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Monash University Department of Medicine, Dandenong Hospital, Melbourne, Victoria, 3175 Australia
Address all correspondence and requests for reprints to: Dr. Helena Teede, Department of Vascular Science and Medicine, Dandenong Hospital, David Street, Dandenong, Victoria, 3175, Australia. E-mail: helena.teede{at}southernhealth.org.au.
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Abstract |
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Objective: The objective of this study was to examine the relationships between IR, metabolic parameters, androgens, and markers of early CV disease in PCOS.
Design: We conducted an observational study examining noninvasive markers of early CV disease in women with PCOS including structural [carotid intimal media thickness (IMT)] and functional measures (arterial function with pulse wave velocity and endothelial function with brachial arterial flow-mediated vasodilation). Metabolic parameters included insulin and glucose during an oral glucose tolerance test and lipid and androgen levels.
Setting: Participants were recruited from the general community.
Patients: Eighty overweight women with PCOS who were nonsmokers and not on oral contraceptives or other medications known to affect IR participated in the study.
Results: Stepwise regression analysis showed that after adjustment for age and body mass index, IMT was significantly correlated with blood pressure (BP) load (P = 0.03) and inversely with dehydroepiandrosterone sulfate (DHEAS) (P = 0.01). After correction for androgen status, IMT was correlated with fasting glucose and area under curve (AUC) insulin. Flow-mediated vasodilation was inversely related to lipids (P = 0.02), whereas pulse wave velocity was related to BP (P < 0.001), AUC insulin (P = 0.04), and AUC glucose (P = 0.035).
Conclusion: In overweight women with PCOS, insulin resistance and BP interacted negatively with arterial structural and functional measures. DHEAS correlated inversely with arterial structure, suggesting possible cardioprotective effects of endogenous DHEAS in women with PCOS. Additional research is needed to clarify these findings.
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Introduction |
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There are limited studies to date suggesting that women with PCOS have subclinical evidence of premature CVD (8, 9). However, long-term outcomes studies examining the prevalence of CVD among women with POCS have failed to demonstrate a significantly increased risk of CV death (10, 11). Possible explanations for this discrepancy include the long lag time between diagnosis of PCOS and that of CV events, leading to data inaccuracy. Also, the young age of subjects in these cohort studies reduces their sensitivity to detect increased CV events. Another possible explanation is that women with PCOS may have a cardioprotective advantage to counteract other increased CV risk factors. Potentially this may be the hyperandrogenemia that occurs in PCOS. There is evidence from studies in both pre- and postmenopausal women that physiological levels of androgens are inversely related to CV risk, although there are conflicting reports in the current literature (12, 13, 14, 15).
Noninvasive surrogate markers of vascular disease are used extensively in studies as markers of early vascular disease. Carotid intima medial thickness (IMT) is an established marker for early atherosclerotic disease that is predictive of future CV events (16). Pulse wave velocity (PWV) is a marker of arterial stiffness and has been shown to be predictive of CV mortality in chronic renal failure (17) and essential hypertension (18, 19). Brachial artery flow-mediated vasodilation (FMD) is a marker of arterial and endothelial function, which is influenced by a variety of CV risk factors; it is also predictive of future CV events. Together, these measurements provide a comprehensive noninvasive assessment of arterial structure and function.
The aim of this study was to examine the relationships between IR, endogenous androgens, and early CVD in overweight women with PCOS.
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Subjects and Methods |
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We recruited 80 overweight [body mass index (BMI) > 27 kg/m2], premenopausal subjects with PCOS from community advertisements.
PCOS was documented by a history of perimenarchal onset of oligo/amenorrhea together with clinical manifestations of hyperandrogenism (hirsutism, acne, or both) and elevation of at least one circulating ovarian androgen. Secondary causes of hyperandrogenism such as hyperprolactinemia and thyroid disease were excluded in all subjects. Specific adrenal disorders were excluded clinically and where indicated biochemically. Subjects who were smokers or had diabetes were excluded, and all participants must have been off hormonal or insulin-modifying therapy for at least 3 months before entry to the study. Pregnancy tests were assessed as being negative in all subjects before enrollment in the study. The Southern Health Research Advisory and Ethics Committee approved the study, and all participants gave written informed consent.
