Effects of hormone therapy on blood pressure and the renin-angiotensin system in postmenopausal women

Observational studies have documented an association between lower rates of cardiovascular disease and hormone therapy (HT). Meanwhile, randomized clinical trials have documented increased rates of myocardial infarction and stroke in women receiving hormone therapy. These seemingly discordant findings have stimulated new research to examine estrogen's effects on the cardiovascular system, including its effects on blood pressure, regulation of the renin-angiotensin system (RAS), and the clinical consequences of hypertension. In the last 6 years several studies have better defined the mechanisms by which HT affect the RAS, blood pressure, and the clinical effects of hypertension. Recent studies documented increases in angiotensinogen synthesis and the suppression of active renin with estrogen replacement. Genotype may be a factor in determining the degree of suppression of angiotensin converting enzyme levels that occurs with estrogen therapy. Estrogen supplementation in postmenopausal women increases systemic angiotensin II, a potent vasoconstrictor. This vasopressor effect is attenuated by an estrogen-induced reduction of angiotensin II type 1 receptor expression. Renal blood flow reduction, in the absence of blood pressure changes, have been reported after estrogen replacement, and an increased risk of total stroke has been demonstrated in hypertensive women on HT compared to normotensive women on this therapy. Estrogen replacement affects many components of the RAS, but its effect on this system has little effect on blood pressure. Further studies are needed to describe the effects of estrogen replacement on abnormal vasculature and how these effects relate to myocardial infarction and stroke.     

Blood pressure in middle-aged women: are androgens involved? A population-based study of Swedish women: the Women's Health in the Lund Area study

OBJECTIVE: To assess the prevalence of hypertension and use of antihypertensive drug therapy in relation to menopausal status and to delineate perceived associations between androgens and blood pressure in perimenopausal women. METHODS: A population-based sample of women aged 50-59 (n = 6893). Women were divided into three groups according to their hormonal status: premenopausal, postmenopausal without hormone therapy, and postmenopausal with hormone therapy. RESULT: In the premenopausal, postmenopausal without hormone therapy, and postmenopausal with hormone therapy groups, the prevalence of high blood pressure (>/= 140 mmHg systolic or >/= 90 mmHg diastolic) was 43.9, 49.9 and 45.8%, respectively. In women with normal blood pressure, adjusting for age, body mass index and smoking, there were negative associations between serum testosterone and systolic blood pressure in the total sample (P < 0.01) and the postmenopausal without hormone therapy group (P < 0.05).In women using antihypertensive drug therapy with a blood pressure of at least 140/90 mmHg, positive associations were found between serum testosterone and systolic blood pressure in the total series (P < 0.05) and in the postmenopausal without hormone therapy group (P < 0.05). CONCLUSION: Abnormal blood pressure is common in middle-aged women regardless of hormonal status. Our findings suggest that testosterone could have a dual influence on blood pressure in perimenopausal women.     

Effects of hormone replacement therapy on the sympathetic nervous system and blood pressure

Hypertension is a major health problem that significantly contributes to heart disease and stroke. While most studies of hypertension have focused on men, women also experience significant hypertension-related morbidity and mortality. However, the incidence of hypertension and cardiovascular disease is significantly lower in premenopausal women compared with men until the onset of menopause, at which time cardiovascular disease incidence increases dramatically in women and eventually approaches that in men. These observations indicate that the loss of estrogen contributes to menopause-related increases in blood pressure and cardiovascular disease, and suggest that the use of estrogen hormone replacement therapy could decrease the incidence of cardiovascular disease in postmenopausal women. However, new findings from the Women’s Health Initiative study suggest that estrogen therapy has few positive benefits and some significant negative effects on the health of postmenopausal women, and these data have caused many to abandon long-term estrogen replacement therapy. Conversely, numerous clinical and basic research studies indicate that estrogen replacement therapy beneficially reduces blood pressure, thereby decreasing the incidence of hypertension and cardiovascular disease. Further, several of these studies suggest that one means by which estrogen lowers blood pressure is by decreasing sympathetic nervous system activity. This review examines the evidence supporting estrogen’s ability to modulate sympathetic nervous system tone and thereby decrease arterial pressure.     

Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study

BACKGROUND: Oral contraceptive use increases risk for venous thromboembolism, but data on the effect of postmenopausal hormone therapy are limited. OBJECTIVE: To determine the effect of therapy with estrogen plus progestin on risk for venous thromboembolic events in postmenopausal women. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 20 clinical centers in the United States. PARTICIPANTS: 2763 postmenopausal women younger than 80 years of age (mean age, 67 years) who had coronary heart disease but no previous venous thromboembolism and had not had a hysterectomy. INTERVENTION: Conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in one tablet (n = 1380) or placebo that was identical in appearance (n = 1383). MEASUREMENTS: Documented deep venous thrombosis or pulmonary embolism. RESULTS: During an average of 4.1 years of follow-up, 34 women in the hormone therapy group and 13 in the placebo group experienced venous thromboembolic events (relative hazard, 2.7 [95% CI, 1.4 to 5.0] [P = 0.003]; excess risk, 3.9 per 1000 woman-years [CI, 1.4 to 6.4 per 1000 woman-years]; number needed to treat for harm, 256 [CI, 157 to 692]). In multivariate analysis, the risk for venous thromboembolism was increased among women who had lower-extremity fractures (relative hazard, 18.1 [CI, 5.4 to 60.4]) or cancer (relative hazard, 3.9 [CI, 1.6 to 9.4]) and for 90 days after inpatient surgery (relative hazard, 4.9 [CI, 2.4 to 9.8]) or nonsurgical hospitalization (relative hazard, 5.7 [CI, 3.0 to 10.8]). Risk was decreased with aspirin (relative hazard, 0.5 [CI, 0.2 to 0.8]) or statin use (relative hazard, 0.5 [CI, 0.2 to 0.9]). CONCLUSIONS: Postmenopausal therapy with estrogen plus progestin increases risk for venous thromboembolism in women with coronary heart disease. This risk should be considered when the risks and benefits of therapy are being weighed.     

Effects of hormone replacement therapy on coagulation and fibrinolysis in postmenopausal women

It has been speculated that hormone replacement therapy (HRT) containing relatively low dose of estrogen would be different from oral contraceptive pills in causing thromboembolism because activation of coagulation depends on the amount of estrogen. In contrast to this knowledge, activation of coagulation pathways has been detected in postmenopausal women treated with HRT in the observational and clinical studies. In this regard, recent studies have reported a 2～4 fold risk of venous thromboembolism or pulmonary embolism in postmenopausal women receiving HRT than in non-users of estrogen. On the other hands, HRT has shown to enhance systemic fibrinolysis with decreased plasma plasminogen activator inhibitor-1 (PAI-1) levels. In addition, levels of D-dimer exhibited a significant inverse correlation with PAI-1 levels, suggesting enhanced fibrinolysis potential. However, small doses of estrogen/ progestogen induce increases in fibrinolytic capacity via a marked reduction of PAI-1. In other words, HRT at conventional dosages may affect fibrinolytic activity to a greater extent than coagulation activity, whereas the converse trend holds at higher estrogen doses. The increase in fibrinolytic potential was independent of any effect on coagulation of CEE at conventional dosages. However, in contrast to healthy postmenopausal women, we recently reported that HRT did not significantly decrease PAI-1 antigen levels and rather, increased tissue factor activity and prothrombin fragment F₁₊₂ levels from baseline in hypertensive and/or overweight postmenopausal women. Activation of coagulation following HRT may not be balanced by activation of fibrinolysis in some postmenopausal women. Thrombogenic events are considered more likely in patients with certain heritable conditions, such as platelet antigen-2 (PIA-2) polymorphisms. Further, Factor V Leiden mutation increases the risk of primary and recurrent venous thromboembolic events by three to sixfold and the risk of myocardial infarction. Indeed, HRT may decrease or increase atherothrombosis risk depending on the presence of Factor V Leiden mutation. Thus, HRT should not be initiated in women with established coronary artery disease or the coexistence of other risk factors for hypercoagulability-malignancy, immobility, obesity, diabetes, advanced age, or inherited traits. However, HRT at conventional dosages improves fibrinolysis potential in healthy postmenopausal women.     

