Hum. Reprod. Advance Access originally published online on December 22, 2005
Human Reproduction 2006 21(4):930-935; doi:10.1093/humrep/dei431
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Do young women with polycystic ovary syndrome show early evidence of preclinical coronary artery disease?
1 Cardiology Department and 2 Obstetrics & Gynecology Department, Konya Teaching and Medical Research Center, Baskent University, Konya and 3 Cardiology Department, Baskent University Faculty of Medicine, Ankara, Turkey
4 To whom correspondence should be addressed at: Cardiology Department Hoca Cihan mah, Konya Teaching and Medical Research Center, Saray Cad, No. 1, Selcuklu, Konya, Turkey. E-mail: semratopcu2003{at}yahoo.com
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Abstract |
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BACKGROUND: It is thought that women with polycystic ovary syndrome (PCOS) are at increased risk of developing cardiovascular diseases. METHODS: In this study, we used transthoracic echocardiography to measure coronary flow reserve (CFR) in 28 women with PCOS and in 26 healthy women. RESULTS: The PCOS and the control groups were similar in terms of age (27.1 ± 4.5 versus 28.8 ± 4.4 years) and BMI (26.6 ± 5.7 versus 24.7 ± 4.4 kg/m2). Fasting insulin levels and homeostasis model assessment insulin resistance index were higher in the PCOS group. LH, the LH/FSH ratio, total testosterone, free testosterone and androstenedione were higher in the PCOS group. FSH, estradiol, prolactin, progesterone, cholesterol, triglyceride and high-sensitive C-reactive protein were similar between the two groups, but homocysteine levels were higher in the PCOS group. Baseline diastolic peak f low velocity (DPFV) (25.0 ± 4.6 versus 23.3 ± 2.7 cm/s, P > 0.05), hyperaemic DPFV (71.2 ± 12.8 versus 73.0 ± 12.9 cm/s, P > 0.05) and CFR (2.8 ± 0.8 versus 3.2 ± 0.8 cm/s, P > 0.05) of the left anterior descending coronary artery were similar between the two groups. CONCLUSION: We conclude that in young women with PCOS and without cardiovascular risk factors, CFR is preserved.
Key words: coronary artery disease/coronary flow reserve/polycystic ovary syndrome
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Introduction |
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Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation and infertility. This endocrinologic disorder affects 5–10% of women of reproductive age (Carmina and Lobo, 1999
). Patients with this syndrome often exhibit insulin resistance, upper body obesity, hypertension and an unfavourable lipid profile (Burghen et al., 1980; Wild et al., 1985). Several studies have suggested that this syndrome is associated with increased cardiovascular risk (Conway et al., 1992; Pasquali et al., 1993; Talbott et al., 1995, 1998). Specifically, it has been shown that some middle-aged women with PCOS have increased carotid artery intima-media thickness (IMT), an indicator of coronary atherosclerosis that can be detected non-invasively (Talbott et al., 2000). As well, one study revealed that a group of women with PCOS had more prevalent calcium deposits in their coronary arteries than healthy controls (Christian et al., 2003). It has also been reported that patients with PCOS exhibit decreased nitric oxide production and/or release as well as impaired flow-mediated dilatation of the brachial artery (Paradisi et al., 2001; Orio et al., 2004). The family histories of these women often feature type 2 diabetes mellitus (DM), insulin resistance, hypertension (Elting et al., 2001) and/or obesity (Pasquali et al., 1993; Talbott et al., 1995, 1998). Some of the metabolic changes in PCOS are associated with insulin resistance (Book and Dunaif, 1999), but it is unclear whether the above-mentioned risk factors for atherosclerosis are associated with increased mortality in women with PCOS. Pierpoint and co-workers concluded that women with PCOS are not at increased risk for cardiovascular mortality (Pierpoint et al., 1998). In contrast, earlier work by Dahlgren et al. (1992) suggested that these women have 7.4-fold higher risk of myocardial infarction.
