Vascular dysfunction and metabolic parameters in polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and the metabolic syndrome; however, the cardiovascular (CV) manifestations of PCOS remain unclear. 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.

Vascular dysfunction and autonomic neuropathy in Type 2 diabetes.

AIMS: To test the hypothesis that arterial dysfunction in Type 2 diabetes is related to autonomic neuropathy. METHODS: Arterial function and autonomic neuropathy were assessed over two consecutive days in 45 Type 2 diabetic and control subjects. Systemic arterial compliance (SAC), arterial stiffness (pulse-wave velocity, PWV) and carotid intima thickness (IMT) were assessed; these markers reflect early vascular disease and predict clinical vascular events. Autonomic neuropathy was assessed using heart rate variability with continuous ECG recording during various breathing and postural manoeuvres and an overall autonomic score was generated. Fasting metabolic parameters including glucose, insulin, HbA(1c) and lipid profile were measured. RESULTS: Autonomic neuropathy tests were all repeatable in diabetic subjects. Compared with controls, diabetic subjects had arterial dysfunction with increased PWV (P = 0.009), IMT (P < 0.001) and reduced SAC (P = 0.053). After adjustment for age, central PWV correlated with fasting insulin (r(2) = 0.45, P < 0.05) and autonomic score (r(2) = 0.44, P < 0.05), peripheral PWV correlated with autonomic score (r(2) = 0.51, P < 0.005) and IMT correlated with fasting insulin (r(2) = 0.5, P < 0.005). The presence of autonomic neuropathy correlated with fasting insulin (P = 0.015), but not age, duration diabetes, lipids or blood pressure. CONCLUSION: Using repeatable measures of autonomic neuropathy and vascular function in Type 2 diabetic subjects, we have demonstrated associations between autonomic neuropathy, vascular dysfunction and hyperinsulinaemia. This may help to explain the excess cardiovascular mortality seen in diabetic subjects with autonomic neuropathy.

Placebo-controlled trial of transdermal estrogen therapy alone in postmenopausal women: effects on arterial compliance and endothelial function.

BACKGROUND: The cardiovascular effects of hormone replacement therapy (HRT) are controversial. Improvement in vascular function, potentially mediated, at least in part, via improvements in lipid profiles, is a proposed mechanism of estrogen action; however, there are few controlled human trials. We have studied the effects of HRT, independent of changes in lipid profile, with transdermal estrogen therapy, focusing on blood pressure, lipid profiles and vascular function, encompassing both biomechanical arterial properties (systemic arterial compliance and pulse wave velocity) and endothelial function (flow-mediated vasodilatation). METHODS: In this 2-year, double-blind, placebo-controlled, cross-over study, 34 healthy postmenopausal women were randomized to transdermal estrogen alone (Menorest, 50 micrograms) or placebo. After withdrawals, 25 women completed measurements at baseline, 6 weeks, 6 months and 12 months during both treatment phases. RESULTS: Transdermal estrogen did not improve blood pressure, lipid profiles or arterial function, compared with placebo. CONCLUSION: From this randomized, controlled trial, it appears that transdermal estrogen alone, in healthy postmenopausal women, does not improve lipid profiles or a spectrum of indices of arterial function, compared with placebo. These results would suggest that there might not be a beneficial effect of transdermal HRT on the vasculature in postmenopausal women.

Dietary soy has both beneficial and potentially adverse cardiovascular effects: a placebo-controlled study in men and postmenopausal women.

To address the cardiovascular effects of dietary soy containing phytoestrogens, we measured blood pressure (BP), lipids, vascular function (systemic arterial compliance and pulse wave velocity), and endothelial function (flow-mediated vasodilation) in a randomized, double-blind trial. Two hundred thirteen healthy subjects (108 men and 105 postmenopausal women), 50-75 yr old, received either soy protein isolate (40 g soy protein, 118 mg isoflavones) or casein placebo for 3 months. There were 34 withdrawals (16%), with 179 subjects (96 men and 83 women) completing the protocol. After intervention in the soy group, compared with casein placebo, urinary phytoestrogens increased, accompanied by a significant fall in BP reflected by the BP model (P < 0.01) encompassing mean change (+/-SEM) in systolic (-7.5 +/- 1.2 vs. -3.6 +/- 1.1 mm Hg, P < 0.05), diastolic (-4.3 +/- 0.8 vs. -1.9 +/- 0.7 mm Hg, P < 0.05), and mean BP (-5.5 +/- 1 vs. -0.9 +/- 1 mm Hg, P < 0.008). In the lipid model, soy induced greater changes, compared with placebo (P < 0.001). On individual analysis, significant contributors included a reduction in the low- to high-density lipoprotein ratio (-0.33 +/- 0.1 vs. 0.04 +/- 0.1 mmol/L, P < 0.05) and triglycerides (-0.2 +/- 0.05 vs. -0.01 +/- 0.05 mol/L, P < 0.05) and an increase in Lp(a) lipoprotein (+/- 95% confidence interval) [42 (range, 17-67) vs. 4 (range, -22-31) mg/L, P < 0.05], whereas total, low-density lipoprotein, and high-density lipoprotein cholesterol improved in both groups; but no treatment effect was demonstrated. The arterial functional model demonstrated no difference between groups; although again, overall function improved in both groups. On individual analysis, peripheral PWV (reflecting peripheral vascular resistance) improved with soy (P < 0.01), whereas flow-mediated vasodilation (reflecting endothelial function) declined (in males only), compared with casein placebo (P < 0.02). No effect of treatment on the hypothalamic-pituitary-gonadal axis was noted in males or females. In normotensive men and postmenopausal women, soy improved BP and lipids but, overall, did not improve vascular function. Potential adverse effects were noted, with a decline in endothelial function (in males only) and an increase in Lp(a). Further research in hypertensive and hyperlipidemic populations is needed.

