Vasodilation In Postmenopausal Women Research Articles

Dydrogesterone does not reverse the effects of estradiol on endothelium-dependant vasodilation in postmenopausal women: a randomised clinical trial

Objectives: The purpose of this study was to evaluate endothelium-dependent flow-mediated dilation (FMD) in the brachial artery and the plasma levels of endothelin-1 in postmenopausal women at risk for coronary artery disease before and after treatment with both estradiol and estradiol plus dydrogesterone. Methods: Sixteen postmenopausal women (PMW) (mean age 58±9 years) with more than two risk factors for coronary artery disease, were randomized to receive either oral estradiol (2 mg) for 28 days or oral estradiol (2 mg) for 14 days and oral estradiol (2 mg) and dydrogesterone (10 mg) for 14 days, in a double-blind, placebo-controlled, single cross-over study. Patients were crossed-over the complementary treatment 7 days after completing the first treatment. The study of forearm blood flow and the measurement of plasma endothelin-1 levels was carried out before and after each treatment. Results: Estradiol significantly increased FMD as compared to baseline; the addition of dydrogesterone did not affect the effect of estradiol on FMD. Similarly reactive hyperemic flow increased after estradiol alone or in association with dydrogesterone compared to baseline. Plasma levels of endothelin-1 were significantly reduced by estradiol both when administered alone or in association with dydrogesterone. Conclusions: Hormone replacement therapy with estradiol and dydrogesterone improves endothelial function and reduces plasma levels of endothelin-1 in PMW at risk for coronary artery disease.

Effect of atorvastatin on endothelium-dependent vasodilation in postmenopausal women with average serum cholesterol levels

After menopause, most healthy women show an impairment of peripheral vasodilation and an increase of plasma cholesterol levels. Statins have been shown to improve endothelial function in hypercholesterolemic men and women. The present study tests whether atorvastatin (10 mg) influences endothelium-dependent vasodilation in postmenopausal normocholesterolemic women. Twenty-eight healthy, postmenopausal women (mean age 51 ± 2 years) with serum total cholesterol and low-density lipoprotein cholesterol within the desirable range entered a double-blind, single-crossover study. Postmenopausal women were randomized to receive either atorvastatin (10 mg/day) or placebo for 10 days and then crossed to the complementary treatment. Endothelium-dependent and -independent responses were assessed by means of strain-gauge plethysmography before and after intra-arterial infusion of acethylcholine (ACh) and sodium nitroprusside, in comparison to physiologic saline. The nitric oxide pathway was evaluated by repeating the infusion of ACh during admininstration of l-arginine and (G)-monomethyl- l-arginine ( l-NMMA). Serum lipoproteins were not significantly modified by the active treatment. The vasodilation induced by ACh was significantly higher in the atorvastatin-treated women compared with the placebo-treated group (24 ± 3 vs 13 ± 2 ml/100 ml tissue/min, p <0.01). In contrast, responses to the endothelium-independent vasodilator sodium nitroprusside were not significantly modified by atorvastatin. The ACh-stimulated vasodilation induced by atorvastatin was additionally potentiated by l-arginine (800 ± 105% vs 370 ± 60%, p <0.05) and blunted by l-NMMA. No correlation was found between changes in plasma cholesterol and improvement in forearm blood flow. Our data show that the beneficial effect of atorvastatin on endothelium-dependent vasodilation is independent from changes in the lipid profile.

The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women

The phytoestrogen genistein improves endothelial dysfunction in ovariectomized rats through a nitric oxide-dependent mechanism. We investigated whether genistein alters the balance between the nitric oxide products and endothelin-1 and influences endothelium-dependent vasodilation in postmenopausal women. Sixty healthy postmenopausal women were enrolled in the study. A double-blind, placebo controlled, randomized design was employed. After a 4-week stabilization on a standard fat-reduced diet, participants to the study were randomly assigned to receive either genistein ( n=30; 54 mg/day) or placebo ( n=30). Flow-mediated, endothelium-dependent vasodilation of the brachial artery, plasma nitric oxide breakdown products and endothelin-1 levels were measured at baseline and after 6 months of genistein therapy. The mean baseline level of nitrites/nitrates was 22±10 μmol/l and increased to 41±10 μmol/ml after 6 months of treatment. The mean baseline plasma endothelin-1 level was 14±4 pg/ml and decreased to 7±1 pg/ml following 6 months of treatment with genistein. The mean baseline ratio of nitric oxide to endothelin also significantly increased at the end of treatment. Flow-mediated, endothelium-dependent vasodilation of the brachial artery was 3.9±0.8 mm at baseline and increased to 4.4±0.7 mm after 6 months of treatment. Placebo-treated women showed no changes in plasma nitrites/nitrates, endothelin-1 levels and flow-mediated vasodilation. Genistein therapy improves flow-mediated endothelium dependent vasodilation in healthy postmenopausal women. This improvement may be mediated by a direct effect of genistein on the vascular function and could be the result of an increased ratio of nitric oxide to endothelin.

