Brian W. Walsh

Effects of Postmenopausal Estrogen Replacement on the Concentrations and Metabolism of Plasma Lipoproteins

Abstract Background. Postmenopausal estrogen-replacement therapy may reduce the risk of cardiovascular disease, and this beneficial effect may be mediated in part by favorable changes in plasma lipid levels. However, the effects on plasma lipoprotein levels of postmenopausal estrogens in the low doses currently used have not been precisely quantified, and the mechanism of these effects is unknown. Methods. We conducted two randomized, double-blind crossover studies in healthy postmenopausal women who had normal lipid values at base line. In study 1, 31 women received placebo and conjugated estrogens at two doses (0.625 mg and 1.25 mg per day), each treatment for three months. In study 2, nine women received placebo, oral micronized estradiol (2 mg per day), and transdermal estradiol (0.1 mg twice a week), each treatment for six weeks. The metabolism of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) was measured by endogenously labeling their protein component, apolipoprotein B. Resu...

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

Coronary artery disease is the leading cause of death among women in the United States, accounting for 23% of all deaths [1, 2]. The incidence of coronary artery disease in women aged 35 to 44 years is 1 per 1000, increasing to 4 per 1000 in women aged 45 to 54 years [3, 4]. Among women in their fifth decade, the incidence of coronary artery disease is one half that of men. By the sixth decade, however, women and men have the same incidence of coronary disease [2, 5, 6]. This disparity between premenopausal women and men of similar age suggests that endogenous sex hormones such as estrogen may have a significant cardioprotective influence. In postmenopausal women, estrogen replacement therapy independently decreases the risk for cardiovascular events and mortality [6, 7]. Estrogen therapy limited the uptake of cholesterol ester into the arterial wall and attenuated the development of dietary-induced atherosclerosis in monkeys and baboons that had ovariectomy [8-10]. Angiographic studies have consistently found less coronary artery disease in women who receive estrogen replacement therapy [7, 11, 12]. Beneficial effects of estrogen replacement therapy include its ability to reduce low-density lipoprotein (LDL) cholesterol levels and increase high-density lipoprotein (HDL) cholesterol levels [13]. Nonetheless, multiple regression analyses suggest that only 25% to 50% of the reduction in cardiovascular events is attributable to the lipid-lowering effects of estrogen replacement therapy [14], suggesting that other mechanisms contribute to its cardioprotective potential. One such mechanism may involve the effect of estrogen on vascular function. Specifically, estrogen may directly enhance the activity of the endothelium-derived relaxing factor nitric oxide [10, 15-17] and thereby lessen the potential for coronary vasoconstriction and thrombosis [18-21]. When administered to rabbits that had ovariectomy, long-term estrogen replacement improved endothelium-dependent relaxation in vitro [15, 16]. In addition, both short-term and long-term estrogen administration improves in vivo the endothelium-dependent vasodilation in coronary arteries of atherosclerotic cynomolgus monkeys that had ovariectomy [10, 17]. Several recent studies have suggested that short-term estrogen administration improves endothelium-dependent vasodilation of the coronary arteries of postmenopausal women [22, 23]. We hypothesized that long-term estrogen administration would improve vasomotor function in postmenopausal women. Accordingly, we conducted a double-blind, randomized, crossover, placebo-controlled trial to assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women. We used high-resolution ultrasonography to serially assess vasomotor function in a peripheral conduit vessel, the brachial artery. Methods Patients The patients enrolled in this study were recruited from a larger cohort that was participating in a clinical research trial investigating the effect of estrogen replacement therapy on lipoprotein metabolism. Thirteen postmenopausal women aged 44 to 69 years (average age, 55 7 years) participated in this study. Women were eligible if menopause had occurred at least 1 year previously. Menopause was confirmed by measuring serum follicle-stimulating hormone levels. No patient had received hormone replacement therapy for at least 2 months before the study began. A history and physical examination were done to exclude persons with clinical evidence of coronary or peripheral atherosclerosis. Initial evaluation included a Papanicolaou smear (if not done in past year), complete blood count, routine chemistry panel, and lipid profile. Inclusion criteria included mild hypercholesterolemia, defined as a serum cholesterol level of 5.17 mmol/L to 6.20 mmol/L and an LDL cholesterol level of 3.36 mmol/L to 4.13 mmol/L. Exclusion criteria included hypertension, diabetes mellitus, tobacco use, obesity (body weight > 135% of ideal weight), history of breast or uterine cancer, thromboembolism, and liver or renal disease. Eligible patients were placed on a low-cholesterol diet (American Heart Association phase I) for 6 weeks before randomization. Patients were randomly assigned to one of three treatment groups: placebo, oral 17 -estradiol (Estrace, Mead Johnson, Evansville, Indiana.) at a dose of 1 mg/d, or oral 17 -estradiol at a dose of 2 