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.
Cross-sectional studies suggest an association between exposure to ambient air pollution and atherosclerosis. We investigated the association between outdoor air quality and progression of ...subclinical atherosclerosis (common carotid artery intima-media thickness, CIMT).
We examined data from five double-blind randomized trials that assessed effects of various treatments on the change in CIMT. The trials were conducted in the Los Angeles area. Spatial models and land-use data were used to estimate the home outdoor mean concentration of particulate matter up to 2.5 micrometer in diameter (PM2.5), and to classify residence by proximity to traffic-related pollution (within 100 m of highways). PM2.5 and traffic proximity were positively associated with CIMT progression. Adjusted coefficients were larger than crude associations, not sensitive to modelling specifications, and statistically significant for highway proximity while of borderline significance for PM2.5 (P = 0.08). Annual CIMT progression among those living within 100 m of a highway was accelerated (5.5 micrometers/yr 95%CI: 0.13-10.79; p = 0.04) or more than twice the population mean progression. For PM2.5, coefficients were positive as well, reaching statistical significance in the socially disadvantaged; in subjects reporting lipid lowering treatment at baseline; among participants receiving on-trial treatments; and among the pool of four out of the five trials.
Consistent with cross-sectional findings and animal studies, this is the first study to report an association between exposure to air pollution and the progression of atherosclerosis--indicated with CIMT change--in humans. Ostensibly, our results suggest that air pollution may contribute to the acceleration of cardiovascular disease development--the main causes of morbidity and mortality in many countries. However, the heterogeneity of the volunteering populations across the five trials, the limited sample size within trials and other relevant subgroups, and the fact that some key findings reached statistical significance in subgroups rather than the sample precludes generalizations to the general population.
Abstract In the late 1980s, several observational studies and meta-analyses suggested that hormone replacement therapy (HRT) was beneficial for prevention of osteoporosis, coronary heart disease, ...dementia and decreased all-cause mortality. In 1992, the American College of Physicians recommended HRT for prevention of coronary disease. In the late 1990s and early 2000s, several randomized trials in older women suggested coronary harm and that the risks, including breast cancer, outweighed any benefit. HRT stopped being prescribed at that time, even for women who had severe symptoms of menopause. Subsequently, reanalyzes of the randomized trial data, using age stratification, as well as newer studies, and meta-analyses have been consistent in showing that younger women, 50–59 years or within 10 years of menopause, have decreased coronary disease and all-cause mortality; and did not have the perceived risks including breast cancer. These newer findings are consistent with the older observational data. It has also been reported that many women who abruptly stopped HRT had more risks, including more osteoporotic fractures. The current data confirm a “timing” hypothesis for benefits and risks of HRT, showing that younger have many benefits and few risks, particularly if therapy is predominantly focused on the estrogen component. We discuss these findings and put into perspective the potential risks of treatment, and suggest that we may have come full circle regarding the use of HRT. In so doing we propose that HRT should be considered as part of a general prevention strategy for women at the onset of menopause.
Abstract
Objective
To update the “Testosterone Therapy in Men With Androgen Deficiency Syndromes” guideline published in 2010.
Participants
The participants include an Endocrine Society–appointed ...task force of 10 medical content experts and a clinical practice guideline methodologist.
Evidence
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.
Consensus Process
One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline.
Conclusions
We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone–binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.
This update to the Endocrine Society’s 2010 testosterone guideline, prepared by an expert panel, describes the diagnosis, screening, treatment, and monitoring of hypogonadal men.
Associations have been found between long-term exposure to ambient air pollution and cardiovascular morbidity and mortality. The contribution of air pollution to atherosclerosis that underlies many ...cardiovascular diseases has not been investigated. Animal data suggest that ambient particulate matter (PM) may contribute to atherogenesis. We used data on 798 participants from two clinical trials to investigate the association between atherosclerosis and long-term exposure to ambient PM up to 2.5 μm in aerodynamic diameter ( PM2.5). Baseline data included assessment of the carotid intima-media thickness (CIMT), a measure of subclinical atherosclerosis. We geocoded subjects' residential areas to assign annual mean concentrations of ambient PM2.5. Exposure values were assigned from a PM2.5surface derived from a geostatistical model. Individually assigned annual mean PM2.5concentrations ranged from 5.2 to 26.9 μ g/ m3(mean, 20.3). For a cross-sectional exposure contrast of 10 μ g/ m3PM2.5, CIMT increased by 5.9% (95% confidence interval, 1-11%). Adjustment for age reduced the coefficients, but further adjustment for covariates indicated robust estimates in the range of 3.9-4.3% (p-values, 0.05-0.1). Among older subjects (≥ 60 years of age), women, never smokers, and those reporting lipid-lowering treatment at baseline, the associations of PM2.5and CIMT were larger with the strongest associations in women ≥ 60 years of age (15.7%, 5.7-26.6%). These results represent the first epidemiologic evidence of an association between atherosclerosis and ambient air pollution. Given the leading role of cardiovascular disease as a cause of death and the large populations exposed to ambient PM2.5, these findings may be important and need further confirmation.
