Trudy L. Bush

Heart and estrogen/progestin replacement study (HERS): Design, methods, and baseline characteristics

The Heart and Estrogen/progestin Replacement Study (HERS) is a randomized, double-blind, placebo-controlled trial designed to test the efficacy and safety of estrogen plus progestin therapy for prevention of recurrent coronary heart disease (CHD) events in women. The participants are postmenopausal women with a uterus and with CHD as evidenced by prior myocardial infarction, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, or other mechanical revascularization or at least 50% occlusion of a major coronary artery. Between February 1993 and September 1994, 20 HERS centers recruited and randomized 2763 women. Participants ranged in age from 44 to 79 years, with a mean age of 66.7 (SD 6.7) years. Most participants were white (89%), married (57%), and had completed high school or some college (80%). As expected, the prevalence of coronary risk factors was high: 62% were past or current smokers, 59% had hypertension, 90% had serum LDL-cholesterol of 100 mg/dL or higher, and 23% had diabetes. Each woman was randomly assigned to receive one tablet containing 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate daily or an identical placebo. Participants will be evaluated every 4 months for an average of 4.2 years for the occurrence of CHD events (CHD death and nonfatal myocardial infarction). We will also assess other major CHD endpoints, including revascularization and hospitalization for unstable angina. The primary analysis will compare the rate of CHD events in women assigned to active treatment with the rate in those assigned to placebo. The trial was designed to have power greater than 90% to detect a 35% reduction in the incidence of CHD events, assuming a 50% lag in effect for 2 years and a 5% annual event rate in the placebo group. The design, analysis, and conduct of the study are controlled by the Steering Committee of Principal Investigators and coordinated at the University of California, San Francisco. HERS is the largest trial of any intervention to reduce the risk of recurrent CHD events in women with heart disease and is the first controlled trial to seek evidence of the efficacy and safety of postmenopausal hormone therapy to prevent recurrent CHD events.

Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. The CHS Collaborative Research Group.

BackgroundPostmenopausal estrogen replacement therapy has been associated with favorable levels of cardiovascular disease risk factors, but these associations and the relations between estrogen use and subclinical disease have not been examined in large samples of older women. Methods and ResultsPresent and past estrogen use was ascertained in 2955 women .65 years old in the Cardiovascular Health Study, a study of risk factors for coronary heart disease and stroke in the elderly. Present estrogen use was reported by 12% of these women and past use by an additional 26.5%. Estrogen use (past or present) was strongly associated with lower low-density lipoprotein cholesterol, fibrinogen, glucose, insulin, obesity, and age and higher high-density lipoprotein cholesterol and socioeconomic status (all P<.0001). Estrogen users also had lower levels of subclinical disease as measured by carotid intimal-medial thickness, carotid stenosis grade, ECG left ventricular mass, and Doppler mitral peak flow velocities (each P<.02). Relations were similar in younger and older women (65 to 74 versus 275 years) and smokers and nonsmokers and were unchanged after women with poor medication compliance were excluded. After adjustment for other factors, estrogen use was associated with decreased carotid wall thickness, although this association was of borderline significance after further adjustment for lipids. ConclusionsPostmenopausal estrogen use in this sample of older women was associated with favorable cardiovascular disease risk factor profiles and with lower measures of subclinical disease. These findings suggest that postmenopausal estrogen use may be associated with lower risk of cardiovascular disease in women well into the eighth decade of life.

Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism

OBJECTIVE To determine the effects of lower doses of conjugated equine estrogens (CEE) alone or CEE and medroxyprogesterone acetate (MPA) on lipoproteins, carbohydrate metabolism, and coagulation/fibrinolytic factors. DESIGN Randomized, double-blind, placebo-controlled study. SETTING Multicenter substudy of the Womens HOPE trial. PATIENT(S) Seven hundred and forty-nine healthy, postmenopausal women. INTERVENTION(S) Women were randomized to receive the following doses in milligrams per day: 0.625 CEE; 0.625 CEE/2.5 MPA; 0.45 CEE; 0.45 CEE/2.5 MPA; 0.45 CEE/1.5 MPA; 0.3 CEE; 0.3 CEE/1.5 MPA; or placebo. MAIN OUTCOME MEASURE(S) Assessment of lipids, lipoproteins, glucose tolerance, and coagulation/fibrinolytic factors at baseline, cycle 6, and year 1. RESULT(S) One year of treatment with any of the CEE or CEE/MPA regimens studied increased high-density lipoprotein cholesterol (HDL-C); the 10% increase in HDL-C for the CEE 0.45/MPA 1.5 group was similar to the CEE 0.625/MPA 2.5 group. Low-density lipoprotein cholesterol was significantly reduced in all of the active treatment groups except the CEE 0.3/MPA 1.5 group at cycle 13. Apolipoprotein A-I and triglyceride levels increased and apolipoprotein B levels decreased in all groups. The lipoprotein (a) level was reduced in the CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, and CEE 0.625/MPA 2.5 groups. Minimal changes were observed in carbohydrate metabolism for all groups. Fibrinogen and PAI-1 activity decreased and plasminogen activity increased in all groups. Decreases in antithrombin III and protein S activities were significant for all active treatment groups except the CEE 0.3/MPA 1.5 group. CONCLUSION(S) Lower doses of CEE and CEE/MPA induce favorable changes in lipids, lipoproteins, and hemostatic factors with minimal changes in carbohydrate metabolism.

Effect of Postmenopausal Hormone Therapy on Lipoprotein(a) Concentration

BACKGROUND Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy. METHODS AND RESULT The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n = 366), 12 months (n = 354), and 36 months (n = 342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (P<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use. CONCLUSIONS Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.

The epidemiology of cardiovascular disease in postmenopausal women

This manuscript has described the principal modifiable risk factors for the major killer of postmenopausal women. Clearly women who smoke should be convinced to quit, and those who have hypertension and hypercholesterolemia should be encouraged initially to adopt hygienic interventions (that is weight reduction and moderate exercise) to lower their blood pressures and cholesterol levels. Further, given the magnitude of the risk reduction in CVD seen in estrogen users, estrogen use ought to be considered as a preventive therapy for postmenopausal women, but particularly for those who are at high risk of cardiovascular disease.

A Case-control Study of Combined Continuous Estrogen—progestin Replacement Therapy among Women with a Personal History of Breast Cancer

Our objective was to examine the effect on all-cause mortality and tumor recurrence rate of combined continuous estrogen-progestin therapy given to symptomatic menopausal women with a personal history of breast cancer. We performed a nested case-control study in a cohort of women with a personal history of breast cancer. The entire database comprised 901 women with surgically confirmed breast cancer attending one of three teaching hospitals in south-eastern Sydney, Australia. Ninety had taken estrogen for relief of severe menopausal symptoms after their diagnosis and treatment of breast cancer. Most were using combined continuous estrogen-progestin therapy, usually an oral estrogen with a moderate dosage progestin. Controls were matched subjects from the same database who had not taken sex steroids after their diagnosis of cancer. The main outcome measures were all-cause mortality and recurrence of breast cancer (or new contralateral breast cancer). Relative risks (RR) were then calculated comparing sex-hormone users with matched controls. Among the 90 estrogen users, there were no deaths and only 7% developed a recurrence, compared to 17% of the nonusers (using two matched controls); RR = 0.40 (95% CI 0.17–0.93). These results suggest that short-term usage of combined continuous hormone replacement therapy (HRT) by women with a personal history of breast cancer may be safe and might even reduce the risk of recurrence. A formal prospective double-blind controlled study is needed to confirm these results.

Prediagnostic serum levels of carotenoids and vitamin E as related to subsequent cancer in Washington County, Maryland.

In 1974 and 1975, serum specimens were collected from 25,802 volunteers in Washington County, Maryland. The serum was kept frozen at -73 degrees C until the time of assay. Prediagnostic samples from 436 cancer cases and 765 matched control subjects have been assayed. Nine sites have been studied: colon, rectum, pancreas, lung, melanoma, basal cell of skin, breast, prostate, and bladder. Serum beta-carotene levels showed a strong protective association with lung cancer, suggestive protective associations with melanoma and bladder cancer, and a suggestive but nonprotective association with rectal cancer. Serum vitamin E levels had a protective association with lung cancer; none of the other sites showed impressive associations. Low levels of serum lycopene were strongly associated with pancreatic cancer and less strongly associated with cancer of the bladder and rectum.

