Fertil Steril 2008.
The Metabolic Syndrome Abnormalities The most prevalent isolated MetS abnormality in women with PCOS was high-density lipoprotein cholesterol levels below 50 mg/dL, present in 69.6% (71 out of 102). Other abnormalities were increased waist circumference in 57.9% (59/102), increased serum triglycerides in 31.4% (32 out of 102), hypertension in 18.6% (19 out of 102), and high fasting glucose concentrations in 2.9% (3 out of 102). Analysis of the prevalence of other PCOS clinical features according to the presence of MetS showed a statistically significant association with the presence of acanthosis nigricans; the condition was more frequent in women with MetS than in women without MetS (Table 4).
DISCUSSION In this study, the prevalence of MetS in Brazilian women with PCOS was 28.4%. There are no published references about age-adjusted prevalence of MetS by sex in the general Brazilian population (24). Limited information can be obtained from a recent study involving a specific sample of a rural population from Bahia, Brazil, which showed a 7% prevalence of MetS for the 25- to 34-year age group, 652
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with higher frequency in women than in men (25). This limitation led us to compare our results with those reported by Ford et al. for the general U.S. population (26). Despite the higher prevalence of obesity in the U.S. population, we found a statistically significant higher prevalence of MetS in our sample of Brazilian women with PCOS than that of U.S. women aged 25 to 34 years. Several studies have been conducted to evaluate the prevalence of MetS in women with PCOS. Glueck et al. (10) and Apridonidze et al. (11) observed that the prevalence of MetS in U.S. women with PCOS was 46% and 43%, respectively, much higher than that observed in our study. Conversely, Vrbıkova et al. (13) did not find a higher prevalence of MetS in Czech women with PCOS, even though those women had higher BMI and waist circumference, higher systolic and diastolic blood pressure, and lower HDL-cholesterol levels than women without PCOS. In Italian women, Carmina et al. (14) observed that MetS was more frequent in women with PCOS than in the general population; however, this prevalence was much lower than in the United States. These differences could be attributed to genetic factors or lifestyle characteristics and dietary habits, such as the higher incidence of obesity in the U.S. population. Vol. 89, No. 3, March 2008
TABLE 4 Prevalence of clinical characteristics in Brazilian women with polycystic ovary syndrome with and without the metabolic syndrome (MetS). Prevalence [N (%)] Variables
MetS (N [ 29)
No MetS (N [ 73)
P valuea
21 (72.4) 18 (62.1) 14 (48.3) 21 (72.4) 21 (72.4) 12 (41.4) 24 (82.8)
58 (79.5) 48 (65.8) 29 (39.7) 29 (39.7) 56 (76.7) 34 (46.6) 50 (68.5)
.44 .72 .62 .005 .89 .44 .34
15 (51.7) 21 (72.4) 13 (44.8)
31 (42.5) 46 (63.0) 24 (32.9)
.62 .51 .28
Amenorrhea Infertility Hirsutism Acanthosis Polycystic ovary morphology FH cardiovascular disease FH systemic arterial hypertension FH obesity FH NIDDM FH dyslipidemia
Note: FH, family history; NIDDM, noninsulin-dependent diabetes mellitus. a Chi-square test. Soares. Metabolic syndrome in Brazilian PCOS. Fertil Steril 2008.