Effect of estrogen on endothelial dysfunction in postmenopausal women with diabetes

Background: Treatment with estrogen causes increased release of nitric oxide and this appears to be an important mechanism involved in the cardioprotective effect of estrogen. Previous studies have clearly shown that estrogen has an acute vasodilatory effect. Recently, abnormality of flow mediated endothelial dilation, which is defined as an endothelial dysfunction, has been proposed as an early manifestation of atherogenesis. However, its effect in type 2 diabetes is unknown. Stimulus-provoked endothelium dependent dilatation, using high-resolution external vascular ultrasound, is a useful method in the measurement of endothelial function. The main advantages of this method are that it is completely non-invasive, accurate and reproducible. This classical method for the measurement of endothelial dysfunction, utilizing non-invasive, high-resolution ultrasonography, has some limitations especially in terms of reproducibility. To improve the accuracy and reproducibility of this method, measurements made for this study involved the use of an additional attachment. This device was an ultrasound probe that was attached to the arm of patient. In addition, this study evaluated not only a change in diameter in terms of flow mediated vasodilation, but also initial and peak response times during this test. The aims of this study are: (1) to evaluate the flow mediated peak vasoreactivity (FMD), the lag time from base line to initiation of vasodilation (IRT) and the peak response of endothelial dependent vasodilation in a control group and in young diabetic patients; and (2) to evaluate the effect of estrogen treatment on flow mediated vasodilation in postmenopausal women with diabetes. Method: Measurements were taken for flow mediated vasodilation (endothelial dependent vasodilation: FMD), endothelial independent vasodilation (EID) and lag time from base line to initial reaction of FMD. The aforementioned non-invasive method and attachment were used. Subjects for the experiment were 12 young people with diabetes (six male and six female, mean age 26.3) and 12 age-matched healthy controls (six male and six female, mean age 25.6). In addition, measurements were taken for FMD, EID and lag time in the brachial artery before and after estrogen supplementation (Premarin 0.625mg for 7 days). Subjects for the experiment were 16 normal postmenopausal women and 18 age-matched postmenopausal women with type 2 diabetes. Result: There is no significant difference in BMI (body mass index), mean age, or blood pressure between the control group and the young diabetic group. There were no differences in age, total and LDL cholesterol levels or body mass index between the groups of postmenopausal women ( P<0.05). However, the HDL cholesterol level was found to be significantly lower in postmenopausal women with diabetes than in normal postmenopausal women (respectively, a mean±SD; 38.95±11.96 mg/dl vs. 52.20±9.55 mg/dl, P<0.05). The FMD of young diabetic patients is slightly lower than that of age-matched young healthy controls (healthy control: 8.9±2.7%, young diabetic patients: 6.3±2.1%, P<0.05). There was no difference in endothelial independent vasodilation between the control group and the young diabetic group. The IRT of FMD was significantly shorter in the healthy control group than in the young diabetic group (healthy control: 20.4±2.8 s, diabetic group: 29.5±5.4 s, P<0.0001). In contrast, the IRT of EID was no different between the two groups. The IRT of FMD showed a significant negative correlation with FMD ( r=−0.61, P<0.01) and a significant negative correlation with high-density lipoprotein (HDL) cholesterol ( r=−0.68, P<0.0001). The basal endothelium dependent vascular reactivity was significantly decreased in postmenopausal women with diabetes compared with normal postmenopausal women (8.0±3.9 vs. 13.7±6.2%, P<0.05). Estrogen supplementation increased endothelium dependent vasodilation not only in postmenopausal women with diabetes (from 8.0±3.9 to 15.1±4.0%, P<0.05) but also in normal postmenopausal women (from 13.7±6.2 to 20.1±4.7%, P<0.05). In contrast, the responses to sublingual nitroglycerin were comparable between postmenopausal women with diabetes (from 21.1±6.0 to 22.1±4.1%, P>0.05) and normal postmenopausal women (from 25.8±7.8 to 25.2±4.5%, P>0.05), both before and after estrogen supplementation. Conclusion: These findings indicate that in addition to the percentage change in FMD, lag time from base line to initial response time (IRT) of FMD is a good indicator for evaluation of endothelial dysfunction. Also, this new parameter may be a more sensitive parameter for differentiation between the diseased state and the normal state of the endothelium than percentage changes in FMD. In terms of postmenopausal women, endothelial dysfunction was prominent in women with diabetes and was significantly improved by estrogen but not reversed. These results suggest that other factors in addition to estrogen deficiency play a role in endothelial dysfunction in postmenopausal women with diabetes mellitus.

