Cardiovascular Events In Postmenopausal Women Research Articles

Effects of low dose hormone replacement therapy on markers of inflammation in postmenopausal women

Objective: Concentrations of soluble fractions of cell adhaesion molecules [sCAM], C-reactive protein (CRP) and serum amyloid A (SAA) are predictive for future cardiovascular events in postmenopausal women. The effect of hormone replacement therapy (HRT) on these inflammatory markers is not uniform. In the presented study the effect of a low-dose HRT preparation, on sCAM, CRP and SAA in healthy postmenopausal women was evaluated. Methods: Serum levels of intracellular adhesion molecules (sICAM-1), vascular cell adhesion molecules (sVCAM-1), P-selectin, CRP and SAA were measured at baseline and after 12 weeks of treatment with continuous combined HRT containing 1 mg micronized 17β-estradiol and 0.5 mg norethisterone acetate. The concentrations of total cholesterol, triglycerides LDL-cholesterol and HDL-c were measured as well. Results: The studied low dose continuous combined therapy significantly reduced the concentration of sICAM-1, sVCAM-1 and P-selectin by 25.3, 20 and 34%, respectively. Despite statistically not significant the concentration of CRP and SAA increased by 35.6 and 9.4%, respectively. A statistically significant decrease in the triglycerides and TC/HDL-cholesterol ratio has been found. Conclusions: The outcomes of the presented study suggest that HRT with low dose continuous combined HRT containing 1 mg micronized 17β-estradiol and 0.5 mg norethisterone acetate have divergent effects on studied parameters of vascular inflammation. These effects are similar to effects of other studied HRT combinations. To our best knowledge this is the first study evaluating the effect of HRT on the concentration of SAA.

Prothrombotic mutations are associated with increased cardiovascular events in postmenopausal women receiving hormone replacement therapy

Prothrombotic mutations are associated with increased cardiovascular events in postmenopausal women receiving hormone replacement therapy

Hormone replacement therapy improves the survival of women undergoing coronary artery bypass grafting

Introduction. In-hospital mortality after coronary artery bypass grafting (CABG) is higher in women than men [1Edwards F.H. Ann Thorac Surg. 1998; 66: 125-131Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. Hormone replacement therapy (HRT) may reduce cardiovascular events in postmenopausal women [2Grodstein F. N Engl J Med. 1996; 335: 453-461Crossref PubMed Scopus (1284) Google Scholar, 3O’Keefe J.H. J Am Coll Cardiol. 1997; 29: 1-5Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. This study investigated the relationship between HRT, mortality, and other morbidity in men and women undergoing CABG.Methods. We reviewed 4,266 consecutive CABG patients aged ≥55 years, including all emergency, redo, and concomitant operations. Univariate associations between potential predictors and outcome were assessed by χ2 followed by stepwise logistic modeling, including all significant (p = 0.10) predictors.Results. Multivariate analysis confirmed that male gender and female gender with HRT were independent predictors of decreased mortality. Mortality was 7.5% in men (n = 3,132), 11.8% in women without HRT (n = 911), and 6.3% in HRT recipients (n = 223) (p = 0.001). Analysis of a subset undergoing elective primary isolated CABG yielded similar results, with in-hospital mortality being 2.6% in men (n = 2,910), 7.1% in women without HRT (n = 637), and 2.4% in HRT recipients (n = 165) (p = 0.0003). Predictors of mortality included age, CHF, IABP, redo, emergency or concomitant procedures, duration of cardiopulmonary bypass, and female gender without HRT. There were no intergroup differences in morbid events, except that perioperative bleeding was more common in women not receiving HRT, whereas thromboembolism was less common in men (p < 0.05).Conclusions. Survival was significantly improved in postmenopausal women receiving preoperative HRT. Introduction. In-hospital mortality after coronary artery bypass grafting (CABG) is higher in women than men [1Edwards F.H. Ann Thorac Surg. 1998; 66: 125-131Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. Hormone replacement therapy (HRT) may reduce cardiovascular events in postmenopausal women [2Grodstein F. N Engl J Med. 1996; 335: 453-461Crossref PubMed Scopus (1284) Google Scholar, 3O’Keefe J.H. J Am Coll Cardiol. 1997; 29: 1-5Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. This study investigated the relationship between HRT, mortality, and other morbidity in men and women undergoing CABG. Methods. We reviewed 4,266 consecutive CABG patients aged ≥55 years, including all emergency, redo, and concomitant operations. Univariate associations between potential predictors and outcome were assessed by χ2 followed by stepwise logistic modeling, including all significant (p = 0.10) predictors. Results. Multivariate analysis confirmed that male gender and female gender with HRT were independent predictors of decreased mortality. Mortality was 7.5% in men (n = 3,132), 11.8% in women without HRT (n = 911), and 6.3% in HRT recipients (n = 223) (p = 0.001). Analysis of a subset undergoing elective primary isolated CABG yielded similar results, with in-hospital mortality being 2.6% in men (n = 2,910), 7.1% in women without HRT (n = 637), and 2.4% in HRT recipients (n = 165) (p = 0.0003). Predictors of mortality included age, CHF, IABP, redo, emergency or concomitant procedures, duration of cardiopulmonary bypass, and female gender without HRT. There were no intergroup differences in morbid events, except that perioperative bleeding was more common in women not receiving HRT, whereas thromboembolism was less common in men (p < 0.05). Conclusions. Survival was significantly improved in postmenopausal women receiving preoperative HRT.