mg/d. At the conclusion of each 9-week treatment period, the patients were given progesterone (Provera, Upjohn, Kalamazoo, Michigan) at 10 mg/d for 10 days. Hormone replacement therapy was discontinued for 3 weeks before patients crossed over to the next treatment regimen. All patients received placebo and the two doses of estrogen in random order. Vascular function studies (described below) were done during the eighth or ninth week of each treatment period. Experimental Protocol Studies were done in a temperature-controlled vascular research laboratory. All patients were placed in the supine position. We studied vascular reactivity in a conduit vessel, the brachial artery, as previously described. An imaging study of the brachial artery was done using a high-resolution ultrasound machine (Toshiba, Model SSA-270, Otawara-shir, Tochigi-Ken, Japan) that was equipped with a 7.5 MHz linear-array transducer. Baseline images of the brachial artery were obtained proximal to the antecubital fossa. Imaging of the artery was done longitudinally, allowing clear visualization of the posterior wall intima-lumen interface and the anterior wall media-adventitial interface. We assessed endothelium-dependent vasodilation by measuring the change in the caliber of the brachial artery during reactive hyperemia, a maneuver that increases flow through the conduit segment being studied (flow-mediated vasodilation). To create this stimulus, a cuff placed on the upper arm was inflated to suprasystolic pressure for 5 minutes, thereby occluding flow to the forearm. This results in dilatation of downstream forearm resistance vessels. After cuff deflation, reactive hyperemia occurs, as brachial artery blood flow increases to accommodate the dilated resistance vessels. Imaging of the brachial artery was continually done for the 5-minute period after cuff deflation until basal conditions were re-established. Thereafter, sublingual nitroglycerin (at a dose of 0.4 mg) was administered to assess endothelium-independent vasodilation. The artery was studied for an additional 5 minutes. Blood pressure and heart rate were monitored continuously throughout the procedure. All images were recorded on Super VHS videotape for subsequent analysis. Image analysis was done on a personal computer that was equipped with a video frame grabber. Images recorded on videotape were analyzed by an investigator blinded to treatment assignment. Previous studies have shown that the peak diameter change during reactive hyperemia occurs approximately 1 minute after cuff deflation and 3 minutes after nitroglycerin administration [41]. We used these time points in our study. Images corresponding to the end of the T wave on a simultaneous electrocardiograph were selected and digitized. Image analysis was then done using a proprietary analysis software that searched for the shortest distance between the points on the arterial wall, creating 10 to 20 paired measurements along a 10-mm length. We measured arterial diameter from the intima-lumen interface on the posterior wall to the media-adventitial interface on the anterior wall. We calculated brachial artery diameter by averaging these paired lumen measurements and reported them in millimeters using calibration factors derived from real-time ultrasonography. We used an average of three separate measurements for each condition. In our laboratory, this technique has a variability of only 0.0 0.1 mm [24]. To assure that the blood flow stimulus during reactive hyperemia was similar during each treatment phase, forearm blood flow was measured by venous occlusion strain gauge plethysmography using calibrated mercury-in-silastic strain gauges as previously described [25]. Statistical Analysis The variables compared during the placebo period and during therapy with each dose of estrogen included blood pressure, heart rate, forearm blood flow, basal brachial artery diameter, and the percentage increase in diameter during reactive hyperemia and after patients received sublingual nitroglycerin. Values are expressed as the mean SE. For statistical analysis, we used repeated-measure analysis of variance and the Scheffe-F post hoc test [26]. Significance was accepted at P 0.05. Results Baseline Hemodynamic Measurements The effect of estrogen treatment on blood pressure, heart rate, forearm blood flow and forearm vascular resistance is presented in Table 1. Estrogen therapy did not affect blood pressure or heart rate. Basal forearm blood flow tended to be higher during both estrogen treatment phases (P = 0.08). Basal forearm vascular resistance was similar during all three treatment phases. The peak forearm blood flow during reactive hyperemia was similar during placebo receipt and each estrogen treatment period. However, peak forearm blood flow was greater when patients received the 1-mg dose of estradiol than when they received the 2-mg dose (P = 0.05). Table 1. Effect of Estrogen Replacement on Hemodynamic Measurements Flow-Mediated Endothelium-Dependent Vasodilation We obtained technically adequate ultrasound images during reactive hyperemia for 12 of the 13 patients. The brachial artery diameter, under basal conditions, measured 3.5 mm, 3.4 mm, and 3.3 mm while patients received placebo, estradiol at 1 mg/d, and estradiol at 2 mg/d, respectively (P > 0.2). The percentage increase in brachial artery diameter during reactive hyperemia for each treatment period is shown in Figure 1. The change in brachial artery diameter was greater when patients received estradiol treatment (13.5% and 11.6

