Calcified plaque in the coronary arteries is a marker for atheromatous-plaque burden and is predictive of future risk of cardiovascular events. We examined the relationship between estrogen therapy ...and coronary-artery calcium in the context of a randomized clinical trial.
In our ancillary substudy of the Women's Health Initiative trial of conjugated equine estrogens (0.625 mg per day) as compared with placebo in women who had undergone hysterectomy, we performed computed tomography of the heart in 1064 women aged 50 to 59 years at randomization. Imaging was conducted at 28 of 40 centers after a mean of 7.4 years of treatment and 1.3 years after the trial was completed (8.7 years after randomization). Coronary-artery calcium (or Agatston) scores were measured at a central reading center without knowledge of randomization status.
The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1) (P=0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared with placebo were 0.78 (95% confidence interval, 0.58 to 1.04), 0.74 (0.55 to 0.99), and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P=0.01), 0.55 (P<0.001), and 0.46 (P=0.001). For coronary-artery calcium scores of more than 300 (vs. <10), the multivariate odds ratio was 0.58 (P=0.03) in an intention-to-treat analysis and 0.39 (P=0.004) among women with at least 80% adherence.
Among women 50 to 59 years old at enrollment, the calcified-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo. However, estrogen has complex biologic effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways. (ClinicalTrials.gov number, NCT00000611.)
To examine the associations between vaginal estrogen use and multiple health outcomes including cardiovascular disease (total myocardial infarction, stroke, and pulmonary embolism/deep vein ...thrombosis), cancer (total invasive, breast, endometrial, ovarian, and colorectal cancer), and hip fracture.
We included postmenopausal women from the Nurses' Health Study (1982-2012) who were not current users of systemic hormone therapy at the start of the study or during follow-up. Vaginal estrogen use was self-reported on the biennial questionnaires. Information on incident health outcomes were self-reported and confirmed by medical records. We used Cox proportional hazards regression to model the multivariable adjusted hazard ratios and the 95% confidence intervals for vaginal estrogen use and multiple health outcomes.
Over 18 years of follow-up, after adjusting for covariates, risks for cardiovascular disease, cancer, and hip fracture were not different between users and nonusers of vaginal estrogen. No statistically significant increase in risk of any health outcome was observed with vaginal estrogen use. In sensitivity analyses, when we examined associations by hysterectomy status, the stratified results were generally similar to those for the total cohort.
Vaginal estrogen use was not associated with a higher risk of cardiovascular disease or cancer. Our findings lend support to the safety of vaginal estrogen use, a highly effective treatment for genitourinary syndrome of menopause.
To evaluate the effect of bazedoxifene/conjugated estrogens (BZA/CE), a tissue selective estrogen complex, on uterine bleeding in postmenopausal women.
International, multicenter, randomized, ...double-blind, placebo- and active-controlled, phase III study (Selective estrogen Menopause And Response to Therapy SMART-1).
Outpatient clinical.
Healthy, postmenopausal women (N = 3,397) aged 40 to 75 years with an intact uterus.
Daily oral therapy with BZA 10, 20, or 40 mg, each with CE 0.625 or 0.45 mg, raloxifene 60 mg, or placebo.
Cumulative amenorrhea profiles and the incidence of bleeding or spotting over 2 years.
Treatment with BZA 20 or 40 mg with CE 0.625 or 0.45 mg was associated with rates of cumulative amenorrhea (>83% during cycles 1–13 and >93% during cycles 10–13) and bleeding or spotting that were comparable to those with placebo. Subjects who received BZA 10 mg/CE 0.625 mg experienced slightly lower cumulative amenorrhea rates throughout the study compared with placebo-treated subjects.
Postmenopausal women treated with BZA 20 or 40 mg with CE 0.625 or 0.45 mg had high rates of cumulative amenorrhea that were similar to those reported with placebo. This new menopausal therapy may offer a favorable bleeding and tolerability profile.
Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether ...MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.
KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation SD = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 × 10(-2) (95% CI, -8.27 × 10(-2) to -2.44 × 10(-2); ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 × 10(-2) (95% CI, -5.09 × 10(-2) to -9.34 × 10(-3); ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y.
The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles.
ClinicalTrials.gov NCT00154180 and NCT00623311.
The aim of this study was to investigate the association between hormone therapy (HT) use and the development of bone fractures.
Using terms related to HT and fractures, we searched PubMed, Embase, ...and the Cochrane library for randomized controlled trials on HT and the associated risk of fractures published before August 2014. Two evaluators independently selected studies on the basis of predetermined selection criteria, and 28 studies were included in the meta-analysis. Summary estimates were obtained using fixed- or random-effects models as appropriate.
