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Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study.

BACKGROUND: Hot flashes are frequent in postmenopausal breast cancer patients, especially when treated with tamoxifen. Estrogen replacement therapy is the most effective treatment for hot flashes, but its use is controversial in breast cancer survivors. Progestins may offer a good alternative for the control of hot flashes in this setting; in particular, oral megestrol acetate has been proven effective in a randomized, placebo-controlled clinical trial. With the aim of further improving these results, we have designed a randomized study comparing oral megestrol acetate with depot intramuscular (i.m.) medroxyprogesterone acetate (MPA) for the control of hot flashes in postmenopausal patients with a history of breast cancer. PATIENTS AND METHODS: Seventy-one postmenopausal patients were randomized to receive an i.m. injection of depot MPA 500 mg on days 1, 14 and 28, or oral megestrol acetate 40 mg daily for 6 weeks. Patients recorded daily the number and severity of their hot flashes; response was defined as a > or =50% decrease in the number and severity of hot flashes. RESULTS: At week 6, hot flashes were reduced by 86% on average in the whole group of patients, without significant differences between the two progestins. Response was obtained by 75 and 67% of patients receiving MPA or megestrol, respectively (P = 0.5). Responders were followed to assess maintenance of response (without further treatment), which was significantly better with i.m. MPA: in this group, 89% of responders still showed a benefit at week 24, compared with 45% in the megestrol group (P = 0.03). CONCLUSIONS: Our study shows that a short cycle of i.m. depot MPA injections provides significant and long-lasting relief from postmenopausal hot flashes in patients with a history of breast cancer, offering an alternative to estrogen replacement therapy or prolonged administration of oral megestrol.

Administration, Oral↗

The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L).

BACKGROUND: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). PATIENTS AND METHODS: MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. RESULTS: Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. CONCLUSIONS: The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.

Aged↗

Genistein stimulates growth of human breast cancer cells in a novel, postmenopausal animal model, with low plasma estradiol concentrations.

We have demonstrated that genistein (GEN) stimulates growth of estrogen-dependent breast tumors in vivo. In this study, we evaluated whether dietary GEN can act in an additive manner with low circulating levels of 17beta-estradiol (E2). We developed an E2 delivery system using silastic implants that yield low circulating plasma E2 levels similar to those observed in postmenopausal women. We inserted various concentrations of E2 silastic implants (1:127, 1:63, 1:31, 1:15 and 1:7 = E2:cholesterol) and injected estrogen-dependent human breast cancer (MCF-7) cells into ovariectomized athymic mice. The E2 implants tested (1:127-1:7) generated 30.1-101.6 pM E2 in plasma, which is comparable to the E2 levels observed in postmenopausal women. The E2 implants stimulated MCF-7 tumor growth in a dose-dependent manner. We selected the 1:31 ratio of E2 implant to evaluate if dietary GEN acts in an additive manner with low E2 levels to influence the growth of MCF-7 tumors. Ovariectomized mice were divided into four groups: MCF-7 control, 500 ppm GEN, 1:31 E2, and 1:31 E2 + 500 ppm GEN. At week 17, the average tumor sizes were 7.6, 32.1, 67.4 and 106.8 mm2 for these groups, respectively (P < 0.05), demonstrating that 500 ppm GEN additively stimulated MCF-7 tumor growth in the presence of low levels of E2. In summary, we established a preclinical mouse model that results in E2 blood concentrations similar to those found in postmenopausal women. Further, we observed that these concentrations regulate the growth rate of MCF-7 breast tumors. Using this model, we demonstrated that dietary GEN in the presence of low levels of circulating E2 act in an additive manner to stimulate estrogen-dependent tumor growth in vivo. Results from this study suggest that consumption of products containing GEN may not be safe for postmenopausal women with estrogen-dependent breast cancer.

Animals↗

Resistive training increases insulin action in postmenopausal women.

