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Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Department of Internal Medicine; Department of Obstetrics and Gynecology (D.A.D.); Division of Cardiovascular Diseases, Department of Internal Medicine (T.B.); Department of Health Sciences Research (A.L.O.); and Department of Radiology (P.F.S.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Lorraine A. Fitzpatrick, M.D., Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, Minnesota 55905. E-mail: fitz{at}mayo.edu.
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Abstract |
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PCOS women had significantly higher levels of serum total and low density lipoprotein cholesterol and testosterone levels than matched controls. PCOS and control women were obese and had a greater mean BMI than community-dwelling women (33 kg/m2 for PCOS vs. 31 kg/m2 for control; P < 0.001). CAC was more prevalent in PCOS women (39%) than in matched controls (21%; odds ratio, 2.4; P = 0.05) or community-dwelling women (9.9%; odds ratio, 5.9; P < 0.001). BMI, waist circumference, and total and low density lipoprotein cholesterol levels predicted CAC prevalence after adjustment for BMI.
CAC is more prevalent in PCOS women than in obese or nonobese women of similar age. PCOS women are at increased risk for atherosclerosis and should be targeted for primary prevention of CHD.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Coronary artery calcium (CAC), a radiographic marker for atherosclerosis, correlates with the extent of coronary atherosclerotic plaque and may be quantified noninvasively by electron beam computed tomography (EBCT) (10, 11, 12). EBCT is used noninvasively to assess the presence and extent of preclinical atherosclerotic disease (13). We hypothesized that atherosclerosis is accelerated in women with PCOS, as demonstrated by EBCT imaging of CAC. Our specific aims in this cross-sectional study were to 1) assess coronary atherosclerosis in asymptomatic premenopausal women with and without PCOS by measuring CAC by EBCT, 2) prospectively compare CAC in PCOS women to that in unaffected women of similar age and body mass index (BMI), and 3) compare CAC in PCOS women retrospectively to an established database of community-dwelling women of similar age.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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All study subjects were premenopausal women, aged 30–45 yr, who were able to give informed consent. PCOS was diagnosed by the findings of hirsutism or biochemical hyperandrogenism and chronic anovulation after exclusion of specific ovarian, adrenal, and pituitary disorders (14). Chronic anovulation was amenorrhea of 3-month duration and/or oligomenorrhea (intermenstrual intervals >35 d) as defined by Dumesic et al. (15).
A cohort of healthy, cycling control volunteers was recruited by advertisement and frequency-matched by age and BMI to the PCOS women. All healthy controls had regular menstrual cycles every 27–32 d, with ovulation confirmed by progesterone levels greater than 3 ng/ml in the luteal phase (d 21) of their menstrual cycle before study testing (15). Women with a history of hirsutism, infertility, or menstrual irregularity were excluded from the control group. Biochemical hyperandrogenism was defined as an elevation in serum testosterone or free testosterone greater than 2 SD above the mean value for the normal premenopausal female population (15).
Premenopausal status was confirmed in all women by serum FSH levels less than 40 ng/ml in the early follicular phase. Pregnancy was excluded by serum human chorionic gonadotropin-ß measurement within 48 h before EBCT testing unless the patient reported prior tubal ligation. Exclusion criteria for all subjects included pregnancy or lactation, diabetes mellitus, current use of lipid-lowering medications, oral hypoglycemic or insulin-sensitizing agents, oral contraceptives, or sex steroids; current infertility treatment; hysterectomy; menopause; or known cardiovascular disease.
Both PCOS women and their BMI-matched controls were obese (mean BMI, 33 and 31 kg/m2, respectively); hence, both groups were at greater than average risk for CHD. Therefore, we compared the prevalence of coronary calcium in our study participants retrospectively to that of an average risk, nonobese (mean BMI, 26 kg/m2) reference population that consisted of community-dwelling women (n = 142), aged 30–45 yr, who had undergone EBCT scanning in the Epidemiology of Coronary Artery Calcification (ECAC) study. The ECAC study compiled an age- and gender-stratified coronary calcium database from a demographically representative sample of asymptomatic healthy men and women more than 19 yr of age residing in Olmsted County, Minnesota (16). The ECAC study measured coronary calcium with the same computed tomography scanner, scanning protocol, software package, and scoring criteria as in our study.
