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Department of Epidemiology, University of Pittsburgh Graduate School of Public Health (E.O.T., J.V.Z., M.Y.B., K.P.M.-P., K.S.-T.), Pittsburgh, Pennsylvania 15261; and University of Rochester School of Medicine (D.S.G.), Rochester, New York 14642
Address all correspondence and requests for reprints to: Dr. Evelyn O. Talbott, Department of Epidemiology, University of Pittsburgh, 130 DeSoto Street, A526 Crabtree Hall/Graduate School of Public Health, Pittsburgh, Pennsylvania 15261. E-mail: eot1{at}pitt.edu.
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Abstract |
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Introduction |
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PCOS has been associated with premature subclinical atherosclerosis (SCA). In a study using carotid intima-media wall thickness (IMT) to measure SCA (38), 267 Caucasian women, aged 30 yr or older (n = 125 PCOS patients and 142 controls) for whom baseline cardiovascular risk factors had been measured 5–7 yr previously, underwent B-mode ultrasonography of the carotid arteries. An increased mean carotid IMT was seen among women with PCOS aged 45 yr or older compared with control subjects of similar age (0.78 vs. 0.70 mm; P = 0.005). PCOS remained an independent predictor of IMT even after adjustment for age and body mass index (BMI; P < 0.05). Increased IMT has been reported to occur relatively early in the atherosclerotic process (12). Prospective studies have demonstrated that increased IMT is a powerful predictor of coronary and cerebrovascular events (13) and has been linked to traditional cardiovascular risk factors, such as increasing age (14), adverse lipid profiles (15), and obesity (16), as commonly observed in PCOS. A significant association between increased carotid IMT and stroke is supported by numerous studies. Aminbakhsh and Mancini (17) conducted a systematic review of 41 population studies and reported on the risk of myocardial infarction and stroke. They concluded that the risk of first MI increased with an IMT of 0.82 mm or more, and that increased risk of stroke was associated with an IMT of 0.75 mm or more (18, 19). The Atherosclerosis Risk in Communities study (19) specifically found that among women aged 45–64 yr, individuals with a mean IMT of 1.0 mm or more, compared with those with a mean IMT less than 0.6 mm, had a hazard rate ratio for incident coronary heart disease (CHD) of 7.4 (95% confidence interval 2.8–19.4), independent of age, race, BMI, and other major CHD risk factors.
More recently, inflammation has been implicated as a novel risk factor in the development and progression of atherosclerosis. Low grade, chronic inflammation has been shown independently to predict CHD (20, 21, 22) and has been linked to IR syndrome (23, 24). Central adiposity (25), dyslipidemia (26), and IR or impaired glucose tolerance (27, 28) have been associated with increased C-reactive protein (CRP) as a surrogate marker for an active inflammatory process. As previously noted, insulin resistance and visceral adiposity are common features of PCOS, and elevated CRP levels have been demonstrated among women affected with this disorder (29, 30).
Although inflammatory markers have been postulated to be more significantly associated with early-onset atherosclerosis than have lipid measurements (31), the strength of the association between elevated CRP levels and increased IMT remains controversial. Recent studies have demonstrated a positive relationship, while others have yielded negative or inconsistent results. Sitzer et al. (32) used a community-based sample of 1018 men and women (women comprised 49.7% of the total population) free of advanced atherosclerotic disease to examine the CRP-IMT association. They found a significant positive relationship between CRP and IMT, which was weakened by adjustment for traditional cardiovascular risk factors and negated by the inclusion of fibrinogen in the multivariate regression model. In general, negative (33), inconclusive (32), or weakly positive (34) results have been found more commonly among population-based studies with healthy participants. Conversely, Wang et al. (15) reported a positive association between CRP and carotid IMT levels in the Framingham Offspring Study population (1508 men and 1665 women). After adjustment for traditional cardiovascular risk factors, a graded association between CRP and carotid IMT was found in women only. They concluded that the gender-specific relationship between CRP and IMT merited additional investigation. Positive associations have also been found between CRP and IMT in populations with dyslipidemia (35), neurological conditions (31, 36), or stroke (37).
Although the overall relationship between CRP and SCA appears to be at least weakly positive in healthy women, it is not known whether these inflammatory processes contribute to premature SCA among middle-aged women with PCOS. The present study was designed 1) to determine the circulating concentration of CRP among women with PCOS aged 45 yr and older in comparison with controls of similar age, and 2) to explore the relationship between inflammation assessed by CRP and current SCA, as indicated by increased carotid IMT in this high risk female subgroup.