BACKGROUND: This study examined the effects of 4 months of resistive training in postmenopausal women on glucose metabolism and peripheral tissue sensitivity to endogenously released insulin. METHODS: Thirteen moderately obese (30-49% body fat) postmenopausal women (50-65 years) participated in the study. The six more obese women were enrolled in the resistive training with weight loss (RT & WL) program, while the remainder participated in resistive training alone (RT). beta-cell sensitivity to glucose and peripheral tissue sensitivity to endogenously released insulin were examined during hyperglycemic clamps (7.9 mmol/L above basal) before and after the intervention(s). RESULTS: The RT program resulted in a significant improvement in upper and lower body strength (p < .01) in all subjects. Body weight, fat mass, and percent body fat decreased with RT & WL (p < .001), but did not change with RT alone. There was no change in fat-free mass or maximal oxygen consumption after the intervention(s). Insulin response during the last 20 min of the 2 hr hyperglycemic clamps (7.9 mmol/L above basal plasma glucose levels) decreased after the intervention(s) in the entire group by 29% (p < .01), but decreased more in the group that lost weight (43%, p < .05) than in women who remained weight stable (16%, p = .05). Glucose utilization did not change. CONCLUSION: RT alone, or in combination with WL, increases insulin action and reduces hyperinsulinemia in postmenopausal women. This suggests that RT has the potential to ameliorate and perhaps prevent the development of insulin resistance and may reduce the risk for glucose intolerance and non-insulin-dependent diabetes mellitus (NIDDM) in postmenopausal women.

Aged↗

Determinants of body composition in postmenopausal women.

BACKGROUND: Little is known about the effects of different levels of long-term physical activity on total body and regional fat and whether hormone replacement therapy interacts with physical activity level to affect body composition in postmenopausal women. METHODS: We determined the associations between different levels of habitual physical activity, hormone replacement therapy (HRT), and total and regional body composition in postmenopausal women. Twenty sedentary, 20 active nonathletic, and 23 endurance-trained women (approximately half on HRT) had total and regional body composition assessed by dual-energy x-ray absorptiometry. The athletes and active nonathletic women had been active for the same number of years and the same number of hours per week. RESULTS: The athletes and sedentary women weighed the same, but the active nonathletic groups on and not on HRT weighed 3-12 kg more (p < .05). Athletes had less trunk, arm, leg, and total body fat than sedentary and active nonathletic women (p < .05). Women on HRT tended to have lower total body (p = .07), but not regional, fat values. Linear regression analyses indicated that VO2max in ml/kg/min was the major independent determinant of total and regional body fat accounting for 52% to 70% of their variances. Athletes had greater caloric and carbohydrate intake than their less active peers, but all groups had similar protein, fat, saturated fat, monounsaturated fat, and polyunsaturated fat intakes. CONCLUSIONS: Intense training, but not low- to moderate-intensity physical activity, is associated with markedly lower levels of total and regional body fat in postmenopausal women. HRT has less of an effect on body composition than intense exercise training in postmenopausal women.

Adipose Tissue↗

Lifestyle intervention of hypocaloric dieting and walking reduces abdominal obesity and improves coronary heart disease risk factors in obese, postmenopausal, African-American and Caucasian women.

