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Original Studies |
Divisions of Endocrinology (K.J.M., B.C.) and Cardiology (S.V., T.J.A.), University of Calgary, Calgary, Alberta, Canada T2N 2T9
Address all correspondence and requests for reprints to: Todd J. Anderson, M.D., F.R.C.P.C., Division of Cardiology, Faculty of Medicine, University of Calgary c849, 1403 29th Street NW, Calgary, Alberta, Canada T2N 2T9. E-mail: todd.anderson{at}crha-health.ab.ca
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Abstract |
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We undertook a cross-sectional evaluation of endothelium-dependent and -independent vascular function using brachial artery ultrasound. We studied healthy women with clinical and laboratory evidence of PCOS (n = 18) and age-matched controls (n = 19), not taking any antihypertensive, cholesterol-lowering, or hormonal therapies. Laboratory parameters of insulin resistance, glycemia, cholesterol status, and hormone levels were also measured. Despite marked differences in glucose/insulin ratio [6.1 ± 1.1 mmol/pmol (PCOS) vs. 9.9 ± 0.6 (controls)] and free androgen index [11.9 ± 2.3 (PCOS) vs. 3.7 ± 0.6 (controls); normal, <5], we did not find evidence of impaired endothelial function in our patients with PCOS. Both endothelium-dependent (8.7 ± 3.1%) and endothelium-independent (23.2 ± 3.4%) vascular responses were normal, and practically identical to the responses seen in the control group (endothelium-dependent, 9.0 ± 0.7; endothelium-independent, 23.0 ± 1.2%). The PCOS women were more obese, but baseline brachial arterial diameters were not different between groups. There was no correlation between degree of insulin resistance or hyperandrogenism and the brachial response.
This group of healthy obese young women with insulin resistance and hyperandrogenism due to PCOS had normal endothelium-dependent and -independent vascular responses compared to age-matched controls. The factors resulting in preservation of these response are unclear and warrant further investigation.
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Introduction |
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Metabolic and hormonal alterations have long been recognized to have relevance in the genesis of cardiovascular disease. More recently, the potential role of insulin resistance in the pathogenesis of cardiovascular disease has come under investigation. Simple, noninvasive testing of endothelial function (11) provides the ability to demonstrate vascular abnormalities in asymptomatic patients with traditional cardiovascular risk factors (12). Abnormalities have been demonstrated in the presence of insulin resistance without traditional cardiovascular risk factors (13). This technique is sensitive to alterations in cholesterol status even in young patients (14), and changes in vascular reactivity have been demonstrated across the menstrual cycle in healthy young women (15). This measure correlates with direct coronary measures of vascular reactivity (16), although no direct link to cardiovascular outcome has been established to date with any measure of vascular reactivity.
Sex steroids also have important effects on cardiovascular disease and endothelial function (17, 18, 19). Overall, available data support the historical supposition that in women, estrogen and progesterone in physiological concentrations confer vascular protection relative to androgens, although the details of this protection remain poorly understood.
Women with PCOS present the opportunity to examine the combined effects of insulin resistance and sex steroid abnormalities on cardiovascular health. Endothelial function among these women has not been reported to date. We therefore set out to perform a cross-sectional assessment of endothelium-dependent and -independent responses using brachial artery ultrasound in healthy obese, insulin-resistant women with PCOS.
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Subjects and Methods |
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Healthy patients without known cardiovascular risk factors participated in a cross-sectional study of endothelial function, measured using brachial artery ultrasound. Patients with a clinical diagnosis of polycystic ovarian syndrome (menstrual irregularity and/or infertility plus clinical and laboratory evidence of hyperandrogenism) were recruited from our out-patient endocrinology clinic (n = 18). Age-matched control patients were recruited from our local hospital and clinic support staff and nurses (n = 19). Exclusion criteria included age over 40 yr, hypertension (blood pressure, >140/90 mm Hg), hypercholesterolemia (total cholesterol, >6.2 mmol/L), current smoking, known cardiovascular disease (not including valvular heart disease), diabetes mellitus, renal failure (creatinine, >150 µmol/L), and current treatment with antihypertensive, antiandrogenic, or estrogenic medications. This project was approved by our institution’s ethical review board, and all subjects gave full informed written consent.
