Polycystic ovary syndrome: A risk for coronary artery disease?

Polycystic ovary syndrome: A risk for coronary artery disease? Robert A. Wild, MD Oklahoma City, Okla OBJECTIVE: The purpose of this study was to evaluate the literature that was pertinent to cardiovascular risk in women with the polycystic ovary syndrome. STUDY DESIGN: Medline, Current Contents, and Pub-Med were searched for human studies from the time of our original interest in this issue in 1975 to the present. Only pivotal articles are presented because of page constraints and reference number limits. RESULTS: Current literature supports the fact that women with this syndrome have risk factors for premature cardiovascular disease. CONCLUSION: Large multisite cooperative studies are necessary to evaluate cardiovascular morbidity and mortality rates from this syndrome. (Am J Obstet Gynecol 2002;186:35-43.)

Key words: Polycystic ovary syndrome, cardiovascular risk, coronary artery disease In current practice, we screen women with the polycystic ovary syndrome (PCOS) for cardiovascular risk. Factors include diabetes/insulin resistance, hypertension, abnormal cholesterol/triglyceride levels, family history, and coronary-prone behavior. Whether women with PCOS are at increased risk for heart disease because of their PCOS status, independent of well-known determinants, is controversial, because research usually involves sample sizes that are too small for meaningful inference or looks at mechanistic questions that focus on intermediate biologic outcomes, not clinical outcomes (cardiovascular events). Even though heart disease is the leading cause of morbidity and death for women, this applies mostly to older women. Women with PCOS usually first seek care in their reproductive years. This is too early for the accumulative effects of risk factors. Educated to diagnose disease, physicians often focus on chief complaints, which can lead to suboptimum screening for cardiovascular risk. Also, large investigations that are pertinent to women and heart disease (eg, Framingham, the Nurses Health Study) ignored the symptoms of hyperandrogenism that are associated with aberrant menses. The true prevalence of women with PCOS in these cohorts cannot be determined. Classic risk factors that women with PCOS commonly display (diabetes mellitus, hypertension, and dyslipidemia) are prevalent and predict poor outcome

for women who are enrolled in these studies. Whether those women found to have cardiovascular disease (CVD) had PCOS is unclear. Post-hoc analysis can only generate hypotheses. One cannot determine the converse either. Are women with PCOS, because of their uniqueness, actually protected and therefore are at reduced risk in spite of clustering coronary vascular risk factors? It is much easier to assess risk factors and/or intermediate biologic surrogate endpoints. A surrogate endpoint is a laboratory measurement or a physical sign that is used to substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions, or survives. The following measures are often used: glucose, insulin, diabetes mellitus, lipids, obesity, coagulation, and asymptomatic atherosclerosis. This contrasts with clinical outcomes: coronary artery disease (CAD) with symptoms, myocardial infarction, stroke, and death (both total mortality and CVD mortality rates). The hazards of an assessment of an intermediate outcome as a surrogate marker for the true outcome are well known. A correlate does not a surrogate make. Three crucial questions must be answered: 1. Are known risk factors for CVD more common in women with PCOS? 2. Are women with PCOS at greater risk for CVD events? 3. Does modification of risk reduce events? Criteria

From the Departments of Obstetrics/Gynecology (Reproductive Endocrinology Section), Medicine (Cardiology), Biostatistics and Epidemiology, Oklahoma University Medical Center. Received for publication January 18, 2001; revised July 19, 2001; accepted July 31, 2001. Reprint requests: Robert A. Wild, MD, MPH, 2410 WP, 920 Stanton L. Young Blvd, Oklahoma City, Oklahoma 73104. E-mail: [email protected]. Copyright © 2002 by Mosby, Inc. 0002-9378/2002 $35.00 + 0 6/1/119180 doi:10.1067/mob.2002.119180

Pertinent investigations are classified by level of evidence. For therapeutic studies, level I is a randomized study, with high alpha and high beta results; level II is randomized, with low alpha and beta results; level III is nonrandomized, with concurrent control subjects (quasiexperimental design); level IV is nonrandomized, with historic control subjects; and level V is a case series. For risk, a prospective longitudinal cohort study of long duration, 35

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Table I. Are women with PCOS more prone to hypertension? Study

Patient population

Mattsson et al3 (1984) 20 PCOS vs 20 normal Zimmermann et al1 (1992) 14 PCOS vs 18 normal control (similar age, race, BMI) Conway et al2 (1992) 102 Lean and obese PCOS; 19 lean PCOS Sampson et al4 (1996)

24 Nonobese PCOS with irregular menses; 26 PCOS by ultrasound scan, regular menses; 10 normal

Holte et al5 (1996)

36 PCOS vs 55 control subjects, matched for BMI

Fridstrom et al6 (1999)

33 PCOS vs 66 normal

Dahlgren et al7 (1992)

