Deborah Grady

Hormone Therapy To Prevent Disease and Prolong Life in Postmenopausal Women

Abstract ▪Purpose:To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong...

Urinary Incontinence: Does it Increase Risk for Falls and Fractures?

OBJECTIVE: To determine if urge urinary incontinence is associated with risk of falls and non‐spine fractures in older women.

Glycemic Effects of Postmenopausal Hormone Therapy: The Heart and Estrogen/progestin Replacement Study: A Randomized, Double-Blind, Placebo-Controlled Trial

Context In observational studies, postmenopausal hormone therapy has been associated with lower fasting glucose levels. No prospective, controlled trial has evaluated the effect of postmenopausal hormone therapy on the development of diabetes mellitus. Contribution Among the 2029 women in the Heart and Estrogen/progestin Replacement Study who had coronary disease but no diabetes at baseline, 6.2% of those receiving 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate and 9.5% of those receiving placebo developed diabetes. Implications Recommendations about combination postmenopausal hormone therapy should consider that for every 30 women treated for 4 years, therapy might prevent one case of diabetes. The Editors Several clinical studies have evaluated the effect of postmenopausal hormone therapy on glucose metabolism and have had disparate results. Results from randomized, controlled trials performed primarily in women without diabetes have found decreased mean fasting glucose or insulin levels among those assigned to hormone therapy (1-5) or no difference between those assigned to hormones and those assigned to placebo (6-10). Fewer clinical trials have evaluated the effect of postmenopausal hormones on fasting glucose and insulin levels among women with type 2 diabetes mellitus, but again, the results have been mixed (11-16). Observational studies have more consistently found that postmenopausal women taking hormone therapy have lower fasting glucose or hemoglobin A1c levels than those not taking hormones (17-24). In addition, some (25, 26) but not all (24, 27) observational studies have noted a decreased incidence of diabetes among users of postmenopausal hormone therapy. No randomized, controlled trial has evaluated the long-term effect of hormone therapy on diabetes incidence. To determine the effect of hormone therapy on subsequent diabetes, we analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS), in which 2763 postmenopausal women with documented coronary heart disease (CHD) were randomly assigned to daily estrogen plus progestin therapy or to placebo. We evaluated the effect of hormone therapy on fasting glucose levels and incident diabetes over 4 years of follow-up. Methods Study Setting, Participants, and Design The design, methods, baseline characteristics (28), and main findings (29) of HERS have been published elsewhere. Briefly, HERS was a randomized, double-blind, placebo-controlled trial performed to evaluate daily doses of 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate for the prevention of coronary events in postmenopausal women with established CHD. The trial enrolled 2763 women at 20 clinical centers in the United States between January 1993 and September 1994 and followed participants for a mean of 4.1 years. To be included in the trial, women had to be younger than 80 years of age and have CHD, as evidenced by previous myocardial infarction, coronary artery bypass graft surgery, mechanical revascularization, or angiographic evidence of coronary stenosis. Women who reported a CHD event within 6 months of randomization or who had used postmenopausal hormone therapy within 3 months of the initial screening were excluded. Those with serum triglyceride levels of 3.39 mmol/L or greater ( 300 mg/dL), fasting blood glucose levels of 16.5 mmol/L or greater ( 300 mg/dL), or uncontrolled hypertension (systolic blood pres sure 200 mg Hg or diastolic blood pressure 105 mm Hg) were also excluded. Computer-generated random numbers were used to specify the allocation sequence. Women were randomly assigned to the two treatment groups by use of a tamper-proof blocked randomization stratified by clinical center. Participants, investigators, and staff at the clinical centers; Wyeth-Ayerst Research; and those adjudicating study outcomes were blinded to medication assignment. Additional details about sample size calculations, randomization, and blinding procedures have been published elsewhere (29). For our analysis, women were classified as having diabetes at the baseline visit if they reported a physician diagnosis of diabetes, were taking diabetes medication, or had a fasting plasma glucose level of 6.9 mmol/L or greater ( 126 mg/dL). Women were classified as having impaired fasting glucose if they had a fasting glucose level of 6.0 to 6.9 mmol/L (110 to 125 mg/dL) at baseline. The remaining women were considered to have normal glucose metabolism. Data Collection At baseline, participants completed a questionnaire to ascertain age, race or ethnicity, education, smoking habits (current, former, or never), alcohol consumption (drinks per week), and