BACKGROUND: There are few empirical data to support the claim that weight loss improves coronary heart disease (CHD) risk factors in postmenopausal women; nor is it known if there are racial differences in changes of body fat distribution, lipids, glucose tolerance, and blood pressure with weight loss. This study determined the efficacy of a lifestyle weight loss intervention in reducing total and abdominal obesity and improving CHD risk factors in obese Caucasian and African-American postmenopausal women. METHODS: Body composition (dual-energy x-ray absorptiometry), abdominal fat areas (computed tomography scan), lipoprotein lipids, insulin, glucose tolerance, and blood pressure were measured before and after 6 months of hypocaloric diet and low-intensity walking in 76 overweight or obese (body mass index > 25 kg/m(2)), Caucasian (72%) or African-American (28%), postmenopausal (age = 60 +/- 5 years) women who completed the study. RESULTS: Absolute amount of body weight lost was similar in Caucasians (-5.4 +/- 3.6 kg) and African Americans (-3.9 +/- 3.6 kg), but Caucasian women lost relatively more fat mass (p <.05). Both groups decreased their subcutaneous abdominal fat, and Caucasian women decreased their visceral fat area, but there were no racial differences in the magnitude of abdominal fat lost. The intervention decreased triglyceride and increased high-density lipoprotein and high-density lipoprotein 2 cholesterol in both races, and it decreased total and low-density lipoprotein cholesterol in Caucasian women (p <.05-.0001). Fasting glucose and glucose area during the oral glucose tolerance test decreased (p <.0001) in Caucasian women, whereas insulin area decreased in both Caucasian (p <.01) and African-American (p <.05) women. Blood pressure decreased the most in women with higher blood pressures at baseline. Changes in lipids, fasting glucose and insulin, their responses during the oral glucose tolerance test, and blood pressure were not different between racial groups. CONCLUSIONS: Weight loss achieved through a lifestyle intervention of energy restriction and increased physical activity is an equally effective therapy in African-American and Caucasian obese, postmenopausal women for improving glucose and lipid CHD risk factors.

Abdomen↗

Intake of dietary phytoestrogens is low in postmenopausal women in the United States: the Framingham study(1-4).

Many plants that are consumed contain phytoestrogens. Only a few published studies have examined the dietary intake of phytoestrogens in the general Western population. The potentially positive health effects of phytoestrogens might be of relevance to postmenopausal women. The aim of the present study was to estimate the intake of dietary isoflavones, coumestans and lignans by healthy Western postmenopausal women. For this purpose, we studied 964 postmenopausal, Caucasian women who participated in the Framingham Offspring Study and completed the Willett food-frequency questionnaire (FFQ). By searching the medical and agricultural literature and contacting experts, we identified food sources of phytoestrogens. The concentrations of the different isoflavones, coumestrol and lignans in each food in the FFQ were scored in seven categories and multiplied by the serving size of the food and the frequency of its consumption. The estimated daily median intake of the isoflavone daidzein was 39 microg (24-57 microg); of genistein, 70 microg (28-120 microg); of formononetin, 31 microg (13-44 microg); and of biochanin A, 6 microg (2-11 microg). Median total intake of isoflavones was 154 microg (99-235 microg). The main sources of isoflavones were beans and peas. The estimated daily intake of coumestans was 0.6 microg (0.2-1.7 microg), with broccoli as the main source. The estimated daily median intake of matairesinol was 19 microg (12-28 microg) and of secoisolariciresinol 560 microg (399-778 microg). The median total intake of lignans was 578 microg (416-796 microg). The main source of the lignans was fruits. The daily dietary intake of phytoestrogens in healthy postmenopausal Caucasian women in the United States is <1 mg.

Diet↗

Higher dietary intake of lignans is associated with better cognitive performance in postmenopausal women.

Data on the relation between phytoestrogens and cognitive function are still sparse. The purpose of this study was to examine the relation between the dietary intake of phytoestrogens and cognitive function in healthy postmenopausal women consuming a Western diet. We conducted a community-based survey among 394 postmenopausal women. Isoflavone and lignan intake was calculated from a validated FFQ. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Data were analyzed using logistic regression with intact cognitive function defined as a score >/= 26 as the outcome variable. After adjustment for confounders, increasing dietary lignans intake was associated with better performance on the MMSE [OR and (95%CI): 1.49 (0.94-2.38)]. Results were most pronounced in women who were 20-30 y postmenopausal [2.02 (1.11-3.71)]. Isoflavone intake was not related to cognitive function. From our results we conclude that higher dietary intake of lignans is associated with better cognitive function in postmenopausal women.

Aged↗

Consumption of soy isoflavones does not affect plasma total homocysteine or asymmetric dimethylarginine concentrations in healthy postmenopausal women.