Coronary flow reserve (CFR) is the capacity of a coronary artery to increase blood flow through reduction of vasomotor tone. CFR is calculated as follows (Caiati et al., 1999a,b):
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In people whose epicardial coronary arteries are not stenotic, CFR can decrease if coronary microvascular circulation is compromised by hypertension (with or without left ventricular hypertrophy) or by DM, hypercholesterolaemia or syndrome X (Dimitrow, 2003). Reduced CFR can be detected before angiographically significant stenosis develops in the epicardial coronary arteries (Gould and Lipscomb, 1974). Measurement of CFR is used to assess epicardial coronary arteries and to evaluate the integrity of coronary microvascular circulation. In recent years, transthoracic second harmonic Doppler echocardiographic determination of CFR in the middle-to-distal portion of the left anterior descending (LAD) coronary artery has become very popular, and several studies have shown that this form of assessment is feasible and easy to perform (Caiati et al., 1999a,b). A recently published study by Britten and co-workers (Britten et al., 2004) suggested that CFR in normal-to-mildly diseased arteries is an independent predictor of atherosclerosis within the next decade. Since women with PCOS have several cardiovascular risk factors, we hypothesized that if these accompanying cardiovascular risk factors are excluded, PCOS itself might not compromise cardiovascular functions. In this study, excluding coronary risk factors, we planned to determine whether CFR is impaired or not in patients with PCOS but without cardiovascular risk factors.
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Methods |
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Subjects
The study involved a patient (PCOS) group and a control group. The patients were 28 women with PCOS who presented to the Obstetrics and Gynecology Clinic of our hospital with infertility or hyperandrogenism. The criteria for diagnosis of PCOS were oligo/amenorrhoea, clinical or laboratory signs of hyperandrogenism and ultrasonographic findings of enlarged ovaries with multiple small subcortical follicles and increased stroma (The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group, 2004
). Clinical hyperandrogenism was quantified by the Ferriman–Gallwey scoring system. All 28 patients had normal renal, hepatic and thyroid function. Women taking oral contraceptives, antiandrogen drugs, antidiabetic treatment, statins or glucocorticoid therapy were excluded. Also excluded were patients with hypertension, family history of coronary artery disease (CAD) and electrocardiographic changes suggestive of CAD. The control group consisted of 26 age-matched healthy women who were menstruating regularly and had normal biochemical and hormonal profiles. For each subject, height and weight measurements were used to calculate BMI. Waist circumference was measured with the subject in standing position and by placing a soft tape measure midway between the lowest rib and the iliac crest. Hip circumference was measured at the level of the major trochanters. The study was conducted according to the recommendations set forth by the Declaration of Helsinki on Biomedical Research involving human subjects. The institutional ethics committee approved the study protocol, and each subject provided written informed consent.
Laboratory tests
A fasting blood sample was obtained from each subject. For those menstruating, this was done during the follicular phase of the menstrual cycle. Serum concentrations of FSH, LH, estradiol (E2), prolactin, free testosterone, progesterone and 17-OHP were measured by chemiluminescent enzyme immunoassay (Immulite 2000, Bio DPC, Los Angeles, CA, USA). Serum androstenedione was measured by radioimmunoassay, and serum glucose was measured spectrophotometrically (Aeroset Automated Analyzer, Abbott Laboratories, Abbott, IL, USA). Serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride were measured by enzymatic methods. Fasting insulin levels were measured using an immunoturbidometric method. Insulin resistance was calculated using the homeostasis model assessment insulin resistance index (HOMA-IR) (Matthews et al., 1985), according to the formula,
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All participants underwent a 75 g oral glucose tolerance test after 3 days on a carbohydrate rich diet.