Women's issues in venous thromboembolism

Women and men experience venous thromboembolism (VTE) at similar rates, but there are several issues unique to women regarding this condition. For example, hormonal contraceptives and pregnancy increase the risk of VTE for women in their childbearing years, whereas hormone replacement therapy increases the risk for postmenopausal women. A woman's thrombotic risk must be considered when prescribing therapy for breast cancer because some treatments are associated with a higher incidence of VTE than others. In this paper, we review VTE in women, using cases from our clinical practice to illustrate some of the unique aspects of caring for this population.     

Female hormones and thrombosis

Exogenous hormones are used by more than a hundred million women worldwide as oral contraceptives or for postmenopausal hormone replacement. Oral contraceptives increase the risk of venous thrombosis, of myocardial infarction, and of stroke. The risk is highest during the first year of use. The venous thrombotic risk of oral contraceptives is high among women with coagulation abnormalities and with so-called third-generation contraceptives (containing desogestrel or gestodene). The risk of myocardial infarction does not appear to depend on coagulation abnormalities or the type of oral contraceptive. Hormone replacement therapy increases the risk of venous thrombosis. This risk is also highest in the first year of use and among women with coagulation abnormalities. The risk becomes very high in women with a previous venous thrombosis. Randomized trials have not confirmed a beneficial effect of postmenopausal hormones on the occurrence of myocardial infarction.     

Hormone replacement therapy and longitudinal changes in blood pressure in postmenopausal women

BACKGROUND: The incidence of hypertension in postmenopausal women exceeds that in age-matched men. Longitudinal studies relating hormone replacement therapy (HRT) to blood pressure changes are sparse. OBJECTIVE: To investigate the association between HRT and longitudinal changes in blood pressure in postmenopausal women. DESIGN: Longitudinal observational study. SETTING: Community-dwelling volunteers. PATIENTS: 226 healthy, normotensive postmenopausal women from the Baltimore Longitudinal Study of Aging with a mean (+/-SD) age of 64 +/- 10 years were followed for 5.7 +/- 5.3 years. Seventy-seven women used both estrogen and progestin, and 149 used neither. MEASUREMENTS: Lifestyle variables, blood pressure, and traditional cardiovascular risk factors were measured at baseline and approximately every 2 years thereafter. RESULTS: Systolic blood pressure at baseline was similar in HRT users and nonusers (133.9 +/- 16.0 mm Hg vs. 132.4 +/- 14.8 mm Hg). Over time, average systolic blood pressure increased less in HRT users than nonusers, independent of other cardiovascular risk factors, physical activity, and alcohol use. For example, HRT users who were 55 years of age at their first Baltimore Longitudinal Study of Aging visit experienced a 7.6-mm Hg average increase in systolic blood pressure over 10 years; in contrast, the average increase in nonusers was 18.7 mm Hg. The lesser increase in systolic blood pressure in HRT users was more evident at older age. Diastolic blood pressure, which did not change statistically over time in either group, was not associated with HRT. CONCLUSION: Postmenopausal women taking HRT have a smaller increase in systolic blood pressure over time than those not taking HRT. This difference is intensified at older ages.     