Evidence That Parenteral Testosterone Therapy May Improve Endothelium-Dependent and -Independent Vasodilation in Postmenopausal Women Already Receiving Estrogen

Evidence That Parenteral Testosterone Therapy May Improve Endothelium-Dependent and -Independent Vasodilation in Postmenopausal Women Already Receiving Estrogen

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.

Subcutaneous testosterone implant therapy improves endothelium-dependent and independent vasodilation in postmenopausal women already receiving oestrogen

Subcutaneous testosterone implant therapy improves endothelium-dependent and independent vasodilation in postmenopausal women already receiving oestrogen

Preserved tissue-type plasminogen activator release and endothelium-dependent vasodilation in postmenopausal women with NIDDM

We have recently shown that the net release of tissue-type plasminogen activator (t-PA) antigen can be rapidly enhanced by the muscarinic receptor stimulation in healthy males. Since diabetes mellitus has been associated with endothelial dysfunction, the aim of the present study was to compare the endothelium-derived local net release of t-PA with vasodilation in response to muscarinic receptor stimulation by metacholine (Mch) and fluid shear stress in a group of postmenopausal women with non-insulin-dependent diabetes mellitus (NIDDM), and to elucidate the influence of estrogen on this process. Six postmenopausal women with NIDDM were in randomized order exposed to step-wise intra-arterial infusions of Mch (0.1–0.8–4.0 μg/min) and nitroprusside (SNP; 0.5–2.5–10.0 μg/min). Forearm blood flow (FBF) was assessed by plethysmography. The infusions with Mch and SNP were repeated during simultaneous intra-arterial infusion of 17-β estradiol (E; 20 ng/min). During placebo infusion, FBF increased significantly in response to Mch and SNP ( p<0.001), but no differences between Mch and SNP were found. In parallel to the blood flow increase in response to Mch stimulation, the t-PA net release was increased over 30 times ( p<0.001). Estrogen did not produce any change in blood flow or net release of t-PA at baseline or in response to either drug (Mch or SNP). The present study demonstrates a preserved endothelium-dependent vasodilation and stimulated tissue-type plasminogen activator release in NIDDM postmenopausal women in response to Mch stimulation. Acute intra-arterial infusion of 17-β estradiol did not affect the vasodilation or the t-PA net release.

Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease

OBJECTIVESWe sought to examine the individual and combined effects of estrogen/progestin therapy versus lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with heart disease.BACKGROUNDLittle information is available regarding the relative benefits of estrogen replacement therapy versus reductase inhibitors and the potential utility of their combination as lipid-lowering therapy for postmenopausal women.METHODSWe conducted a randomized, double-blind, crossover trial in 24 postmenopausal women, each of whom received the following drug regimens during three consecutive six-week treatment periods: 1) hormone replacement (oral dose of 0.625 mg/day conjugated equine estrogens and 2.5 mg/day medroxyprogesterone acetate); 2) 20 mg lovastatin/day and 3) hormone replacement plus lovastatin.RESULTSTotal and low density lipoprotein (LDL) cholesterol were significantly lowered and high density lipoprotein (HDL) cholesterol was significantly increased by all three regimens compared with baseline (p < 0.05). Lovastatin was more effective than estrogen/progestin in reducing LDL (p < 0.001), but estrogen/progestin was slightly more effective in increasing HDL. The hormone replacement and lovastatin regimen blocked the estrogen-associated increase in triglycerides. Hormone replacement (alone and with lovastatin) resulted in increases in brachial artery flow-mediated vasodilator capacity (p = 0.01 for both regimens) and the area under the curve (p = 0.016 and p = 0.005, respectively) compared with baseline. Percent dilation was greatest after the hormone replacement regimen, whereas the area under the curve was greatest after hormone replacement plus lovastatin (69% improvement vs. baseline).CONCLUSIONSIn postmenopausal women with coronary disease and hyperlipidemia, conjugated equine estrogen produced significant improvements in lipids and vasodilator responses despite the concurrent administration of low dose medroxyprogesterone acetate. Low dose lovastatin produced greater reductions in LDL, but less dramatic improvements in vasodilator responses. Estrogen/progestin plus lovastatin may provide additional benefits via a greater reduction in the LDL/HDL ratio and attenuation of estrogen-associated hypertriglyceridemia. More information is needed about the safety and efficacy of such combinations of hormone replacement and reductase inhibitor therapy.