Brachial ultrasound
Vascular reactivity was assessed using brachial artery ultrasound. A 7.5-MHz linear phased array ultrasound transducer was used to image the dominant arm brachial artery longitudinally just above the antecubital fossa. After an overnight fast, all patients rested for 10–15 min in a quiet room at room temperature. After a baseline image was obtained, a blood pressure cuff was inflated to 200 mm Hg on the distal portion of the arm for 5 min and then released. The increased flow in the artery after removal of the blood pressure cuff is termed reactive hyperemia and results in flow-mediated dilation (FMD) (20). Images were obtained for the first 2 min after cuff deflation. This FMD was used as a measure of endothelium-dependent vasodilation (21, 22). The brachial artery was then allowed to return to normal (5 min), and repeat baseline images were obtained. Then, 0.3 mg sublingual nitroglycerin were given, and the brachial artery was imaged for the ensuing 4 min. The response to nitroglycerin is a measure of endothelium-independent vasodilation (23). Blood pressure and heart rate were recorded during each stage of the investigation.
Analysis
Images were recorded on VHS videotape. Three sequential end-diastolic frames for each intervention (baseline, reactive hyperemia, repeat baseline, and nitroglycerin) were digitized and saved to a computer. Previous studies have shown that maximal arterial dilatation occurs 1 min after cuff deflation and 3 min after the administration of nitroglycerin (24). Arterial diameter was determined over a 1-cm straight segment by locally developed software. The average diameter from each of the three frames was used to calculate the end point of interest, which was the percent diameter change in the brachial artery in response to reactive hyperemia or nitroglycerin. In our laboratory, the intraobserver and interobserver variability for repeated measurements are 0 ± 0.02 and 0.03 ± 0.11 mm, respectively. When reactive hyperemia studies are performed on 2 separate days, the mean difference in brachial vasodilator response in absolute terms is 3.1 ± 2.9%.
Laboratory
Insulin resistance was estimated using the ratio of simultaneous steady state (fasting) insulin and glucose measurements. This ratio has been shown to correlate well with more formal dynamic and steady state measurements of insulin resistance in women with PCOS (25). Fasting bloodwork was collected after the ultrasound study, measuring insulin sensitivity, lipid levels, and sex steroid levels. All assays were performed in our local hospital’s clinical laboratory. Insulin levels were measured using a double antibody RIA (Pharmacia & Upjohn, Inc., Mississauga, Canada), with observed intraassay coefficients of variation of 2.4% at 51 pmol/L and 6.1% at 741 pmol/L. the interassay coefficient of variation is reported at 5.8% across the range of standards. Insulin measurements were performed in duplicate in a single laboratory.
Standard methodologies for glucose, cholesterol, and triglyceride measurements were used. 17ß-Estradiol levels were measured with a RIA kit (ICN, Costa Mesa, CA). Testosterone and progesterone levels were measured with a chemiluminescent immunoassay (Chiron Corp., Markham, Canada), and sex hormone-binding globulin levels were assessed with an immunoradiometric assay (Farmos Diagnostica, Sweden). The free androgen index was calculated from the total testosterone and sex hormone-binding globulin levels.
Studies were performed in the morning, after an overnight fast. Women with PCOS, who by definition had irregular or unpredictable menstrual bleeding, were studied at random with regard to their menstrual timing. Control subjects were studied between days 5 and 10 of their menstrual cycle (early to midfollicular phase), at which time the endogenous sex steroid levels are low and most comparable to those typical of women with PCOS.
Statistics
Statistical analysis was performed using StatView 5.0 (SAS Institute, Inc., Cary, NC). When data were normally distributed, unpaired t tests were used to compare parameters between groups. The Mann-Whitney test was used to compare parameters between groups when the data were skewed. Pearson’s correlations with r to z significance calculations were performed. Predictors of brachial artery vasodilator responses to reactive hyperemia were obtained by univariate regression analysis. Those with P < 0.05 were entered into a multivariate regression model. Statistical significance was defined as a two-sided P < 0.05. All data are expressed as the mean ± SE.
In our laboratory the typical SDfor flow-mediated dilation
measurements is about 3%. To find a clinically relevant difference of
3% in FMD (i.e. a normal FMD of 9% in controls and <6%
in PCOS subjects) with ß = 0.85 and 
= 0.05, we
therefore set recruitment targets of 18 patients in each group.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patient characteristics are presented in Table 1
. Normal lipid and blood pressure values
were as expected in light of our exclusion criteria; although within
the normal range, the PCOS patients had higher blood pressure and
higher low density lipoprotein (LDL) cholesterol levels than the
control patients. Of note, the high density lipoprotein (HDL)
cholesterol levels were well within the protective range for both
groups. The PCOS patients were moderately obese, and the groups
differed significantly with regard to body mass index (BMI) and
waist/hip ratio. The women with PCOS had evidence of insulin
resistance; they were hyperinsulinemic compared to the controls (Table 1), and the glucose/insulin ratio (GIR) was significantly lower (Table 1).