National Study of Physician Awareness and Adherence to Cardiovascular Disease Prevention Guidelines

Background—Few data have evaluated physician adherence to cardiovascular disease (CVD) prevention guidelines according to physician specialty or patient characteristics, particularly gender. Methods and Results—An online study of 500 randomly selected physicians (300 primary care physicians, 100 obstetricians/gynecologists, and 100 cardiologists) used a standardized questionnaire to assess awareness of, adoption of, and barriers to national CVD prevention guidelines by specialty. An experimental case study design tested physician accuracy and determinants of CVD risk level assignment and application of guidelines among high-, intermediate-, or low-risk patients. Intermediate-risk women, as assessed by the Framingham risk score, were significantly more likely to be assigned to a lower-risk category by primary care physicians than men with identical risk profiles (P<0.0001), and trends were similar for obstetricians/gynecologists and cardiologists. Assignment of risk level significantly predicted recommendations for lifestyle and preventive pharmacotherapy. After adjustment for risk assignment, the impact of patient gender on preventive care was not significant except for less aspirin (P<0.01) and more weight management recommended (P<0.04) for intermediate-risk women. Physicians did not rate themselves as very effective in their ability to help patients prevent CVD. Fewer than 1 in 5 physicians knew that more women than men die each year from CVD. Conclusions—Perception of risk was the primary factor associated with CVD preventive recommendations. Gender disparities in recommendations for preventive therapy were explained largely by the lower perceived risk despite similar calculated risk for women versus men. Educational interventions for physicians are needed to improve the quality of CVD preventive care and lower morbidity and mortality from CVD for men and women.

Estradiol Therapy Combined With Progesterone and Endothelium-Dependent Vasodilation in Postmenopausal Women

BACKGROUND Epidemiological studies indicate that estrogen replacement therapy decreases the risk of cardiovascular events in postmenopausal women. Estrogen may confer cardiovascular protection by improving endothelial function because it increases endothelium-dependent vasodilation. It is not known whether progesterone attenuates the beneficial effects of estrogen on endothelial function. METHODS AND RESULTS Seventeen postmenopausal women with mild hypercholesterolemia were enrolled in a placebo-controlled, crossover trial to evaluate the effect of transdermal estradiol, with and without vaginal micronized progesterone, on endothelium-dependent vasodilation in a peripheral conduit artery. Brachial artery diameter was measured with high-resolution B-mode ultrasonography. To assess endothelium-dependent vasodilation, brachial artery diameter was determined at baseline and after a flow stimulus induced by reactive hyperemia. To assess endothelium-independent vasodilation, brachial artery diameter was measured after administration of sublingual nitroglycerin. During estradiol therapy, reactive hyperemia caused an 11.1+/-1.0% change in brachial artery diameter compared with 4. 7+/-0.6% during placebo therapy (P<0.001). Progesterone did not significantly attenuate this improvement. During combined estrogen and progesterone therapy, flow-mediated vasodilation of the brachial artery was 9.6+/-0.8% (P=NS versus estradiol alone). Endothelium-independent vasodilation was not altered by estradiol therapy, either with or without progesterone, compared with placebo. There was a modest decrease in total and LDL cholesterol during treatment both with estradiol alone and when estradiol was combined with progesterone (all P<0.001 versus placebo). In a multivariate analysis that included serum estradiol, progesterone, total and LDL cholesterol concentrations, blood pressure, and heart rate, only the estradiol level was a significant predictor of endothelium-dependent vasodilation. CONCLUSIONS The addition of micronized progesterone does not attenuate the favorable effect of estradiol on endothelium-dependent vasodilation. The vasoprotective effect of hormone replacement therapy may extend beyond its beneficial actions on lipids.

Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial

Alendronate and estrogen are effective therapies for postmenopausal osteoporosis, but their efficacy and safety as combined therapy are unknown. The objective of this study was to evaluate the addition of alendronate to ongoing hormone replacement therapy (HRT) in the treatment of postmenopausal women with osteoporosis. A total of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least 1 yr, were randomized to receive either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Changes in bone mineral density (BMD) and biochemical markers of bone turnover were assessed. Compared with HRT alone, at 12 months, alendronate plus HRT produced significantly greater increases in BMD of the lumbar spine (3.6% vs. 1.0%, P < 0.001) and hip trochanter (2.7% vs. 0.5%, P < 0.001); however, the between-group difference in BMD at the femoral neck was not significant (1.7% vs. 0.8%, P = 0.072). Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase and urine N-telopeptide) decreased significantly at 6 and 12 months with alendronate plus HRT, and they remained within premenopausal levels. Addition of alendronate to ongoing HRT was generally well tolerated, with no significant between-group differences in upper gastrointestinal adverse events or fractures. This study demonstrated that, in postmenopausal women with low bone density despite ongoing treatment with estrogen, alendronate added to HRT significantly increased bone mass at both spine and hip trochanter and was generally well tolerated.

Thermal Balloon and Rollerball Ablation to Treat Menorrhagia: A Multicenter Comparison ☆

Objective To compare the clinical efficacy and safety of a thermal uterine balloon system with hysteroscopic rollerball ablation in the treatment of dysfunctional uterine bleeding. Methods Two hundred fifty-five premenopausal women were treated in a randomized multicenter study comparing thermal uterine balloon therapy with hysteroscopic rollerball ablation for the treatment of menorrhagia. Preproce-dural and postprocedural menstrual diary scores and quality-of-life questionnaires were obtained. Twelve-month follow-up data are presented on 239 women. Results Twelve-month results indicated that both tech-niques significantly reduced menstrual blood flow with no clinically significant difference between the two groups as reflected by return to normal bleeding or less (balloon 80.2% and rollerball ablation 84.3%). Multiple quality-of-life ques-tionnaire results were also similar, including percent of patients highly satisfied with their results (balloon 85.6% compared with rollerball 86.7%). A 90% decrease in diary scores was seen in more than 60% of patients in both groups. Procedural time was reduced significantly in the uterine balloon therapy group. Intraoperative complications oc-curred in 3.2% of the hysteroscopic rollerball patients, whereas no intraoperative complications occurred in the thermal balloon group. Conclusion In the treatment of dysfunctional uterine bleeding, uterine balloon therapy is as efficacious as hysteroscopic rollerball ablation and may be safer.

Estradiol With or Without Progesterone and Ambulatory Blood Pressure in Postmenopausal Women

The purpose of this study was to determine whether transdermal estradiol and intravaginal progesterone given in doses to mimic the premenopausal state would lower blood pressure (BP) in postmenopausal women. Fifteen healthy postmenopausal women were studied in each of 3 conditions: on placebo, after 8 weeks of transdermal estradiol 0.2 mg twice per week, and again 2 weeks after addition of intravaginal progesterone 300 mg/d. Women were studied at each point after 2 days of 100 mmol/d sodium intake. Twenty-four-hour ambulatory BP monitoring was performed, and blood was assayed for estradiol, progesterone, and hormones of the renin-angiotensin-aldosterone system (RAAS). ANOVA with pairwise comparisons was used for analysis. Urinary sodium excretion was similar at each time point. Levels of estrogen and progesterone similar to those in premenopausal women were achieved. On estradiol, nocturnal systolic BP (110+/-3 mm Hg), diastolic BP (63+/-2 mm Hg), and mean BP (77+/-2 mm Hg) fell significantly (P<0.02) compared with placebo systolic BP (116+/-2 mm Hg), diastolic BP (68+/-2 mm Hg), and mean BP (82+/-2 mm Hg). Daytime BP followed the same trend but was significantly lower only for mean BP. There was no activation of the RAAS. The addition of progesterone resulted in no further fall in BP but a significant activation of the RAAS. Thus, contrary to what is often assumed, administration of estradiol with or without progesterone not only did not raise BP but rather substantially lowered BP. This BP-lowering effect may be responsible for the lower incidence of hypertension in premenopausal than in postmenopausal women.