Study design
Study subjects were assessed at the General Clinical Research Center after a 12-h fast. Control women were evaluated in the follicular phase of the menstrual cycle, and PCOS women were evaluated while amenorrheic. A 120-min oral glucose tolerance test was performed with blood samples drawn for insulin and glucose levels at 0, 30, 60, 90, and 120 min. Blood samples were drawn for testing of all other parameters (i.e. lipid and hormone levels) at baseline before ingestion of the glucose load. Hirsutism was assessed in all women by one examiner using the modified Ferriman-Gallwey (F-G) score, in which a score greater than 7 indicates hirsutism (17). The waist and hip circumferences were measured in centimeters at the level of the umbilicus (waist) and at the level of the greater trochanters (hip) by the same examiner. Mean systolic and diastolic blood pressures were determined from two blood pressure readings at 5-min intervals with the subject seated quietly.
EBCT protocol
High resolution, noncontrast, enhanced EBCT (Imatron C-150, GE-Medical Systems, South San Francisco, CA) was performed on each subject. Two separate, but sequential, scanning sequences were obtained during suspended respiration. Each scanning sequence consisted of 40 contiguous, 3-mm thick transaxial images beginning at the aortic root and proceeding caudally through the apex of the heart. To eliminate motion artifact, EBCT image acquisition was triggered by the subject’s electrocardiogram, so that consecutive cuts were obtained in diastole. Scans were scored blindly by an experienced clinician. A positive scan contained 1 or more foci of calcium, defined as 4 or more contiguous pixels in the region of a coronary artery, with each pixel having a signal intensity exceeding 130 Hounsfield units. A calcium score was calculated by the Agatston method from calcium area and signal intensity and represents the total amount of intracoronary calcium (18). Each subject’s calcium score was calculated as the average of scores from the two consecutive scanning sequences.
Laboratory analysis
All assays were performed at the Immunochemical Core Laboratory of the General Clinical Research Center. Total and HDL cholesterol, glucose, and triglycerides were measured using reagents from Roche (Somerville, NJ). Total cholesterol had interassay coefficient of variation (CV) of 4% and an intraassay CV of 0.7% at 114 mg/dl (2.95 mmol/liter). HDL cholesterol assay had an intraassay CV of 5.5% at 50 mg/dl (1.30 mmol/liter) and an interassay CV of 8%. Triglyceride levels had an intraassay CV of 1.3% at 112 mg/dl (1.27 mmol/liter) and an interassay CV of 4%. Plasma glucose had an intraassay CV of 0.6% at 85 mg/dl (4.72 mmol/liter) and an interassay CV of 8%.
Testosterone was measured using competitive chemiluminescent immunoassay (Bayer Corp., Tarrytown, NY) with an intraassay CV of 8% at 98 ng/dl (3.40 nmol/liter) and an interassay CV of 10% at 74 ng/dl (2.57 nmol/liter). Free testosterone was measured by a double antibody RIA with a labeled testosterone analog with low affinity for SHBG and albumin (Diagnostic Systems Laboratories, Inc., Webster, TX). Intraassay CV were 9.5%, 3.3%, and 4.0% at 0.34 (1.18), 2.63 (9.12), and 7.61 (26.38 nmol/liter) ng/dl, respectively, and the interassay CV was 10% at 0.26 ng/dl.
SHBG was measured by a solid phase, two-site chemiluminescent immunometric assay (Diagnostic Products, Los Angeles, CA). Intraassay CV were 4.5% and 5.1% at 26.4 and 142 nmol/liter, respectively. Interassay CV were 6.7% and 8.8% at 5.1 and 77.0 nmol/liter.
Insulin was measured with a two-site immunoenzymatic assay (Beckman, Chaska, MN) with intraassay CV of 2% at 6.75 µU/ml (48.43 pmol/liter) and 2.6% at 116 µU/ml (832.30 pmol/liter), and interassay CV of 3.9% at 12.7 µU/ml (91.12 pmol/liter), 3.9% at 48.8 µU/ml (350.14 pmol/liter), and 4.6% at 121 µU/ml (868.18 pmol/liter).
