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Increased C-Reactive Protein Levels in the Polycystic Ovary Syndrome: A Marker of Cardiovascular Disease

Reproductive Endocrinology, Departments of Obstetrics and Gynecology (Z.B.) and Internal Medicine D (N.B., Y.L.), Department of Clinical Biochemistry (O.Z.), and Statistical Unit (R.L.), Rambam Medical Center, Rappaport Faculty of Medicine, Technion 31096, Israel; and Institute of Technology and Meuhedet Medical Services (S.S., R.L.), Haifa 31096, Israel

Address all correspondence and requests for reprints to: Z. Blumenfeld, M.D., Reproductive Endocrinology, Rambam Medical Center, Haifa 31096, Israel. E-mail: bzeev{at}techunix.technion.ac.il.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The polycystic ovary syndrome (PCOS), one of the most common reproductive abnormalities, shares some components of the metabolic cardiovascular syndrome. Therefore, PCOS patients may represent the largest group of women at high risk for the development of early-onset cardiovascular disease (CVD) and/or diabetes. C-reactive protein (CRP) is a strong independent predictor of future CVD and/or stroke. Only one small published study has looked for such an association (17 PCOS patients vs. 15 controls). The objective of this study was to compare the levels of CRP and other risk factors of CVD in a large group of PCOS patients and controls. CRP measurements were undertaken in 116 PCOS patients and 94 body mass index-matched controls with regular menstrual cycles. Whereas 36.8% of the PCOS patients had CRP levels above 5 mg/liter, only 9.6% of the controls exhibited high CRP levels (P < 0.001). The mean ± SD was 5.46 ± 7.0 in the PCOS group vs. 2.04 ± 1.9 mg/liter in the control (P < 0.001). The body mass index, white blood cell count, TSH, glucose, cholesterol, and homocysteine levels were not significantly different between the two groups. CRP levels are elevated in patients with PCOS and may be a marker of early cardiovascular risk in these patients. High CRP levels may explain why some PCOS women may possibly be at an increased risk for the development of early-onset CVD. Consequently, whether treatment regimens directed toward lowering CVD risk factors should be more aggressive for those PCOS women with increased CRP levels, awaits further clinical experience.

	Introduction

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THE POLYCYSTIC OVARY syndrome (PCOS) is one of the most common reproductive abnormalities, affecting 5–10% of the population in the reproductive age (1). Most physicians would agree that PCOS can be diagnosed clinically in a woman who has hirsutism, irregular menstrual cycles, obesity, and a classic ovarian morphology (2). After considerable debate at a 1990 National Institutes of Health conference on PCOS, two minimal criteria were proposed (3): 1) menstrual irregularity due to oligo- or anovulation, and 2) evidence of hyperandrogenism, either clinical or biochemical.

PCOS shares some or most components of the metabolic cardiovascular syndrome (syndrome X), manifested by abdominal obesity, insulin resistance, dyslipidemia, and atherosclerosis (4). For example, 40% of obese PCOS women share diagnostic criteria for impaired glucose tolerance or type 2 diabetes by age 26 yr (5), 3-fold increased prevalence of hypertension (6), high low density lipoprotein (LDL) and low high density lipoprotein (HDL) cholesterol (LDL-C and HDL-C) levels compared with regularly menstruating women (7). Indeed, Glueck et al. (8) recently found that 46% of their 138 PCOS patients fulfilled the criteria of the metabolic syndrome.

Moreover, a significant difference was observed in the distribution of carotid plaques using carotid ultrasound in PCOS patients and controls (7.2 vs. 0.7%) (9). Thus, PCOS patients may represent the largest group of young women at high risk for the possible development of early-onset cardiovascular disease (CVD), diagnosed many years before the clinical onset of the symptoms of CVD (8).

More recently, Christian et al. (10) measured coronary artery calcium, a marker of coronary atherosclerosis, by electron beam computer tomography in PCOS patients and premenopausal controls. They found coronary artery calcium to be more prevalent in PCOS patients than in obese or non-obese controls, concluding that PCOS women are at an increased risk of atherosclerosis and coronary heart disease (10). On the other hand, Wild et al. (11, 12) challenged the understanding that PCOS patients are at an increased morbidity and mortality risk from CVD, because they did not find a significant difference between the PCOS patients and controls after adjustment for body mass index (BMI), diabetes, hypertension, and hypercholesterolemia. Nevertheless, these investigators (11) did find an increased prevalence of nonfatal cerebrovascular disease and cardiovascular risk factors, including diabetes, hypertension, hypercholesterolemia, hypertriglyceridemia, and increased waist/hip ratio in PCOS women compared with controls. It seems, therefore, that the issue of whether the PCOS women are or are not at increased risk for CVD is still debatable and equivocal. We thought, therefore that C-reactive protein (CRP), a possible marker of CVD, may add some new information and a novel perspective on the debatable question.