exercise or walking activity. Physical examination variables measured at baseline were body weight, height, waist and hip circumference, and systolic and diastolic blood pressure. At baseline, at year 1, and at the end-of-trial visit, participants had fasting blood tests for levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) measured by the Lipoprotein Analytical Laboratory at Johns Hopkins Hospital, Baltimore, Maryland. Fasting serum glucose level was measured at baseline, at year 1, and at the end-of-trial visit. Venous blood was obtained in the morning after a 12-hour fast, and SmithKline Beecham Clinical Laboratory, Van Nuys, California, analyzed the samples using the hexokinase enzymatic method. We determined coefficients of variation by using ChemTrac (Medical Analysis Systems, Inc., Camarillo, California) control. The coefficient of variation for serum glucose level was 1.6% at a mean value (SD) of 4.2 0.05 mmol/L (77 1.0 mg/dL) and 1.1% at a mean value (SD) of 14.6 0.16 mmol/L (266 3.0 mg/dL). Adherence to study medication was reassessed every 4 months, at each visit. Ascertainment of Outcomes Diabetes incidence was not a secondary end point of the main HERS trial, but blood glucose level was prespecified as a variable that may mediate the effects of hormone therapy on CHD outcomes. We defined incident cases of diabetes by the presence of a fasting glucose level of 6.9 mmol/L or greater ( 126 mg/dL) at year 1 or at the end-of-trial visit, self-report of new diabetes or a complication directly related to diabetes, or initiation of hypoglycemic medication at any point during follow-up. Self-reported complications included diabetic neuropathy, diabetic retinopathy, diabetic foot ulcer, and diabetic renal disease. Hypoglycemia was considered a complication of diabetes if a participant taking an antidiabetic medication reported it to the study staff as an adverse event. Statistical Analysis To compare fasting glucose levels by treatment assignment at baseline, at year 1, and at the end-of-trial visit, t-tests were used. In addition, mixed linear models for repeated measures were used to assess treatment effects on fasting glucose level measured at year 1 and at the end-of-trial visit. Since mean values changed little after the year 1 visit, treatment effects were modeled by using the interaction between treatment assignment and an indicator for follow-up compared with baseline. These analyses were repeated after stratification by baseline diabetes status (diabetes, impaired fasting glucose, or normal glucose metabolism). We calculated the number needed to treat for benefit by taking the inverse of the absolute risk reduction of incident diabetes between the treatment groups. The effect of treatment assignment on incident diabetes was assessed by using Cox proportional-hazards models. Primary analyses used unadjusted intention-to-treat models; in supplementary analyses, we adjusted first for age and then for a range of potential confounders selected a priori, including age; ethnicity; education; current smoking; alcohol use; exercise; body mass index; waist circumference; and baseline use of diuretics, -blockers, angiotensin-converting enzyme inhibitors, and statins. In addition to intention-to-treat analyses, we also performed as treated analyses to determine whether the observed effect of hormone therapy on glucose levels and incident diabetes was also seen among women who adhered to the study medication. In these analyses, follow-up was censored at the beginning of the first 2-week period in which participants did not adhere to medication. To minimize potential confounding, these analyses were adjusted for baseline variables that differed between adherent and nonadherent women. We hypothesized that certain characteristics (body mass index, waist circumference, weight change, smoking, triglyceride level, high-density lipoprotein cholesterol level, hypertension, and certain cardiac medications) may mediate the effect of hormone therapy on fasting glucose level and diabetes incidence. To test this theory, we added postrandomization values of one or more hypothesized mediators as covariates to Cox regression models for incident diabetes. All analyses were conducted by using SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). A P value less than 0.05 was considered statistically significant. Role of the Funding Sources The funding sources had no role in the design or conduct of this analysis or in the decision to submit the paper for publication. Results Characteristics of women enrolled in HERS did not differ substantially between the hormone therapy group and the placebo group (Table 1). At the baseline examination, 734 women (26.6%) were classified as diabetic based on self-report of diagnosis or medication use (n = 640 [87.2%]) or by a fasting serum glucose level of 6.9 mmol/L or greater ( 126 mg/dL) (n = 101 [13.8%]). Impaired fasting glucose (fasting serum glucose level, 6.0 to 6.9 mmol/L [110 to 125 mg/dL]) was noted in 218 women (7.9%), and 1811 women (65.5%) were classified as nondiabetic (Table 2). Women with diabetes had higher body mass index, waist circumference, systolic