Study design
If considered to be eligible after telephone screening by an endocrinologist (C.M.), participants were assessed with a detailed medical examination and history after an overnight fast. A 120-min 75-g oral glucose tolerance test (OGTT) was performed with blood samples drawn for insulin and glucose at 0, 30, 60, and 120 min. Blood samples were drawn for testing of all other parameters (i.e. androgens and lipid levels) before ingestion of the glucose load. Hirsutism was assessed by one examiner using the modified Ferriman-Gallwey score in which a score greater than 7 indicates hirsutism (20). After the OGTT, a blood pressure (BP) monitor was fitted for 2- h ambulatory BP recording. The next day, participants returned to the study center for measurement of the arterial parameters. All arterial parameters were measured by an experienced research assistant (D.K.). Studies were performed after a 12-h fast; during this period, caffeine-containing drinks were avoided. All studies were performed in a darkened, quiet, air-conditioned clinical laboratory after 10 min of rest in the supine position. Published repeatability data from our lab demonstrates the accuracy and repeatability of the vascular end-points (21).
24-h Ambulatory BP monitoring (ABPM)
ABPM was performed using a portable lightweight device (Accutracker, model II; Suntech Medical Instruments, Raleigh, NC). The accuracy of the ABPM was confirmed in each subject twice by simultaneous auscultation and sphygmomanometry; systolic and diastolic BP readings differed by less than 5 mm Hg. Patients wore the device for 26 h with measurements every 30 min during the day and hourly overnight. Subjects received verbal and written instructions on the monitors and completed a diary to record posture, activity, sleep, medication, and symptoms.
Arterial parameters
PWV.
PWV was determined from recorded pressure waveforms over the aorto-femoral arterial segments (21). Pulse transit time was defined as the time between the foot of simultaneously recorded pressure waves, occurring at the end of diastole and the beginning of systole, averaged over 10 cardiac cycles. Velocity was derived from computer-generated pulse transit times and measured distances between the two recording sites, as previously described (21). PWV was calculated based on the formula PWV= D/
t (m/sec), where D is distance and t is time interval.
Carotid IMT. This parameter was derived from noninvasive ultrasound of the common carotid arteries, using a high-resolution ultrasound machine (Diasonics DRF-400, Diasonics Pty, Ltd., Victoria, Australia) with 7.5-MHz mechanical sector transducer (7.5-SPC). The IMT was defined as the distance between the blood-intima and media-adventitia boundaries on B-mode imaging (16). The far wall of the right common carotid artery 1 cm proximal to the origin of the bulb was selected because it has been shown to be the most reproducible (22). Three B-mode images were recorded from different angles and then digitized and saved on computer via a customized computer program (A House of Windows, C. Smith, Auckland, New Zealand) as previously described (23). Brachial BP was recorded every 5-min throughout the imaging period using a Dinamap device (Critikon 1846 SX; Critikon, Inc., Tampa, FL). Image analysis was performed using a standardized measurement protocol, using 30 data points per subject, by the same sonographer. Measurements were automatically transferred and saved in a database (Quest for Windows, version 2.1). The results are reported as mean common carotid IMT.
Brachial artery FMD
Brachial artery diameter was measured from B-mode ultrasound images captured on a Diasonics DRF-400 machine using a 10-MHz transducer, while an electrocardiogram trace was simultaneously recorded. Longitudinal scanning identified the clearest image of the brachial artery above the elbow, with continuous scanning held for 30 sec before and 4 min after ischemia, induced via a pneumatic tourniquet inflated around the upper arm to 40 mm Hg above systolic pressure for 4 min. Vessel diameter was measured during systole and diastole and averaged over five cardiac cycles. FMD was determined as the percentage change from baseline to 60 sec after ischemia, the point of maximal dilation (21).
Statistics
Results are shown as average, SD, and range for all variables. Data were normally distributed. Stepwise multiple regression analysis was carried out to test out the joint effect of different variables on vascular parameters. In the three stepwise regression models, the vascular parameters were entered as the dependent variable with androgens, lipids, and measures of IR as the independent variables. Each analysis was adjusted for age and BMI. Correlation coefficients were used as a measure of association. The area under the curve (AUC) for glucose and insulin were calculated from the values obtained during the OGTT using the formula as outlined by Biswas et al. (24). P values of <0.05 were considered statistically significant.
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Results |
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. All vascular parameters correlated with age, but no correlations with BMI were noted (Tables 2 and 3). BMI distribution is noted in Fig. 1.