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Subjects and Methods |
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Detailed study methodologies have been published previously (10). Briefly, women diagnosed with PCOS between 1970–1993 were identified from the records of an academic reproductive endocrine practice located at Magee-Womens Hospital (Pittsburgh, PA) and were recruited from 1992–1994 (n = 244). The clinical diagnosis of PCOS was made if there was a history of chronic anovulation in association with either 1) clinical evidence of androgen excess (hirsutism) or biochemical evidence of an elevated total testosterone concentration (>57.64 ng/dl; 2 nmol/liter) or 2) a ratio of LH to FSH greater than 2.0. Age (±5 yr)- and race-matched neighborhood control subjects (n = 244) were selected using a combination of voter registration tapes for 1992 from the greater Pittsburgh area and Cole’s Cross Reference Directory of Households. Talbott et al. (38) was the preliminary study for defining the population used in the present study, as detailed above.
The subjects in the present cross-sectional analysis include Caucasian participants from the original cohort (1992–1994) who were 45 yr or older at the time of follow-up clinic visit (1996–1999; n = 106). A total of 47 patients and 59 controls were included in this new analysis, which represents a subgroup of those cases and controls 45 yr of age or older (106 of 335 cases and controls) of the original study sample (38). There were no other exclusionary criteria applied to this study analysis.
Unlike our previous study (38), CRP and other risk factors for this manuscript were measured concurrently with IMT as the variable of interest. As the information on both outcome (IMT) and dependent variables BMI, CRP, age, etc. were obtained in a cross-sectional manner, this design can address associations between variables, but not predictive relationships. The protocol for this study was approved by the University of Pittsburgh biomedical institutional review board. All participants gave written informed consent, which is currently on file in the study office.
Risk factor assessment
Height was measured to the nearest 0.5 in. on a wall-mounted Harpenden (Cambridge, MA) stadiometer; weight was measured to the nearest 0.5 lb. BMI, a measure of relative obesity, was calculated as a mathematical function of weight and height (kilograms per meter squared). Waist and hip circumferences (centimeters) were measured in duplicate with an inelastic tape at the level of the umbilicus and greater trochanter, respectively; the average value was recorded. The waist/hip ratio was calculated as the waist circumference divided by the hip circumference. Visceral (or intra-) abdominal fat was measured at the level of L5 using a minimal slice computed tomography scanning procedure. Using a pixel range of –30 to –190 Hounsfield units as the range for fat, the area of fat within the region of interest was determined using image analysis. The fat within this circle is considered to be intraabdominal. Blood pressure was assessed in duplicate after a 30-min caffeine restriction and 5-min rest using a random zero sphygmomanometer. A questionnaire was administered that included medical and surgical histories, menstrual and reproductive information, a review of medication use, lifestyle factors, and family history of PCOS.
A 12-h fasting blood sample was obtained for lipid and hormone assays. Serum concentrations of total cholesterol, high density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), triglycerides, insulin, and glucose were measured in the Heinz Lipid Laboratory, University of Pittsburgh. Total cholesterol was determined by the enzymatic method (39). HDLc was determined by the method described above after selective precipitation by heparin/manganese and removal by centrifugation of very low density lipoprotein and LDLc. LDLc was calculated using the Friedewald formula (40). Triglycerides were determined using the enzymatic procedure described by Bucolo and David (41). Plasma glucose was analyzed by using enzymatic assay (Yellow Springs Glucose Analyzer, YSI, Inc., Yellow Springs, OH), and plasma insulin was determined by RIA. Total testosterone levels, measured at the Reproductive Endocrinology Laboratory, University of Pittsburgh Medical Center, were determined using a highly specific dextran-charcoal RIA after extraction of serum with dimethyl ether. Tracer testosterone (1ß,2ß-N-3H; DuPont NEN Life Science Products, Wilmington, DE) was purified on Sephadex LH-20 before use. The antiserum was used at a final dilution of 1:175,000. The University of Vermont coagulation laboratory performed the analysis of CRP. CRP was measured by ultrasensitive competitive immunoassay based on purified protein and polyclonal anti-CRP antibodies (Calbiochem, La Jolla, CA). The CRP assay had a sensitivity of 0.08 µg/ml and an average interassay coefficient of variation of 8.0%. This assay is sensitive to values within the normal range, and CRP levels obtained at one point in time have been shown to be both reproducible and representative over extended periods of time (42).
