Donna Shoupe

Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial.

Coronary heart disease is the leading cause of death in women, and mortality rates from this disease substantially and steadily increase after menopause (13). Population studies indicate that estrogen reduces the incidence of coronary heart disease in women. Bilateral oophorectomy before natural menopause increases the risk for coronary heart disease (4). This pattern of risk for coronary heart disease suggests that endogenous estrogens, including 17-estradiol, play a cardioprotective role before menopause. More than 40 observational studies have suggested that hormone replacement therapy (HRT) reduces cardiovascular morbidity and mortality in postmenopausal women (5, 6). Most of these studies were conducted in healthy postmenopausal women who used unopposed estrogen replacement therapy (ERT). Although observational studies are important, selection bias is a potential problem, especially when studying HRT, since healthier women tend to use hormones (7). Only randomized, controlled trials can ensure that patients are assigned to treatment in an unbiased manner and can establish the efficacy of HRT for reducing the progression of atherosclerosis and its clinical sequelae. The effect of unopposed ERT on progression of atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease remains untested in randomized, controlled trials. We report the results of the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), a randomized, double-blind, placebo-controlled trial designed to test whether unopposed micronized 17-estradiol reduces progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. Our primary hypothesis was that unopposed ERT significantly reduces the progression of subclinical atherosclerosis. Methods Study Design Potential participants were prescreened by telephone and seen at three screening visits 2 to 4 weeks apart to collect baseline data and to determine final study eligibility. Women were eligible if they were postmenopausal (serum estradiol level < 73.4 pmol/L [<20 pg/mL]), 45 years of age or older, and had a low-density lipoprotein (LDL) cholesterol level of 3.37 mmol/L or greater ( 130 mg/dL). Women were excluded if breast or gynecologic cancer had been diagnosed in the past 5 years or if these cancers were identified during screening; if they had previously used HRT for more than 10 years or had used HRT within 1 month of the first screening visit; if they had five or more hot flushes daily that interfered with daily activity and precluded randomization, diastolic blood pressure greater than 110 mm Hg, untreated thyroid disease, life-threatening disease with a survival prognosis of less than 5 years, total triglyceride level of 4.52 mmol/L or greater ( 400 mg/dL), high-density lipoprotein (HDL) cholesterol level less than 0.78 mmol/L (<30 mg/dL), or serum creatinine concentration greater than 221 mol/L (>2.5 mg/dL); or if they were current smokers. All women, including those with diabetes mellitus, were included provided that their fasting blood glucose level was less than 11.1 mmol/L (<200 mg/dL). All participants gave written informed consent, and the study protocol was approved by the University of Southern California Institutional Review Board. Packets of study medications were prepared in a blinded manner (to both the clinical staff and participants) before the start of the study. Computer-generated random numbers were used to assign participants to unopposed estradiol or placebo in one of eight strata, defined by LDL cholesterol level (<4.15 mmol/L [<160 mg/dL] or 4.15 mmol/L), previous duration of HRT use (<5 years or 5 years), and diabetes mellitus (yes or no). As a new participant was determined to be eligible for randomization, the next packet in sequence in the appropriate stratum was obtained and recorded. The Data Coordinating Center monitored adherence to sequential assignment of medication packets. The participants, gynecologists, clinical staff, and image analysts were blinded to treatment assignment. The data monitor and data analyst were blinded to treatment assignment until analyses were completed. Participants were followed every month for the first 6 months and every other month thereafter for a total of 2 years. All participants received dietary counseling according to step II American Heart Association dietary recommendations: 200 mg of cholesterol or less per day, 25% of energy as total-fat calories, and 7% of energy as saturated-fat calories. Dietary intake was monitored at each clinic visit by using 3-day dietary booklets (Nutrition Scientific, South Pasadena, California). Participants received lipid-lowering medication (primarily hydroxymethylglutaryl coenzyme A reductase inhibitors) if their LDL cholesterol level exceeded 4.15 mmol/L (160 mg/dL). Vital signs; clinical events; adherence; and use of nonstudy medications, dietary supplements, and nutriceuticals were ascertained at each visit. Carotid artery ultrasonography was performed at baseline (two visits 1 to 3 weeks apart) and every 6 months thereafter. The baseline intimamedia thickness was the average of the two measurements. Pelvic examination (and uterine ultrasonography in participants with a uterus), Papanicolou smear, and mammography were done yearly in all participants. Uterine biopsy was performed if endometrial thickness was 5 mm or more. Adverse clinical symptoms and bleeding were assessed by the study gynecologist, who was blinded to treatment assignment. The primary trial end point was the rate of change in intimamedia thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms (815). Power calculations indicated that a sample size of 200 (100 participants per treatment group) was needed to detect a treatment effect size (the standardized difference in progression rates between the two treatment groups) of 0.40 or greater with 80% power. Two hundred twenty-two participants (111 per treatment group) were recruited to accommodate the anticipated dropout rate. Assessment of the Progression of Subclinical Atherosclerosis High-resolution B-mode ultrasonograms of the right common carotid artery were obtained by using a 7.5-MHz linear-array transducer attached to a Toshiba SSH 140A ultrasonography system (Toshiba Corp., Tokyo, Japan). The ultrasonographers were blinded to treatment assignment. Participants were placed in a supine position with the head rotated to the left by using a 45-degree head block. The jugular vein and carotid artery were located in the transverse view, with the jugular vein stacked above the carotid artery according to modification of a procedure described by Beach and colleagues (16). The transducer was then rotated 90 degrees around the central line of the transverse image of the stacked jugular vein and carotid artery to obtain a longitudinal image while the stacked position of the vessels was maintained. All images contained anatomic landmarks for reproducing probe angulation, and a hard copy of each participants baseline image was used as a guide for follow-up examinations. For each participant, the depth of field, gain, monitor intensity setting, and other instrumentation settings used at baseline examination were used at all follow-up examinations. These techniques significantly reduce measurement variability (14, 15). All images were recorded with the electrocardiogram tracing on super-VHS video tape. An image analyst who was blinded to treatment assignment measured the intimamedia thickness of the distal common carotid artery far wall with automated computerized edge detection using an in-house software package (Prosound, University of Southern California, Los Angeles, California), as described elsewhere (14, 15). Carotid intimamedia thickness was the average of approximately 70 to 100 individual measurements between the intimalumen and mediaadventitia interfaces along a 1-cm length just distal to the carotid artery bulb. This method standardized the location and the distance over which intimamedia thickness was measured and ensured that the same portion of the arterial wall was measured in each image and compared within and across all participants. Laboratory Measurements Participants fasted for 8 hours before sample collection. Total plasma cholesterol and triglyceride levels were measured by using an enzymatic method of the Standardization Program of the National Centers for Disease Control and Prevention. High-density lipoprotein cholesterol levels were measured after lipoproteins containing apolipoprotein B were precipitated in whole plasma by using heparin manganese chloride. Low-density lipoprotein cholesterol levels were estimated by using the Friedewald equation (17). Serum estradiol and fasting insulin levels were measured by using radioimmunoassay. Fasting serum glucose levels were measured by using the glucose oxidase technique on a Beckman Glucose II analyzer (Beckman Instruments, Brea, California). Hemoglobin A1c levels were measured by using high-performance liquid chromatography (Bio-Rad Diamat, Bio-Rad Corp., Hercules, California). Statistical Analysis We compared demographic and baseline clinical and laboratory values between the estradiol and placebo groups by using a t-test for independent samples for means or a chi-square test for proportions. At each study visit, adherence to study treatment was determined by calculating the percentage pill adherence (number of pills consumed divided by the number that should have been consumed) and by measuring estradiol levels. The average percentage pill adherence (over the entire study and by 6-month study period) and average serum estradiol levels (over the entire study) were compared between treatment groups by using a t-test for independent samples. The preplanned intention-to-treat analysis of the primary study end point, progression of subclinical atherosclerosis (def