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Two patients in the PCOS group had progesterone levels in the luteal
phase range, resulting in different means between the groups. Excluding
these two patients from all analyses resulted in comparable mean
progesterone levels between groups, but did not change our results. As
expected, the androgen levels were significantly higher among the women
with PCOS, and these levels were strongly correlated with the
calculated insulin resistance index (r = 0.671; P
< 0.001; see Table 4).
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There was no difference in endothelium-dependent (FMD) or
endothelium-independent (NTG) vascular responses between the women with
PCOS and the normal healthy controls (Table 2 and Fig. 1). Despite the difference in BMI, the
groups were well matched for baseline brachial arterial diameter (Table 2), which is the principal determinant of vascular response (11). This
allows comparison of vascular responses between the groups despite the
difference in BMI.
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and 4 examine correlations of various
metabolic parameters with FMD and insulin resistance. FMD (Table 3) was
not significantly correlated with any of the measured hormonal
parameters, in particular with GIR or free androgen index. Insulin
resistance (Table 4), on the other hand, did correlate significantly
with BMI, waist/hip ratio, free androgen index, LDL cholesterol, and
triglyceride levels.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The PCOS patients had higher blood pressure, total cholesterol, and LDL cholesterol than controls. These differences would be expected to bias against the PCOS patients in the measurement of vascular reactivity, but despite this we found normal conduit vessel responses. Our statistical power was conservatively established to find a clinically meaningful absolute difference in FMD of 3% between groups 85% of the time this sample size was used. From the observed results, the risk of falsely accepting the null hypothesis (committing a type 2 statistical error) is only 5.8%. In other words, we were powered to detect a minimal, but clinically relevant, difference, but found no difference between groups despite biases in favor of finding a difference. Therefore, we believe that the result is true and not an artifact of study design.
CV risk in PCOS
Women with PCOS typically carry greater cardiovascular risk than women without PCOS, including having an increased prevalence of hypertension, unfavorable lipid profiles, and insulin resistance/type 2 diabetes (3, 4, 5, 6). These components of the dysmetabolic syndrome (syndrome X) predict cardiovascular events in other populations (26, 27) and have been linked with endothelial dysfunction in the forearm and coronary vasculatures (28). Furthermore, there is now evidence that the rate and severity of cardiovascular disease may be increased among women with PCOS (7, 10), supporting the extrapolation of the available epidemiological data to this group. Our results are therefore unexpected.
Endothelial function
At present, there are no reports directly examining endothelial function in women with PCOS. One group has examined cardiac dynamics, which are in part determined by endothelial factors, among women with PCOS (29). Their patients were lean hyperinsulinemic women with PCOS and were found to have unfavorable changes in variables of cardiac flow that correlated with fasting serum insulin levels, but not with androgen levels. Paradisi et al. presented results in abstract form (30) documenting markedly diminished endothelium-dependent and insulin-mediated flow responses in the femoral artery among women with PCOS, with a dominant dependence of flow response on androgen levels. The question of the relative roles of hyperandrogenism and insulin resistance remains open.
We did not find a dependence of brachial artery endothelium-dependent responses on ambient insulin resistance. Studies showing a link between endothelial function and insulin resistance have been reported (13, 31, 32), but these studies are countered by evidence against such a relationship (33, 34), and this question is unanswered. In particular, the effects of physiological or pharmacological modifiers on this relationship, for example sex steroids, have not been systematically studied.
Two studies of the relationship between insulin resistance and vascular function have included female subjects. Serne et al. studied skin microvascular responses to topical application of acetylcholine in 18 normotensive, glucose-tolerant subjects, 12 of whom were female (35). Within the normal range of insulin resistance, this group showed a dependence of microvascular endothelial function on endogenous insulin resistance. Sung et al. compared hemodynamic responses to mental arithmetic and handgrip between premenopausal obese insulin-resistant women and lean controls (36). They found an exaggerated response to stress among the insulin-resistant women, with a good correlation of GIR with peak stress blood pressure (36). In both of these reports, insulin resistance was found to affect vascular responses despite ongoing physiological sex steroid exposure.