Venous thromboembolism and hormone replacement therapy

There is evidence that postmenopausal women who take hormone replacement therapy develop biochemical hypercoagulability, expressed by increased activity of coagulation enzymes. Such effects are observed whether estrogen is given alone or in combination with progestogens, orally or transdermally. Two recent randomized, double-blind clinical trials have shown that hormone replacement therapy leads to an increased risk of venous thromboembolism (VTE) in postmenopausal women. Generally, in women with no additional risk factors for VTE, the excess risk due to hormone replacement therapy is rather small. However, women with a history of VTE should not be prescribed hormone replacement therapy.     

Effects of hormone replacement therapy on coagulation and fibrinolysis in postmenopausal women

It has been speculated that hormone replacement therapy (HRT) containing relatively low dose of estrogen would be different from oral contraceptive pills in causing thromboembolism because activation of coagulation depends on the amount of estrogen. In contrast to this knowledge, activation of coagulation pathways has been detected in postmenopausal women treated with HRT in the observational and clinical studies. In this regard, recent studies have reported a 2 to approximately 4 fold risk of venous thromboembolism or pulmonary embolism in postmenopausal women receiving HRT than in non-users of estrogen. On the other hands, HRT has shown to enhance systemic fibrinolysis with decreased plasma plasminogen activator inhibitor-1 (PAI-1) levels. In addition, levels of D-dimer exhibited a significant inverse correlation with PAI-1 levels, suggesting enhanced fibrinolysis potential. However, small doses of estrogen/progestogen induce increases in fibrinolytic capacity via a marked reduction of PAI-1. In other words, HRT at conventional dosages may affect fibrinolytic activity to a greater extent than coagulation activity, whereas the converse trend holds at higher estrogen doses. The increase in fibrinolytic potential was independent of any effect on coagulation of CEE at conventional dosages. However, in contrast to healthy postmenopausal women, we recently reported that HRT did not significantly decrease PAI-1 antigen levels and rather, increased tissue factor activity and prothrombin fragment F(1+2) levels from baseline in hypertensive and/or overweight postmenopausal women. Activation of coagulation following HRT may not be balanced by activation of fibrinolysis in some postmenopausal women. Thrombogenic events are considered more likely in patients with certain heritable conditions, such as platelet antigen-2 (PIA-2) polymorphisms. Further, Factor V Leiden mutation increases the risk of primary and recurrent venous thromboembolic events by three to sixfold and the risk of myocardial infarction. Indeed, HRT may decrease or increase atherothrombosis risk depending on the presence of Factor V Leiden mutation. Thus, HRT should not be initiated in women with established coronary artery disease or the coexistence of other risk factors for hypercoagulability-malignancy, immobility, obesity, diabetes, advanced age, or inherited traits. However, HRT at conventional dosages improves fibrinolysis potential in healthy postmenopausal women.     

Risk of thromboembolism and arteriosclerosis in women

Young women are at a 3-fold higher risk of experiencing venous thromboembolism compared to young men. This risk is further increased by oral contraceptives, smoking, hereditary thrombophilia and/or low socioeconomic status. There are also hints for gender-specific differences in the arterial system. Coronary heart disease which is particularly important, develops in women 10-15 years later than in men. However, the clinical course in women is often more complicated. In women, thrombophilic predispositions play a more important role before menopause and metabolic risk factors after menopause compared to men. Thrombus formation needs to be initiated by disturbances of at least one element of the Virchow trias. There is principally no difference between men and women. However, all three elements are influenced by estrogen, resulting in gender-specific differences. There is a favorable influence on blood flow by the inhibition of atherogenesis and on the endothelial function by increased NO release, and the unfavorable influence on hemostasis resulting in hypercoagibility. Thus, particularly non-selective hormone replacement therapy for the inhibition of atherogenesis may be questionable due to increased thrombogenicity. The solution may be more selective estrogen receptor modulators. Clinical trials are still needed for both hormone replacement therapy and the therapy of venous and arterial thromboembolism, which have been studied in predominantly male patient cohorts so far.     