33 PCOS; 132 age-matched referents; wedge resection 346 PCOS patients by telephone; age-specific; rates of Dutch women

Elting et al8 (2001)

with appropriate sample size, provides much more evidence than small sample studies. A cross-sectional study can generate hypotheses; it cannot determine causality. Panel design (a series of cross-sectional looks over time) can provide more inference. A case/control study is helpful for rare disorders. Matched studies suffer from dilemmas of complete matching of known or unknown characteristics; the population that is studied determines, in part, the relevance. Inclusion and exclusion criteria are crucial. For outcome, issues regarding validity include the following questions: 1. Is there a well-defined, representative sample of patients that was assembled at a common early point in the course of the disease? 2. Is patient follow-up sufficiently long and complete? 3. Were objective outcome criteria applied in a blinded manner? 4. If subgroups with different prognoses were identified, was there adjustment for important prognostic factors? Was there validation in an independent group of “test-set” patients? Independent studies that validate the predictive power of prognostic factors are very helpful. Question I: Are CVD risk factors more common in women with PCOS? Hypertension (Table I). Zimmermann et al1 measured 24-hour ambulatory systolic and diastolic blood pressure and left ventricular mass by echocardiography. Average blood pressure was similar between women with PCOS and control subjects, and there was no difference in left ventricular mass. Conway et al2 compared lean and obese women with PCOS to women with normal ovaries. Obese women with PCOS had higher systolic blood pressure.

Findings Blood pressure higher in PCOS No difference in blood pressure, left ventricular hypertrophy Lean PCOS with higher insulin than normal; obese PCOS had higher blood pressure No difference for 24-hr ambulatory blood pressure; PCOS with menstrual disturbance; higher fasting insulin and plasminogen activator inhibitor levels Higher ambulatory mean arterial blood pressure; higher daytime systolic blood pressure; no difference in diastolic blood pressure Higher blood pressure, third trimester of pregnancy in PCOS retrospective Greater prevalence of physician diagnosed hypertension, PCOS Hypertension, 2.5 times higher in PCOS; hypertension, obesity more in the younger (35-44 y) PCOS group (n = 233)

Level of evidence III III III III

III

III III IV

Mattsson et al3 compared women with PCOS with irregular menses to regularly menstruating women without androgen excess and found increased blood pressure. Sampson et al4 performed a cross-sectional study of 3 groups: (1) nonobese women with a classic ovarian ultrasound scan appearance of PCOS with extreme menstrual disturbance, (2) normal menstruating women and ultrasound scan appearance of PCOS, and (3) normal menstruating women with normal ovarian ultrasound scan. They could not find differences in 24-hour, daytime, or nighttime ambulatory blood pressure. Holte et al5 evaluated office and 24-hour blood pressure in women with PCOS and normal control subjects in relation to insulin sensitivity in women who were matched for body mass index (BMI). Greater pulse rate (70% higher) from nighttime to daytime recordings, higher daytime systolic pressure, and mean ambulatory arterial blood pressure were found. The groups did not differ significantly in nighttime diastolic blood pressure. This higher daytime blood pressure persisted after an adjustment for BMI, body fat distribution, and insulin resistance. The suggestion was that labile blood pressure might indicate a prehypertensive state. The objective of the case-control study by Fridstrom et al6 was whether there is an increased risk for hypertension during pregnancy in women with PCOS that is associated with adverse pregnancy outcome. Pregnancy outcomes were gestational length, birth weight, and a need for neonatal intensive care. There was no difference in blood pressure during the first and second trimesters. During the third trimester and during labor, women with PCOS had higher blood pressure levels. Apart from a tendency toward reduced growth of twins, babies were healthy overall, with few problems in the neonatal period and no major difference in outcomes. Dahlgren et al7

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Table II. Are women with PCOS at greater risk for abnormal glucose/diabetes mellitus? Study

Patient population

Findings

Dahlgren et al7 (1992)

33 PCOS; 132 age-matched referents; wedge resection 122 PCOS

Greater prevalence of physiciandiagnosed diabetes mellitus in PCOS Glucose intolerance, 45%; IGT, 35%; NIDDM, 10% Prevalence of glucose intolerance: IGT, 38.6%-31.1%; diabetes mellitus, 7.5%; nonobese PCOS: IGT, 10.3%; diabetes mellitus, 1.5%

Ehrmann et al9 (1999) Legro et al10 (1999)

Cibula et al11 (2000)