Comorbidity measurement in elderly female breast cancer patients with administrative and medical records data

The inter-rater reliability, cross-source (Medicare claims versus medical record) agreement, and ability to predict all-cause mortality of three aggregate comorbidity indices were evaluated in a group of 404 elderly, incident breast cancer cases identified from the Virginia Cancer Registry and linked to Medicare administrative data files. Comorbidity was based on both medical records and Medicare claims data using indices from Charlson et al (1987), Satariano and Ragland (1994), and Kaplan and Feinstein (1974). Inter-rater agreement was good for all indices (kappas > or = 0.80). Agreement between comorbidity indices measured by claims and medical records was considerably poorer (kappas between 0.30 and 0.40). However, claims-based and medical records-based comorbidity indices were similarly associated with mortality. For the Charlson index, the index best predicting survival, the adjusted relative risk for an increase from a lower to higher comorbidity category was 1.48 (95% confidence interval 1.23, 1.78) based on medical records compared to 1.53 (95% confidence interval 1.23, 1.93) based on Medicare claims. The claims-based Charlson index score still appeared to be associated with survival (relative risk = 1.30; 95% confidence interval = 1.00, 1.70) after controlling for the medical records-based score. This suggests that both comorbidity data sources add valuable prognostic information and, conversely, that the use of either source alone will result in some misclassification of comorbidity.

Body mass and stage of breast cancer at diagnosis

Obesity is a well‐known risk factor for postmenopausal breast cancer. In contrast, the relationship between obesity and stage of breast cancer at diagnosis is less clear. We hypothesized that increased breast size in obese women may delay discovery of breast tumors. Thus, the purpose of our study was to examine whether there is an association between body mass and stage of breast cancer at diagnosis using hospital medical records. Newly diagnosed breast cancer cases (n = 966) in the Baltimore metropolitan area from 1991 to 1997 were included in our study. Patient information including age, ethnicity, weight, height and pathology data were obtained from hospital medical records. High body mass was significantly associated with late stage of breast cancer at diagnosis. Women who were obese (body mass index [BMI] ≥ 27.3) were more likely to be at an advanced stage at diagnosis compared with women with a BMI of < 27.3 (multivariate‐adjusted odds ratio [OR] 1.57, 95% confidence interval [CI] 1.15–2.14). The association between body mass and stage at diagnosis was stronger among women younger than 50 years (OR 2.34, 95% CI 1.34–4.08) compared with women 50 years or older (OR 1.30, 95% CI 0.89–1.91). Our study suggests that higher body mass is associated with advanced stage of breast cancer at diagnosis. This finding may be of considerable concern, given the increasing prevalence of obesity in women in the United States and the poor prognosis associated with late‐stage tumors.

Hormone replacement therapy and breast cancer: a qualitative review.

OBJECTIVE To assess whether recent epidemiologic evidence supports an association between use of estrogen replacement therapy or hormone replacement therapy and risk of breast cancer. DATA SOURCES The keywords “estrogen,” “estrogen replacement therapy,” or “hormone replacement therapy,” and “breast cancer” or “breast neoplasm,” were used to search for articles published from 1975–2000 in MEDLINE and Dialogweb. Only articles published in peer‐reviewed journals and containing original data were included in this review. METHODS Unadjusted or age‐adjusted risk estimates for breast cancer among ever users of estrogen therapy compared with never users were abstracted from published articles or calculated using the data provided in the published reports. TABULATION, INTEGRATION, AND RESULTS We found little consistency among studies that estimated the risk of breast cancer in hormone users compared with nonusers and in studies assessing the risk by duration of use. However, there was consistently a lower risk of death from breast cancer in hormone users compared with nonusers. CONCLUSION The evidence did not support the hypotheses that estrogen use increases the risk of breast cancer and that combined hormone therapy increases the risk more than estrogen only. Additional observational studies are unlikely to alter this conclusion. Although a small increase in breast cancer risk with hormone therapy or an increased risk with long duration of use (15 years or more) cannot be ruled out, the likelihood of this must be small, given the large number of studies conducted to date.