FSH was measured by a two-site chemiluminescent sandwich immunoassay (Bayer Corp.). Intraassay CV were 5.6%, 4.3%, and 3.5%, and interassay CV were 6.0%, 4.0%, and 2.8% at 4.6, 25.4, and 61.7 IU/liter, respectively. Progesterone was measured by a competitive binding immunoenzymatic assay (Beckman) with intraassay CV of 7.9%, 6.3%, and 4.4% at 1.04 (0.03), 7.04 (0.21), and 21.75 (0.65) ng/ml, respectively, and interassay CV of 15.5%, 8.8%, and 4.9% at 0.61 (0.02), 16.2 (0.49), and 17 (0.51) ng/ml, respectively.
Framingham CHD score
A Framingham CHD score was calculated by algorithm from parameters measured for each subject at the time of their study visit. The Framingham algorithm predicts the 10 yr risk of coronary events using the following risk factor measurements: age, gender, HDL and LDL cholesterol levels, diabetes, smoking, and systolic and diastolic blood pressures (19).
Statistical analysis
Study group characteristics that were dichotomous variables (e.g. smoking and impaired glucose tolerance) were compared by 
2 tests; the medians of all other variables were compared between groups by Wilcoxon rank-sum tests. For consistency, all continuous data are expressed as the median (range). For modeling purposes, calcium score and F-G score were transformed to the natural log (Ln) scale due to marked skewness in distribution. A t test was used to compare mean BMI between our study subjects and women in the ECAC study, as only summary statistics were available for ECAC study subjects.
Logistic regression was used to assess predictors of CAC. Both univariate and BMI-adjusted multivariate comparisons were made between PCOS and control study subjects to assess the predictive value of CHD risk factors. Univariate comparisons were made between study subjects and women in the ECAC study database without adjusting for BMI or other CHD risk factors. Analysis of covariance was used to compare LDL cholesterol levels between PCOS and control women, adjusting for BMI or waist circumference.
Median calcium scores of PCOS and control women were compared by Wilcoxon rank-sum tests. Linear regression was used to determine the univariate predictors of calcium score on the Ln scale in all women with positive scans. Significant univariate predictors of Ln calcium score were examined in stepwise procedures.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical characteristics and CHD risk factors of the study participants are listed in Table 1
. As PCOS women (n = 36) were matched by age and BMI to ovulatory control women (n = 71), these variables did not differ significantly between the two groups. The majority of all women were obese (median BMI, 31.2 kg/m2; mean BMI, 31.6 kg/m2) and had an upper body pattern of fat distribution (median waist circumference, 95 cm), indicative of visceral obesity (20, 21). The PCOS women had higher F-G scores (P < 0.001), lower levels of SHBG (P = 0.04), and greater serum levels of total (P < 0.00001) and free (P < 0.00001) testosterone than the ovulatory controls.
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). Notably, the Framingham CHD scores did not vary significantly, nor did they indicate increased CHD risk (i.e. Framingham score >0) (19) in either group. EBCT measurement of CAC
Prevalence of CAC.
One or more foci of CAC were detected by EBCT in 39% of PCOS women and 21% of control women. PCOS women were more likely to have CAC than control women, with an odds ratio (OR) of 2.37 [95% confidence interval (CI) = 0.99–5.73; P = 0.05] before adjustment for CHD risk factors. In the ECAC study 9.9% of healthy women (n = 142; age, 30–45 yr) had CAC, as determined by EBCT (16). PCOS women were significantly more likely to have CAC than community-dwelling women in the ECAC study, with an OR of 5.89 (95% CI = 2.46–13.97; P < 0.001; Figs. 1 and 2). Control women were also more likely to have CAC than women in the ECAC study, with an OR of 2.47 (95% CI = 1.12–5.46; P = 0.03). The mean BMI of our PCOS study subjects (33 kg/m2) was significantly greater than that of the women aged 30–45 yr in the ECAC study (26 kg/m2; P < 0.001).