Effects of oestrogen on cardiovascular events in postmenopausal women

A number of randomized clinical trials have investigated the role of hormone replacement therapy (HRT) in primary and secondary prevention of clinical and anatomical manifestations of atherosclerosis. There is mounting evidence that HRT does not slow the progression of clinical or anatomical manifestations of atherosclerosis in women with established disease. Indeed, there appears to be a pattern of increased risk among new users of HRT. In contrast, there are encouraging new data that suggest that HRT may be more effective in women who have not yet developed clinical manifestations of coronary disease.

Effects of oestrogen on cardiovascular events in postmenopausal women

A number of randomized clinical trials have investigated the role of hormone replacement therapy (HRT) in primary and secondary prevention of clinical and anatomical manifestations of atherosclerosis. There is mounting evidence that HRT does not slow the progression of clinical or anatomical manifestations of atherosclerosis in women with established disease. Indeed, there appears to be a pattern of increased risk among new users of HRT. In contrast, there are encouraging new data that suggest that HRT may be more effective in women who have not yet developed clinical manifestations of coronary disease.

Role of tumor necrosis factor-α and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women

Observational studies 1 Cushman M Meilahn E.N Psaty B.M Kuller L.H Dobs A.S Tracy R.P Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol. 1999; 19: 893-899 Crossref PubMed Scopus (220) Google Scholar , 2 Ridker P.M Hennekens C.H Rifai N Buring J.E Manson J.E Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation. 1999; 100: 713-716 Crossref PubMed Scopus (424) Google Scholar and randomized trials 3 van Baal W.M Kenemans P van der Mooren M.J Kessel H Emeis J.J Stehouwer C.D Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. Thromb Haemost. 1999; 81: 925-928 PubMed Google Scholar , 4 Cushman M Legault C Barrett-Connor E Stefanick M.L Kessler C Judd H.L Sakkinen P.A Tracy R.P Effect of postmenopausal hormones on inflammation-sensitive proteins The postmenopausal Estrogen/Progestin interventions (PEPI) study. Circulation. 1999; 100: 717-722 Crossref PubMed Scopus (621) Google Scholar have demonstrated that estrogen therapy with and without concomitant progestin increases the serum level of C-reactive protein (CRP) in postmenopausal women. CRP, a circulating marker of inflammation, is an independent risk factor for cardiovascular events in healthy postmenopausal women. 5 Ridker P.M Hennekens C.H Buring J.E Rifai N C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 1999; 342: 836-843 Crossref Scopus (4967) Google Scholar The serum concentration of CRP correlates with that of tumor necrosis factor-α (TNF-α) 6 Ridker P.M Rifai N Pfeffer M Sacks F Lepage S Braunwald E Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation. 1999; 101: 2149-2153 Crossref Scopus (824) Google Scholar and interleukin-6 (IL-6), 7 Ridker P.M Rifai N Stampfer M.J Hennekens C.H Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 1999; 101: 1767-1772 Crossref Scopus (1986) Google Scholar the primary stimulant of hepatic CRP production. 8 Baumann H Gauldie J The acute phase response. Immunol Today. 1999; 15: 74-80 Abstract Full Text PDF Scopus (428) Google Scholar Raloxifene is a selective estrogen receptor modulator used clinically for the prevention and treatment of postmenopausal osteoporosis, 9 Kauffman R.F Bryant H.U Yang N Harper K Huster W.J Walls E Lufkin E.G Preventing postmenopausal osteoporosis An update on raloxifene. Drug News Perspect. 