B-Mode carotid ultrasound protocol
A Toshiba SSA-270A (Toshiba Medical Systems, Tustin, CA) scanner equipped with a 5-MHz linear array-imaging probe was used. Two sonographers performed all scans for this study. Both were certified using standard IMT measures, with recertification performed annually. The University of Pittsburgh Ultrasound Research Laboratory has a continuous quality improvement program, which includes careful training and certification of sonographers and ongoing assessment of reproducibility. In our laboratory, replicate measures of IMT have consistently had an absolute difference in replicate observations of.03 mm (between readers), 0.04 mm (between sonographers), and 0.06 mm (within sonographers, between visits) (43). This compares favorably with other studies in the literature, where absolute differences generally run 0.11 mm and higher for average IMT (44, 45, 46, 47). In addition, laboratory and clinical information on PCOS cases and controls was collected in a separate location, and the ultrasonographer was blinded as to case/control status.
Sonographers scanned the right and left common carotid arteries, carotid bulb, and the first 1.5 cm of the internal and external carotid arteries. For each location, the sonographer imaged the vessel in multiple planes and then focused on the interfaces required to measure IMT and also any areas of focal plaque. The best images were digitized for later scoring. Trained readers measured the average IMT across 1-cm segments of the near and far walls of the distal common carotid artery, the far wall of the carotid bulb, and the internal carotid artery on both right and left sides. Measures from each location were then averaged to produce an overall measure of carotid IMT. A computerized reading program developed for the Cardiovascular Health Study and modified in Pittsburgh was used.
Statistical analysis
All statistical analyses were performed using SPSS (version 11.0.5, SPSS, Inc., Chicago, IL). Baseline cardiovascular risk factors and hormone levels were determined during the 1992–1994 clinic visit. Follow-up cardiovascular risk factors and hormone levels were determined during the 1996–1999 clinic visit and were used to predict concurrent carotid IMT evaluated by ultrasound. Descriptive statistics, including measurements of central tendency and dispersion, were computed for PCOS cases and controls and were compared by t test for independent samples for normally distributed continuous data, which included CRP, and the Mann-Whitney U test for nonnormally distributed continuous data. A Pearson’s 
2 test was conducted for comparison of current smoking and current hormone use (oral contraception (OC)/hormone replacement therapy/HRT) in PCOS cases and controls. The distribution of carotid IMT was markedly skewed; a reciprocal exponential transformation was performed to normalize the distribution for regression modeling. Due to the effect of reciprocal transformation, the ß values were in the opposite direction from associations noted between risk variables and raw IMT. The ß values were multiplied by –1 for ease of interpretation.
Exploratory univariate regressions were used to identify cardiovascular risk factors that were associated with IMT as the dependent continuous variable. Cardiovascular variables explored in these analyses included age, BMI, insulin, visceral fat, total cholesterol, HDLc, LDLc, triglycerides, glucose, ever smoking, current hormone use, and CRP. BMI stratification was used to better assess the potential confounding effect of obesity on IMT. Only variables with a significant univariate association with IMT were entered into the multivariable model.
Multivariable linear regression modeling of carotid IMT with specific cardiovascular risk factors was subsequently conducted. In the multivariable modeling, the effect of PCOS on carotid IMT, independent of age, BMI, CRP, and those cardiovascular risk factors found to be significant in univariate regression analysis, was assessed.
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Results |
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)The mean age at clinic visit was similar among PCOS cases and controls (49.2 vs. 49.5 yr, respectively). Significant differences were noted between PCOS cases and controls in BMI (32.4 vs. 26.0 kg/m2; P < 0.001), waist circumference (94.2 vs. 81.6 cm; P < 0.001), waist/hip ratio (0.83 vs. 0.78; P < 0.001), and visceral fat (16,876 vs. 9,010 mm2; P < 0.001). Although current smoking was more prevalent among PCOS patients (23.5% vs. 11.9%), the difference was not statistically significant. OC/HRT use was also similar between PCOS cases and controls. Among cases, three were currently using OC (6.4%), and 11 were currently using HRT (23.4%) compared with control four controls using OC (6.8%) and 17 controls using HRT (28.8%)y. These were considered an early analysis and contributed little to our models.