Hormone therapy: evolving concepts

OBJECTIVE: To review the medical literature published in 2002 regarding menopausal hormone therapy and its impact on clinical practice. METHODS: A literature search was performed using MEDLINE with the keywords of menopause, sex steroids, and hormone replacement therapy. Randomized clinical trials were reviewed. An evidence-based review is presented. RESULTS: Menopausal hormone therapy has undergone radical change since the publication of the Women's Health Initiative randomized prospective trial of combined estrogen plus progestin therapy for disease prevention. After a mean of 5.2 years of follow-up, the E + P versus placebo trial of 16,608 women was stopped because the health risks of taking E + P exceeded the benefits. An increase in breast cancer risk, coupled with an adverse trend in overall risk-benefit ratio, reached the preset stopping boundaries. In addition, there was an increased risk of nonfatal myocardial infarction, stroke, and pulmonary embolism. The decreased risks seen for osteoporotic fracture and colorectal cancer were outweighed by the above risks. The FDA has required mandatory label changes for all hormone products based on these findings. The Women's Health Initiative found that treatment with estrogen plus progestin for up to 5 years is not beneficial overall. There is early harm for coronary heart disease, continuing harm for stroke and venous thromboembolism, and increasing harm for breast cancer. This risk-benefit profile is not consistent with a viable intervention for primary prevention of chronic diseases in postmenopausal women. Menopausal hormone therapy should be reserved for women with moderate to severe vasomotor symptoms. CONCLUSIONS: In the past 20 years, menopause has become a household word, with much better understanding of its consequences. The growing numbers of menopausal women and clinical trials have coincided to draw increasing attention to the perimenopausal and menopausal years. Better studies of older therapies and the expanded number of new choices today, with more in development and evaluation, have complicated provider and patient choices but greatly improved the potential for effective intervention.     

Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies.

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 +/- 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n=17), 60 mg raloxifene (n=23), 150 mg raloxifene (n=20) or placebo (n=23) for 24 months. At baseline and after 6, 12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 +/- 2.4 years) randomly received 120 mg raloxifene (n=15) or placebo (n=15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 +/- 0.82 to 2.87 +/- 0.86 at 24 months (P <0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance.     

Hormone therapy and thromboembolic disease

PURPOSE OF REVIEW: Hormone therapy increases the risk of venous thromboembolism (VTE). To reduce this risk, changes in dosage, composition and route of administration have been made over the years. This review provides a summary of the available evidence and an update on the most recent findings on the issue. RECENT FINDINGS: Contraceptives containing third-generation progestagens confer a higher risk of VTE than second-generation compounds. Little data are available on preparations containing less than 30 micarog of estrogen, new progestagens or levonorgestrel-releasing intrauterine devices. Hormone replacement therapy increases the risk of VTE by 2 to 3-fold. Transdermal administration may be less thrombogenic than oral administration, while different estrogens and progestagens may carry a different risk. VTE risk is further increased in carriers of inherited thrombophilia. Despite a similar increase in relative risk of thrombosis associated with hormone therapy, absolute risk is lower in fertile women and higher in postmenopausal ones. Universal screening for thrombophilia before prescribing hormone replacement therapy might be cost-effective. SUMMARY: Careful evaluation of individual risk factor is warranted before prescribing hormone therapy. Further investigations are needed to establish whether or not newer compounds are safer than older ones with respect to the risk of thrombosis.     

Relation between blood pressure and stroke mortality.

