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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2114-2118
Copyright © 2004 by The Endocrine Society

Metabolic Cardiovascular Disease Risk Factors in Women with Self-Reported Symptoms of Oligomenorrhea and/or Hirsutism: Northern Finland Birth Cohort 1966 Study

Saara Taponen, Hannu Martikainen, Marjo-Riitta Järvelin, Ulla Sovio, Jaana Laitinen, Anneli Pouta, Anna-Liisa Hartikainen, Mark I. McCarthy, Stephen Franks, Mika Paldanius and Aimo Ruokonen

Departments of Clinical Chemistry (S.T., A.R.) and Obstetrics and Gynecology (S.T., H.M., A.-L.H.), University of Oulu and Oulu University Hospital; and Department of Public Health Science and General Practice, University of Oulu (S.T., M.-R.J., A.P.), 90014 Oulu, Finland; Oulu Regional Institute of Occupational Health (J.L.) and National Public Health Institute (M.P.), 90220 Oulu, Finland; Department of Epidemiology and Public Health, Imperial College London (M.-R.J., U.S.), London, United Kingdom W2 1PG; Oxford Center for Diabetes, Endocrinology, and Metabolism (M.I.M.), Oxford, United Kingdom OX3 7LJ; Wellcome Trust Centre for Human Genetics (M.I.M.), Oxford, United Kingdom OX3 7BN; and Institute of Reproductive and Developmental Biology, Imperial College London (S.F.), London, United Kingdom W12 0NN

Address all correspondence and requests for reprints to: Dr. Saara Taponen, Department of Clinical Chemistry, University of Oulu, PL 5000, 90014 Oulu, Finland. E-mail: saara.taponen{at}mail.suomi.net.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The metabolic cardiovascular disease (CVD) risk factors of women with self-reported oligomenorrhea and/or hirsutism, which are symptoms of polycystic ovary syndrome (PCOS), were investigated in a general population-based Northern Finland Birth Cohort 1966 Study to determine whether women with PCOS symptoms at 31 yr would be distinguishable from asymptomatic controls in terms of CVD risk factors. A total of 518 cases with oligomenorrhea and/or hirsutism and 1036 randomly selected controls were analyzed. C-Reactive protein (CRP; median, 0.70 vs. 0.60 mg/liter; P = 0.026), triglycerides (mean, 0.97 vs. 0.91 mmol/liter; P = 0.039), body mass index (BMI; mean, 25.1 vs. 24.2 kg/m2; P < 0.001), and waist/hip ratio (mean, 0.82 vs. 0.81; P = 0.001) were significantly higher, and high-density lipoprotein cholesterol levels were lower (mean, 1.60 vs. 1.66 mmol/liter; P = 0.002) in the cases compared with the controls. Total cholesterol, low-density lipoprotein cholesterol, and blood pressure showed no statistically significant differences between the cases and the controls. In terms of metabolic CVD risk factors, women reporting hirsutism alone were indistinguishable from the control group, and those who reported both oligomenorrhea and hirsutism had the most severe changes in risk factor profiles. Because obesity is strongly related to PCOS symptoms, the analyses were stratified by BMI. After stratification into normal weight (BMI, <25 kg/m2), overweight (25 kg/m2 <= BMI <30 kg/m2), and obese (BMI, >=30 kg/m2) groups, the waist/hip ratio was significantly higher among the overweight cases (mean, 0.84 vs. 0.83; P = 0.04). Among the obese women, high-density lipoprotein cholesterol was significantly lower (mean, 1.32 vs. 1.48 mmol/liter; P = 0.002) among the cases, and triglycerides tended to be higher (mean, 1.43 vs. 1.27 mmol/liter; P = 0.068) than in controls. In conclusion, these results indicate that self-reported symptoms of oligomenorrhea and/or hirsutism, particularly in the presence of both symptoms, may be helpful to identify women with metabolic cardiovascular risk factor accumulation associated with PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE FACT THAT metabolic disturbances in polycystic ovary syndrome (PCOS), typical in even nonobese women with PCOS, correlate with cardiovascular disease (CVD) risk (1, 2) has led to the suggestion that women with PCOS are at increased risk for CVD.