A total of 28 studies included 33,426 participants and 2,516 fractures cases. The overall relative risk of HT was 0.74 (95% confidence interval CI 0.69-0.80) for total fractures, 0.72 (95% CI 0.53-0.98) for hip fractures, and 0.63 (95% CI 0.44-0.91) for vertebral fractures. In subgroup analyses, women of an age less than 60 years had lower risk of total fractures compared with women of an age more than 60 years (P = 0.003). Estradiol led to greater decrease in the risk of total fractures compared with conjugated equine estrogens (P = .01). There is greater reduction in total fracture risk in trials of follow-up less than 36 months than that of follow-up more than 36 months (P = 0.003). No increase in the incidence of total cancer events but an increase in the incidence of thrombus was found to be associated with HT.
HT is associated with a reduced risk of total, hip, and vertebral fractures, with a possible attenuation of this protection effect after it is stopped or when it is begun after 60 years. However, there may be an increase in the incidence of thrombus formation associated with HT.
The Women's Health Initiative Estrogen-Aone trial comparing conjugated equine estrogens (CEE) with placebo was stopped early because of an increased stroke incidence and no reduction in risk of ...coronary heart disease. Preliminary results suggesting possible reduction in breast cancers warranted more detailed analysis.
To determine the effects of CEE on breast cancers and mammographic findings.
Following breast cancer risk assessment, 10,739 postmenopausal women aged 50 to 79 years with prior hysterectomy were randomized to CEE or placebo at 40 US clinical centers from 1993 through 1998. Mammography screenings and clinical breast examinations were performed at baseline and annually. All breast cancers diagnosed through February 29, 2004, are included.
A dose of 0.625 mg/d of CEE or an identical-appearing placebo.
Breast cancer incidence, tumor characteristics, and mammogram findings.
After a mean (SD) follow-up of 7.1 (1.6) years, the invasive breast cancer hazard ratio (HR) for women assigned to CEE vs placebo was 0.80 (95% confidence interval CI, 0.62-1.04; P = .09) with annualized rates of 0.28% (104 cases in the CEE group) and 0.34% (133 cases in the placebo group). In exploratory analyses, ductal carcinomas (HR, 0.71; 95% CI, 0.52-0.99) were reduced in the CEE group vs placebo group; however, the test for interaction by tumor type was not significant (P = .054). At 1 year, 9.2% of women in the CEE group had mammograms with abnormalities requiring follow-up vs 5.5% in the placebo group (P<.001), a pattern that continued through the trial to reach a cumulative percentage of 36.2% vs 28.1%, respectively (P<.001); however, this difference was primarily in assessments requiring short interval follow-up.
Treatment with CEE alone for 7.1 years does not increase breast cancer incidence in postmenopausal women with prior hysterectomy. However, treatment with CEE increases the frequency of mammography screening requiring short interval follow-up. Initiation of CEE should be based on consideration of the individual woman's potential risks and benefits.
clinicaltrials.gov Identifier: NCT00000611.
•Ring B unsaturated estrogens are formed by an alternate steroidogenesis.•Ring B unsaturated estrogens express biological activity mainly via ER β.•Some protective effects of CEE may involve ...inhibition of LDL and HDL oxidation.•CEE components modulate apoptosis and inhibit this form of cell death in neurons.•Eqn, Δ8-E1 and Δ3-17β-E2 may help prevent cardiovascular and Alzheimer's disease.
Oral conjugated equine estrogens (CEE) are the most used estrogen formulation for postmenopausal hormone therapy either alone or in combination with a progestin. CEE is most commonly used for the management of early menopausal symptoms such as hot flashes, vaginitis, insomnia, and mood disturbances. Additionally, if used at the start of the menopausal phase (age 50–59 years), CEE prevents osteoporosis and may in some women reduce the risk of cardiovascular disease (CVD) and Alzheimer's disease (AD). There appears to be a common mechanism through which estrogens can protect against CVD and AD.
CEE is a natural formulation of an extract prepared from pregnant mares’ urine. The product monogram lists the presence of only 10 estrogens consisting of the classical estrogens, estrone and 17β-estradiol, and a group of unique ring B unsaturated estrogens such as equilin and equilenin. The ring B unsaturated estrogens are formed by an alternate steroidogenic pathway in which cholesterol is not an obligatory intermediate. Both the route of administration and structure of these estrogens play a role in the overall pharmacology of CEE. In contrast to 17β-estradiol, ring B unsaturated estrogens express their biological effects mainly mediated by the estrogen receptor β and not the estrogen receptor α.
All estrogen components of CEE are antioxidants, and some ring B unsaturated estrogens have several fold greater antioxidant activity than estrone and 17β-estradiol. The cardioprotective and neuroprotective effects of CEE appear to be, to some extent, due to its ability to prevent the formation of oxidized LDL and HDL, and by inhibiting or modulating some of the key proteases involved in programmed cell death (apoptosis) induced by the excess neurotransmitter glutamate and other neurotoxins.
Selective combinations of ring B unsaturated estrogens have the potential of being developed as novel therapeutic agents for the prevention of cardiovascular disease and Alzheimer's disease in both aging women and men.
This article is part of a Special Issue entitled ‘Menopause’.
Heart disease is a major cause of illness and death in women. To understand better the role of estrogen in the treatment and prevention of heart disease, more information is needed about its effects ...on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects.