1999; 12: 223-233 Google Scholar and is also under investigation for its effect on the risk of major cardiovascular events in postmenopausal women. 10 Barrett-Connor E Wenger N.K Grady D Mosca L Collins P Kornitzer M Cox D.A Moscarelli E Anderson P.W Hormone and nonhormone therapy for the maintenance of postmenopausal health The need for randomized controlled trials of estrogen and raloxifene. J Women’s Health. 1999; 7: 839-847 Crossref Scopus (70) Google Scholar Unlike estrogen, raloxifene does not increase CRP levels in postmenopausal women, 11 Walsh B.W Paul S Wild R.A Dean R.A Tracy R.P Cox D.A Anderson P.W The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women A randomized, controlled trial. J Endocrinol Metabol. 1999; 85: 214-218 Google Scholar , 12 Blum A Schenke W.H Hathaway L Mincemoyer R Csako G Waclawiw M.A Cannon R.O Effects of estrogen and the selective estrogen receptor modulator raloxifene on markers of inflammation in postmenopausal women. Am J Cardiol. 1999; 86: 892-895 Abstract Full Text Full Text PDF Scopus (37) Google Scholar although the mechanism for this difference remains unclear. We hypothesized that the differing effects of hormone replacement therapy (HRT) and raloxifene on serum CRP concentrations may be due to different effects on selected proinflammatory cytokines, such as IL-6 and TNF-α. This study compared the effects of HRT and raloxifene on the serum concentrations of TNF-α and IL-6, and assessed the relation between these effects and changes in serum CRP observed in the same population of postmenopausal women.

Renal insufficiency and cardiovascular events in postmenopausal women with coronary heart disease

OBJECTIVESThis study sought to determine the independent association of renal insufficiency with cardiovascular risk among women with known coronary heart disease (CHD).BACKGROUNDAlthough patients with end-stage renal disease and proteinuria are at high risk for cardiovascular events, little is known about the cardiovascular risk associated with moderate renal insufficiency.METHODSThe Heart and Estrogen/progestin Replacement Study (HERS) was a clinical trial among 2,763 women with coronary disease who were randomized to conjugated estrogen plus progestins or identical placebo and followed for a mean of 4.1 years. Women were categorized as having normal renal function (creatinine < 1.2 mg/dl; n = 2,012), mild renal insufficiency (1.2 mg/dl to 1.4 mg/dl; n = 567) and moderate renal insufficiency (>1.4 mg/dl; n = 182). We examined the independent association of renal function with incident cardiovascular events including CHD death, nonfatal myocardial infarction, hospitalization for unstable angina, stroke and transient ischemic attacks.RESULTSCompared with women with normal renal function, those with mild and moderate renal insufficiency were older, more likely to be black, have a history of hypertension and diabetes and have higher serum levels of triglycerides and lipoprotein(a). After multivariate adjustment, both mild (relative hazards [RH] = 1.24; 95% confidence interval [CI]: 1.0 to 1.5) and moderate renal insufficiency (RH = 1.57; 95% CI: 1.2 to 2.1) were independently associated with increased risk for cardiovascular events compared with women with normal renal function.CONCLUSIONSRenal insufficiency is an independent risk factor for cardiovascular events in postmenopausal women with known coronary artery disease. Renal function may add helpful information to CHD risk stratification.

Cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia.

Although estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanism for this benefit remains unclear. Because nitric oxide (NO) is considered an important endothelium-derived relaxing factor and may function to protect blood vessels against atherosclerotic development, we investigated the acute effects of physiological levels of estrogen on NO release from human internal thoracic artery endothelia and human arterial endothelia in culture. We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase activity in human endothelial cells by acting on a cell-surface receptor. NO release was measured in real time with an amperometric probe. 17beta-Estradiol exposure to internal thoracic artery endothelia and human arterial endothelia in culture stimulated NO release within seconds in a concentration-dependent manner. 17beta-Estradiol conjugated to bovine serum albumin also stimulated NO release, suggesting action through a cell-surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized this action. We further showed with the use of dual emission microfluorometry that 17beta-estradiol-stimulated release of endothelial NO was dependent on the initial stimulation of intracellular calcium transients. Physiological doses of estrogen immediately stimulate NO release from human endothelial cells through activation of a cell-surface estrogen receptor that is coupled to increases in intracellular calcium.

Beyond the null hypothesis—do the HERS results disprove the estrogen/coronary heart disease hypothesis?

T purpose of the recently published Heart and Estrogen/Progestin Replacement Study (HERS) was to determine if hormone replacement therapy (HRT) decreases the risk for subsequent cardiovascular events in postmenopausal women with established coronary heart disease (CHD).1 HRT has many potential cardioprotective biologic effects.2 Most observational studies such as the Nurses’ Health Study indicated that women who “self-select” to take HRT have approximately a 50% lower risk of CHD.3 However, a few studies did not find HRT to be cardioprotective.4 HERS was the first prospective randomized, double-blind, placebo-controlled trial of the effects of HRT (with conjugated estrogen and medoxyprogesterone acetate) on CHD risk. It enrolled 2,763 postmenopausal women (average age 67 years). Surprisingly, after 4 years of follow-up, there were 179 CHD events in the HRT group and 182 in the placebo group with 57 events in the HRT group and 38 in the placebo group in year 1 (relative hazard [RH] 1.5).5 In the first 4 months of the trial there was an RH of 2.3. However, in years 4 and 5 there were 40 events in the HRT group and 53 in the placebo group (RH 0.75).5 Because of this late trend for benefit, the HERS investigators are following 2,297 participants for at least 3 more years, while they continue with their assigned treatment groups. This study extension is known as HERS II. The failure of HERS to achieve a positive result does not disprove the estrogen/heart disease hypothesis, since the trial was significantly underpowered. The average duration of follow-up was nearly 7 months less than originally planned. This resulted from enrollment of a large percentage of the participants within the final 6 months of the 18-month recruitment period. There was a higher than expected crossover rate between the groups. There was a 1.7%/ year crossover rate from placebo to HRT (1%/year was expected), and an 18% crossover from HRT to placebo in the first year (5% rate was expected). The event rate in HERS was lower than expected, 3.3%/ year, rather than the 5% that was predicted. It was predicted that the event rate in the placebo group would be 24%, but the actual rate was 13%. The incremental benefit of HRT may not be as great as had been predicted, because many more women are now treated with proven preventive therapies. More women than ever before are being treated with statins, aspirin, b blockers, and angiotensin-converting enzyme inhibitors, all of which decrease events in patients with CHD.6 Another potential explanation for the neutral outcome of HERS is that progestin may attenuate the cardioprotective effect of estrogen. Medroxyprogesterone acetate has been shown to decrease the beneficial effects of estrogen on coronary vasoreactivity and inhibition of atherosclerosis in cynomolgus monkeys.7 Perhaps another type of progestin that is less androgenic may have led to better results.8 However, recent data indicate that the HRT regimen used in HERS does indeed improve brachial artery vasoreactivity to a greater degree than does statin therapy.9 The early increase in CHD events observed in HERS may possibly be due to a thrombogenic effect of HRT in a small percentage of “susceptible” women. A possible thrombogenic risk may have been increased by HRT in smaller, thinner women because the dose was not adjusted for body mass. The HERS investigators will need to determine if the women who sustained CHD events during the first year of the trial had a more “thrombogenic profile” or if they had more extensive coronary disease at baseline. Potential thrombogenic risk factors include Factor V Leiden10 and platelet genetic polymorphisms such as platelet antigen-2 (PlA2).11 The interaction between these risk factors and hormones will need to be investigated further. Prospective identification of women who are susceptible to the potential thrombogenic effects of HRT could allow clinicians to limit prescription of the therapy to appropriate women.5 The HERS investigators also need to report if there were subgroups of women who derived clinical benefit from HRT, such as those with low high-density lipoprotein cholesterol or high lipoprotein(a), because HRT significantly improves these lipid fractions. Most women receiving HRT in observational studFrom The Departments of Medicine/Cardiology and Obstetrics & Gynecology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and The Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Manuscript received August 31, 1999; revised manuscript received and accepted November 3, 1999. Address for reprints: Roger S. Blumenthal, MD, The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Carnegie 538, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, Maryland 21287. E-mail: rblument@jhmi.edu.