254 PCOS 14-44 y; prospectively, 1 urban ethnically diverse (n = 110); 1 rural ethnically homogeneous (n = 144); rural PCOS and 80 control subjects of similar weight, ethnicity, and age 28 Select patients with ovarian wedge resection compared with 752 control subjects who were selected by age (45-59 y) from random population

published a retrospective cohort follow-up of patients with PCOS. The women came from hospital clinics, and the referents came randomly from another population study. Questionnaire data were supplemented by an interview in connection with a clinical examination. Women with PCOS showed more hypertension. Elting et al8 evaluated 346 patients with PCOS by telephone. The mean age was 38.7 years (range, 30.3-55.7 years); and the mean BMI was 24.4 kg/m2 (range, 17.5-55.8 kg/m2). Hypertension was 2.5 times higher (P < .01) than in the corresponding age group of the Dutch female population and more in the younger women. This age group was significantly more obese, however, when compared with obesity in the general Dutch female population. These studies conflict. In the study by Dahlgren et al,7 wedge-resection patients were evaluated. This procedure might change the natural history of disease progression. The histologic diagnosis of PCOS was controversial, not standardized, and not uniformly recognized among pathologists 22 to 31 years ago. The numbers are small. Questionnaire data can be unreliable unless designed well. The use of a trained interviewer is helpful. An ideal response rate is 80%. Control subjects were randomly picked. Telephone interviewing has potential problems with selection bias. Frequently, there is not strict attention to detail and accuracy in measuring blood pressure, including consistent use of a calibrated instrument. Whether the rate of hypertension is different is a difficult question to study. Numerous factors (including genetics, inactivity, stress, salt loading) affect the risk and are often not controlled in the studies. We need large prospective data sets to determine whether women with PCOS, per se, are at increased hypertensive risk. Metabolic ward studies, in which exercise and diet are accurately controlled, are in order. Whether women with PCOS who are insulin resistant and not obese are more likely to develop hypertension over time must be determined.

PCOS, aged 45-54 y (n = 32), prevalence of diabetes mellitus was 4 times higher

Level of evidence III IV III, IV

IV

Insulin resistance, impaired glucose tolerance (IGT), and diabetes mellitus (Table II). Ehrmann et al9 characterized the prevalence of IGT in a large cohort of women with PCOS. The aim was to determine the natural history of glucose tolerance in a subset. Women with non–insulin-dependent diabetes mellitus (NIDDM) had a 2.6-fold higher prevalence of first-degree relatives with NIDDM and were significantly more obese. Among those women with IGT, fasting glucose was poorly predictive of the 2-hour level. After 2.4 years, 25 women underwent a second evaluation. The prevalence of IGT and NIDDM was substantially higher than expected when compared with age- and weight-matched women without PCOS. The researchers suggested that the conversion from IGT to diabetes mellitus is accelerated in women with PCOS. Legro et al10 studied 14- to 44-year-old patients prospectively at 2 centers; 1 center was urban and ethnically diverse, and 1 center was rural and ethnically homogeneous. The prevalence of glucose intolerance was significantly higher in women with PCOS. Variables that were most associated with postchallenge glucose levels were fasting glucose, PCOS status, waist/hip ratio, and BMI. The authors suggest that women with PCOS are at significantly increased risk for IGT and type 2 diabetes mellitus at all weight levels and at a young age and that PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women. Cibula et al11 selected 28 women from a large group who had undergone wedge ovarian resection and compared them with 752 control subjects who were selected by age (45-59 years) from a random female population sample. There was no difference in BMI, waist circumference, or waist/hip ratio. Both groups had identical family histories of NIDDM, hypertension, CAD, and smoking habits. The prevalence of NIDDM was higher in women with PCOS. In women with PCOS who were aged 45 to 54 years (n = 32 women), the prevalence of diabetes mellitus was 4 times higher (P < .05).

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The evaluation by Ehrmann et al9 lacks follow-up of all patients. At baseline, 45% of women with PCOS had abnormal glucose tolerance. Although one cannot determine causality, this suggests that the prevalence of abnormal glucose tolerance is high in women with PCOS. For the small subset, there was a deterioration of glucose tolerance. The study by Legro et al10 is a prevalence study with concurrent and historic control subjects. They found similar prevalence in 2 different populations. Women with and without PCOS were followed to determine the incidence of carbohydrate deterioration. Whether the risk is equivalent in nonobese patients with PCOS cannot be determined. The study by Cibula et al11 included 28 women from a large group who had undergone wedge resection. How representative the 28 women who were selected were of the group that was not selected or who did not undergo wedge resection remains unknown. From a pathophysiology perspective, it seems intuitive that both obesity and PCOS status should confer risk for diabetes mellitus. When a woman becomes diabetic, she removes her selective female advantage. It is unknown whether women with PCOS and diabetes mellitus are as likely to die of CVD as are women with diabetes mellitus but not PCOS. PCOS is frequently associated with central obesity and is associated with varying states of altered glucose metabolism, from minor deviations to overt hyperglycemia with or without diabetes mellitus. It is a reflection of the gender bias in publication that most outcome studies that are pertinent to the relationship between glucose abnormality and CVD have been in men. There is an association between cardiovascular risk and fasting and postprandial blood glucose levels in nondiabetic patients. The United Kingdom Prospective Diabetes Study (level of evidence, I) clearly showed that blood glucose and blood pressure control reduced the risk for vascular complications in patients with diabetes mellitus. IGT is prevalent with or without PCOS. It appears that women with PCOS are more likely to experience it early. Dyslipidemia (Table III). Wild et al12 evaluated women with PCOS and normal women by comparing lipoprotein lipid and androgen profiles. Women with PCOS had higher triglyceride, very low-density lipoprotein (VLDL) cholesterol, and lipoprotein C-III levels and lower highdensity lipoprotein (HDL2) cholesterol and apolipoprotein A-I/A-II ratios.12a Although women with PCOS were heavier, they had higher blood pressure, were more sedentary, and had diets higher in saturated fat and lower in fiber. This difference held even when women with PCOS and control subjects were matched for weight.12b Slowinska-Srzednicka et al13 studied obese and nonobese women with PCOS and compared them with lean and obese control subjects. Lower levels of HDL2 cholesterol and higher apolipoprotein B were found in obese and