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. Median BMI, waist circumference, and waist to hip ratio were significantly greater in women with CAC than in those without CAC. Ninety percent (26 of 29) of women with CAC were obese, with a median BMI of 38.5 kg/m2, whereas subjects with no detectable CAC had a median BMI of 29.2 kg/m2. F-G scores; systolic and diastolic blood pressures; fasting levels of free testosterone, insulin, glucose, total cholesterol, LDL cholesterol, and triglycerides; and CHD score were significantly higher in women with CAC than in those without CAC (Table 2). SHBG levels were significantly lower in women with CAC, consistent with their higher levels of free testosterone. Total testosterone levels did not vary between groups.
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compares variables between women with CAC by group. Although age and BMI did not vary significantly, waist circumference (P = 0.005) and total and LDL cholesterol levels (P < 0.0001) were greater in PCOS women with CAC than in control women with CAC. HDL cholesterol and triglyceride levels did not vary between groups. None of these factors varied between PCOS and control women without CAC.
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After adjusting for BMI, only total cholesterol (P = 0.004), LDL cholesterol (P = 0.01), and triglyceride (P = 0.03) levels predicted CAC. PCOS did not predict the presence of coronary calcium after adjusting for BMI (OR = 1.99; P = 0.21).
Coronary calcium score. Consistent with the ECAC database, median CAC scores were 0 in all groups. The maximal calcium scores were 102.5 in PCOS women, 19.2 in matched control women, and 107.15 for women in the ECAC database. Mean calcium scores were 8.9 ± 22.0 in PCOS women, 1.7 ± 4.1 in control women, and 1.3 ± 9.3 in women of similar age in the ECAC database. The mean calcium score was significantly greater in PCOS than in their BMI-matched ovulatory controls (P = 0.03). BMI (P = 0.04), waist circumference (P = 0.01), fasting glucose (P = 0.04), HDL cholesterol (P = 0.03), and triglycerides (P = 0.02) were significant univariate predictors of calcium score. PCOS did not predict calcium score independently of these risk factors (P = 0.26).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study was powered to demonstrate a 3-fold or greater increase in CAC prevalence between PCOS women and matched controls. We did not anticipate the impact of high BMI in normally cycling volunteers on their risk of CAC. The power calculations were based on an assumed prevalence of CAC of 10% in normally cycling women of this age, based on the ECAC database. We found a prevalence of 21% in our cycling, normal volunteers, much greater than predicted. Therefore, our OR did not achieve statistical significance with this sample size. However, the OR of 5.89 for PCOS women is highly significant (P < 0.001) compared with nonobese community-dwelling women in the ECAC database.
Although obesity is a known independent CHD risk factor, visceral fat is more closely associated with CHD risk than either sc or total body fat (20). Visceral adipose tissue may regulate cytokines associated with inflammation and endothelial dysfunction, processes critical to atherogenesis (20, 26). In our study increased visceral fat, as indicated by elevated waist circumference and triglyceride levels, predicted the presence and extent of coronary calcium. Waist circumference was significantly greater in PCOS women with CAC, who had higher calcium scores than control women with CAC.
The contribution of visceral adiposity to the increased CAC observed in PCOS women may have been underestimated in this study. Visceral adiposity, as indicated by crude anthropometric criteria (waist circumference and waist to hip ratio), did not differ between PCOS women and ovulatory controls, but significant differences in body fat distribution have been detected radiographically between PCOS and BMI-matched non-PCOS women of similar waist circumference (27). Waist circumference and waist to hip ratio were marginally significant predictors of CAC after adjustment for BMI (P < 0.06; Table 4).
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1.70 mmol/liter) or more (28). Waist to hip ratio, triglyceride levels, blood pressure, and diabetes were used in Dahlgren’s risk factor model, which predicted a relative risk of 4.2 for CHD in 40- to 49-yr-old PCOS women (5). Similarly, we found that each element of the metabolic syndrome, except for HDL cholesterol, predicted coronary calcification. However, in the context of risk factors for the metabolic syndrome, only triglyceride levels, which reflect visceral adiposity, predicted CAC independently of BMI. Although the metabolic syndrome predicts CAC in premenopausal women, it does not explain the greater prevalence of CAC in PCOS women compared with their BMI-matched controls. Metabolic syndrome features characterized both the PCOS and control women; only diastolic blood pressure was significantly greater in PCOS women (74.8 vs. 71.5 mm Hg, PCOS vs. controls, respectively; P = 0.03). Elevated LDL cholesterol was the lipid abnormality that distinguished PCOS women from the BMI-matched controls.