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)Selected blood analyte and hormone levels at both baseline and follow-up were significantly higher among PCOS cases than controls. In 1992–1994, total testosterone (46.1 vs. 29.1 ng/dl; P = 0.001), triglycerides (152.6 vs. 75.9 mg/dl; P < 0.001), and insulin (23.7 vs. 14.0 µU/ml; P = 0.001) levels were significantly increased; conversely, HDLc levels (50.4 vs. 60.0 mg/dl; P = 0.001) were significantly lower in women with PCOS compared with controls. At follow-up, PCOS cases had higher levels of total testosterone, cholesterol, triglycerides, LDLc, glucose, and insulin and decreased SHBG and HDLc levels. However, significant differences between PCOS cases and controls were found only in SHBG (181 vs. 261 nmol/liter; P = 0.002), triglycerides (177.5 vs. 128.4 mg/dl; P = 0.019), HDLc (57.4 vs. 63.3 mg/dl; P = 0.034), glucose (127.9 vs. 105.6 mg/dl; P = 0.014), and insulin (22.2 vs. 12.6 µU/ml; P = 0.002). In contrast to baseline results, the mean total testosterone level at follow-up among women with PCOS, although still higher, was not significantly increased compared with the control value (34.6 vs. 24.5 ng/dl; P = 0.225). However, the power to detect significant differences may have been lost in the follow-up analysis, because approximately 50% of the controls did not have total testosterone measured in 1996–1999. CRP levels were significantly elevated among PCOS patients compared with controls (3.4 vs. 2.1 mg/dl; P = 0.002). When stratified by BMI, CRP levels remained significantly increased in PCOS patients compared with controls in the BMI 25 or greater subgroups only (4.1 vs. 2.6 mg/dl; P = 0.008; data not shown).
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As reported previously (38), the mean carotid IMT was significantly greater among PCOS cases compared with controls among women aged 45 yr and older (0.78 vs. 0.70; P = 0.005). A univariate scattergram of BMI measured cross-sectionally at the time of the ultrasound and negative log-transformed carotid IMT among patients and controls (Fig. 1) demonstrated that patients in general have a higher mean IMT than controls at any given BMI level.
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)Exploratory multiple linear regression was conducted to assess the independent effects of PCOS and CRP on carotid IMT. In univariate analyses, PCOS was a significant predictor of carotid IMT (P = 0.004) and remained an independent risk factor after adjustment for age (P = 0.003). Exogenous hormone use was also assessed, but was collinear with age in its effect on IMT and was not included in subsequent models. When CRP was added to the PCOS-age model, both PCOS (P = 0.019) and CRP (P = 0.040) remained independent risk factors for increased IMT. The addition of BMI as a measure of general adiposity greatly attenuated the association of PCOS (P = 0.109) with IMT and eliminated the CRP effect (P = 0.739). As a potential surrogate for BMI, insulin also attenuated the association of CRP with IMT (P = 0.197), but had less of an effect on PCOS (P = 0.033) than BMI. The addition of visceral fat (P = 0.089) had a similar attenuating influence as BMI on the CRP-IMT association (P = 0.550), but considerably less of an effect on the PCOS-IMT relationship (P = 0.040, respectively). In a final multivariable model, after adjustment for age, BMI, and insulin, both PCOS and CRP were no longer significant (P = 0.116 and P = 0.792, respectively) as independent risk factors for increased IMT. These variables accounted for 43% of the overall variability in IMT.
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There were eight patients and one control who reported a history of type 2 diabetes. The multivariate regression model of IMT was conducted removing those with a history of type 2 diabetes. The pattern of significance of the variables in the model was similar to that in our previous model, except the effect of visceral fat on IMT in the model adjusting for PCOS, age, and CRP became significant (P = 0.01). In addition, there was only one woman who in 1997 at the time of her second visit reported taking a statin for therapy.
To address the relative contributions of cardiovascular risk factors on carotid IMT, a series of adjusted r2 values was calculated for each model and is shown as the footnote in Table 3
. PCOS alone accounted for approximately 7% of the variability of IMT in this population. Moreover, with the addition of age and CRP, approximately 12% of the variance was explained. With the addition of BMI, 15.2% of IMT variability was accounted for in the model. Insulin did not have an appreciable effect on the model to the exclusion of BMI. However, visceral fat had a variance similar to that found with the inclusion of BMI (14.9%). The final model, with the inclusion of insulin and BMI, did not increase variance beyond that found in the model of PCOS, age, CRP, and BMI alone.