The relation between stroke mortality and blood pressure was investigated in 10,186 hypertensive patients followed up in the Department of Health Hypertension Care Computing Project for an average of 9 years. An untreated blood pressure measurement was available in 3,472 men and 3,405 women. The age-adjusted risk of stroke death increased by 1% for every 1 mm Hg increase in untreated systolic blood pressure. The relative hazard rate was 1.014 (95% confidence interval [CI], 1.007, 1.021) in men and 1.009 (1.003, 1.016) in women. The corresponding increases for 1 mm Hg for untreated diastolic blood pressure were almost 3% in men and again 1% in women (relative hazard rate 1.026 [95% CI, 1.014, 1.038] in men and 1.010 [1.000, 1.021] in women). Treated blood pressure measurements were available in 3,073 men and 3,148 women. Stroke mortality increased by 2% for a 1 mm Hg increase in treated systolic pressure and 3% for the corresponding increase in diastolic blood pressure. The relation between stroke mortality and blood pressure was similar over and under the age of 65, although the increase in mortality with pressure was greater for treated diastolic blood pressure in women under the age of 65 than over this age. There was no evidence for a J-shaped relation between stroke mortality and either systolic or diastolic pressure in men. In women there was a suggestion of such a relation, but since this relation was also observed for untreated pressures, any increase in risk at lower pressures is unlikely to be a result of treatment.     

Effect of hormonal changes in women on hemostasis

Oral contraception and hormonal postmenopausal treatment is used worldwide by more than 100 million women. Since 1960 it is known that female sex hormones increase the risk of venous thrombosis, myocardial infarction and acute cerebrovascular attacks. This risk diminishes when small doses of oral contraceptives are administered but it still remains the main cause of thromboembolism in young women. The risk is greatest during the first year of contraceptive use, in women taking desogestrel and gestoden (so-called third generation progesterones) and in women with a prethrombotic predisposition. Hormonal substitution treatment (HRT) increases the risk of venous thrombosis, in particular in the first year of HRT use. In women pregnancy and the puerperium are risks for the development of venous thromboembolism.     

Hypertension as a Risk Factor for Ischemic Stroke in Women

Women have a high lifetime risk of stroke, and hypertension (HTN) is a major stroke risk factor. We conducted a literature review of studies evaluating blood pressure (BP) and ischemic stroke risk in women; 18 studies were identified. The stroke risk increases in a graded manner with BP levels above 115/75 mm Hg. A 10-mm Hg increase in systolic BP has been associated with a 38% increased stroke risk in women. Women with mild HTN have a higher stroke risk than in men. Increased BP variability also augments the ischemic stroke risk. Antihypertensive therapy has been associated with a significant reduction in stroke incidence. A 10-mm Hg decrease in systolic BP with antihypertensive treatment was associated with a stroke risk reduction of 31%, regardless of the type of antihypertensive agent used. A dose-response relationship has been shown between the magnitude of BP lowering and stroke risk reduction. Discontinuation of antihypertensive treatment may lead to a higher ischemic stroke risk in women than in men. Optimal BP thresholds and targets for women need to be evaluated. Hormone therapy (especially combined therapy) increases the stroke risk, mostly in older hypertensive women compared with younger and normotensive women. Hypertensive disorders of pregnancy also increase stroke risk. Age and ethnicity may modify the magnitude of the effect of HTN on ischemic stroke risk. Strategies tailored to women for the prevention and treatment of HTN are needed to prevent stroke.     