Effects of combined oral hormone replacement therapy on tissue factor pathway inhibitor and factor VII.

Oral combined hormone replacement therapy (HRT) with oestradiol and norethisterone increases plasma levels of prothrombin fragment 1+2 (F1+2), indicating an increase in thrombin generation, but the mechanisms underlying this increase are uncertain. The aim of this randomized, placebo-controlled study was to determine whether an increase in factor VII, a factor that combines with tissue factor to activate the extrinsic pathway, or a decrease in tissue factor pathway inhibitor (TFPI), an inhibitor of extrinsic pathway activation, may contribute to increases in thrombin generation occurring with HRT. Healthy postmenopausal women aged 50-75 years received placebo (n=19) or oral combined HRT (n=18) and had blood collected for measurement of factor VII coagulation activity (VIIc), activated factor VII (VIIa) and TFPI at baseline and at 6 weeks. Baseline characteristics were similar in the two groups, including age, body mass index and cholesterol levels. As reported previously, HRT increased the F1+2 concentration by 20%. Placebo had no effect on VIIc, VIIa or TFPI, but 6 weeks of combined HRT decreased VIIc [from 1.11+/-0.06 (mean+/-S.E.M.) to 1.03+/-0.06 i.u./ml; P<0.03], VIIa [from 43.9; 10.8-198.3 (median; range) to 35.0; 6.3-66.8 m-units/ml; P<0.03] and TFPI [from 81.3+/-6.5 to 60.4+/-5.5 ng/ml; P<0.0001]. The decrease in TPFI with HRT was not correlated with the elevation in F1+2 levels. In conclusion, the increase in thrombin generation seen with HRT is not due to an effect on factor VII; in addition, while a contribution from the decrease in TFPI is possible, increased thrombin generation is not directly related to the decrease in TFPI.

Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen.

The gender difference in cardiovascular disease has been partly attributed to higher androgenic hormone levels. Although testosterone in women may not affect lipids, it remains unknown whether it negates favorable estrogenic effects on endothelial function. We have investigated the effects of testosterone implant therapy on arterial reactivity encompassing endothelial-dependent and -independent vasodilation in women using hormone replacement therapy (HRT). B-mode ultrasound measurements of resting brachial artery diameter, following reactive hyperemia [endothelium-dependent flow- mediated dilation (FMD)] and following glyceryl trinitrate (GTN) (endothelium-independent dilation), were recorded in 33 postmenopausal women stabilized on HRT (>6 months), at baseline, and 6 weeks after a testosterone implant (50 mg), with 15 postmenopausal nonusers of HRT serving as controls. In the brachial artery, baseline resting diameter was similar (0.40 +/- 0.01 vs. 0.41 +/- 0.01 cm, P = 0.5). In the treated group, testosterone levels increased (0.99 +/- 0.08 to 4.99 +/- 0.3 nmol/L, P < 0.001), associated with a mean 42% increase in FMD (6.4% +/- 0.7 to 9.1% +/- 1.1, P = 0.03). The control group did not change (8.1% +/- 1.4 to 5.6% +/- 1.0, P = 0.4). ANOVA of repeated measures (P = 0.04) and mean change (P = 0.02) in FMD both demonstrated significantly greater improvement with testosterone compared with controls. GTN induced vasodilation increased with testosterone treatment (14.9% +/- 0.9 to 17.8% +/- 1.2, P = 0.03). Our preliminary data indicate that parenteral testosterone therapy improves both endothelial-dependent (flow-mediated) and endothelium-independent (GTN-mediated) brachial artery vasodilation in postmenopausal women using long-term estrogen therapy. The mechanisms underlying these potentially beneficial cardiovascular effects require further investigation.