Effects of Menopause and Estrogen Replacement Therapy or Hormone Replacement Therapy in Women With Diabetes Mellitus

Given that the prevalence of non-insulin-dependent diabetes mellitus (type 2 DM) is increasing in postmenopausal women and type 2 DM substantially increases the risk for cardiovascular events in postmenopausal women, a population that is at higher risk for coronary heart disease, The North American Menopause Society (NAMS) developed a consensus opinion on appropriate management strategies for postmenopausal women who have or who are at risk for developing type 2 DM.NAMS held a closed conference of experts in the field to evaluate the published clinical data on the effects of menopause, type 2 DM, and estrogen or hormone replacement therapy (ERT/HRT) in women, especially the effects on cardiovascular risk factors, and to discuss therapeutic options. The proceedings of the conference were used to assist the NAMS Board of Trustees in developing this consensus opinion.On the basis of the current knowledge, NAMS established consensus on the following issues: (1) Controlling cardiovascular risk factors through pharmacologic and nonpharmacologic means can significantly decrease the risk for developing cardiovascular events. (2) A broad-based recommendation for ERT/HRT cannot be made; rather, the benefits and risks must be weighed in the context of each woman's risk factors. (3) When ERT/HRT is recommended, the greatest benefits may be obtained from the use of transdermal estrogen preparations, low doses of oral estrogens, progesterone instead of progestin, and/or nonandrogen preparations, although more research is needed in this area. (4) Counseling can help maximize the patient's adherence to multiple medication regimens and increase her understanding of the potential benefits and risks of ERT/HRT.Controlling an individual woman's risk factors for cardiovascular events should be the focus of any management strategy for a postmenopausal woman who has or is at risk for developing type 2 DM.

The Acute Effect of Estrogen on Vascular Responses and Plasma Endothelin-1 Level in Postmenopausal Women