Postmenopausal women are at increased risk for cardiovascular disease because many risk factors are aggravated by menopause. Phytoestrogens may modulate risk factors favorably, involving mechanisms similar to estrogen. The effect of phytoestrogens on the atherogenic amino acids homocysteine and asymmetric dimethylarginine (ADMA) was investigated in a controlled intervention study in healthy postmenopausal women. A multicenter, double-blind, crossover intervention trial in 89 postmenopausal women from Denmark, Germany, and the UK was performed. Subjects consumed fruit cereal bars with or without soy isoflavones (50 mg/d) for 8 wk each with an 8-wk washout period in between. Urinary phytoestrogens increased significantly after isoflavone intervention (P < 0.001). Isoflavone supplementation did not affect plasma total homocysteine or ADMA. For homocysteine, changes from baseline were 0.32 micromol/L (range: -0.31-0.92; 95% CI 0.13-0.72), and 0.29 micromol/L (range: -0.45-1.09; 95% CI 0.01-0.63, P = 0.286) for isoflavone treatment and placebo, respectively. For ADMA concentrations, changes from baseline were -0.02 micromol/L (range: -0.08-0.03; 95% CI -0.04-0.01, and 0.00 micromol/L (range: -0.05-0.03; 95% CI -0.03-0.01, P = 0.397) for isoflavone treatment and placebo, respectively. There was no association between plasma total homocysteine and ADMA. Changes from baseline in plasma ADMA and folate were negatively correlated (r = -0.18, P = 0.017). These results challenge the overall health effect of isoflavone supplementation in healthy postmenopausal women.

Aged↗

Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study.

Japanese fermented soybeans (natto in Japanese), which contain a large amount of menaquinone-7, may help prevent the development of osteoporosis. We assessed the possibility of an association between habitual natto intake and bone mineral density (BMD) and BMD change over time in healthy Japanese women who participated in a large representative cohort study (Japanese Population-based Osteoporosis Study: JPOS study). The BMD was measured at the spine, hip, and forearm in 944 women (20-79 y old) at baseline and at a follow-up conducted 3 y later. Dietary natto intake was assessed by a FFQ on both occasions. Additional covariates including age, height, weight, lifestyle factors, dietary calcium intake, and the intake of other soybean products, were also measured. The total hip BMD at baseline increased (P for trend = 0.0034) with increasing habitual natto intake in the postmenopausal women, although this was not the case at other skeletal sites. There were significant positive associations between natto intake and the rates of changes in BMD at the femoral neck (P < 0.0001) and at the distal third of the radius (P = 0.0002) in the postmenopausal women. The association in the femoral neck persisted even after adjusting for covariates. No significant association was observed between the intake of tofu or other soybean products and the rate of BMD change in the postmenopausal women. Natto intake may help prevent postmenopausal bone loss through the effects of menaquinone 7 or bioavailable isoflavones, which are more abundant in natto than in other soybean products.

Adult↗

Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women.

BACKGROUND: A positive relationship has generally been observed between plasma estrogen levels and breast cancer risk in postmenopausal women, but most of these studies have been small and few have evaluated specific estrogen fractions (such as percent bioavailable estradiol). In addition, few studies have evaluated plasma androgen levels in relation to breast cancer risk, and their results have been inconsistent. We prospectively evaluated relationships between sex steroid hormone levels in plasma and risk of breast cancer in postmenopausal women by use of a case-control study nested within the Nurses' Health Study. METHODS: Blood samples were collected during the period from 1989 through 1990. Among postmenopausal women not using hormone replacement therapy at blood collection (n = 11,169 women), 156 women were diagnosed with breast cancer after blood collection but before June 1, 1994. Two control subjects were selected per case subject and matched with respect to age, menopausal status, month and time of day of blood collection, and fasting status at the time of blood collection. RESULTS: From comparisons of highest and lowest (reference) quartiles, we observed statistically significant positive associations with risk of breast cancer for circulating levels of estradiol (multivariate relative risk [RR] = 1.91; 95% confidence interval [CI] = 1.06-3.46), estrone (multivariate RR = 1.96; 95% CI = 1.05-3.65), estrone sulfate (multivariate RR = 2.25; 95% CI = 1.23-4.12), and dehydroepiandrosterone sulfate (multivariate RR = 2.15; 95% CI = 1.11-4.17). We found no substantial associations with percent free or percent bioavailable estradiol, androstenedione, testosterone, or dehydroepiandrosterone. The positive relationships were substantially stronger among women with no previous hormone replacement therapy. CONCLUSION: Our data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.