Despite strong evidence of unfavorable CVD risk factors [body mass index (BMI), waist/hip ratio (WHR), insulin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, blood pressure (BP), and high-density lipoprotein cholesterol (HDL-C)] among PCOS patients compared with their controls (3, 4), higher rates of mortality or morbidity from circulatory diseases were not observed in two follow-up studies (5, 6). However, two studies with relatively small sample sizes have shown an increased predisposition to atherosclerosis among PCOS patients over 45 yr of age, with greater carotid intima-media thickness (7) and increased prevalence of carotid plaque (8). Recently, coronary artery calcium, a marker for coronary atherosclerosis, was shown to be more prevalent in obese PCOS women than in age- and BMI-matched controls, although after adjustment for other risk factors, PCOS did not predict coronary artery calcium (9). Furthermore, several studies suggest that low grade inflammation, reflected by elevated C-reactive protein (CRP) levels, can contribute to the development of arteriosclerosis (10, 11, 12). Kelly et al. (13) first reported that PCOS is associated with slightly elevated CRP levels.

Recently, Solomon et al. (14), using a symptom-based approach similarly to that used in our study (15), showed in two large prospective cohort studies that those women who reported usually irregular or very irregular cycles had a significantly increased risk for coronary heart disease and type 2 diabetes (14, 16). They concluded that menstrual cycle irregularity, the most frequent cause of which is PCOS (17), may be a marker of metabolic abnormalities predisposing to an increased risk for CVD (14), but no laboratory measures were studied.

However, the association between PCOS and increased CVD risk has been questioned because of the heterogeneity of diagnostic criteria, small sample sizes, limited follow-up times, and the use of populations of reproductive age in studies (18). As CVD events mostly occur in postmenopausal women, ovarian surgery, such as wedge resection, which was used to treat PCOS (19), and fading of the reproductive phenotype with age (20) may obscure the relation between CVD and PCOS.

A symptom-based approach to investigate the association of cardiovascular and type 2 diabetes risk factors with oligomenorrhea and hirsutism in a large general population was used in the present study. As we previously showed, questioning symptoms of oligomenorrhea and/or hirsutism in a general population is a useful tool to identify a group of women with insulin resistance and hormonal changes that are characteristics of PCOS (15). In the present study we wanted to determine whether women with symptoms of oligomenorrhea and/or hirsutism would differ from their controls in metabolic and inflammatory CVD risk factor profiles. We hypothesized that metabolic alterations linked with PCOS, CVD, and type 2 diabetes could be seen in women with oligomenorrhea and/or hirsutism compared with women with no symptoms.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

A nested sample of women with (cases) and without (controls) symptoms typical of PCOS, previously described in detail (15), were derived from the Northern Finland Birth Cohort 1966,who were followed from the mother’s pregnancy until the offspring’s age of 31 yr (21). In 1966, 5964 females were born; 5889 were live births. At 14 and 31 yr, the subjects answered a postal questionnaire. Of the women who returned the questionnaire at 31 yr (n = 4523), 24% reported symptoms of hirsutism and/or oligomenorrhea (including subjects with amenorrhea), 10.4% reported hirsutism alone, 10.2% reported oligomenorrhea alone, and 3.4% reported both symptoms. The questions were as follows. 1) Is your menstrual cycle often (more than twice a year) more than 35 d? 2) Do you have excessive growth of body hair? Those living in the original target or capital city area (n = 4074) were invited to a clinical examination and venipuncture. Of these, 981 did not attend the clinical examination or did not fill in the postal questionnaire, and 16 refused the use of data for research purposes in written informed consent. Those who reported symptoms of hirsutism and/or oligomenorrhea (including amenorrhea) were defined as cases. An asymptomatic control group (2 controls to 1 case) was selected randomly from the same cohort of those who did not report hirsutism or oligo/amenorrhea. Those who used hormonal contraception (n = 859), were pregnant (n = 211), or used medication for diabetes (n = 13) and those who reported eating, drinking, or smoking during the fasting time (n = 42) were excluded from the statistical analyses of glucose, insulin, and triglycerides. The final study population consisted of 518 cases and 1036 controls. This study has been approved by the ethical committee of the University of Oulu.

Blood samples and laboratory methods

The blood samples were drawn after overnight fasting from 2200 h until blood sampling in the morning (between 0800 and 1100 h). Samples were stored at –80 C until analyzed. Fasting serum total cholesterol and triglycerides were determined using an Hitachi 911 automatic analyzer and commercial reagents (Roche, Mannheim, Germany). HDL- and LDL-C were also determined using the same analyzer and methods previously described (22, 23). Serum CRP concentrations were determined by immunoenzymometric assay (Medix Biochemica, Espoo, Finland). The intra- and interassay coefficients of variation were 0.7 and 1.5% for total cholesterol, 0.5 and 3.2% for HDL-C, 1.6 and 2.6% for LDL-C, 0.9 and 2.4% for triglycerides, and 4.2 and 5.2% for CRP. The sensitivity of the CRP assay was 0.08 mg/liter. The data from the analyses of testosterone, SHBG, free androgen index, insulin, and glucose were reported in our previous study (15).