We randomly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day, or placebo. The women were followed for a mean (+/-SD) of 3.2+/-0.6 years. Base-line and follow-up coronary angiograms were analyzed by quantitative coronary angiography.
Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels (9.4 percent and 16.5 percent, respectively) and significant increases in high-density lipoprotein cholesterol levels (18.8 percent and 14.2 percent, respectively); however, neither treatment altered the progression of coronary atherosclerosis. After adjustment for measurements at base line, the mean (+/-SE) minimal coronary-artery diameters at follow-up were 1.87+/-0.02 mm, 1.84+/-0.02 mm, and 1.87+/-0.02 mm in women assigned to estrogen, estrogen plus medroxyprogesterone acetate, and placebo, respectively. The differences between the values for the two active-treatment groups and the value for the placebo group were not significant. Analyses of several secondary angiographic outcomes and subgroups of women produced similar results. The rates of clinical cardiovascular events were also similar among the treatment groups.
Neither estrogen alone nor estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis in women with established disease. These results suggest that such women should not use estrogen replacement with an expectation of cardiovascular benefit.
To explore the potential occurrence of long-term side effects and tolerability of gonadotropin-releasing hormone agonist (GnRHa) plus 2 different add-back regimens in adolescent patients with ...endometriosis.
Follow-up questionnaire sent in 2016 to patients who participated in a drug trial between 2008 and 2012.
Tertiary care center in Boston, Massachusetts.
Female adolescents with surgically confirmed endometriosis (n = 51) who enrolled in a GnRHa plus add-back trial as adolescents.
Leuprolide depot 11.25 mg intramuscular injection every 3 months, plus oral norethindrone acetate 5 mg daily or oral norethindrone acetate 5 mg daily and oral conjugated equine estrogens 0.625 mg daily.
Side effects during and after treatment, irreversible side effects, changes in pain, overall satisfaction.
The response rate was 61% (25 of 41; 10 subjects could not be located). Almost all (24 of 25) reported side effects during treatment; 80% (16 of 21) reported side effects lasting longer than 6 months after stopping treatment. Almost half (9 of 20) reported side effects they considered irreversible, including memory loss, insomnia, and hot flashes. Despite side effects, participants rated GnRHa plus add-back as the most effective hormonal medication for treating endometriosis pain; two-thirds (16 of 25) would recommend it to others. More participants who received a modified 2-drug add-back regimen vs standard 1-drug add-back would recommend GnRHa and believed it was the most effective hormonal medication.
Subjects believed that GnRHa used with add-back was effective and would recommend it to others, despite significant side effects. Those who received 2-drug add-back reported more success than those who received standard add-back. A subset of patients reported side effects they consider to be irreversible.
The Women's Health Initiative Memory Study (WHIMS) previously found increased risk for dementia and no effect on mild cognitive impairment (MCI) in women treated with conjugated equine estrogens ...(CEE) plus medroxyprogesterone acetate (MPA).
To determine the effects of CEE alone and CEE plus MPA on incidence of probable dementia and MCI in older women.
Randomized, double-blind, placebo-controlled clinical trials of CEE (estrogen-alone trial) or CEE plus MPA (estrogen plus progestin trial) in community-dwelling women aged 65 to 79 years, conducted from June 1995 to July 8, 2002 (estrogen plus progestin; n = 4532), or to February 29, 2004 (estrogen-alone; n = 2947), in 39 of the 40 WHI clinical centers.
In the estrogen-alone trial, 1 daily tablet containing either 0.625 mg/d of CEE vs matching placebo; in the estrogen plus progestin trial, 1 daily tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) vs matching placebos.
Probable dementia and MCI.
In the estrogen-alone trial, 47 participants were diagnosed with probable dementia, of whom 28 were assigned to CEE and 19 to placebo (hazard ratio HR, 1.49; 95% confidence interval CI, 0.83-2.66). Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial (45 vs 22 per 10 000 person-years for CEE plus MPA vs placebo, respectively; P =.11). When data were pooled per the original WHIMS protocol, the overall HR for probable dementia was 1.76 (95% CI, 1.19-2.60; P =.005). After excluding participants with baseline Modified Mini-Mental State Examination scores at or below the screening cut point, the HR was 1.77 (95% CI, 0.74-4.23; P =.20) in the estrogen-alone trial and 2.19 (95% CI, 1.25-3.84; P =.006) in the pooled trials. In the estrogen-alone trial, 76 participants were diagnosed with MCI in the CEE group vs 58 in the placebo group (HR, 1.34; 95% CI, 0.95-1.89). In the combined trial data, the HR was similar (1.25; 95% CI, 0.97-1.60). In the estrogen-alone trial, 93 participants receiving CEE were diagnosed with either probable dementia or MCI vs 69 receiving placebo (HR, 1.38; 95% CI, 1.01-1.89; P =.04).
Estrogen therapy alone did not reduce dementia or MCI incidence and increased the risk for both end points combined. Pooling data for estrogen alone and estrogen plus progestin resulted in increased risks for both end points. Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended.
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