Adult↗

Relation of sex hormones and dehydroepiandrosterone sulfate (DHEA-SO4) to cardiovascular risk factors in postmenopausal women.

Sex hormones play a major role in determining the risk of cardiovascular disease. While several studies have shown that reduced sex hormone-binding globulin is associated with an atherogenic pattern of lipoproteins and increased glucose concentrations in premenopausal women, little data are available examining the association of sex hormone-binding globulin and sex hormones with cardiovascular risk factors in postmenopausal women, a group with high rates of cardiovascular disease. The investigators hypothesized that in postmenopausal women decreased sex hormone-binding globulin and increased testosterone would be associated with an atherogenic pattern of cardiovascular risk factors. The sex hormone-binding globulin, total and free testosterone, estrone, and dehydroepiandrosterone sulfate (DHEA-SO4) in 253 postmenopausal women who were not taking hormones were measured in a population-based study, the Beaver Dam Eye Study (Beaver Dam, Wisconsin, 1988-1990). Sex hormone-binding globulin was significantly inversely correlated with body mass index (r = -0.53, p 0.001), glycosylated hemoglobin (r = -0.34, p < 0.001), and diastolic blood pressure (r = -0.25, p < 0.001), and positively correlated with high density lipoprotein cholesterol (HDL cholesterol) (r = 0.31, p < 0.001), and HDL cholesterol/total cholesterol (r = 0.31, p < 0.001). Total (r = -0.20, p < 0.01) and free (r = -0.14, p < 0.05) testosterone were significantly inversely correlated with HDL cholesterol/total cholesterol ratio. Total testosterone concentrations were also significantly positively correlated with total cholesterol (r = 0.15), body mass index (r = 0.16), and systolic (r = 0.17) and diastolic (r = 0.18) blood pressures (all p < 0.01). DHEA-SO4 was not associated with any of the metabolic variables, while estrone was inversely associated only with the HDL cholesterol/total cholesterol ratio (r = 0.13, p < 0.05). The authors conclude that increased androgenization in postmenopausal women is associated with atherogenic changes in cardiovascular risk factors.

Adult↗

Acute effect of oestrogen replacement therapy on treadmill performance in postmenopausal women with coronary artery disease.

The significant reduction in cardiovascular morbidity and mortality following oestrogen replacement therapy in postmenopausal women is only partly explained by an improved lipid profile. Given acutely, oestradiol causes vasodilatation and increases coronary blood flow and, in large doses, improves treadmill performance in postmenopausal women with coronary artery disease. However, the significance of oestrogen-mediated vasodilatation is unknown since the acute effects of oestradiol in doses and preparations commonly used clinically have not been tested. The aim of this study was to evaluate the acute effects of conventional replacement therapy with 17 beta-oestradiol on treadmill performance in 16 postmenopausal women with angina in a randomized, double-blind, placebo-controlled cross-over trial. Following baseline treadmill testing a transdermal oestrogen patch releasing 50 micrograms oestradiol. 24 h-1 or matching placebo was applied and the exercise test repeated 24 h later. The patch was then removed. Seven to 14 days later the sequence was repeated using the alternative patch. The changes in time to angina, time to 1 mm ST segment depression and total exercise time for each treatment compared with the corresponding baseline test were calculated. Plasma 17 beta-oestradiol increased with active therapy from 56 +/- 30 pmol.l-1 to 204 +/- 90 pmol.l-1, indicating adequate replacement. Compared with their respective baseline exercise tests there were no differences between active and placebo patches for time to angina (active: 13 +/- 55 s vs placebo: 10 +/- 47 s), time to 1 mm ST segment depression (active: -30 +/- 52 s vs placebo: 24 +/- 71 s) or total exercise time (active: 14 +/- 45 s vs placebo: 13 +/- 35 s). Despite the recognized acute vasodilator action of larger doses of oestrogen, doses conventionally used in hormone replacement therapy had no acute effect on treadmill performance in this group of postmenopausal women with coronary artery disease.