Other clinical measures

Systolic and diastolic BP were measured twice with a mercury sphygmomanometer in a sitting position from the right arm after 15-min rest by trained nurses using a standardized procedure (24) and ongoing quality control. The averages of the two measurements of systolic and diastolic BP were used. The BMI (kilograms per meter squared) was calculated at the age of 31 yr. Because obesity is related to PCOS (25) and also independently to the metabolic measures studied here, the analyses were stratified by BMI. BMI was classified as follows: normal weight (<25 kg/m2), overweight (25.0–29.9 kg/m2), and obese (>=30.0 kg/m2). The WHR was measured at 31 yr, as the ratio between the circumferences of the waist (at the level midway between the lowest rib margin and the iliac crest) and the hip (at the widest trochanters).

Statistical methods

Means and SD values for the normally distributed variables are reported. Log transformation was used on triglycerides and WHR to normalize distribution before statistical testing with a two-tailed t test. CRP distribution was strongly skewed; therefore, medians and quartiles are reported, and accordingly, differences between the groups were tested with the nonparametric Mann-Whitney U test. The analyses were stratified by BMI; the results are given separately for normal weight, overweight, and obese women.

Statistical analyses were performed using SPSS version 10.1 for Windows (SPSS, Inc., Chicago, IL). The level chosen for statistical significance was P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The means and 95% confidence intervals of total cholesterol, HDL-C, LDL-C, triglycerides, BMI, WHR, and BP and the medians and quartiles of CRP for all cases; separately for women with only hirsutism, only oligomenorrhea, and both hirsutism and oligomenorrhea; and controls are reported in Table 1Go. The group with oligomenorrhea and hirsutism clearly had the least favorable risk factor profile, showing significantly higher triglycerides, CRP, BMI, WHR, and systolic and diastolic BP and lower HDL-C than controls. Compared with the controls, all cases had significantly lower HDL-C and significantly higher triglycerides, CRP, BMI, and WHR. For total cholesterol and LDL-C levels, there were no statistically significant differences between the groups. The group reporting hirsutism alone was indistinguishable from the asymptomatic control group.


View this table:
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  		TABLE 1. Means (95% confidence interval) or medians (25th and 75th quartiles of CRP, insulin, and glucose) of total cholesterol, HDL-C, LDL-C, triglycerides, CRP, BMI, WHR, BP, insulin, and glucose in controls, those who reported both symptoms, those who reported only hirsutism, those who reported only oligomenorrhea, and all cases

 
We assessed the validity of hirsutism by using a cut-off level of testosterone greater or less than 3 nmol/liter. Those who had only hirsutism and testosterone levels greater than 3 nmol/liter and those who did not report hirsutism but had testosterone levels greater than 3 nmol/liter were similar to the group with both symptoms with respect to CVD risk factors, whereas those with hirsutism and testosterone levels less than 3 nmol/liter were similar to the controls.

Table 2Go shows the metabolic measures for cases and controls stratified by BMI. There were no statistically significant differences between the BMIs of the cases and the controls within each BMI stratum. In the obese group, HDL-C was significantly lower and triglycerides tended to be higher (P = 0.068) among the cases compared with the controls. For other groups, normal or overweight in the stratified analysis, total cholesterol, LDL-C, triglycerides, CRP, WHR, and BP increased, and HDL-C decreased as BMI increased, but no significant differences between the case and control groups were found, except that WHR was significantly higher in the cases compared with the controls in the overweight group. The estimates for many of the measures were in all weight groups less favorable in the cases compared with the controls, although differences were not statistically significant.


View this table:
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  		TABLE 2. Means (SD) or medians (25th and 75th quartiles of CRP, insulin, and glucose) of total cholesterol, HDL-C, LDL-C, triglycerides, CRP, WHR, BP, insulin, and glucose in cases and controls stratified by BMI

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study shows that using self-reported symptoms of oligomenorrhea and hirsutism as screening tools to find a group of women with cardiovascular and type 2 diabetes risk factor indications associated with PCOS is feasible. The group of women selected from a general population based on their report of typical symptoms of PCOS had less favorable metabolic changes and a slightly elevated CRP level compared with controls at 31 yr of age. These changes were partly, but not completely, associated with the greater body size of the cases.