A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease

BACKGROUND: Most primary prevention studies have found that long-term users of postmenopausal hormone therapy are at lower risk for coronary events, but numerous questions remain. An adverse influence of hormone therapy on cardiovascular risk has been suggested during the initial year of use; however, few data are available on short-term hormone therapy. In addition, the cardiovascular effects of daily doses of oral conjugated estrogen lower than 0.625 mg are unknown, and few studies have examined estrogen plus progestin in this regard. OBJECTIVE: To investigate duration, dose, and type of postmenopausal hormone therapy and primary prevention of cardiovascular disease. DESIGN: Prospective, observational cohort study. SETTING: Nurses' Health Study, with follow-up from 1976 to 1996. PATIENTS: 70 533 postmenopausal women, in whom 1258 major coronary events (nonfatal myocardial infarction or fatal coronary disease) and 767 strokes were identified. MEASUREMENTS: Details of postmenopausal hormone use were ascertained by using biennial questionnaires. Cardiovascular disease was established by using a questionnaire and was confirmed by medical record review. Logistic regression models were used to calculate relative risks and 95% CIs, adjusted for confounders. RESULTS: When all cardiovascular risk factors were considered, the risk for major coronary events was lower among current users of hormone therapy, including short-term users, compared with never-users (relative risk, 0.61 [95% CI, 0.52 to 0.71]). Among women taking oral conjugated estrogen, the risk for coronary events was similarly reduced in those currently taking 0.625 mg daily (relative risk, 0.54 [CI, 0.44 to 0.67]) and those taking 0.3 mg daily (relative risk, 0.58 [CI, 0. 37 to 0.92]) compared with never-users. However, the risk for stroke was statistically significantly increased among women taking 0.625 mg or more of oral conjugated estrogen daily (relative risk, 1.35 [CI, 1.08 to 1.68] for 0.625 mg/d and 1.63 [CI, 1.18 to 2.26] for >/=1.25 mg/d) and those taking estrogen plus progestin (relative risk, 1.45 [CI, 1.10 to 1.92]). Overall, little relation was observed between combination hormone therapy and risk for cardiovascular disease (major coronary heart disease plus stroke) (relative risk, 0.91 [CI, 0.75 to 1.11]). CONCLUSIONS: Postmenopausal hormone use appears to decrease risk for major coronary events in women without previous heart disease. Furthermore, 0.3 mg of oral conjugated estrogen daily is associated with a reduction similar to that seen with the standard dose of 0.625 mg. However, estrogen at daily doses of 0.625 mg or greater and in combination with progestin may increase risk for stroke.     

Pulse pressure and cardiovascular events in postmenopausal women with coronary heart disease

BACKGROUND: Pulse pressure (PP) has been shown to predict risk for cardiovascular events in men; however, this association has not been well established in women. Hormone replacement therapy may improve arterial compliance, but findings from cross-sectional and prospective studies report inconsistent results. We sought to examine the relationship between PP and risk for cardiovascular events, and to determine the effect of hormone therapy on PP in postmenopausal women with coronary heart disease (CHD). METHODS AND RESULTS: A total of 2,763 postmenopausal women (mean age, 66 +/- 7 years [+/- SD]) with CHD in the Heart and Estrogen/Progestin Replacement Study, a randomized, placebo-controlled, secondary CHD prevention trial of estrogen plus progestin, were followed up on average for 4.1 years. BP was measured at baseline and annually. Mean baseline PP was 62 +/- 16 mm Hg. There were 361 myocardial infarctions (MIs) or CHD deaths, 265 hospitalizations for congestive heart failure (CHF), and 215 strokes or transient ischemic attacks (TIAs). Women in the highest quartile of PP at baseline had a 47% increase in risk for MI or CHD death and more than a twofold increase in risk for stroke and TIA events or hospitalization for CHF (p < 0.01 for each outcome). After adjustment for other cardiovascular risk factors and mean arterial pressure, PP remained significantly associated with incident stroke or TIA events (odds ratio, 1.25; p = 0.02) and hospitalizations for CHF (odds ratio, 1.31; p < 0.01) but not with MI or CHD death. After adjustment for diastolic BP, systolic BP was similarly associated with stroke or TIA (odds ratio, 1.30; p < 0.01) and hospitalized CHF (odds ratio, 1.30; p < 0.01) and was also weakly associated with risk for MI and CHD death (odds ratio, 1.18; p = 0.02). Mean PP was 1- to 2-mm Hg higher in women randomized to hormone replacement therapy vs those receiving placebo (p < 0.01). CONCLUSIONS: PP had predictive value for CHF and stroke or TIA, but not MI or CHD death in this cohort of postmenopausal women with CHD. Use of hormone replacement therapy produced a small, statistically significant increase in PP. Further research is necessary to determine the clinical utility of PP as a potential therapeutic target.