Estrogen for Alzheimer’s disease in women: Randomized, double-blind, placebo-controlled trial

Background: AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. Methods: Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. Results: Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer’s Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. Conclusions: Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

Ovarian Conservation at the Time of Hysterectomy and Long-Term Health Outcomes in the Nurses' Health Study

OBJECTIVE: To report long-term health outcomes and mortality after oophorectomy or ovarian conservation. METHODS: We conducted a prospective, observational study of 29,380 women participants of the Nurses’ Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy, and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes. RESULTS: Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy compared with ovarian conservation, the multivariable hazard ratios (HRs) were 1.12 (95% confidence interval [CI] 1.03–1.21) for total mortality, 1.17 (95% CI 1.02–1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98–1.33) for stroke. Although the risks of breast (HR 0.75, 95% CI 0.68–0.84), ovarian (HR 0.04, 95% CI 0.01–0.09, number needed to treat=220), and total cancers (HR 0.90, 95% CI 0.84–0.96) decreased after oophorectomy, lung cancer incidence (HR=1.26, 95% CI 1.02–1.56, number needed to harm=190), and total cancer mortality (HR=1.17, 95% CI 1.04–1.32) increased. For those never having used estrogen therapy, bilateral oophorectomy before age 50 years was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span after surgery, one additional death would be expected for every nine oophorectomies performed. CONCLUSION: Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer but an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer. In no analysis or age group was oophorectomy associated with increased survival. LEVEL OF EVIDENCE: II

Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate

OBJECTIVE To evaluate the efficacy of lower doses of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy. DESIGN A randomized, double-blind, placebo-controlled trial (the Womens Health, Osteoporosis, Progestin, Estrogen study). SETTING Study centers across the United States. PATIENT(S) Two thousand, six hundred, seventy-three healthy, postmenopausal women with an intact uterus, including an efficacy-evaluable population (n = 241 at baseline). INTERVENTION(S) Patients received for 1 year (13 cycles; in milligrams per day) CEE, 0.625; CEE, 0.625 and MPA, 2.5; CEE, 0.45; CEE, 0.45 and MPA, 2.5; CEE, 0.45 and MPA, 1.5; CEE, 0.3; CEE, 0.3 and MPA, 1.5; or placebo. MAIN OUTCOME MEASURE(S) Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy. RESULT(S) In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups. CONCLUSION(S) Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses.

Ovarian conservation at the time of hysterectomy for benign disease

Objective: Prophylactic oophorectomy is often recommended concurrent with hysterectomy for benign disease. The optimal age for this recommendation in women at average risk for ovarian cancer has not been determined. Methods: Using published age-specific data for absolute and relative risk, both with and without oophorectomy, for ovarian cancer, coronary heart disease, hip fracture, breast cancer, and stroke, a Markov decision analysis model was used to estimate the optimal strategy for maximizing survival for women at average risk of ovarian cancer. For each 5-year age group from 40 to 80 years, 4 strategies were compared: ovarian conservation or oophorectomy, and use of estrogen therapy or nonuse. Outcomes, as proportion of women alive at age 80 years, were measured. Sensitivity analyses were performed, varying both relative and absolute risk estimates across the range of reported values. Results: Ovarian conservation until age 65 benefits long-term survival for women undergoing hysterectomy for benign disease. Women with oophorectomy before age 55 have 8.58% excess mortality by age 80, and those with oophorectomy before age 59 have 3.92% excess mortality. There is sustained, but decreasing, benefit until the age of 75, when excess mortality for oophorectomy is less than 1%. These results were unchanged following multiple sensitivity analyses and were most sensitive to the risk of coronary heart disease. Conclusion: Ovarian conservation until at least age 65 benefits long-term survival for women at average risk of ovarian cancer when undergoing hysterectomy for benign disease.

Insulin resistance in polycystic ovary syndrome

Patients with polycystic ovary syndrome (PCO) who are obese and exhibit acanthosis nigricans have been reported to have insulin resistance. We studied 21 euglycemic, euprolactinemic patients with PCO without acanthosis nigricans. Eleven of these patients were hirsute and the remaining 10 were not. Eight women with chronic anovulation, who were weight matched with the PCO patients, were studied along with the 11 ovulatory control subjects. Compared to control subjects, women with chronic anovulation had similar levels of immunoreactive luteinizing hormone (LH), bioactive LH, 17 beta-estradiol, testosterone (T), and dehydroepiandrosterone sulfate but significantly higher fasting immunoreactive insulin levels (p less than 0.05). The nonhirsute patients with PCO had higher immunoreactive insulin levels compared to patients with chronic anovulation and control subjects (p less than 0.05) while hirsute patients with PCO had higher immunoreactive insulin levels than nonhirsute ones (p less than 0.05). There was a significant positive correlation between fasting immunoreactive insulin levels and serum T. Fasting immunoreactive insulin also showed a significant correlation with serum LH and bioactive LH. After receiving 100 gm of oral glucose, hirsute patients with PCO had significantly higher insulin responses compared to those of control subjects despite similar glucose responses. Red blood cell insulin-binding sites and receptor affinities were similar in hirsute patients and control subjects. These data suggest that the hyperinsulinemia of patients with PCO may be related, in part, to the elevated LH and androgen levels and may be a postreceptor defect.