Administration, Cutaneous↗

Calculation of cross-sectional geometry of bone from CT images with application in postmenopausal women.

OBJECTIVE: The objectives of this study were to develop a software program that calculates bone cross-sectional area (CSA) and moments of inertia from digital images, test the computations for accuracy, and implement the software in a study of longitudinal changes in bone properties in a large group of postmenopausal women. MATERIALS AND METHODS: A program called SLICE was adapted to use computed tomography (CT) bone images as input. The main outcome variables of the resulting program, SLICE_CT, were bone CSA, areal moments of inertia, and mass-weighted moments of inertia. SLICE_CT was tested for accuracy using representative arrays of CT numbers that approximate cross-sections of cortical bone. Then the technique was applied to images from a 3 year longitudinal study of the radius in 86 postmenopausal women who underwent quantitative CT of the dominant radius at 30% the distance from the wrist to the elbow. The mean age of the subjects at entry into the study was 57 years. Images at baseline and at 3 years were analyzed, and the null hypothesis of no change in cross-sectional geometry was tested by a paired difference two-tailed t test. RESULTS: The error of SLICE_CT was < 1% with proper segmentation, using half-maximal height as the threshold. In the longitudinal study of postmenopausal women, the mean change of CSA of the radius was -1.4% (SD = 3.0%; p < 0.001). However, there was a compensatory 2.4% increase in the cross-sectional second polar moment of inertia (SD = 3.7%; p < 0.001). CONCLUSION: SLICE_CT is an accurate method with which to determine cross-sectional geometry of digital images and can be used to detect changes in cross-sectional geometry of the radius with age in postmenopausal women. The results indicate that the radius remodels to compensate for bone loss and decreasing material properties of bone associated with aging.

Bone and Bones↗

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).

Aged↗

Chronic consumption of flavanol-rich cocoa improves endothelial function and decreases vascular cell adhesion molecule in hypercholesterolemic postmenopausal women.

Endothelial dysfunction characterizes many disease states including subclinical atherosclerosis. The consumption of flavanol-rich cocoa and cocoa-based products has been shown to improve endothelial function in both compromised and otherwise normal, healthy individuals when administered either acutely or over a period of several days, or weeks. Women experience increased risk for cardiovascular disease after menopause, which can be associated with endothelial dysfunction. Whether a flavanol-rich cocoa-based product can improve endothelial function in hypercholesterolemic postmenopausal women is not known. The purpose of the present study was to determine whether chronic dietary administration of flavanol-rich cocoa improves endothelial function and markers of cardiovascular health in hypercholesterolemic postmenopausal women. Thirty-two postmenopausal hypercholesterolemic women were randomly assigned to consume a high-flavanol cocoa beverage (high cocoa flavanols (CF)--446 mg of total flavanols), or a low-flavanol cocoa beverage (low CF--43 mg of total flavanols) for 6 weeks in a double-blind study (n=16 per group). Endothelial function was determined by brachial artery-reactive hyperemia. Plasma was analyzed for lipids (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), hormones (follicle-stimulating hormone), total nitrate/nitrite, activation of cellular adhesion markers (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-Selectin, P-Selectin), and platelet function and reactivity. Changes in these plasma markers were then correlated to brachial reactivity. Brachial artery hyperemic blood flow increased significantly by 76% (P<0.05 vs. baseline) after the 6-week cocoa intervention in the high CF group, compared with 32% in the low CF cocoa group (P=ns vs. baseline). The 2.4-fold increase in hyperemic blood flow with high CF cocoa closely correlated (r2=0.8) with a significant decrease (11%) in plasma levels of soluble vascular cell adhesion molecule-1. Similar responses were not observed after chronic use of low CF. There were no significant differences between high and low CF in other biochemical markers and parameters measured. This study is the first to identify beneficial vascular effects of flavanol-rich cocoa consumption in hypercholesterolemic postmenopausal women. In addition, our results suggest that reductions in plasma soluble vascular cell adhesion molecule-1 after chronic consumption of a flavanol-rich cocoa may be mechanistically linked to improved vascular reactivity.