Background and Objectives:Although estrogen replacement therapy has been associated with reduction of cardiovascular events in postmeno-pausal women (PMW, the underlying mechanisms are pooly understood. Because the beneficial effect of estrogen on vasomotor function and production of vasoconstrictive endothelin-1 may be a mechanism by which cardiovascular disease events are reduced, we accessed the acute effect of estrogen on endothelial dependent, independent vasodilaton and plasma endothelin-1 level and investigated whether the acute effect of estrogen on vascular response is related to reduced circulating plasma endothelin-1 level. Materials and Method:The diameter of the brachial artery at rest, during reactive hyperemia (FMV and to response to nitroglycerine (NMV were measured using high resolution ultrasound. Twenty-one PMW, 523 years old, 8 of whom had hypercholesterolemia were included and randomized to receive placebo, conjugated estrogen 2.5 mg and 5.0 mg with one week between each investigation. FMV and plasma endothelin-1 were assessed before and 30 minutes after iv administration of each substance. Sublingual nitroglycerine (NG was given at the end of each investigation and NMV was measured. Results:FMV and plasma endothelin-1 were not changed after placebo administration. FMV increased sinigicantly only after administration of CE 5.0 mg in healhy PMW and both after administration of CE 2.5 and 5.0 mg in PMW with hypercholesterolemia. NG induced more significant vasodilation after administration of estrogen than placebo in only PMW with hypercholesterolemia. Plasma endothelin-1 level decreased significantly after administration of CE 5.0 mg in PMW with hypercholesterolemia. We could not find direct correlation between increase of FMV and decrease of plasma endothelin-1 level. Conclusion:IV administration of conjugated estrogen improves endothelium- dependent vasodilation in PMW and may improve endothelium-independent vasodilation in PMW with hypercholesterolemia. These finding may be partly originated by reduced plasma endothelin-1 level after estrogen administration. (Korean Circulation J 1998;28(7 :1112-1121

Gender Difference in Improvement of Endothelium-Dependent Vasodilation After Estrogen Supplementation

Objectives. We examined whether there is a gender difference in the improvement of endothelium-dependent vasodilation after estrogen supplementation.Background. Estrogen therapy reduces the risk of cardiovascular events in postmenopausal women, and the augmented release of endothelium-derived nitric oxide (NO) by estrogens has been suggested to be one of the mechanisms for the cardioprotective effects of estrogen.Methods. With ultrasound technique, we measured the diameter and blood flow of the brachial artery at rest, during reactive hyperemia after transient occlusion and after nitroglycerin administration before and after estradiol supplementation in 15 postmenopausal women (mean 63 years) and in 15 men matched for age and risk factors for atherosclerosis.Results. Estradiol supplementation augmented the flow-mediated vasodilation and serum level of nitrite/nitrate (metabolites of NO) in women (respectively, from a mean ± SEM of 8.0 ± 0.6% to 12.9 ± 0.6% [p < 0.01 by analysis of variance (ANOVA)] and from 64.9 ± 8.7 to 93.7 ± 9.4 μmol/liter [p < 0.05 by ANOVA]) but not in men (respectively, from 8.1 ± 0.6% to 8.3 ± 0.7% and from 57.8 ± 6.7 to 60.8 ± 5.4 μmol/liter). The increases in blood flow during reactive hyperemia and in diameter after nitroglycerin administration were not affected by estradiol supplementation in either men or women.Conclusions. Estradiol supplementation improves endothelium-dependent vasodilation in women, probably because of augmented NO production/release, but not in men. Thus, there may be gender differences in the effects of estrogen therapy on endothelial functions and NO production/release.

Effects of estrogen replacement therapy on peripheral vasomotor function in postmenopausal women

Hormone replacement therapy is associated with a reduction in cardiovascular events in postmenopausal women. We have recently found that acute 17β-estradiol administration improves endothelium-dependent vasodilation in both the peripheral and coronary circulations of postmenopausal women. The current study was undertaken in 33 estrogen-deficient postmenopausal women ( mean age 59 ± 7 years) to determine if short-term estrogen replacement therapy also improves endothelium-dependent vasodilation in peripheral circulation. Acute intraarterial infusion of estradiol, which increased forearm venous estradiol levels from 16 ± 11 to 345 ± 202 pg/ ml, potentiated forearm vasodilation induced by the endothelium-dependent vasodilator acetylcholine by 49 ± 67% ( p <0.001). Acute estradiol also potentiated vasodilation induced by the endothelium-independent vasodilator nitroprusside by 5 ± 31% ( p = 0.04). However, after 3 weeks of transdermal estradiol administration (0.1 mg/day), which achieved an estradiol level of 120 ± 57 pg/ ml, the vasodilator responses to acetylcholine and to sodium nitroprusside were unchanged from initial measurements obtained before acute administration of estradiol. Repeat intraarterial infusion of estradiol in 8 women, while receiving transdermal estradiol, increased forearm venous estradiol levels to 268 ± 105 pg/ ml and again potentiated the vasodilator response to acetylcholine to a similar degree as that observed in the initial study after acute administration of estradiol. Thus, although acute intraarterial infusion of 17β-estradiol potentiates endothelium-dependent vasodilation in the forearms of postmenopausal women, this effect is not maintained with a 3-week cycle of systemic estradiol administration. The different effects of acute and chronic estradiol may be due to the lower plasma levels achieved with chronic estrogen administration.