A placebo-controlled trial of long-term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function.

OBJECTIVE: To study the effects of long-term combined continuous oral hormone replacement therapy (HRT) on vascular function in healthy postmenopausal women. BACKGROUND: The cardiovascular effects of HRT are controversial. Improvement in vascular function is a proposed mechanism of oestrogen action but there are no long-term controlled human trials in this area. In this study, we examined the effects of HRT on lipid profiles and vascular function, encompassing both biomechanical arterial properties [systemic arterial compliance (SAC) and pulse wave velocity (PWV)] and endothelial function [flow-mediated vasodilation (FMD)]. METHODS: In this 2-year, double-blind, placebo-controlled study, 59 healthy postmenopausal women were randomized to oral combined continuous oestrogen and progesterone [Kliogest, oestradiol (2 mg), norethisterone (1 mg)] or placebo, with end-points measured at baseline, 6 weeks and after 6,12 and 24 months of treatment. RESULTS: Oral combined HRT reduced lipoprotein a [Lp(a)], although other lipid benefits were not observed. There were no significant changes in SAC, PWV or FMD with oral combined HRT, compared to placebo. CONCLUSION: In this long-term, randomized placebo-controlled trial, oral continuous HRT with combined oestradiol and norethisterone in healthy postmenopausal women did not improve a spectrum of indices of arterial function compared to placebo. These results suggest that HRT might not be of cardiovascular benefit in postmenopausal women.

Impact of physical and physiological factors on arterial function.

1. Arterial function measurements are increasingly used as surrogate markers of cardiovascular disease and it is important to define which non-pathological factors may influence these measurements. 2. The present study examined the influence of gender, height, body mass index (BMI), waist : hip ratio, heart rate and arterial pressure on pulse wave velocity (PWV), systemic arterial compliance (SAC) and central pressure augmentation index (AI) in 285 normal subjects, 98 males and 187 females, aged 50-82 years. 3. There were significant gender differences in PWV (higher in men), SAC (higher in men) and central pressure AI (lower in men). 4. Both SAC and AI were correlated with height in men and women and height largely accounted for gender differences. 5. Systemic arterial compliance was positively, whereas AI was negatively, correlated with BMI. 6. Both PWV and AI were significantly correlated with heart rate and central pulse pressure. 7. These findings may have implications for cardiovascular disorders. Reduced central arterial compliance and increased central pressure augmentation are potential mediators for the increased cardiovascular risk of short stature. A slow heart rate may contribute to increased central arterial pressure with potentially adverse consequences in older subjects.

Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis.

Hormone replacement therapy (HRT) appears to be cardioprotective in postmenopausal women; however, concerns exist over its thrombogenic effects. To address the effects of combined HRT on coagulation and fibrinolysis, we have measured circulating markers of these processes in a double-blind placebo-controlled trial. Forty-two healthy postmenopausal women aged 50 to 75 years received continuous combined HRT with 2 mg estradiol+1 mg norethisterone or placebo for 6 weeks. Hormone profiles were measured at baseline, and lipid and hemostatic parameters were measured at baseline and after 6 weeks of therapy. Baseline characteristics were similar in the 2 groups. With change from baseline the main outcome measure, HRT increased the markers of coagulation (prothrombin fragments 1+2, 0.20+/-0.06 versus 0.06+/-0.04 nmol/L, P=0.0005; soluble fibrin, 2.3+/-0.4 versus 0.25+/-0.3 microgram/mL, P=0.0004), reduced plasma fibrinolytic inhibitory activity (plasminogen activator inhibitor-1, -0.67+/-0.16 versus 0.24+/-0.21 U/mL, P=0.002), and increased fibrinolysis (D-dimer, 24+/-12 versus -6+/-8 ng/mL, P=0.04) compared with placebo. Increases in soluble fibrin and D-dimer were positively correlated (r=0.59, P=0.02), but changes in plasminogen activator inhibitor-1 and D-dimer were unrelated. Although baseline hemostatic and lipid parameters were correlated, there were no associations between changes in hemostatic markers and lipids after treatment. Short-term oral combined continuous HRT (estradiol and norethisterone) increased thrombin and fibrin generation, reduced plasma fibrinolytic inhibitory activity, and increased fibrinolysis. Enhanced fibrinolysis was related to increased fibrin generation but not reduced plasma fibrinolytic inhibitory activity. Coagulation activation may partly explain the increases in venous thrombosis and cardiovascular events reported with the use of combined HRT.

The effects of soy protein containing phytoestrogens on menopausal symptoms in postmenopausal women.