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.
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.
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.
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.).
HIV-infected persons have an increased risk of atherosclerosis relative to uninfected individuals. Inflammatory processes may contribute to this risk. We evaluated the associations of 10 biomarkers ...of systemic inflammation (CRP, IL-6, sTNF-αR1 and 2), monocyte activation (CCL2, sCD163, sCD14), coagulation (fibrinogen, D-dimer), and endothelial dysfunction (ICAM-1) with subclinical carotid atherosclerosis among participants in the Multicenter AIDS Cohort Study (MACS).
Carotid plaque and intima media thickness (IMT) in the common carotid (CCA-IMT) and bifurcation region were assessed by B mode ultrasound among 452 HIV-infected and 276 HIV-uninfected men from 2010-2013. Associations between levels of each biomarker and presence of focal plaque and IMT were assessed by logistic and linear regression models, adjusting for demographics, risk behaviors, traditional cardiovascular disease (CVD) risk factors, and HIV disease characteristics.
Compared to HIV-uninfected men, HIV-infected men had significantly higher levels of 8 of the 10 biomarkers. Overall, men with sCD163, CCL2, IL-6, and CRP levels in the highest quintile had approximately 2 times the odds of carotid plaque relative to those with levels in the lowest quintile, independent of demographic and CVD risk factors. Fibrinogen levels were positively associated with CCA-IMT while ICAM-1, CCL2, and sTNF-αR1 levels were positively associated with bifurcation-IMT. Among HIV-uninfected men, higher levels of sTNF-αR2 were positively associated with CCA-IMT, fibrinogen with bifurcation-IMT and carotid plaque, and ICAM-1 with carotid plaque.
In addition to greater levels of systemic inflammation, heightened monocyte activation (sCD163, CCL2) may contribute to the burden of atherosclerosis among HIV-infected persons.
The totality of evidence indicates menopausal hormone replacement therapy (HRT) effects are determined by timing of initiation according to age and/or time since menopause, underlying health of ...target tissue, and duration of therapy. Initiated in women at younger than 60 years and/or at or near menopause, HRT significantly reduces all-cause mortality and cardiovascular disease (CVD), whereas other primary CVD prevention therapies such as lipid-lowering fail to do so. The magnitude and type of HRT-associated risks, including breast cancer, stroke, and venous thromboembolism, are rare (<10 events/10,000 women), not unique to HRT, and comparable with other medications. Hormone replacement therapy is a sex-specific and time-dependent primary CVD prevention therapy that concomitantly reduces all-cause mortality, as well as other aging-related diseases with an excellent risk profile. Keeping in mind that prevention strategies must be personalized, health care providers and patients can use cumulated HRT data in making clinical decisions concerning chronic disease prevention including CVD and mortality reduction.
Background. The relationships between soluble CD 14 (sCD14), endotoxin (lipopolysaccharide LPS), and progression of atherosclerosis have not been defined in human immunodeficiency virus (HIV) ...infection. Methods. We retrospectively assessed serum sCD14 and LPS levels of 91 subjects in a prospective 3-year study of carotid artery intima-media thickness (CIMT) (AIDS Clinical Trials Group ACTG 5078), where subjects were enrolled as risk factor-controlled triads of HIV-uninfected (n = 36) and HIV-infected individuals with (n = 29) or without (n = 26) protease inhibitor (PI)-based therapy for ≥2 years. The primary end point was the yearly rate of change of CIMT (∆CIMT). Results. In multivariate analysis of the HIV-infected subjects, each 1 μg/mL above the mean of baseline serum sCD14 corresponded to an additional 1.52 μm/y (95% confidence interval, .07-2.98; P= .04) in the ∆CIMT. Every 100 pg/mL above the mean of baseline serum LPS corresponded to an additional 0.49 μm/y (95% confidence interval, .18–. 81; P =. 003) in the ∆CIMT. However, in univariate analysis in the HIV-uninfected group sCD14 (P = .33) and LPS (P = .27) levels were not associated with higher ∆CIMT. HIV infection and PI therapy were not associated with baseline serum LPS and sCD14 levels (P > .1). Conclusions. Our data are among the first to suggest that serum biomarkers of microbial translocation (LPS) and macrophage activation (sCD14) predict subclinical atherosclerosis progression in HIV-infected persons.
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