Beverages↗

Cardiorespiratory fitness and cardiovascular disease risk factors in postmenopausal women.

PURPOSE: The purpose of the present study was to determine if individuals with high levels of cardiorespiratory fitness have better levels of the cardiovascular disease (CVD) risk factors of total cholesterol (TC), HDL cholesterol (HDL), total cholesterol/HDL cholesterol ratio (TC/HDL), triglycerides (TG), and fibrinogen (FIB) when compared with those with low fitness, in 283 nonsmoking, postmenopausal women. Second, we examined the relation between fitness and CVD risk after controlling for use of hormones and other possible confounding factors. METHODS: These analyses were done on a subset of nonsmoking, postmenopausal women in the Aerobics Center Longitudinal Study (ACLS). Records of postmenopausal women who completed a preventive medicine physical examination between 1987 and 1995 were examined. Cardiorespiratory fitness level was determined by total treadmill time to exhaustion on a graded exercise test; CVD risk factors were assessed via blood analysis. RESULTS: On cross-sectional regression analysis, fitness was significantly associated (P < or = 0.005) with TC (r2 = 0.08), TC/HDL (r2 = 0.12), TG (r2 = 0.09), and FIB (r2 = 0.06), and an increase in HDL (r2 = 0.04). After controlling for hormone status, age, year of testing, and blood glucose, each outcome variable remained significantly associated with cardiorespiratory fitness (P < 0.05). TC/HDL and TG continued to be significantly related to cardiorespiratory fitness after adjusting for body mass index (BMI) as a control variable (P < 0.01). The lack of significance between TC, HDL, and FIB with cardiorespiratory fitness after adjusting for BMI is likely due to the biological relationship between cardiorespiratory fitness and BMI (r2 = 0.19). CONCLUSIONS: We conclude that cardiorespiratory fitness is an important independent determinant of blood lipid and FIB levels in nonsmoking postmenopausal women, with or without HRT.

Cardiovascular Diseases↗

Estrogen replacement therapy: implications for postmenopausal women with end-stage renal disease.

Little information is available about either the potential beneficial or harmful effects of estrogen replacement therapy in postmenopausal women with end-stage renal disease. Although evidence supports a role for estrogen replacement therapy in postmenopausal women in the prevention of cardiovascular disease and bone loss, possible improvement in cognitive function, and the relief of menopausal symptoms, these conclusions may not be applicable to patients with end-stage renal disease, since these studies have generally excluded such women. This issue is of considerable importance since cardiovascular causes account for more than 50% of the all-cause mortality in patients with end-stage renal disease. However, estrogen replacement therapy may also have untoward effects in patients with the disease, including an increased risk of dialysis access thrombosis and potentially worsening coronary artery disease in postmenopausal patients. Furthermore, dosing of estrogens needs to be done carefully since renal excretion is important for the elimination of estrogen metabolites. Low dose or alternate day dosing in addition to monitoring estrogen levels may be warranted when prescribing estrogen replacement therapy to women with end-stage renal disease. In this review, it is our objective to analyze the evidence published in the literature so far and to weigh the risks and benefits of estrogen therapy in postmenopausal women with end-stage renal disease.

Estrogen Replacement Therapy↗