Effects of Physiological Levels of Estrogen on Coronary Vasomotor Function in Postmenopausal Women

BACKGROUNDEstrogen replacement therapy has been associated with a reduction in cardiovascular events in postmenopausal women. One of the mechanisms responsible may be a beneficial effect of estrogen on coronary vascular function. We therefore studied the short-term effects of estrogen on coronary artery dimensions and microvascular resistance in postmenopausal women.METHODS AND RESULTSTwenty postmenopausal women 61 +/- 7 years old participated in this study. Seven had angiographic evidence of atherosclerosis of the left coronary artery. Coronary artery diameters were measured by quantitative coronary angiography. Blood flow velocity was measured with a Doppler wire placed in a proximal left coronary artery segment. Left coronary artery infusions of acetylcholine (range, 10(-8) to 10(-5) mol/L estimated delivered concentrations) and of adenosine (n = 18) and sodium nitroprusside (n = 10) were performed before and during concomitant continuous intracoronary infusion of 17 beta-estradiol to test endothelium-...

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.

Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women.

Estrogen replacement therapy has been associated with a reduction in cardiovascular events in postmenopausal women. One of the mechanisms responsible may be a beneficial effect of estrogen on coronary vascular function. We therefore studied the short-term effects of estrogen on coronary artery dimensions and microvascular resistance in postmenopausal women. Twenty postmenopausal women 61 +/- 7 years old participated in this study. Seven had angiographic evidence of atherosclerosis of the left coronary artery. Coronary artery diameters were measured by quantitative coronary angiography. Blood flow velocity was measured with a Doppler wire placed in a proximal left coronary artery segment. Left coronary artery infusions of acetylcholine (range, 10(-8) to 10(-5) mol/L estimated delivered concentrations) and of adenosine (n = 18) and sodium nitroprusside (n = 10) were performed before and during concomitant continuous intracoronary infusion of 17 beta-estradiol to test endothelium-dependent and independent vasodilation, respectively. Intracoronary infusion of estradiol increased coronary sinus estradiol levels from postmenopausal (16 +/- 11 pg/mL) to premenopausal (282 +/- 121 pg/mL) levels. Estradiol did not affect basal coronary artery diameter, blood flow, or resistance. Epicardial coronary artery constriction induced by acetylcholine infusion in the control study (maximum, 10 +/- 15% from baseline) was prevented during repeat acetylcholine infusion with concomitant estradiol administration (P < .001). Estradiol potentiated the vasodilator coronary microvascular response to acetylcholine as manifest by significantly greater coronary flow (P < .001) and lower coronary resistance (P < .02). The reduction in coronary resistance from baseline in response to acetylcholine was significantly potentiated by estradiol (P = .01), with a mean decrease in coronary vascular resistance during acetylcholine infusion of 20 +/- 38% before and 35 +/- 33% during concomitant estradiol administration. The effect of estradiol on coronary dynamics was similar in women with and women without angiographically apparent left coronary artery atherosclerosis and was most prominent in women with the most impaired responses to acetylcholine at both the epicardial (r = -.72, P < .001) and microvascular (r = -.59, P = .006) coronary artery levels. In contrast, estradiol did not affect the coronary epicardial or microvascular vasodilator responses to adenosine or sodium nitroprusside. Physiological levels of 17 beta-estradiol acutely and selectively potentiate endothelium-dependent vasodilation in both large coronary conductance arteries and coronary microvasuclar resistance arteries of postmenopausal women. This effect may contribute to the reduction in cardiovascular events observed with estrogen replacement therapy.