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Stepwise multiple regression analysis was performed using IMT as the dependent variable. After adjusting for age, the analysis showed that dehydroepiandrosterone sulfate (DHEAS) was negatively correlated with IMT (P = 0.003), whereas BP load (P = 0.027) was positively related to IMT (model R2 = 0.34). After correcting for BMI, these relationships remained significant in the multiple regression analysis: DHEAS (P = 0.01) and BP load (P = 0.03). Pearson’s correlation coefficients for each of the variables are listed in Table 2
. Testosterone and AUC glucose were both significantly related to IMT in the individual Pearson’s correlations; however, they failed to reach significance in the regression model. Further evaluation of the relationship between carotid IMT and androgens showed that higher tertiles of DHEAS corresponded to significantly lower IMT (Fig. 2).
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FMD
After adjustment for age, stepwise multiple regression analysis using FMD as the dependent variable demonstrated a significant positive relationship between FMD and free androgen index (FAI) (P = 0.014) and lipid parameters (P = 0.02) (model R2 = 0.26). This relationship with lipids remained after correction for BMI; however, the relationship with FAI just failed to reach statistical significance (P = 0.06).
There was no association between FMD and measures of IR.
PWV
Stepwise multiple regression analysis using central PWV as the dependent variable demonstrated a significant relationship between PWV and BP (P < 0.001), AUC insulin (P = 0.04) and AUC blood glucose (P = 0.03) after adjustment for age (model R2 = 0.56). These relationships remained after correction for BMI.
There was no relationship between lipid parameters, BMI, androgens, and PWV.
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Discussion |
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PWV is a marker of arterial stiffness and is a robust predictor of clinically relevant CVD in populations including those with renal failure and hypertension (17, 18, 19). Additional research is needed to clarify the structural and functional status of the CVS and ultimately the CVD risk in PCOS. However, those with PCOS do have increased CV risk factors, and a previous study has suggested that women with PCOS have stiffer arteries (higher PWV) compared with controls, suggesting early accelerated CVD (25). In focusing on contributors for accelerated CVD, we have demonstrated that PWV was correlated with insulin, glucose, and BP but was not related to androgen status in overweight women with PCOS. These findings are consistent with previous studies in non-PCOS populations, which have demonstrated that arterial stiffness is correlated with both glycemic control and hyperinsulinemia in diabetic (26, 27) and nondiabetic (28, 29) subjects. In nondiabetic women, a 25% increase in fasting glucose has been shown to correlate with a 15% (1 SD) decrease in arterial stiffness, whereas an 80% increase in fasting insulin (1 SD) predicted a 7.5% increase in arterial stiffness (28).
Both arterial structure (IMT) and endothelial function (FMD) have been previously correlated with traditional CV risk factors including IR and lipids and are predictive of CV events (16). The inverse relationship between IMT and FMD noted here is consistent with observations in diabetes, supporting the association between endothelial dysfunction and atherogenesis (30). Endothelial dysfunction has been shown to occur early in the development of atherosclerosis, preceding the onset of increased IMT (31); however, it appears that various risk factors may contribute differentially to the development of endothelial (FMD) vs. medial (PWV) vs. intimal atherosclerotic disease (IMT). The relationships suggested in the current study, between indices of androgenicity and both FMD and IMT, suggest an impact of androgens primarily on the endothelium and atherogenesis. In contrast to this, it appears that indices of glucose metabolism such as hyperinsulinemia predominantly exert their effect on the CVS through the arterial media as evidenced by their relationship with arterial stiffness or PWV.
In the current study of women with PCOS, endothelial function correlated with lipids independent of BMI but not with IR, whereas lipids did not correlate with IMT, and interestingly, measures of IR correlated with IMT only after correction for androgen status (DHEAS and testosterone levels). In the current study, IMT correlated inversely with androgen status reflected by DHEAS and testosterone levels, with the relationship with DHEAS persisting on multiple regression and after correction for BMI. Potentially, in this population, hyperandrogenism may counteract the known deleterious effect that hyperinsulinemia has on IMT.
The potential protective effect of DHEAS on CVD has been suggested previously; however, there are conflicting reports in the literature. In studies of both pre- and postmenopausal women, Bernini et al. (32) have shown that IMT is negatively correlated with both DHEAS and androstenedione. In women with documented coronary stenosis, plasma levels of DHEAS were significantly lower than healthy controls (12). In contrast, a prospective study in 900 postmenopausal women has demonstrated that higher levels of DHEAS were positively associated with several major CV risk factors but were unrelated to fatal CV events (15).