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Discussion |
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The results of this current cross-sectional analysis suggest that PCOS exerts an effect on IMT independent of CRP levels. However, given the attenuation of the effect of both PCOS and CRP after adjustment for BMI, the influence of these independent risk factors is at least partially mediated by general obesity. Hyperinsulinemia and/or insulin resistance also appear to play a role in the association between inflammation and IMT, as evidenced by the reduction in the CRP-related contribution to IMT after adjustment for insulin. However, the PCOS-IMT association, although also somewhat attenuated by insulin, was affected to a lesser degree, suggesting that current BMI may be a stronger predictor of IMT among women with PCOS than currently elevated insulin levels.
Wild et al. (7) followed 319 women with PCOS from the original McKeigue and Pierpoint study and investigated the prevalence of CHD and CHD risk factors. BMI and waist/hip ratio were significantly greater in the PCOS group compared with the control group. Moreover, women with PCOS had more diabetes and hypertension. History of CHD was not more common, but the odds ratio for nonfatal stroke was 2.8 (1.1–7.1). This indicates that the increased IMT noted in our earlier study as well as hyperinsulinemia may predispose to a higher rate of cerebrovascular disease in this population. IMT thickness has been significantly correlated with atherosclerosis over the entire vascular bed, and this implies both cerebrovascular and cardiovascular diseases.
Although hyperinsulinemia, insulin resistance, and increased CRP levels are often driven by obesity, particularly visceral or central obesity, as observed in PCOS, the association between PCOS and premature SCA does not itself appear to be explained by inflammatory processes. Rather, previously described dimensions of PCOS (e.g. insulin resistance, low HDLc, and high triglycerides) and potentially undetermined aspects of general adiposity appear to exert a greater influence on wall thickening among affected women.
Takami et al. (49) recently determined that overall body fatness, assessed by BMI, was a strong predictor of early carotid atherosclerosis, and that after adjustment for general obesity, CT-assessed intraabdominal fat made no independent contribution to the determination of IMT, similar to our findings among women with PCOS. Certain adipokines, including TNF-
and others (IL-6, plasminogen activator inhibitor type 1, and adiponectin) associated with increased overall and/or sc fat may influence the vascular endothelium in PCOS in a manner independent of elevated CRP and inflammatory changes (50, 51, 52).
The current study has several strengths, including a well defined PCOS cohort that has been longitudinally followed; reliable collection of personal, anthropometric, and cardiovascular risk factors; as well as multiple measurements of adiposity and body composition (computed tomographic measurement of sc and visceral fat). Certain limitations should also be noted, including the single measurement of CRP to assess systemic inflammation. CRP concentrations have been shown to have considerable within-subject variation upon repeated measurements (53). In addition, the cross-sectional study design does not permit evaluation of a temporal relationship among PCOS, elevated CRP concentrations, and increased IMT. However, the data from this study indicate that for PCOS cases and controls 45 yr of age and older, BMI is significantly associated with both current CRP levels as well as SCA (IMT). The information from this study indicates that CRP levels in middle-aged women 45 yr of age or older should not be considered a stand-alone independent risk factor for CHD above and beyond BMI. We cannot comment on the usefulness of the CRP measurement over and above obesity in younger women with PCOS.
A statistically significant association of PCOS with IMT, independent of BMI, was previously established by Talbott et al. (38) in a prospective study design using baseline risk factors to predict IMT 5 yr later, but was not replicated in this analysis with concurrent measurement of BMI and IMT. Residual confounding by BMI, particularly in the overweight subgroup, may also be a factor. PCOS was no longer significantly associated with IMT in this cross-sectional analysis after adjustment for age and BMI. Finally, it should be acknowledged that the smaller number of cases limits the ability to assess independent effects of multiple covariates simultaneously as predictors of IMT.
In conclusion, elevated CRP levels do not appear to appreciably mediate the influence of PCOS on IMT. The associations of both PCOS and CRP on IMT are influenced by obesity. The attenuation of the PCOS-IMT association by BMI is not explained completely by hyperinsulinemia (IR) or increased visceral fat and may be explained by other undetermined aspects of PCOS-related adiposity. This observation should be explored in future studies evaluating potential predictors of premature atherosclerosis among middle-aged women with PCOS.
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Footnotes |
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Abbreviations: BMI, Body mass index; CHD, coronary heart disease; CRP, C-reactive protein; HDLc, high density lipoprotein cholesterol; HRT, hormone replacement therapy; IMT, intima-media wall thickness; IR, insulin resistance; LDLc, low density lipoprotein cholesterol; OC, oral contraceptive treatment; PCOS, polycystic ovary syndrome; SCA, subclinical atherosclerosis.
Received December 10, 2003.
Accepted September 12, 2004.
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