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nonobese women with PCOS. In obese women with PCOS, this was associated with lower levels of HDL cholesterol and apolipoprotein A-I and higher levels of triglycerides and VLDL cholesterol. Talbott et al14 recruited women with PCOS by using records from a large reproductive endocrinology practice. Women with PCOS had significantly increased BMI, insulin, and triglyceride levels, decreased total HDL and HDL2 cholesterol levels, and increased total and fasting LDL cholesterol levels. This group reported on the same expanded cohort. Women with PCOS had substantially higher LDL and total cholesterol at each age group that was <45 years, after an adjustment was made for BMI, hormone use, and insulin level. Over age 40 years, little difference was found. Among cases and control subjects (<40 years), PCOS predicted LDL cholesterol, total cholesterol, and triglyceride levels. These authors suggested LDL cholesterol increased with age in the control subjects. Velazquez et al15 found greater triglyceride response to a fat load in women with PCOS. Dyslipidemia studies are level of evidence III studies. Concurrent control subjects were in a clinical research center or in the community. Patients were age-matched in 1 of the studies by Talbott et al.14 In each instance, women with PCOS had a characteristic profile of lower HDL cholesterol (and lower apolipoprotein A1), higher triglyceride and VLDL levels, and, in some instances, higher apolipoprotein B and LDL cholesterol levels. The dyslipidemia is present in different populations of patients with PCOS at different sites throughout the world. None of the lipid values is extreme. Most heart attacks occur in women who do not have extreme values, however. Each study found significant associations with insulin levels as a marker for insulin resistance in nondiabetic women. Poorly controlled diabetes mellitus is associated with altered lipid metabolism and, at times, markedly abnormal lipid profiles. Obesity/metabolism. Obesity is a prominent feature in PCOS. In many studies, 50% of patients with PCOS are obese. Obesity appears to exert an additive, synergistic effect on the manifestations of PCOS. In particular, abdominal obesity leading to an increased waist/hip ratio appears common. The issue of obesity or even abdominal obesity in lean women with PCOS due only to this syndrome is unclear. Korhonen et al16 recruited 204 patients from a random sample of women in 5 age groups (range, 35-54 years) who lived in a defined area. The metabolic syndrome was considered present if 3 of 8 overt criteria were fulfilled. The frequency of the metabolic syndrome was 106 of 543 cases (19.5%). The control groups consisted of 62 overweight women without central obesity or metabolic syndrome and 53 healthy lean women (BMI, <27 kg/m2. The group with the metabolic syndrome differed from the other women according to most of the selection criteria and also had the highest free testosterone

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Table III. Are women with PCOS at greater risk for dyslipidemia? Study

Patient population

Findings

Wild et al12 (1985)

29 PCOS vs 30 control subjects

Wild et al12b (1988) Slowinska-Srzednicka et al13 (1991)

13 PCOS; 13 control subjects, matched for BMI 49 Glucose tolerant women, lean and obese, PCOS vs normal

Wild et al12a (1992)

47 Hirsute vs 15 control subjects

Talbott et al12a (1992)

206 PCOS and control subjects, voter registration tapes, and directories of households; subjects matched by age, race, and neighborhood 18 Hispanic PCOS vs 9 control subjects

Higher triglyceride, lower HDL cholesterol levels in PCOS Higher triglyceride and VLDL cholesterol levels, lower HDL cholesterol levels in PCOS Lower HDL2 and higher apolipoprotein B levels in obese, nonobese PCOS; obese PCOS, higher triglyceride, VLDL cholesterol, lower HDL cholesterol levels Higher triglyceride, VLDL cholesterol, apolipoprotein C-III, AI/AII levels, and lower HDL cholesterol levels Increased triglyceride, decreased total HDL and HDL2 cholesterol, increased total cholesterol and LDL levels