Effect of conjugated estrogen on peripheral flow-mediated vasodilation in postmenopausal women

Estrogen replacement protects against cardiovascular morbidity and mortality in postmenopausal women. Conjugated estrogen is the main hormone used in these studies. However, the vascular effects of this type of estrogen are, to a large extent, unexplored. The objective of this study was to evaluate short-term endothelium-dependent vascular effects of intravenously conjugated estrogen at 2 dose levels. Eleven postmenopausal women were included. Each study subject was given 2.5 and 5 mg of conjugated estrogen or placebo in random order with at least 1 week between each investigation in a double-blind study design. The vascular reactivity of the brachial artery was studied using the duplex technique before and 30 minutes after the intravenous administration of study drug. Reactive hyperemia was used to study the flow-mediated vasodilation. Serum estradiol increased significantly and dose dependently 5 minutes after conjugated estrogen infusion. The flow-mediated vasodilation at baseline before drug administration was 1.8 ± 2.0% (mean ± SD) after an average 400% increase in local blood flow. Conjugated estrogen at a dose of 2.5 mg caused an increase in flow-mediated vasodilation from 1.8 ± 2.1% at baseline to 5.4 ± 2.8% after infusion (p <0.05 vs placebo), whereas 5 mg caused an increase from 1.9 ± 1.5% at baseline to 7.0 ± 3.3% after infusion (p <0.05 vs placebo). Intravenous injection of conjugated estrogen significantly improves the peripheral vascular reactivity in postmenopausal women.

Estrogen Replacement Reverses Endothelial Dysfunction in Postmenopausal Women

Purpose: To measure the effect of long-term clinical hormone replacement therapy on brachial artery vasomotor responses, and to compare these responses in premenopausal and postmenopausal women. Patients and Methods: We studied 23 postmenopausal women, including 18 who were evaluated prior to starting clinically indicated oral hormone replacement therapy. Twelve postmenopausal women received estrogen alone, the other 6 were treated with estrogen/medroxyprogesterone combinations. Eleven premenopausal volunteers served as a comparison group. Change in brachial artery diameter in response to postischemic hyperemic flow and sublingual nitroglycerin was measured by ultrasound. Results: The 18 postmenopausal subjects receiving hormone replacement showed a progressive improvement in their postischemic vasodilation. Mean (±SD) postischemic vasodilation was 0.4% ± 7.1% prior to estrogen replacement. There were significant increases in postischemic vasodilation of 4.8% ± 6.6% after 1 month and 8.3% ± 3.4% after 6 months of estrogen replacement. The response to nitroglycerin was similar at all time points studied. Women with the most abnormal responses to hyperemic flow at baseline demonstrated the greatest improvement after 6 months of hormone replacement therapy. Premenopausal and postmenopausal subjects differed in their response to hyperemic flow, with premenopausal women showing 5.8% vasodilatation compared with a 0.6% vasodilation in postmenopausal women ( P = 0.046). Conclusions: Endothelial function is abnormal in many postmenopausal women compared with premenopausal women, and in some postmenopausal women it can be enhanced by estrogen replacement therapy. This effect may increase with prolonged use.

Short-term estrogen augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilation in postmenopausal women.

Estrogen is known to improve in the short term the impaired endothelium-dependent vasodilating responses in postmenopausal women, which may account in part for the beneficial cardiovascular effects of the female hormone. Endothelium-dependent vasodilation is achieved by combined effects of endothelium-derived prostacyclin, nitric oxide (NO), and hyperpolarizing factor. In this study, we investigated our hypothesis that short-term estrogen improves both NO-mediated and non-NO-mediated endothelium-dependent vasodilation in postmenopausal women. The study included 12 postmenopausal women (aged 64 +/- 3 years). The forearm blood flow was measured by strain-gauge plethysmography. The forearm vascular responses to the endothelium-dependent vasodilators, acetylcholine and substance P, were examined before and after intravenous administration of conjugated estrogen and subsequently after intraarterial infusion of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Short-term estrogen augmented the forearm vasodilating responses to both acetylcholine and substance P. The treatment with L-NMMA almost abolished the augmented response to acetylcholine but did not affect that to substance P. The forearm vascular response to sodium nitroprusside was unchanged by the estrogen administration. These results indicate that estrogen augments (in the short-term) both NO-mediated and non-NO-mediated endothelium-dependent forearm vasodilation in postmenopausal women. Thus the beneficial effect of estrogen on endothelial vasodilator function appears to extend to non-NO-dependent mechanism(s).