The occurrence of low HDL-C was the most frequent individual MetS component in Brazilian women with PCOS, followed by increased waist circumference and increased serum triglycerides. Other studies have reported similar results and point to the fact that dyslipidemia is the most common metabolic abnormality in PCOS, with a prevalence of up to 70% according to NCEP criteria (6, 11, 27). Furthermore, it is important to observe that the majority of our patients (85.3%) had at least one MetS abnormality, a finding similar to that found by Apridonidze et al. (11). A very consistent finding is that the prevalence of MetS is highly age and BMI dependent (28, 29). In our study, the prevalence of MetS in women with PCOS aged 20 to 24 years was 12.1%, with a progressive increase to 31.7% in the 25- to 29-year group and 42.9% in the 30- to 34-year group. A previous case-control study involving 86 women with PCOS aged between 18 and 22 years found a MetS prevalence of 11%, supporting the idea that the prevalence of MetS in women with PCOS is high in all age groups (30). Many women with PCOS (between 38% and 88%) are overweight or obese, and there is no doubt that adiposity plays a crucial role in the development and maintenance of PCOS and strongly influences the severity of both its clinical and endocrine features in many women (31). Obesity seems to contribute as an independent factor for MetS abnormalities (32, 33), and our results are in accordance with this idea, given that increased waist circumference and hypertension showed an increasing prevalence with BMI. Nevertheless, the rates of dyslipidemia and impaired glucose tolerance showed no statistically significant difference among the BMI groups, an important finding corroborating the releFertility and Sterility
vance of screening for MetS and other cardiovascular risk factors in all women with PCOS, regardless of obesity. Insulin resistance is associated with MetS, and is considered a common denominator of metabolic alterations that characterize the syndrome (34, 35). Our data support this hypothesis, with the finding of a statistically significant lower QUICKI index in women with PCOS and MetS when compared with those without MetS. Corroborating this finding, we also observed that acanthosis nigricans was more prevalent in women with PCOS and MetS. Recently, several clinical, epidemiological, and biochemical studies have supported the concept that insulin resistance is accompanied by many other alterations that are not included in the diagnostic criteria for MetS. These conditions include nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis, obstructive sleep apnea, and increased levels of prothrombotic factors, homocysteine, and proinflammatory cytokines (8). Results of our observations in women with PCOS show higher gamma-glutamyltransferase serum levels in women with MetS than in women without MetS, which is in accordance with published data on the subject. Whitfield et al. (36) showed that changes in enzyme gamma-glutamyltransferase and alanine-aminotransferase are associated with cardiovascular risk factors. In the Brazilian population, Araujo et al. (37) found that gamma-glutamyltransferase activity was associated with the number of MetS abnormalities in obese women. Additionally, Setji et al. (38) observed that abnormal aminotransferase activity is common in women with PCOS (about 15%), and is significantly associated to dyslipidemia and hyperinsulinemia. Taken together, these data suggest that women with PCOS may have an increased risk of developing 653
many of the consequences of MetS, including nonalcoholic steatohepatitis. Despite these relevant findings, it is important to point out the limitations of our study. We included only cross-sectional measures; prospective data from this cohort study will be available in the future to determine conclusively the association between PCOS and cardiovascular disease in Brazilian women. Other limitations include the relatively small sample size and the fact that only one diagnostic criteria for MetS were considered. Additionally, the results may be influenced by the way in which PCOS and MetS were diagnosed. The findings of this study confirm that the prevalence of MetS and its individual components, particularly a decreased high-density lipoprotein cholesterol level, is substantially higher in women with PCOS than in the general population. However, the prevalence of MetS in Brazilian women with PCOS appears to be much lower than that found in the U.S. population, as previously reported in other non-U.S. studies. Thus, these women are at increased risk of diabetes mellitus and cardiovascular disease; it is therefore important to screen all women with PCOS for cardiovascular risk factors. Identification and clinical management of this highrisk group is an important aspect of coronary heart disease prevention, and better understanding of these issues is critical to preventing mortality from cardiovascular disease in these patients.
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36. Whitfield JB, Zhu G, Nestler JE, Heath AC, Martin NG. Genetic covariation between serum gamma-glutamyl-transferase activity and cardiovascular risk factors. Clin Chem 2002;48:1426–31. 37. Araujo LM, Lima DS, Daltro C. Association of gamma-glutamyl transferase and the metabolic syndrome in obese women. Arq Bras Endocrinol Metab 2005;49:557–62. 38. Setji TL, Holland ND, Sanders LL, Pereira KC, Diehl AM, Brown AJ. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:1741–7.
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