Velazquez et al15 (2000)

concentration. There were no differences between the groups regarding parity, infertility problems, or obstetric outcome. Oligomenorrhea was more common in women with metabolic syndrome, especially in those women with more severe symptoms (46.2%), than in obese (25.4%) and lean (15.1%) control subjects. Polycystic-like ovaries by vaginal ultrasonography were of similar frequency in women with metabolic syndrome, obese women, and lean women (13.1%, 15.3%, and 13.2%, respectively). Surprisingly few women with metabolic syndrome had symptoms suggestive of PCOS in comparison with obese and lean women. The Korhonen et al16 study results suggest that, at the population level, women with PCOS are a distinct subgroup. However, this analysis may suffer from selection bias that is inherent in the inclusion criteria. Obesity is a well-known risk factor for hypertension and CVD. Cardiovascular risk goes up when each element of clustered risk factors is present. Family history. Many of the families of women with PCOS have a high prevalence of relatives with PCOS. They cluster hyperandrogenism. Vascular disease is a frequent cause of death in the families. A dominant mode of inheritance is suggested. Most of the genetic investigations into women with PCOS are level of evidence V studies. They tend to ignore those women with PCOS with few affected relatives in the pedigree. The study by Fox17 on the prevalence of diabetes mellitus is a level of evidence III study. Families of women with PCOS had at least 1 member who was affected by type NIDDM (39.1% of the PCOS group and 7.6% of the control subjects). Both obese (54.8%) and nonobese (24.2%) women with PCOS had an increased prevalence of NIDDM within their families; paternal and maternal sides had similar proportions. Jahanfar et al18 studied a group of 19 monozygotic and 15 dizygotic twin pairs identified from the national

Lean and obese PCOS increased triglyceride levels after fat load

Level of evidence III III III

III III

III

twin register. Ultrasound, clinical, and biochemical parameters defined PCOS. Eleven pairs (5 monozygotic, 6 dizygotic pairs) were scan discordant (ie, 1 twin had ultrasound evidence of polycystic ovaries and the cotwin did not). They found that the monozygotic intraclass correlation exceeded that of dizygotic twin pairs for all the lipid variables. The heritability estimates for lipoprotein(a), apolipoprotein B, total cholesterol, and HDL cholesterol were 0.95, 0.56, 0.48, and 0.54, respectively. The intraclass correlation coefficient for triglycerides was not significantly different between monozygotic and dizygotic twins. Maximum likelihood analysis indicated that at least 10% of the variance of the triglyceride concentration was genetic. Model fitting suggested fasting insulin levels, androstanediolglucuronide levels, and BMI were significantly influenced by genetics. This suggests that PCOS is not only the result of a single autosomal genetic defect, but that PCOS may be an Xlinked disorder or the result of polygenic factors. Fasting insulin levels, androstanediol-glucuronide levels, and BMI did appear to be under significant genetic influence. It is likely that environmental factors are important in the development of the PCOS phenotype in those patients with genetic propensity. Intrauterine and extrauterine determinants are being studied. Coagulation factors. In the same cohort, Dahlgren et al7 reported fibrinogen, von Willebrand factor antigen, factor VII procoagulant activity, factor VII antigen, and plasminogen activator inhibitor levels. There was a strong positive correlation between triglyceride, basal insulin, abdominal obesity, plasminogen activator inhibitor, fibrinogen, and von Willebrand factor antigen levels among women with PCOS and referents. Fibrinogen and factor VII:Ag was higher in referents. The mean values of most of the hemostatic variables were not different.

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Table IV. Do women with PCOS have more coronary/carotid plaque? Study

Patient population

Findings

Wild et al19 (1990)

102 Consecutive patients underwent angiography 143 Consecutive patients underwent angiography; pelvic ultrasound scan, <60; none with oophorectomy Carotid ultrasound scan for 16 PCOS premenopausal women; 16 age-matched control subjects 46 PCOS vs 59 control subjects by carotid scanning

PCOS more likely positive; hirsutism, acne, waist/hip; CAD PCOS in 42%, associated with hirsutism; previous hysterectomy; higher free testosterone, triglyceride, and C-peptide levels; lower HDL cholesterol levels; PCOS more CAD Intima-media thickness greater than PCOS; 5 cases; 2 control subjects with plaque (NS)

Birdsall et al20 (1997)

Guzick (1996) Talbott et al14 (1998) Christiansen et al21 (2000)

EBCT (30-45 y), PCOS, and normal; historic community control subjects that were age and BMI matched; women, 175; men, 154; previous EBCT