Total and LDL cholesterol levels, in addition to BMI and visceral adiposity, may contribute significantly to the excess coronary calcium in PCOS women. LDL-C levels predicted CAC after adjustment for BMI (OR = 1.03; 95% CI = 1.01–1.05; P = 0.01) and among women with CAC, LDL cholesterol levels were higher in PCOS women than in the similarly obese control women (P = 0.04). As in earlier observational studies (3), LDL cholesterol levels were significantly greater in PCOS women than in control women independent of BMI (P = 0.03) or waist circumference (P = 0.04). Additionally, LDL cholesterol levels were significantly greater in the hyperandrogenic sisters of PCOS women than in unrelated controls after adjustment for BMI (29); this familial clustering of traits suggests a genetic linkage between LDL phenotype and PCOS.
In a retrospective United Kingdom study, PCOS women were not significantly more likely to have a history of CHD (OR = 1.5; 95% CI = 0.7–2.9, P > 0.05) than women in the general population, but were more likely to have diabetes mellitus (OR = 2.2) and hypercholesterolemia (OR = 3.2) than age-matched controls (9). However, only 26% of the PCOS women in this United Kingdom study were obese; their mean BMI (27 kg/m2) was similar to that of healthy United States women in the ECAC database (26 kg/m2). In contrast, over 60% of PCOS women in the United States are obese (3). We have demonstrated that obesity markedly increases the risk of coronary calcification in PCOS women; accordingly, the lower than predicted prevalence of CHD risk in the United Kingdom cohort may be due in part to their lower BMI. Our study had too few nonobese subjects to allow us to draw conclusions regarding the risk of coronary calcification in normal weight PCOS women. In addition, the cross-sectional nature of this study limits the conclusions due to the fact that CAC risk factors may vary over time, and we have assessed only one time point.
A strength of our study is that we confirmed premenopausal status in every participant, as no prospective clinical trials have determined whether differences in metabolic and hormonal parameters persist between PCOS and healthy women after menopause. We used the criteria of hyperandrogenism and chronic anovulation to select our PCOS cohort, rather than ovarian ultrasound (14). The polycystic ovary morphology is detected on ultrasound in up to one third of healthy cycling women and correlates poorly with the endocrine and metabolic features of PCOS (30, 31, 32). Inclusion of women who had polycystic ovary on ultrasound, but lacked the PCOS metabolic phenotype, would underestimate CHD risk in PCOS women.
In conclusion, PCOS women have a greater prevalence and extent of coronary calcification, a predictor of atherosclerosis, than do unaffected women. Obese young women with or without PCOS are at significantly increased risk for coronary calcification compared with a nonobese reference population. Obesity and visceral adiposity, which are endemic in PCOS women, may account for much of their increased risk of atherosclerosis in a nondiabetic cohort. Additionally, higher levels of LDL cholesterol in PCOS women may confer an increased risk independent of BMI or visceral adiposity. Our findings suggest that obese PCOS women should be targeted for primary prevention of CHD in adolescence or early adulthood when the diagnosis of PCOS is made. Early lifestyle interventions aimed at treating obesity and dyslipidemia in PCOS women may prevent or delay atherosclerosis in this high risk population.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; CAC, coronary artery calcium; CHD, coronary heart disease; CI, confidence interval; CV, coefficient(s) of variation; EBCT, electron beam computed tomography; ECAC, Epidemiology of Coronary Artery Calcification; F-G, Ferriman-Gallwey; HDL, high density lipoprotein; IGT, impaired glucose tolerance; LDL, low density lipoprotein; Ln, natural log; OR, odds ratio; PCOS, polycystic ovary syndrome.
Received February 27, 2003.
Accepted March 21, 2003.
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