Prevalence of urinary incontinence and associated risk factors in postmenopausal women

Abstract Objective: To determine the prevalence of stress, urge, and mixed urinary incontinence and associated risk factors in postmenopausal women. Methods: Before enrollment in a 4-year, randomized trial of combination hormone therapy to prevent coronary heart disease, 2763 participants completed questionnaires on prevalence and type of incontinence. We measured factors potentially associated with incontinence including demographics, reproductive and medical histories, height, weight, and waist-to-hip circumference ratio. We used multivariate logistic models to determine independent associations between those factors and weekly incontinence by type. Results: The mean (± standard deviation [SD]) age of the participants was 67 ± 7 years; 89% were white and 8% were black. Fifty-six percent reported weekly incontinence. In multivariate analyses, the prevalence of weekly stress incontinence was higher in white than black women (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.6, 5.1), in women with higher body-mass index (BMI) (OR 1.1 per 5 units, 95% CI 1.0, 1.3), and higher waist-to-hip ratio (OR 1.2 per 0.1 unit, 95% CI 1.0, 1.4). The prevalence of weekly urge incontinence was higher in older women (OR 1.2 per 5 years, 95% CI 1.1, 1.3), diabetic women (OR 1.5, 95% CI 1.1, 2.0) and women who had reported two or more urinary tract infections in the prior year (OR 2.0, 95% CI 1.1, 3.6). Conclusion: Stress and urge incontinence are common in postmenopausal women and have different risk factors, suggesting that approaches to risk-factor modification and prevention also might differ and should be specific to types of incontinence.

Meta-analysis of exercise testing to detect coronary artery disease in women.

To determine the accuracy of the exercise electrocardiogram (ECG), exercise thallium, and exercise echocardiogram (echo) for the diagnosis of coronary artery disease in women, English language studies published between 1966 and 1995 were identified through a MEDLINE search. Studies that contained data on at least 50 women who underwent both an exercise test and coronary angiography were examined. Studies were reviewed for sensitivity, specificity, and methodologic characteristics by 2 independent reviewers. Nineteen studies met the inclusion criteria for exercise electrocardiography, 5 studies for exercise thallium, and 3 studies for exercise echo. The exercise ECG had a weighted mean sensitivity, specificity, and a likelihood ratio (LR) of 0.61 (95% confidence intervals 0.54 to 0.68), 0.70 (0.64 to 0.75), (+) LR 2.25 (1.84 to 2.66), (-) LR 0.55 (0.47 to 0.62), respectively. The exercise thallium had a weighted mean sensitivity, specificity, and LRs of 0.78 (0.72 to 0.83), 0.64 (0.51 to 0.77), (+) LR 2.87 (1.0 to 4.96), (-) LR 0.36 (0.27 to 0.45). The exercise echo had a weighted mean sensitivity, specificity, and LRs of 0.86 (0.75 to 0.96), 0.79 (0.72 to 0.86), (+) LR 4.29 (2.93 to 5.65), (-) LR 0.18 (0.05 to 0.31). Thallium subset analysis revealed that studies using planar imaging were more specific than those using tomographic imaging. Thus, currently available exercise tests are only moderately sensitive and specific for the diagnosis of coronary artery disease in women.