In contrast, our patients’ endothelial function was unaffected by the combination of excess androgen exposure and insulin resistance. It is not clear what accounts for this protection. The observed hyperandrogenemia and insulin resistance were of sufficient degree to expect effects on endothelial function. Furthermore, differences in obesity and metabolic status (in particular, LDL concentrations) should have predisposed against this negative finding. A protective effect of ongoing exposure to sex steroids (despite the shift in androgen/estrogen balance) or the relatively elevated HDL cholesterol levels might account for these observations.
We did not find a dependence of endothelium-dependent or -independent responses on sex steroid levels, including androgen levels. The lack of a negative effect of androgen levels is an important observation, as this is a principal difference among normal women, women with PCOS, and men and might have been predicted to alter endothelial responses directly. There are known effects of menstrual timing on vascular responses among young healthy women (15). Women studied in the early follicular phase have little augmentation of their responses. Our study was designed to allow direct comparison of vascular responses at comparable sex steroid levels between PCOS subjects and controls. However, this may be masking a difference between the groups, for example, in the augmentation of vascular responses afforded by cyclical estrogen exposure. Alternatively, ongoing low level exposure to estrogen may be exerting a favorable effect that helps overcome the influence of both the androgens and the insulin resistance. This is not easily reconciled, though, with the studies discussed above, which did not demonstrate a protection from the effects of insulin resistance despite normal cyclical sex steroid exposures.
A vascular protective role of elevated HDL cholesterol has been proposed previously. A strong favorable relationship of endothelium-dependent responses and HDL cholesterol levels has been reported among men with type 2 diabetes mellitus (37). Also, among 26 patients with coronary disease, including 4 women, abnormal coronary vasomotor responses to endothelium-dependent stimulation were significantly blunted in patients with HDL cholesterol in the top quartile (38). Although no dependence of FMD on any lipid parameter, including HDL, was seen in our patients, this remains a plausible effect that might account for our observations. Furthermore, the interaction of lipid and hormonal effects might result in a more favorable net effect than either factor alone. Perhaps the balance is such that vascular function is relatively preserved until the frank onset of one or more traditional cardiovascular risk factors. In this regard, the exclusion of diabetes mellitus and the young age of the patients studied may have selected for a subset of patients whose vasculature is unaffected by the metabolic alterations due to their PCOS.
Limitations
The difference in BMI between our study groups is an important potential confounding factor in the interpretation of our results. However, as discussed above, the effect of patient size on variation in vascular response is through differences in vessel size, and this parameter was well matched between the groups. The comparison of vascular responses is therefore valid.
We did not measure oxidative stress, although none of our subjects was taking any supplemental antioxidants. However, we cannot rule out a differential oxidative balance between patient groups that might account for our observations.
Although our study population was relatively small, and conclusions arising from our multivariate linear analyses are accordingly limited, the validity of the overall relationships is supported by the expected finding of a dependence of FMD on baseline brachial diameter.
The metabolic profile of our study population was more normal than expected, and therefore, the cumulative effect of the metabolic syndrome was less apparent among our patients than other groups of women with PCOS. However, this allows us to comment on the effect of obesity/insulin resistance in this context without the confounding effects of other risk factors.
Finally, the choice of studying control subjects in the early follicular phase may have masked a difference in overall biology. However, the question of vascular responses at comparable sex steroid levels, which our study was designed to address, in itself is important and relevant to our overall understanding of vascular biology.
Conclusion
Using brachial artery ultrasound, we studied a group of young, obese, insulin-resistant, hyperandrogenemic women with PCOS compared to age-matched controls. With the exception of androgen levels, sex steroid levels were comparable between patients and controls. Despite these metabolic abnormalities, we were unable to demonstrate a defect in endothelium-dependent or endothelium-independent vascular responses. Further, there was no dependence of these responses on the degree of insulin resistance, assessed using the glucose/insulin ratio, or on the free androgen index. Although we were unable to demonstrate a difference between these women with PCOS and controls, this does not rule out the existence of a defect in vascular reactivity in PCOS patients with more overt cardiovascular risks. Protective effects of estrogen exposure and/or elevated HDL cholesterol may have prevented the expected adverse effects of these metabolic factors on vascular responses.
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Acknowledgments |
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Footnotes |
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2 Research Fellow of the Alberta Heritage Foundation for Medical
Research.
3 Supported by the Alberta Heritage Foundation for Medical Research
and the Canadian Diabetes Association.
4 Clinical investigator with the Alberta Heritage Foundation for
Medical Research.
Received August 2, 1999.
Revised December 1, 1999.
Accepted January 21, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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