In an attempt to improve global cardiovascular risk prediction, significant efforts have focused on CRP, a marker of inflammation that has been demonstrated in multiple prospective epidemiological studies to predict incident myocardial infarction, stroke, peripheral arterial disease, and sudden death (13).

Several large-scale prospective studies have demonstrated that CRP is a strong independent predictor of future CVD and/or stroke (13, 14). Previous studies have found that the measurement of CRP compared with screening based on lipid levels may provide an improved method of identifying women at risk for CVD (15). These highly consistent clinical data are supported by abundant laboratory and experimental evidence demonstrating that atherothrombosis, in addition to being a disease of lipid accumulation, also represents a chronic inflammatory process (16). CRP seems to be more potent as a predictor of cardiovascular events than LDL-C, and it adds prognostic information at all levels of calculated Framingham risk and at all levels of the metabolic syndrome (15). Using widely available high sensitivity assays, CRP levels of less than 1, 1–3, and more than 3 mg/liter correspond to low, moderate, and high risk groups for future cardiovascular events, respectively. Individuals with LDL-C concentrations less than 130 mg/dl and CRP levels more than 3 mg/liter represent a high risk group often missed in clinical practice (16). CRP was a strong predictor of cardiovascular disease even after 8 yr after the initial testing (17). Therefore, in light of its possible ability to predict CVD in apparently healthy women with normal or high LDL-C, prone to cardiovascular morbidity and mortality, CRP may be an ideal marker for screening of apparently healthy young PCOS patients.

Theoretically CRP may differentiate between those PCOS women who are at higher risk of developing type II diabetes and CVD. Only two published studies have looked into the CRP levels in PCOS women, finding an increased incidence of high levels of CRP in PCOS patients compared with controls. The authors of these studies concluded that women with PCOS have significantly increased CRP concentrations relative to controls (18, 19). To confirm or rebute such an association, we measured CRP levels in a larger group of PCOS patients compared with BMI-matched controls.

	Subjects and Methods

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We designed a retrospective, case-control, cross-sectional study to compare the levels of CRP in a large group of PCOS patients and controls. PCOS was defined as menstrual irregularity due to oligomenorrhea (fewer than nine menstrual periods per year) or amenorrhea (no menstrual periods for 3 or more months) and clinical evidence of hyperandrogenism (hirsutism, acne, or male pattern balding).

None of the patients or controls was treated with hormonal contraceptives, aspirin, statins, or any other medication for at least 2 months before blood examination. None of the subjects was diabetic. We did not perform a glucose tolerance test on the subjects in either group.

The patients were recruited from Rambam Medical Center and Meuhedet Medical Services (Haifa, Israel). Control patients, recruited from the Rambam Medical Center staff, who experienced regular menstrual cycles and no clinical evidence of hyperandrogenism. To adjust for body mass-related increase in CRP, the two groups were BMI-matched. Therefore, the controls were chosen according to their weight and BMI. None of the patients had clinical evidence of recent or acute infection. The study was approved by the Rambam Medical Center institutional committee for human experimentation based on the Helsinki II regulations. One hundred and sixteen PCOS patients and 94 BMI-matched controls participated in the study.

Methods

CRP concentrations were determined in serum of 116 PCOS patients and 94 BMI-matched controls experiencing regular menstrual cycles. Being a retrospective study, homocysteine, lipids, TSH, white blood cell (WBC), and glucose measurements were not available for all the patients or controls.

Venous samples were collected from each subject after a 12-h fast and used for assay of glucose, total and HDL-C, and triglycerides. Determinate of total cholesterol, HDL-C, triglycerides, and glucose were carried out on the Roche/Hitachi 74 analyzer using Roche reagents. HDL-C was measured by the phosphotungstate method. LDL-C was computed by the Friedewald formula. Complete blood cell count were performed with standard techniques. Homocysteine was analyzed by a fluorescence polarization immunoassay for the quantitative measurement of total L-homocysteine in human serum or plasma on the AxSYM system.