Left ventricular pseudoaneurysm

Left ventricular (LV) pseudoaneurysms form when cardiac rupture is contained by adherent pericardium or scar tissue. Although LV pseudoaneurysms are not common, the diagnosis is difficult and they are prone to rupture. We evaluated the clinical presentation, diagnostic accuracy of imaging modalities, results of therapy and prognosis of 290 patients with LV pseudoaneurysms. Most cases of LV pseudoaneurysm were related to myocardial infarction (particularly inferior wall myocardial infarction) and cardiac surgery. Congestive heart failure, chest pain and dyspnea were the most frequently reported symptoms, but >10% of patients were asymptomatic. Physical examination revealed a murmur in 70% of patients. Almost all patients had electrocardiographic abnormalities, but these were usually nonspecific ST segment changes; only 20% of patients had ST segment elevation. Although radiographic findings were also usually nonspecific, the appearance of a mass was present in more than one half of patients and may be an important clue to the correct diagnosis. Left ventricular angiography was the most definitive test and can be useful in planning surgery since concomitant coronary angiography can be performed. Regardless of treatment, patients with LV pseudoaneurysms had a high mortality rate, especially those who did not undergo surgery. Because the symptoms, signs, electrocardiographic abnormalities and radiographic findings seen in patients with LV pseudoaneurysms can be indistinguishable from those in patients with coronary disease alone, a high clinical index of suspicion is needed to avoid missing the diagnosis.

Postmenopausal Hormones and Incontinence: The Heart and Estrogen/Progestin Replacement Study

Objective To determine whether postmenopausal hormone therapy improves the severity of urinary incontinence. Methods We included measures of incontinence and voiding frequency in the Heart and Estrogen/Progestin Replacement Study, a randomized, blinded trial of the effect of hormone therapy among 2763 postmenopausal women younger than 80 years with coronary disease and intact uteri. This report includes 1525 participants who reported at least one episode of incontinence per week at baseline. Participants were randomly assigned to 0.625 mg of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate in one tablet daily (n = 768) or placebo (n = 757) and were followed for a mean of 4.1 years. Severity of incontinence was classified as improved (decrease of at least two episodes per week), unchanged (change of at most one episode per week), or worsened (increase of at least two episodes per week). Results Incontinence improved in 26% of the women assigned to placebo compared with 21% assigned to hormones, while 27% of the placebo group worsened compared with 39% of the hormone group (P = .001). This difference was evident by 4 months of treatment and was observed for both urge and stress incontinence. The number of incontinent episodes per week increased an average of 0.7 in the hormone group and decreased by 0.1 in the placebo group (P < .001). Conclusion Daily oral estrogen plus progestin therapy was associated with worsening urinary incontinence in older postmenopausal women with weekly incontinence. We do not recommend this therapy for the treatment of incontinence.

Hysterectomy and urinary incontinence: a systematic review

BACKGROUND Serious complications after hysterectomy are estimated to occur in around six women per 10,000 hysterectomies in the USA. We did a systematic review of evidence that hysterectomy is associated with urinary incontinence. METHODS We identified English-language and non-English-language articles registered on MEDLINE from January, 1966, to December, 1997, did manual review of references, and consulted specialists. We identified 45 articles reporting on the association of urinary incontinence and hysterectomy. We selected reports that presented original data on development of incontinence in women who underwent hysterectomy compared with those who did not. Results were abstracted by two independent reviewers and summarised with a random-effects model. FINDINGS 12 papers met our selection criteria--eight cross-sectional studies, two prospective cohort studies, one case-control study, and one randomised controlled trial. The summary estimate was consistent with increased odds for incontinence in women with hysterectomy. Because incontinence might not develop for many years after hysterectomy, we stratified the findings by age at assessment of incontinence. Among women who were 60 years or older, the summary odds ratio for urinary incontinence was increased by 60% (1.6 [95% CI 1.4-1.8]) but odds were not increased for women younger than 60 years. INTERPRETATION When women are counselled about sequelae of hysterectomy, practitioners should discuss the possibility of an increased likelihood of incontinence in later life.

Cognitive function in postmenopausal women treated with raloxifene.

Background In postmenopausal women, estrogen may have a beneficial effect on cognition or reduce the risk of decline in cognitive function. Whether raloxifene, a selective estrogen-receptor modulator, might have similar actions is not known. Methods As part of the Multiple Outcomes of Raloxifene Evaluation trial, we studied 7478 postmenopausal women with osteoporosis (mean age, 66 years), who were enrolled at 178 sites in 25 countries. The women were randomly assigned to receive raloxifene (60 mg or 120 mg) or placebo daily for three years. We compared the mean scores of the groups on six tests of cognitive function, which were administered at base line and at six months and one, two, and three years. Women were classified as having a decline in cognitive function if the change in their scores at three years was in the worst 10 percent. Results The mean cognitive scores in the three groups of women were similar at base line. The scores improved slightly in all three groups during the three-year study peri...

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.