As with DHEAS, testosterone may also affect atherosclerosis. In a case control study of 182 postmenopausal women, those in the highest quartile of testosterone had a lower odds ratio of atherosclerosis (as assessed by carotid IMT) compared with the lowest quartile (odds ratio, 0.38; 95% confidence interval, 0.2–0.7) (33). However, conflicting reports note increased CVD in postmenopausal women with higher levels of testosterone (14, 34). Currently, the CV effects of androgens remain unclear; this is an area that requires clarification. The PCOS population is an important group in which to address this issue because this population has a clustering of CV risk factors and are characterized by hyperandrogenism. Furthermore, medical therapies with the oral contraceptive pill primarily target a reduction in androgen levels and may exacerbate IR, a combination of effects that may not be appropriate given the suggested relationships between androgens and CV risk factors noted here.
Overweight/obesity is an integral component of PCOS, occurring in the majority of women with the condition. It compounds many of the metabolic features of the syndrome such as IR, hypertension, and dyslipidemia. Whether these CV risk factors are related to the presence of PCOS per se or are related to the associated central obesity remains unclear. In the current study, we have demonstrated age-adjusted correlations between early structural arterial disease (IMT) and measures of androgenicity and BP. These relationships remained after correction for BMI, suggesting that they occur independent of obesity itself.
Finally, we have also demonstrated a positive association between FAI and increased FMD, as a marker of endothelial function. Limited interventional studies have examined testosterone effects on vascular function; however, most are conducted in men and are of limited relevance because androgens appear to have sex-specific effects (35, 36). We have previously demonstrated that testosterone therapy improves endothelial function in postmenopausal women. Six weeks after the insertion of a 50-mg testosterone implant, FMD increased a mean of 42% compared with baseline preimplant FMD. Improvements were seen in both endothelium-dependent and -independent vasodilation (37). In contrast to this, a small study by Paradisi et al. (38) has found a positive association between androgens and endothelial dysfunction, measured using an alternative invasive technique. Although the association in the current study between FAI and FMD may be suggestive that testosterone influences endothelial function, it is acknowledged that testosterone and DHEAS levels were not significantly related to FMD.
Estrogen is known to impact on FMD and arterial function. Androgens are a source of estrogen with conversion occurring in peripheral tissues. Any effect of androgens therefore may be indirectly mediated via estrogen, but this cannot be elucidated in the current study. Additional research is required to clarify the effects of androgens and the mechanisms of their actions on the CVS in women.
The limitations of the current study include that it is observational and therefore can raise only the possibility of relationships between parameters including androgens and early CVD. Also, some of the studied factors including insulin and androgen levels are collinear, a factor that may have influenced the analysis. The lack of a control group was a limitation of the current study, and as such it cannot address the important but separate question of whether or not overweight women with PCOS have evidence of early CVD compared with BMI-matched controls. Additional research is required to clarify the state of the CVS in women with PCOS compared with controls and to determine the relative contribution of factors including IR, androgen status, and BMI as well as PCOS per se to early CVD.
Conclusion
In the current study, we have demonstrated that elevated insulin, glucose, and BP adversely impact on arterial stiffness, a robust marker of early CVD. This is consistent with literature in non-PCOS populations. Furthermore, BP adversely impacts on early atherosclerotic disease, and dyslipidemia is related to endothelial dysfunction. We have also suggested that DHEAS may have a protective role in early atherosclerotic arterial disease (carotid IMT) in overweight women with PCOS. Potentially these findings may be relevant when considering the medical management of PCOS. We postulate that in PCOS, traditional medical therapy with the oral contraceptive pill, aimed primarily at lowering serum androgens, including DHEAS, while potentially increasing IR, may have adverse effects on long-term CVD risk. Further clarification of the effects of androgens and IR on the CVS as well as the effects of interventions that modulate IR and androgen status in women with PCOS is needed.
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Footnotes |
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Abbreviations: ABPM, Ambulatory blood pressure monitoring; AUC, area under the curve; BMI, body mass index; BP, blood pressure; CV, cardiovascular; CVD, CV disease; CVS, CV system; DHEAS, dehydroepiandrosterone sulfate; FAI, free androgen index; FMD, flow-mediated vasodilation; IMT, intimal media thickness; IR, insulin resistance; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; PWV, pulse wave velocity.
Received July 27, 2004.
Accepted April 27, 2005.
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