PROLONGED INTRAUTERINE CONTRACEPTION: A SEVEN-YEAR RANDOMIZED STUDY OF THE LEVONORGESTREL 20 mcg/DAY (LNg 20) AND THE COPPER T380 Ag IUDS

A levonorgestrel-releasing IUD and the Copper T 380Ag IUD were in randomized comparison for seven years in five clinics. In two other clinics the randomized study was truncated at five years, but use of the Copper T continued. No pregnancies occurred to users of either device in years 6 and 7. Cumulative pregnancy rates were 1.1 per 100 at seven years for the steroid-releasing and 1.4 per 100 for the copper-releasing IUDs. Cumulative rates of PID did not differ between devices. Infection rates appeared to be lowest during the sixth and seventh years of the study. Termination attributable to amenorrhea was the principal contributor to differences in cumulative continuation rates between devices. At the five clinics that carried the comparative study to seven years, cumulative continuation rates were 24.9 per 100 for LNg20 IUD users and 29.4 per 100 for TCu 380Ag users. Women who used either method for periods of five to seven years experienced, on average, marked to mild increases in hemoglobin as compared with levels at admission. The Copper T380 family and the LNg20 IUDs represent the most effective reversible contraceptive methods yet studied in long-term randomized trials.

A randomized comparison of nonoral estradiol delivery in postmenopausal women

We compared the transdermal and subdermal routes of estrogen administration with respect to the constancy of estrogen delivery and metabolic effects. Twenty postmenopausal women were randomized to receive either two 25 mg estradiol pellets subdermally (n = 10) or a 0.1 mg estradiol transdermal patch twice weekly (n = 10). Blood was sampled at 0, 2, 4, 6, 8, 12, 24, and 72 hours and 1, 2, 4, 8, 12, 16, 20, and 24 weeks (fasting samples at 0, 12, and 24 weeks), and a fasting urine was obtained after diuresis at 0, 12, and 24 weeks. In a 72-hour profile, serum estradiol levels (mean +/- SE) were highest at 24 hours (179 +/- 20 pg/ml) and fell to 139 +/- 16 pg/ml at 72 hours in the pellet group. In the patch group, estradiol levels rose rapidly to 152 +/- 33 pg/ml at 4 hours, remained relatively constant over 8 hours, and fell to 46 +/- 10 pg/ml at 72 hours. At 1 week, estradiol levels in the pellet group were 113 +/- 12 pg/ml and remained relatively constant for 24 weeks. In contrast, estradiol levels in the patch group were 52 +/- 11 pg/ml at 1 week and then varied widely until 24 weeks, when the levels were 89 +/- 26 pg/ml. The mean estradiol/estrone ratio ranged between 1 and 2.5 in both groups but fluctuated widely in the patch group. Follicle-stimulating hormone was suppressed in both groups; however, the decrement in the pellet group was greater (p less than 0.002). There was a significant increase in high-density lipoprotein cholesterol and a decrease in total cholesterol/high-density lipoprotein cholesterol at 12 weeks with the pellet but only at 24 weeks with the patch. The urinary calcium/creatinine ratio was reduced more consistently with the pellet than with the patch. Hot flushes were eliminated in all subjects.

Long-term contraception with the levonorgestrel 20 mcg/day (LNg 20) and the Copper T 380Ag intrauterine devices: A five-year randomized study

An intrauterine device, releasing approximately 20 micrograms/day of levonorgestrel (LNg 20), used by 1124 women, was studied in a randomized trial of five years duration in comparison with the Copper T, model TCu 380Agm in 1121 women. At five years, the gross cumulative pregnancy rate of 1.1 +/- 0.5 per 100 among users of the LNg 20 devices was not significantly different from the rate of 1.4 +/- 0.4 per 100 experienced by users of the Copper T 380Ag. The steroid-releasing IUD had significantly higher termination rates for expulsion and amenorrhea, a significantly lower termination rate for other menstrual problems and pain, and a lower continuation rate. The five-year continuation rate among women using the TCu 380Ag was 40.6 per 100 as compared with that of 33.0 per 100 among women randomized to the LNg 20 device (P less than .001). Terminations attributed to amenorrhea with the LNg device primarily account for differences in continuation. These two intrauterine devices are the most effective long-term, reversible IUDs yet reported in the literature. No other contraceptive methods have exhibited such low long-term pregnancy rates in randomized comparative trials.

Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

BACKGROUND Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested. METHODS A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen. RESULTS After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum. CONCLUSIONS Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).