Women with altered metabolic profiles had affected hemostatic factors, but PCOS in itself did not relate. Patients were age and BMI matched. The use of coagulation factors as a surrogate endpoint is difficult. Thrombotic events are effected, in part, by a constantly changing thrombosis/antithrombosis system. The meaning for the risk of coronary events is unclear because of family history, situational context, and other factors. The concept of triglyceride alterations that are associated with differences in clotting profiles is important to cardiovascular risk in a mechanistic sense. Question 2: Are women with PCOS at greater risk for events? This is a much more difficult question to answer! The surrogate endpoints that follow are often used in an attempt to predict the risk of an event (Table IV). Vascular lesions CORONARY ARTERY ANGIOGRAPHY. Wild et al19 studied women with coronary artery catheterization for past signs and symptoms of androgen excess. A history of significant hirsutism and acne was more common in those women with confirmed CAD. Waist/hip ratio was associated with hirsutism and with CAD. The strongest associations were in older women (≥60 years). Birdsall et al20 conducted a prevalence study of women who had been referred for coronary angiography for the assessment of chest pain or valvular disease. Women who had undergone bilateral oophorectomy were excluded. Quantitative angiography determined the extent of the lesions. Polycystic ovaries were present in 42% of women, and coronary lesions were associated with hirsutism, previous hysterectomy, lower HDL cholesterol levels, and higher free testosterone, triglyceride, and C-peptide levels. Women with PCOS had more extensive CAD. These are level of evidence III studies. The surrogate outcome, confirmed coronary artery lesions, was matched

Level of evidence III III

III

Carotid artery index worse in PCOS; correlated III with age, BMI, diastolic blood pressure, and LDL cholesterol level Coronary calcification more prevalent in III-IV PCOS (odds ratio, 2.52) vs community dwelling women (odds ratio, 5.5); similar age; equivalent to men

blindly with the clinical data to avoid interpretation bias. Evaluating consecutive patients without regard to the outcome helps avoid bias of ascertainment. With adequate numbers, it is unlikely there would be an uneven distribution of risk factors. Patients were referred for angiography for chest pain or suspected CAD or valvular disease. Angiography is not without risk. This tool examines atherosclerotic burden relatively late in the process. Less-advanced lesions might actually be more likely to culminate in heart attacks and sudden death. The study of Birdsall et al20 has the advantage and disadvantage of ultrasound scanning (a polycystic ovary is a sign, not a diagnosis). Those women with the sign were more likely to be hirsute. Oophorectomy is associated with premature coronary heart disease; this may be true in women with or without PCOS. These studies establish the prevalence in women who come to angiography on each service; we cannot rule out some factor that biases referral, although there is no reason to believe that this is operative. ELECTRON BEAM COMPUTED TOMOGRAPHY (EBCT). Christian et al21 determined the prevalence of subclinical CAD by EBCT in a cohort of women with PCOS, aged 30 to 45 years, who were matched to 2 ovulatory control subjects by age and BMI. Women and men who previously had undergone EBCT for the Rochester Family Heart Study served as additional historic community control subjects. The study concluded that the prevalence of coronary artery calcification in premenopausal women with PCOS is significantly greater than that of community-dwelling women (odds ratio, 5.5) and is similar to that of men of comparable age. This noninvasive study has the advantage of evaluating premenopausal women with PCOS before events have occurred (levels of evidence, III and IV). The disadvantage is that coronary calcium scores do not perfectly predict coronary artery events. PCOS seems to be associated with a greater prevalence of coronary calcium, independent

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of known risk factors for CAD, even as early as before menopause. CAROTID. A total testosterone concentration of ≥2.0 nmol/L, intima-media thickness, plaque, BMI, fasting insulin, and lipid levels have been assessed in premenopausal women who were ≥40 years of age with a history of PCOS. Intima-media thickness was greater in women with PCOS. Talbott et al22 extended these studies and analyzed for potential associations with risk factors. The carotid atherosclerotic index (the overall mean of the intima-media thickness mean measurements at 8 sites) was associated with age, BMI, diastolic blood pressure, and LDL cholesterol level. The difference remained after the adjustment for age and BMI. Carotid change is a surrogate marker for CAD and stroke. Arteriosclerotic changes do not necessarily translate into more events. Progression of lesions can be stopped with vigorous prevention efforts. Women with PCOS appear to be more likely to have carotid disease early in life. ENDOTHELIAL DYSFUNCTION. Balletshofer et al23 found associations between endothelial dysfunction and insulin resistance in normotensive and normoglycemic first-degree relatives of patients with type 2 diabetes mellitus. Endothelial dysfunction has been associated with PCOS.24 Dysfunctional endothelium is an early step in atherosclerosis. Measures of sheer stress in capacitance and resistance vessels might be a useful clinical tool as an indicator of endothelial dysfunction. Endothelium governs a broad range of critical vascular functions and adapts to local requirements in a rapid temporal fashion. Dysfunction is present when its properties, either in the basal or stimulated state, are operative in a fashion that is inappropriate to the preservation of organ function. When the endothelium is operationally intact and its functions are summed, the overall effects include physiologically appropriate vasodilatation and effective dampening of proinflammatory and procoagulant processes. Newly available technologies allow endothelial function to be studied longitudinally. The number of factors that can affect endothelial function are legion. Measurements at the periphery seem to correlate well with coronary measurements. There are data in men that endothelial dysfunction correlates with subsequent events. Although controversial, a number of interrelated variables that are involved in insulin resistance (including dyslipidemia, dysglycemia, and hyperinsulinemia) may play a role in progression to CVD, all of which involve endothelial dysfunction in different vascular beds. CVD death. Wild et al25 reported findings in women with PCOS that were diagnosed in the United Kingdom between 1930 and 1979. Women were followed historically for an average of 30 years, and standardized mortality ratios (SMRs) were calculated to compare the death rates with national rates. The SMR for all causes was 0.90