CFR measurement
Each subject underwent transthoracic second harmonic Doppler echocardiography. All these examinations were performed using an Acuson Sequoia C256® Echocardiography System (Acuson Corporation, Mountain View, CA, USA) equipped with a high-resolution transducer with second harmonic capability (5V2c). The echocardiographic images were recorded on VHS videotape, and two experienced echocardiographers who were blinded to the clinical data analysed the recordings. The distal LAD was visualized using a modified, foreshortened, two-chamber view. This was done by first positioning the transducer for an apical two-chamber view and then sliding it cranially and medially to achieve the best possible alignment with the interventricular sulcus. Once the transducer was in the desired position, blood flow in the distal LAD was examined by colour Doppler flow mapping of the epicardial portion of the anterior wall. For this, the colour Doppler velocity was set at 8.9–24.0 cm/s, and the colour gain was adjusted to provide optimal images (Lambertz et al., 1999). Blood flow in the middle-to-distal portion of the LAD was examined by colour Doppler flow mapping. Spectral Doppler of the LAD showed the characteristic biphasic flow pattern with larger diastolic and smaller systolic components. Diastolic peak velocities were measured at baseline and after the dipyridamole infusion (0.84 mg/kg over 6 min) by averaging the three highest Doppler signals for each measurement. CFR was calculated as the ratio of hyperaemic diastolic peak flow velocity (DPFV) to the baseline DPFV. CFR = 2.0 cm/s was considered normal (Lambertz et al., 1999). We were able to successfully determine CFR in all 54 subjects. To test the reproducibility of the CFR results, we repeated the measurements 2 days later in 10 of the control subjects. The intraobserver intraclass correlation coefficient for CFR measurement was 0.948.
Each subject’s left ventricular mass was calculated from M-mode records taken from parasternal long axis images, according to Devereux’s formula (Devereux and Reichek, 1977).
Statistics
Statistical analyses were performed using the SPSS 9.0 (SPSS for Windows 9.0, Chicago, IL, USA). Numeric values are expressed as mean ± SD. The Student’s t-test was used to compare PCOS group and control group findings. Correlation analysis was used to test for relationships between CFR and biochemical and metabolic parameters. Pearson’s bivariate correlation test was used. P-values <0.05 were considered significant.
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Results |
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The demographic features, hormonal and biochemical results for the PCOS and control groups are given in Table I. There were no significant differences between the groups with respect to mean age or mean BMI. Waist/hip ratio was similar between the two groups (Table I). The PCOS group had significantly higher fasting insulin levels and HOMA-IR than the control group (insulin 10.5 ± 4.0 versus 6.9 ± 2.3 mU/ml, respectively, P = 0.001; HOMA-IR 2.5 ± 1.2 versus 1.5 ± 0.5, respectively, P = 0.005). These findings indicated insulin resistance in the PCOS group. The PCOS group had significantly higher serum levels of several hormones than the control group: LH (9.2 ± 6.7 versus 4.2 ± 0.5 mIU/l, respectively, P < 0.0001), total testosterone (1.1 ± 0.6 versus 0.6 ± 0.2 ng/dl, respectively, P = 0.002), free testosterone (1.6 ± 0.8 versus 0.8 ± 0.3 ng/dl, respectively, P < 0.0001), androstenedione (2.1 ± 1.1 versus 1.1 ± 0.3 ng/ml, respectively, P < 0.0001) and dehydroepiandrosterone sulphate (180.1 ± 101.2 versus 77.9 ± 49.6 ng/ml, respectively, P < 0.0001). The patients also had a significantly higher mean LH : FSH ratio than the controls (1.8 ± 1.4 versus 0.8 ± 0.2, respectively, P < 0.0001). The group means for serum FSH, E2, prolactin and progesterone were similar. There were no significant differences between the PCOS and control groups with respect to serum levels of total cholesterol, HDL-C, LDL-C, triglyceride and high-sensitive C-reactive protein; however, homocysteine levels were higher in the PCOS group than in the control group (9.3 ± 3.1 versus 6.4 ± 1.2 mg/dl, respectively, P < 0.05). The echocardiographic findings and related parameter calculations for the PCOS and control groups are shown in Table II. There were no significant differences between the groups with respect to left atrial diameter, left ventricular diameter, left ventricular systolic function or left ventricular mass index (LVMI). The groups’ mitral E velocities, mitral A velocities and mitral E/A ratios also were similar. There were also no significant differences between the group findings related to coronary flow velocity: baseline DPFV (25.0 ± 4.6 versus 23.3 ± 2.7 cm/s, respectively), hyperaemic DPFV (71.2 ± 12.8 versus 73.0 ± 12.9 cm/s, respectively) and CFR (2.8 ± 0.8 versus 3.2 ± 08, respectively) (all P > 0.05). Correlation analysis revealed weak inverse relationships between CFR and serum levels of LH, androstenedione and LDL-C (r = – 0.270, r = – 0.319 and r = – 0.286, respectively) (Table III). Analysis with the PCOS patients divided into subgroups with insulin resistance (n = 11) and without insulin resistance (n = 17) revealed no significant differences with respect to baseline DPFV, hyperaemic DPFV or CFR (Table IV).