CRP measurements were determined by two different methods: highly sensitive CRP (HS-CRP) and regular CRP (R-CRP). High sensitivity CRP (HS-CRP) analysis was carried out using a nephelometry system (Behring Diagnostics, Deerfield, IL) (20). In this method, polystyrene particles coated with monoclonal antibodies to CRP are agglutinated when mixed with samples containing CRP. The intensity of the scattered light in the nephelometer depends on the CRP content of the sample, and therefore, the CRP concentration can be determined vs. dilutions of a standard of known concentration. The method was standardized against the International Federation of Clinical Chemistry/Community Bureau of Reference of the Commission of the European Communities/College of American Pathologists reference preparation (21, 22). The intra- and interassay coefficients of variation for CRP were 3.3 and 3.2%, respectively. The reproducibility at the assay detection limits was 3.1%.

Regular CRP analysis was carried out using System Reagent CRP (latex, Olympus, Melville, NY). According to this method the sample is mixed with buffer and latex suspension. CRP reacts specifically with antihuman CRP antibodies on the latex particles to yield insoluble aggregates. The absorbance of these aggregates is proportional to the CRP concentration in the sample (21).

Standard curves were linear up to 5 mg/liter and were logarithmic thereafter. Using the two methods (HS-CRP and R-CRP) provided an extended measuring range from 0.05–170 mg/liter.

To examine the difference between methods we analyzed the samples from 49 subjects by two different methods: R-CRP and HS-CRP (20, 21, 22). No significant difference was detected between the methods (using paired t test) for values of 5 mg/liter or greater. For lower levels, however, the highly sensitive method resulted in significantly different values; therefore, only the HS-CRP was used for the low range levels (<5 mg/liter).

Statistics

CRP concentrations were skewed and transformed onto a logarithmic scale before analysis. Results are shown as the mean ± SD. Data from the two groups were compared using standard statistical tests. The data were analyzed with SPSS (version 10.5, SPSS, Inc., Chicago, IL) program for Windows; P < 0.05 was considered statistically significant. The measured parameters in the two groups (PCOS vs. controls) were compared by unpaired t test. Correlations of the parameters in the two groups were examined using the ² test. Linear correlations between clinical parameters were assessed within each group by the Pearson correlation.

	Results

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The mean age of the PCOS group was 27.5 ± 8 yr, and the mean age of the controls was 30.4 ± 8 yr. There were no other differences in patients characteristics between the two groups (Table 1). Whereas 36.8% of the PCOS patients had CRP levels above 5 mg/liter, only 9.6% of the controls exhibited such CRP levels (P < 0.001; Fig. 1). Whereas 46.5% of the PCOS patients had CRP levels above 3 mg/liter, only 27.7% of the BMI-matched controls exhibited such CRP levels (P = 0.005; Fig. 2). A decreasing linear trend was found between CRP levels for the control group, and an inverse, increasing CRP linear tendency was detected in the PCOS group (Table 2). Whereas most controls (72.4%) had CRP levels less than 3 mg/liter, almost half (46.5%) of the PCOS patients had CRP greater than 3 mg/liter (Fig. 2), and over one third (36.8%; Fig. 1) had levels above 5 mg/liter.

View larger version (29K): [in this window] [in a new window]   FIG. 1. The significantly different prevalences of high CRP level (>5 mg/liter) in PCOS vs. control groups.

View larger version (52K): [in this window] [in a new window]   FIG. 2. The significantly different (P = 0.0004) distributions of CRP levels (<1, 1–3, and >3 mg/liter) between PCOS and control groups. The apparent trend of decreasing CRP prevalence levels in controls is the opposite of that in PCOS patients, in whom the prevalence of high CRP increases linearly.

	Discussion

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Although still debatable and equivocal, there have recently been increasing suggestions that PCOS women without any other apparent chronic disease may be at increased risk for CVD compared with normal cycling women of similar age and BMI (8, 10, 11, 12, 19). Many PCOS patients have an adverse lipid profile and an increased prevalence of glucose intolerance, type 2 diabetes, and hypertension (5, 8, 23, 24). These women may also have an increase in subclinical atherosclerotic disease, as suggested by greater carotid intima-media thickness and higher levels of coronary calcifications (10, 25). Dahlgren et al. (26) have calculated, using a risk model analysis, that PCOS patients had a 4- to 7-fold higher risk of myocardial infarction compared with age-matched controls. Birdsall et al. (27) studied the association between PCO and coronary artery disease in 143 women, aged 60 yr or younger, undergoing cardiac catheterization. PCO was detected in 42% of the patients, and those patients with PCO more frequently exhibited coronary artery segment with greater than 50% stenosis and more severe IHD than women with normal ovaries. By multivariate regression analysis, the extent and severity of coronary artery disease have been independently associated with PCO (P = 0.032) as was a family history of cardiac ischemia (P = 0.022) (28). Although the association between PCOS and CVD has been repeatedly suggested by several reports (5, 8, 19, 23, 29), it has not yet been unequivocally substantiated (11, 12, 28).