Wild 41

(0.69-1.17), with 59 deaths. Fifteen deaths were from circulatory disease; 13 deaths were from ischemic heart disease, and 2 deaths were from other circulatory disease. Deaths from NIDDM were higher than expected (odds ratio, 3.6 [range, 1.5-8.4]). Breast cancer was the most common cause of death. The authors concluded that women with PCOS do not have markedly higher-thanaverage mortality rates from circulatory disease, although the condition is strongly associated with diabetes mellitus, lipid abnormalities, and other cardiovascular risk factors. They hypothesized that the characteristic endocrine profile of women with PCOS may protect against circulatory disease. Diagnosis was made primarily from ovarian wedge material. Clinical indices, androgen excess, and abnormal menses were not assessed. A polycystic ovary is a sign; it is not a diagnosis. There is a large differential diagnosis of the polycystic ovary phenotype. Indications for wedge resection (no longer performed) were often liberal and not consistent. Androgen and estrogen milieu change after wedge resection. The authors suggest that, because these patients underwent wedge resection, metabolic risk factors should be more severe. However, the main indication for wedge resection historically was for fertility, not severity. Often women with severe metabolic disturbances were not good candidates for wedge resection. Of all patients who were potentially available, many records were not retrieved. Selection bias is a problem. Regional differences in CVD rates are well known. SMRs came from a national database, not taking into account regional rates. The hazards of using death certificate data and the problems with their accuracy are well known. In spite of these limitations, there was no increase in premature CVD deaths. It is also striking that deaths from diabetes mellitus were markedly elevated. A random selection of women with PCOS and community control subjects with more complete retrieval would reduce potential biases about known and unknown factors. Optimally, patients with PCOS without resection and appropriate control subjects can be observed until later years when CVD is prevalent. In the Nurses Health Study, increased BMI predicts death in women. Weight gain (≥10 kg after age 18 years) and a BMI of ≥22.0 kg/m2 at age 18 years are predictors of overall death and death from CVD in middle adulthood. After controlling for the confounding effects of smoking and disease, there is a direct association between BMI and all-cause death and death from specific causes. The lowest mortality rate is in the leanest women who never smoked and whose weight has remained stable since age 18 years. Risk for death is positively associated with waist:hips girth ratio, which increases monotonically across each quintile of waist:hips girth ratio. Increased triglyceride levels and abdominal adiposity are associated with increased risk for total death and death from myocardial infarction.

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Question 3: Does modifying risk factors for CVD in women with PCOS reduce events? This remains unknown. The effects of an intervention on the surrogate must reliably predict the overall effect on the clinical outcome. It is a common misconception that, if an outcome is a correlate for a true clinical outcome, it is a valid surrogate endpoint. Proper justification for such replacement requires that the effect of an intervention on the surrogate endpoint can predict the true effect on the clinical outcome. To do so, it must fully capture the net effect of the treatment on the clinical outcome. There are many examples of treating surrogate endpoints that caused more harm than good. Some of the reasons include the following: (1) a therapy may affect the surrogate, not the disease; (2) the converse may happen, and the disease may progress without a change in the surrogate; or (3) the intervention may affect an outcome independently of either the surrogate or the disease progression. No studies have had the adequate power that was necessary to assess fully the net effects of therapy on coronary vascular morbidity or mortality rates in women with PCOS. The value of lipid-lowering therapy in the primary and secondary prevention of heart disease since 1994 is no longer in doubt. The predicted life-years saved by lowering the lipid levels and blood pressure are significant. Primary prevention should assess global CVD risk rather than individual risk factors. Existing cardiovascular conditions are a clear indication for instituting preventive measures, regardless of risk factor status. Summary There is little doubt that women with PCOS cluster risk factors for CVD. Whether having PCOS is an independent risk factor for CVD remains unclear. Most studies have looked at surrogate endpoints. Invasive and noninvasive evaluations have found greater arteriosclerotic burden in PCOS, in different vascular beds. We need long-term event studies. Clinical trials must assess the net effects of any treatment. Any chronic therapy must couple lifestyle interventions with patient choice. Whether the surrogate markers that are available are useful clinical indicators of meaningful outcomes requires further investigation. Issues of premature diabetes mellitus and/or CVD and the prevalence of PCOS suggest that this is a major public health issue. REFERENCES