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Discussion |
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PCOS develops early in adolescence and may result in premature atherosclerosis (Conway et al., 1992
; Talbott et al., 1998). This syndrome is associated with increased risk of DM (Legro et al., 1999), hypertension (Holte et al., 1996; Sampson et al., 1996) and hyperlipidaemia (Wild et al., 1985; Talbott et al., 1995). Previous studies have shown that increased central adiposity, high total cholesterol and LDL-C, low HDL-C and insulin resistance are more prevalent in women with this disorder (Wild et al., 1985; Talbott et al., 1995; Legro et al., 2001; Vryonidou et al., 2005). Surrogate markers of coronary atherosclerosis, such as increased carotid IMT (Talbott et al., 2000; Vryonidou et al., 2005), impaired elasticity of carotid and brachial artery walls (Lakhani et al., 2002) and increased coronary artery calcium (as detected by electron beam computed tomography) (Christian et al., 2003) have been identified in women with PCOS. In this study, we compared transthoracic second harmonic Doppler echocardiography findings in a control group and a group of relatively young women with PCOS who had no major cardiovascular risk factors. The data revealed normal CFR in the PCOS group, indicating normal coronary microvascular function. Previous studies have demonstrated that DM (Strauer et al., 1997), hypertension (Galderisi et al., 2002), hypercholesterolaemia (Kaufmann et al., 2000; Laaksonen et al., 2002) and left ventricular hypertrophy (Galderisi et al., 2003) can impair CFR and coronary microvascular function. We excluded patients with overt DM, hypertension, dyslipidaemia and/or left ventricular hypertrophy (interventricular septum or left ventricular posterior wall diastolic diameter = 11 mm) in order to investigate whether PCOS alone affects CFR and coronary microvascular function. We found that left ventricular diastolic function was similar in the PCOS and control groups. However, Yarali et al. (2001) reported different findings in a group of PCOS patients who were similar in age to our patients. These authors observed that a group of PCOS patients had slower mitral E velocity, a lower mitral E/A ratio and shorter isovolumic relaxation time than a group of healthy controls (Yarali et al., 2001). These findings all indicated impaired left ventricular diastolic function in the PCOS group compared to normal controls. However, in that study, the two groups were not matched for coronary risk factors, and their subjects had higher total cholesterol, triglyceride, LDL-C and homocysteine values compared to our subjects. To date, several studies have suggested possible associations between PCOS and different forms of cardiovascular disease. Vryonidou et al. (2005) found increased carotid IMT in young women with PCOS (mean age, 24 ± 5 years) compared to healthy controls. In contrast, Talbott et al. (2000) observed that a group of PCOS patients younger than 45 years had similar carotid IMT to that in an age-matched group of healthy controls. However, the same study also revealed that, even after adjusting for BMI, a group of PCOS patients older than 45 had significantly greater carotid IMT than a group of age-matched controls. None of the PCOS patients in the study by Talbott and co-workers had been treated for cardiovascular risk factors that are well-known characteristic of PCOS. Therefore, the difference in carotid IMT between the last two groups (the older PCOS patients and controls) might have been attributed to cardiovascular risk factors that accompany PCOS. The data from our carefully selected PCOS group revealed no impairment of CFR. Paradisi and colleagues documented diminished flow-mediated dilatation response in women with PCOS, a finding that is associated with insulin resistance and elevated androgen levels (Paradisi et al., 2001). They concluded that, given a certain degree of adiposity, hyperandrogenism appears to have an additive negative effect on endothelial function. The mean BMI of their patients with PCOS was 36.7 ± 1.6 kg/m2. Our patients were leaner than this study population. We found that the mean HDL-C level in our PCOS group was similar to that in the healthy control group. In contrast, Paradisi et al. (2001) observed significantly lower HDL-C levels in their study group with PCOS than in a group of healthy women. However, Mather et al. (2000) noted normal endothelium-dependent and endothelium-independent responses in a group of patients with PCOS, even though these patients had higher cholesterol levels, testosterone levels and BMI than a group of controls. The same study revealed higher androgen levels and a higher frequency of insulin resistance in the women with PCOS.