A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium

Objective To determine the effects of a selective estrogen receptor modulator, raloxifene, on postmenopausal endometrium. Methods Healthy postmenopausal women (n = 415) were randomly assigned to one of the following four groups: 60 or 150 mg/day raloxifene hydrochloride, 0.625 mg/day conjugated equine estrogens, or placebo, and treated for 1 year. Endometrial biopsies were obtained in a blinded fashion at baseline and every 6 months after the ultrasound studies. Transvaginal ultrasound, with uterine size measurements, was done at baseline and at 3-month intervals. Saline-infusion sonohysterography was done at baseline and every 6 months. Results There were no statistically significant differences in baseline characteristics. Mean endometrial thickness, measured by transvaginal ultrasound, was unchanged from baseline to end point in the placebo and raloxifene groups, whereas in the estrogen group it was significantly thicker by 5.5 mm (P < .001). Mean uterine volume, calculated from transvaginal ultrasound measurements, was higher in the estrogen group only (22 cm3, P < .001). Of the 358 women with paired biopsies, endometrial hyperplasia was present in 2.1%, 0%, and 26.1% of the end-point biopsies in the placebo, raloxifene, and estrogen groups, respectively (P < .001). Proliferative endometrium was present in 2.1% of the end-point biopsies in the placebo group, 1.7% in the combined raloxifene groups, and 39.8% in the estrogen group (P < .001). Conclusion Raloxifene, at 60 or 150 mg/day for 1 year, did not stimulate the postmenopausal endometrium. End-point endometrial thickness, morphology, and uterine volume in the raloxifene groups were similar to those observed at baseline and in the placebo group.

Evidence-based guidelines for cardiovascular disease prevention in women. American Heart Association scientific statement.

Significant advances in our knowledge about interventions to prevent cardiovascular disease (CVD) have occurred since publication of the first female-specific recommendations for preventive cardiology in 1999.1 Despite research-based gains in the treatment of CVD, it remains the leading killer of women in the United States and in most developed areas of the world.2–3⇓ In the United States alone, more than one half million women die of CVD each year, exceeding the number of deaths in men and the next 7 causes of death in women combined. This translates into approximately 1 death every minute.2 Coronary heart disease (CHD) accounts for the majority of CVD deaths in women, disproportionately afflicts racial and ethnic minorities, and is a prime target for prevention.1–2⇓ Because CHD is often fatal, and because nearly two thirds of women who die suddenly have no previously recognized symptoms, it is essential to prevent CHD.2 Other forms of atherosclerotic/thrombotic CVD, such as cerebrovascular disease and peripheral arterial disease, are critically important in women. Strategies known to reduce the burden of CHD may have substantial benefits for the prevention of noncoronary atherosclerosis, although they have been studied less extensively in some of these settings. In the wake of the reports of the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study (HERS), which unexpectedly showed that combination hormone therapy was associated with adverse CVD effects, there is a heightened need to critically review and document strategies to prevent CVD in women.4–7⇓⇓⇓ These studies underscore the importance of evidence-based practice for chronic disease prevention. Optimal translation and implementation of science to improve preventive care should include a rigorous process of evaluation and clear communication about the quantity and quality of evidence used to support clinical recommendations. Recently, there has …

Sex hormones and lipoprotein metabolism.

Previous findings of increased production of large VLDL particles by estrogen have been confirmed in a trial using estrogen-dominant oral contraceptives. Estrogen has been found to have LDL subclass-specific effects and to shift the distribution of apolipoprotein (apo)E from HDL to VLDL. Several recent studies document decreases in lipoprotein (a) [Lp(a)] levels, but the metabolic mechanism is yet unknown. The effects of progestational agents on lipoprotein metabolism remain unclear in view of conflicting reports.