1. Zimmermann S, Phillips RA, Dunaif A, Finegood DT, Wilkenfeld C, Ardeljan M, et al. Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance. J Clin Endocrinol Metab 1992;75:508-13. 2. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol 1992;37:119-25.

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3. Mattsson LA, Cullberg G, Hamberger L, Samsioe G, Silfverstolpe G. Lipid metabolism in women with polycystic ovary syndrome: possible implications for an increased risk of coronary heart disease. Fertil Steril 1984;42:579-84. 4. Sampson M, Kong C, Patel A, Unwin R, Jacobs HS. Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin Endocrinol 1996;45:623-9. 5. Holte J, Gennarelli G, Berne C, Bergh T, Lithell H. Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state? Hum Reprod 1996;11:23-8. 6. Fridstrom M, Nisell H, Sjoblom P, Hillensjo T. Are women with polycystic ovary syndrome at an increased risk of pregnancyinduced hypertension and/or preeclampsia? Hypertens Pregnancy 1999;18:73-80. 7. Dahlgren E, Johansson S, Lindstedt G, Knutsson F, Oden A, Janson PO, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992;57:505-13. 8. Elting MW, Korsen TJ, Bezemer PD, Schoemaker J. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod 2001;16:556-60. 9. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22:141-6. 10. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165-9. 11. Cibula D, Cifkova R, Fanta M, Poledne R, Zivny J, Skibova J. Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome. Hum Reprod 2000;15:785-9. 12. Wild RA, Painter PC, Coulson PB, Carruth KB, Ranney GB. Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1985;61:946-51. 12a. Wild RA, Bartholomew MJ. the influence of body weight on lipoprotein lipids in patients with polycystic ovary syndrome. Am J Obstet Gynecol 1988;159:423-7. 12b.Wild RA, Alaupovic P, Parker IJ. Lipid and apolipoprotein abnormalities in hirsute women. I. The association with insulin resistance. Am J Obstet Gynecol 1992;166:1191-6. 13. Slowinska-Srzednicka J, Zgliczynski S, Wierzbicki M, Srzednicki M, Stopinska-Gluszak U, Zgliczynski W, et al. The role of hyperinsulinemia in the development of lipid disturbances in nonobese and obese women with the polycystic ovary syndrome. J Endocrinol Invest 1991;14:569-75. 14. Talbott E, Guzick D, Clerici A, Berga SL, Kuller L, Detre K, et al. Coronary risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 1995;15:821-6. 15. Velazquez ME, Bellabarba GA, Mendoza S, Sanchez L. Postprandial triglyceride response in patients with polycystic ovary syndrome: relationship with waist-to-hip ratio and insulin [in process citation]. Fertil Steril 2000;74:1159-63. 16. Korhonen S, Hippelainen M, Niskanen L, Vanhala M, Saarikoski S. Relationship of the metabolic syndrome and obesity to polycystic ovary syndrome: a controlled, population-based study. Am J Obstet Gynecol 2001;184:289-96. 17. Fox R. Prevalence of a positive family history of type 2 diabetes in women with polycystic ovarian disease. Gynecol Endocrinol 1999;13:390-3. 18. Jahanfar S, Eden JA, Nguyen T, Wang XL, Wilcken DE. A twin study of polycystic ovary syndrome and lipids. Gynecol Endocrinol 1997;11:111-7.

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19. Wild RA, Grubb B, Hartz A, Van Nort JJ, Bachman W, Bartholomew M. Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil Steril 1990;54:255-9. 20. Birdsall MA, Farquhar CM, White HD. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization [see comments]. Ann Intern Med 1997;126:32-5. 21. Christian RC, Behrenbeck T, Fitzpatrick LA. Clinical hyperandrogenism and body mass index predict coronary calcification in premenopausal women with polycystic ovary syndrome (PCOS) [abstract]. Endocr Soc Abstracts 2000:400. 22. Talbott EO, Guzick DS, Sutton-Tyrrell K, McHugh-Pemu KP, Zborowski JV, Remsberg KE, et al. Evidence for association be-

tween polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol (Online) 2000;20:2414-21. 23. Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, et al. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation 2000;101:1780-4. 24. Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard MK, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 2001;103:1410-5. 25. Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol 2000;52:595-600.

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