In this general population-based study, women with self-reported symptoms of oligomenorrhea and/or hirsutism had lower HDL-C and higher triglycerides, CRP, and WHR than their asymptomatic controls. These changes were pronounced in those who reported hirsutism and oligomenorrhea, who also had significantly higher systolic and diastolic BP than the controls. When stratified by BMI, significantly lower HDL-C levels and a tendency toward higher triglyceride levels were noticed in obese cases, and significantly higher WHR was found in the overweight cases. These findings indicate that CVD risk factors are more prominent in a group selected from the general population by inquiry about symptoms of oligomenorrhea and hirsutism, even after stratification by BMI. The clinical significance of these changes is currently unknown. However, at the group level a BP difference of 1.5–2 mm Hg could have a large impact on population CVD risk (26). Thus, the difference of 6 mm Hg in systolic BP means between those who reported hirsutism and oligomenorrhea and the controls in our study strongly suggests clinical relevance.

Our study also showed that the levels of metabolic measures changed unfavorably among both the cases and the controls with increasing BMI, and in this set-up the differences between the cases and controls were relatively small. However, we have to keep in mind that when stratified, the study loses some of its power, and because the women who used oral contraceptives or hormonal treatment had to be excluded from the study, it is possible that the individuals with the most severe symptoms who had sought help were therefore left out. Also, the case group probably includes women with mild symptoms and no notable biochemical changes, because the cases were defined by self-reported symptoms, which are subjective. These facts may lead to underestimation of differences between the cases and controls. This study covered those women who were living in the original target area in northern Finland or in the Helsinki area, which introduces a hypothetical risk of selection bias, but, for example, regarding their circumstances earlier in life, they well represent the entire female cohort.

Obesity obviously is a central part of the development of metabolic abnormalities related to PCOS, perhaps due to genetic susceptibility or changes in the intrauterine programming of body functions. Based on our study, particularly obese women with PCOS symptoms seem to be at higher CVD risk. Our results agree with those of earlier studies in which several cardiovascular risk factors, including higher total cholesterol, LDL-C (4, 27, 28), very low density lipoprotein cholesterol (29, 30), and triglycerides (4, 28, 29) and lower HDL-C levels (4, 28, 30, 31) were reported among women with PCOS compared with controls. Diamanti-Kandarakis et al. (32), who reported higher type 2 diabetes risk factors among women with both hirsutism and oligomenorrhea compared with controls, did not find a difference in BP and did not report lipid profiles. In our study, increased risk factors, including dyslipidemia, were observed in a general population in women with just self-reported symptoms of PCOS.

CRP, indicating low grade chronic inflammation, independently seems to predict coronary heart disease (12, 33) and has been shown to be associated with insulin resistance (10, 34), although the role of inflammation in the etiology of CVD and other metabolic diseases is still disputed and is not generally accepted (35, 36, 37, 38). In the present study, CRP levels were higher among the cases than the controls, but after stratification by BMI, no differences persisted between the CRP levels of the cases and the controls, indicating that BMI functions as an effect modifier (obvious intermediate factor) and that higher CRP among cases relates to their greater body size. Two large cross-sectional studies could not demonstrate either differences in CRP levels of women with and without CVD (35) or association between CRP and prevalent coronary heart disease, carotid intima-media thickness, or carotid plaque after adjustment for risk factors (36). CRP was, however, the strongest univariate predictor of the risk of cardiovascular events in a prospective study of 28,263 postmenopausal women (12), and one study suggested that markers of low grade chronic inflammation independently predict those at high risk for type 2 diabetes (39). The study by Kelly et al. (13), in agreement with our results, indicated low grade chronic inflammation to be present in PCOS women based on higher CRP levels in cases than controls (13), which may contribute to the increased level of CVD and type 2 diabetes risk in women with PCOS.

In conclusion, symptoms of oligomenorrhea and hirsutism, especially when both are present and associated with obesity, may be signs of underlying metabolic disorder, leading to greater CVD risk in women. Coexistence of hirsutism and oligomenorrhea suggests membership in a high risk group, most likely PCOS, in which CVD risk should be assessed and on-going surveillance into middle age accomplished.


   Acknowledgments
 
The authors thank Ms. Anja Heikkinen and Ms. Salli Kämäräinen for excellent technical assistance.


   Footnotes
 
This work was supported by the Academy of Finland, the European Commission Quality of Life and Management of Living Sources Program (Contract QLG1-CT-2000-01643), the Foundation of the University of Oulu, the Oskar Öflund Foundation, and the Finnish Gynecological Association.

Abbreviations: BMI, Body mass index; BP, blood pressure; CRP, C-reactive protein; CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCOS, polycystic ovary syndrome; WHR, waist/hip ratio.

Received October 2, 2003.

Accepted February 3, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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