P124 Effects of low-dose HRT on arterial elasticity and flow-mediated endothelium-(in)dependent vasodilation in postmenopausal women

P124 Effects of low-dose HRT on arterial elasticity and flow-mediated endothelium-(in)dependent vasodilation in postmenopausal women

Estrogen Improves Endothelium-Dependent, Flow-Mediated Vasodilation in Postmenopausal Women

Objective: To assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women. Design: Double-blind, placebo-controlled, cross-over trial. Setting: U...

Estrogen Improves Endothelium-Dependent, Flow-Mediated Vasodilation in Postmenopausal Women

To assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women. Double-blind, placebo-controlled, crossover trial. University medical center. 13 postmenopausal women aged 44 to 69 years (average age, 55 +/- 7 years). Patients were randomly assigned to receive placebo, oral estradiol at a dose of 1 mg/d, and oral estradiol at a dose of 2 mg/d. Each treatment phase lasted 9 weeks. High-resolution ultrasonography was used to measure vascular reactivity in a peripheral conduit vessel, the brachial artery. Endothelium-dependent vasodilation was determined by measuring the change in brachial artery diameter during increases in flow induced by reactive hyperemia. Endothelium-independent vasodilation was measured after sublingual nitroglycerin was administered. Flow-mediated, endothelium-dependent vasodilation of the brachial artery was greater when patients received estradiol (13.5% and 11.6% for 1-mg and 2-mg doses, respectively) than when patients received placebo (6.8%; P < 0.05 for each dose compared with placebo). In contrast, estrogen administration had no effect on endothelium-independent vasodilation as assessed by sublingual nitroglycerin. Short-term estrogen replacement therapy improves flow-mediated endothelium-dependent vasodilation in postmenopausal women. This improvement may be mediated by a direct effect of estrogen on vascular function or may be induced through modification of lipoprotein metabolism.

Acute vascular effects of estrogen in postmenopausal women.

Although hormone replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanisms that mediate this apparent benefit are unclear. Because improvement in vasomotor function may represent one of the beneficial effects of estrogen administration, we investigated the acute effects of physiological levels of estrogen on the vascular responses of estrogen-deficient postmenopausal women. The study included 40 postmenopausal women 60 +/- 8 years old (mean +/- SD), 20 of whom had one or more conditions associated with vascular dysfunction (hypertension, hypercholesterolemia, diabetes, or coronary artery disease). The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine were studied before and during infusion of 17 beta-estradiol into the ipsilateral brachial artery. In 31 subjects, the effect of estradiol on the responses to the endothelium-independent vasodilator sodium nitroprusside was also studied. Women with risk factors for vascular dysfunction had significantly reduced vasodilator responses to acetylcholine (P = .01) and to sodium nitroprusside (P < .001) compared with healthy subjects. Intra-arterial infusion of 17 beta-estradiol increased the forearm venous estradiol concentration from 16 +/- 10 to 318 +/- 188 pg/mL, levels typical of reproductive-age women at midcycle, but caused no vasodilation. However, estradiol potentiated the forearm vasodilation induced by acetylcholine by 18 +/- 30% (P < .001) in women with risk factors for vascular dysfunction and by 14 +/- 23% (P = .03) in healthy women. Estradiol also potentiated the forearm vasodilation induced by sodium nitroprusside in women with risk factors for vascular dysfunction by 14 +/- 21% (P < .001) but not in healthy women. Physiological levels of 17 beta-estradiol selectively potentiate endothelium-dependent vasodilation in healthy postmenopausal women and potentiate both endothelium-dependent and endothelium-independent vasodilation in post-menopausal women with risk factors for atherosclerosis and evidence of impaired vascular function. These vascular effects may be partly responsible for the long-term benefit of estrogen therapy on cardiovascular events in postmenopausal women.