OBJECTIVE: To analyze the impact of soy protein dietary supplements containing phytoestrogens on menopausal symptoms in healthy postmenopausal women. METHODS: A double-blind, placebo-controlled trial was conducted in 94 healthy postmenopausal women aged 50-75 years, with 44 randomized to soy supplements containing 118 mg of isoflavones (daidzein, genistein, glycitein and their respective glycosides), and 50 to an identically presented casein placebo. A validated questionnaire on menopausal symptoms was administered at baseline and at 3 months of treatment. Compliance was assessed by high-performance liquid chromatography assay of urinary phytoestrogens. Statistical analysis was completed using non-parametric statistical methods and multivariate analysis. RESULTS: At baseline 80% of women recruited were experiencing menopausal symptoms, although symptom severity was mild. Those consuming phytoestrogen supplements had 13- and 17-fold increases in urinary excretion of genistein and daidzein, respectively, with no change in the placebo group. Active soy supplements did not significantly alter either individual symptoms or specific symptom category scores when compared to placebo. Within-group comparisons revealed that the active group reported a significant improvement in vaginal dryness (p = 0.01), libido (p = 0.009), facial hair (p = 0.04) and dry skin (p = 0.027). However, similarly, those on placebo reported an improvement in libido (p = 0.015), facial hair (p = 0.014) and dry skin (p = 0.011) but not vaginal dryness. CONCLUSIONS: In this group of 94 older postmenopausal women with a high frequency of mild menopausal symptoms, 3 months of soy supplements containing phytoestrogens did not provide symptomatic relief compared with placebo.

Non-invasive measurements of arterial structure and function: repeatability, interrelationships and trial sample size.

1. Repeatability of measurements of arterial compliance and flow-mediated dilation of the brachial artery has been infrequently reported, despite increasing use in interventional and risk-factor modification studies. Furthermore, little is known about the interrelationships of the various indices. The purposes of this study were to determine the repeatability and interrelationships of a range of arterial indices.2. Fifty healthy volunteers, 20 men and 30 women, aged 20-70 (mean 46.5) years, were studied on two occasions, using an identical protocol, at a mean interval of 2.5 weeks. Tonometry, ultrasound and Doppler technique were used to measure the following: carotid wall intima-media thickness (IMT), total systemic artery compliance (SAC), arterial pulse wave velocity [PWV aorto-femoral (A-F), and femoral-dorsalis pedis (F-D)], carotid distensibility coefficient (DC) and carotid augmentation index (AI). Brachial flow-mediated dilation was measured in 30 subjects with analysis of diameter change for 4 min post ischaemia.3. There were no systematic differences over the observed range of measurements for any of the reported parameters. Coefficients of variation were as follows: IMT 2.8%, SAC 9.2%, PWV(A-F) 3.2%, PWV(F-D) 5.0%, DC 10.0%, AI 1.3%. Brachial flow-mediated dilation curves were not different between visits; changes were maximum 60-s post ischaemia. All indices of arterial compliance were significantly correlated with age. The three different indices of central arterial compliance [SAC, PWV(A-F) and AI] were significantly correlated with carotid intima-media thickness.4. Under controlled experimental conditions there was good repeatability of measurements of indices between sessions of both intrinsic and functional arterial mechanical properties (central and carotid arterial compliance, intima-media thickness and brachial flow-mediated dilation). Sample size tables for clinical trials using these indices are presented.

Reproducibility of arterial compliance and carotid wall thickness measurements in normal subjects.

1. Non-invasive techniques to measure indices of arterial function and wall thickness are frequently used as surrogate markers of cardiovascular disease. Reproducibility of measurements of arterial compliance has been infrequently reported and little is known about the interrelationships of the various indices in vivo. 2. The present study was designed to assess reproducibility and interrelationships of indices of systemic arterial compliance, pulse wave velocity, carotid compliance and intima-media thickness (IMT). 3. Fifty healthy volunteers (20 male and 30 female: aged 20-70 years, mean 46.5 years), participated in the present study. Each subject was studied on two occasions by the same investigators, using an identical protocol at an interval of 1-5 weeks (mean 2.5 weeks) without lifestyle change. 4. There were no significant differences between visits for any recorded general data, except resting blood pressure, which was lower on the second occasion. There were no systematic differences within each pair over the range of measurements for any of the variables. Bland-Altman plots of repeatability of changes in indices showed that the mean values between visits were not significantly different. All indices of central arterial compliance were significantly related to age and IMT. 5. Thus, under controlled experimental conditions, there was satisfactory repeatability of measurements of indices of both intrinsic and functional arterial mechanical properties (central and carotid arterial compliance and IMT). This type of information will permit the construction of sample size tables for clinical trials using these indices. 6. Central arterial compliance may be an important determinant of IMT.