These findings and high CRP in the PCOS group suggest that women with PCOS may indeed be at risk for early-onset CVD. As previous reports referred to CRP greater than 5 mg/liter and the more recent studies to CRP greater than 3 mg/liter as correlated to CVD, we looked at levels of CRP above each of these reported levels.

Moreover, a recent prospective study has linked menstrual irregularity, about 80% of which is attributed to PCOS, to an increased risk of mortality due to fatal coronary heart disease (28).

Whereas a small preliminary study (18) has found a difference in CRP levels between PCOS patients and controls, it was based on only 15–17 subjects in each group. Our study based on findings in 210 subjects (116 PCOS patients and 94 controls) confirms the finding of the preliminary study by Kelly et al. (18) despite different inclusion criteria and suggests that CRP may be a marker for possible prospective identification of young PCOS women prone to develop CVD in the future. Despite the fact that none of the PCOS patients had any sign of inflammation, the significantly higher erythrocyte sedimentation rate in this group compared with controls is in keeping with the study by Kelly et al. (18) that suggested a chronic subclinical inflammatory process as a possible underlying mechanism of atherosclerosis in some PCOS patients (16).

The mean CRP concentrations were significantly higher in the PCOS subgroups at normal BMI (<25) and in the obese group (BMI, >30) compared with the control subgroups of similar BMI (P < 0.001). For the subgroup of overweight PCOS and controls (BMI, 25–29), the CRP was higher in the PCOS subgroup (3.55 vs. 2.08, respectively), but the difference did not reach statistical significance (P = 0.07), probably due to the smaller number of patients in this subgroup (n = 17 vs. 31–68 in the two other PCOS subgroups of BMI).

Even though not all patients underwent all of the biochemical tests in addition to CRP, there was no difference between the PCOS and control groups in glucose, lipoproteins, TSH, homocysteine, or in WBC concentrations. Although mean ages are different, this does not weaken the difference in CRP levels between PCOS and controls; on the contrary, one may speculate that for younger controls the CRP concentrations might have been even lower, thus accentuating even further the difference detected between the two groups.

In the National Health and Nutrition Examination Survey III study, the metabolic syndrome was found in 23.7%, of 1887 Caucasian women (8, 30). The 27.7% prevalence of CRP greater than 3 mg/liter in our preselected (high BMI) control group is keeping with this finding in the National Health and Nutrition Examination Survey III cohort study (8, 30).

In this study we did not measure androgen levels in all our patients or controls, because previous publications did not find any correlation between CRP and testosterone levels (18) or between testosterone and lipid or lipoprotein concentrations in PCOS patients (31, 32). Similarly, androgen output was not correlated to an increased risk of CVD in women (18, 33). The lack of difference between the PCOS and control group does not contradict the clinical signs of hyperandrogenism, as testosterone was measured in only 39 PCOS patients and eight controls. Moreover, the total testosterone levels may be similar, and, due to low SHBG, the free testosterone level may be higher, accounting for the clinical hyperandrogenism in the PCOS group.

We did not measure insulin sensitivity or levels in all of our patients and controls. Although Kelly et al. (18) found that, on adjustment for insulin sensitivity, log CRP was no longer different between their groups, we still believe CRP to be a more readily available and simpler measurement than the determination of insulin resistance. Our results suggest that CRP levels may be considered among the battery of tests for PCOS patients as a possible risk factor analysis for future cardiovascular events.

Treatment regimens directed toward lowering CRP levels, (such as diet, smoking cessation, exercise, blood pressure control, low dose aspirin, metformin, and possibly statins) (11, 31, 34) in the future should probably be more aggressive for those PCOS women with increased CRP, as recently suggested by Glueck et al. (8). Of course, the applicability and efficiency of this hypothesis await the results of long-term clinical testing.

	Footnotes

 
Abbreviations: BMI, Body mass index; CRP, C-reactive protein; CVD, cardiovascular disease; HDL, high density lipoprotein; HDL-C, high density lipoprotein cholesterol; HS-CRP, high sensitivity C-reactive protein analysis; LDL, low density lipoprotein; LDL-C, low density lipoprotein cholesterol; PCOS, polycystic ovary syndrome; R-CRP, regular C-reactive protein analysis.

Received June 30, 2003.

Accepted February 1, 2004.

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