Christian et al. (2003) observed that a group of women with PCOS had more calcium deposits in their coronary arteries than a group of BMI-matched controls or a group of healthy controls with normal BMI. Their analysis showed that BMI, waist circumference, LDL-C and HDL-C levels were independent predictors of coronary artery calcium deposits. The mean age of the women with PCOS was 38.5 years, and diastolic blood pressure, total cholesterol and LDL-C levels in the PCOS group were all significantly higher than the corresponding control values. Multivariate analysis after correcting for BMI showed that after adjusting for BMI, PCOS was not an independent predictor for coronary artery calcium deposition. Although these authors suggested that PCOS alone independently increases cardiovascular risk, but in our study, comparison with findings in healthy controls revealed that our PCOS patients had normal CFR.
Only one study in the literature has investigated mortality in women with PCOS, and this showed no increase in deaths from coronary heart disease (Pierpoint et al., 1998). It has been shown that, even if there is no stenosis in coronary arteries, DM is associated with structural and functional abnormalities of the coronary microcirculation and marked impairment of CFR (Nitenberg et al., 1993). Insulin resistance has been shown to be strongly linked to several CAD risk factors such as arterial hypertension, obesity, dyslipidaemia and impaired glucose tolerance (Reaven, 1988). Dagres et al. (2004) measured whole-body insulin sensitivity and measured CFR by intracoronary Doppler wire in 18 subjects (men and women, mean age 48 ± 1.3 years) with normal coronary angiography and with no known cardiovascular risk factors. Their data suggested that greater insulin sensitivity is associated with greater CFR; thus, they concluded that insulin resistance is likely associated with coronary microvasculature abnormalities in non-diabetic patients (Dagres et al., 2004). In another study, Yokoyama et al. (1998) found that reduced CFR was associated with hyperglycaemia (not insulin resistance) in patients with non-insulin-dependent DM who had no signs or symptoms of ischaemic heart disease. In our study, comparison of the subgroups of PCOS patients with insulin resistance (n = 11) and without insulin resistance (n = 17) revealed no significant difference in CFR. To our knowledge, this is the first study that has examined the effects of PCOS on CFR. Our PCOS group and control group were similar with respect to age, BMI, smoking status and family history of CAD, and the group means for blood pressure, serum glucose and serum cholesterol parameters were normal. Our data indicate that, compared to healthy women of the same age, young women with PCOS and without cardiovascular risk factors are no more likely to have impaired coronary microvascular function or reduced CFR. In a broader sense, these findings suggest that young women with PCOS and without cardiovascular risk might not have any direct adverse effects of PCOS on the cardiovascular system, provided that associated metabolic disturbances are carefully controlled.
Study limitations
Most women with PCOS have undesirable metabolic changes such as obesity, insulin resistance, hypertension and hyperlipidaemia accompanying the PCOS. Our study population with the strict selection criteria cannot be a true example of women with PCOS. Considering the fact that atherosclerotic process is very slow and younger age of our subjects, our results should not be generalized to an overall population. An additional limitation of the study is the small sample size, and further studies with older subjects and larger sample sizes are needed.
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Submitted on August 22, 2005; resubmitted on October 5, 2005; accepted on October 13, 2005.
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