Dataset Information

The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

ABSTRACT:

Objective

The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address gaps in understanding the effects of timely menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women's Health Initiative.

Method

The KEEPS was a randomized, double-blinded, placebo-controlled trial to test the hypothesis that initiation of HT (oral conjugated equine estrogens [o-CEE] or transdermal 17β-estradiol [t-E2]) in healthy, recently postmenopausal women (n = 727) would slow the progression of atherosclerosis as measured by changes in carotid artery intima-media thickness (CIMT).

Results

After 4 years, neither HT affected the rate of increase in CIMT. There was a trend for reduced accumulation of coronary artery calcium with o-CEE. There were no severe adverse effects, including venous thrombosis. Several ancillary studies demonstrated a positive effect on mood with o-CEE, and reduced hot flashes, improved sleep, and maintenance of bone mineral density with both treatments. Sexual function improved with t-E2. There were no significant effects of either treatment on cognition, breast pain, or skin wrinkling. Variants of genes associated with estrogen metabolism influenced the age of menopause and variability in effects of the HT on CIMT. Platelet activation associated with the development of white matter hyperintensities in the brain.

Conclusions

KEEPS and its ancillary studies have supported the value and safety of the use of HT in recently postmenopausal women and provide a perspective for future research to optimize HT and health of postmenopausal women. The KEEPS continuation study continues to pursue these issues.

SUBMITTER: Miller VM

PROVIDER: S-EPMC6738629 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

Miller Virginia M VM Naftolin Fredrick F Asthana Sanjay S Black Dennis M DM Brinton Eliot A EA Budoff Matthew J MJ Cedars Marcelle I MI Dowling N Maritza NM Gleason Carey E CE Hodis Howard N HN Jayachandran Muthuvel M Kantarci Kejal K Lobo Rogerio A RA Manson JoAnn E JE Pal Lubna L Santoro Nanette F NF Taylor Hugh S HS Harman S Mitchell SM

Menopause (New York, N.Y.) 20190901 9

<h4>Objective</h4>The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address gaps in understanding the effects of timely menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women's Health Initiative.<h4>Method</h4>The KEEPS was a randomized, double-blinded, placebo-controlled trial to test the hypothesis that initiation of HT (oral conjugated equine estrogens [o-CEE] or transdermal 17β-estradiol [t-E2]) ...[more]

PMID: 31453973

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Project description:ImportanceSexual dysfunction, an important determinant of women's health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition.ObjectiveTo determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women.Design, setting, and participantsAncillary study of the Kronos Early Estrogen Prevention Study (KEEPS), a 4-year prospective, randomized, double-blinded, placebo-controlled trial of menopausal hormone therapy in healthy, recently menopausal women. Of 727 KEEPS enrollees, 670 agreed to participate in this multicenter ancillary study. Women were 42 to 58 years old, within 36 months from last menstrual period. Data were collected from July 2005 through June 2008 and analyzed from July 2010 through June 2017.InterventionsWomen were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 µg/d transdermal 17β-estradiol (t-E2), or placebo. Participants also received 200 mg oral micronized progesterone (if randomized to o-CEE or t-E2) or placebo (if randomized to placebo estrogens) for 12 days each month.Main outcomes and measuresAspects of sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain) were assessed using the Female Sexual Function Inventory (FSFI; range, 0-36 points; higher scores indicate better sexual function). Low sexual function (LSF) was defined as an FSFI overall score of less than 26.55. Distress related to low FSFI score (required for the diagnosis of sexual dysfunction) was not evaluated.ResultsThe 670 participants had a mean (SD) age of 52.7 (2.6) years. The t-E2 treatment was associated with a significant yet moderate improvement in the FSFI overall score across all time points compared with placebo (average efficacy, 2.6; 95% CI, 1.11-4.10; adjusted P = .002). With o-CEE treatment, there was no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, -0.1 to 2.8; adjusted P = .13). There was no difference in FSFI overall score between the t-E2 and o-CEE groups on average across 48 months (adjusted P = .22). In the individual domains of sexual function, t-E2 treatment was associated with a significant increase in mean lubrication (0.61; 95% CI, 0.25-0.97; P = .001) and decreased pain (0.67; 95% CI, 0.25-1.09; P = .002) compared with placebo. Overall, the proportion of women with LSF was significantly lower after t-E2 treatment compared with placebo (67%; 95% CI, 55%-77% vs 76%; 95% CI, 67%-83%; P = .04). For o-CEE there was no significant reduction in the odds of LSF.Conclusions and relevanceTreatment with t-E2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known.Trial registrationclinicaltrials.gov Identifier: NCT00154180.

Project description:BackgroundCardiac fat is emerging as an important parameter for cardiovascular risk stratification. Accurate and reproducible volumetric measurements can facilitate in the serial assessment of cardiac fat by computed tomography (CT). We assessed the intra- and inter-observer variability of cardiac fat volumetric measurements using a semi-automated CT software.MethodsWe used non-contrast coronary calcium CT scans to quantify epicardial and intra-thoracic fat volumes. Two expert readers analyzed baseline and follow up CT scans of 45 subjects by using a semi-automated CT software (QFAT 2.0, Cedars Sinai-Medical Center). Correlation and Bland-Altman analysis was performed for both intra- and inter-observer comparisons for each cardiac fat type.ResultsThe intra-observer correlation coefficients ranged between 0.86 to 0.99 and 0.87 to 0.99 for epicardial (median fat per reader (cm3) 20.9 to 25.7) and intra-thoracic (median fat per reader (cm3) 27.1 to 31.6) fat volumes respectively, with no significant differences between individual data points (all p > 0.38). The inter-observer correlation coefficient was 0.99 (p < 0.0001 for correlation) for both epicardial and intra-thoracic fat. By Bland-Altman analysis for epicardial fat measurements, mean difference of intra-observer was 0.90 cm3 with 95% confidence intervals (0.22,1.7) and -1.8 cm3 for inter-observer, with 95% CI (-2.9, -0.69). Bland-Altman plots for intra-thoracic fat measurements were similarly impressive for both inter- and intra-observer reads.ConclusionsOur data showed that measuring epicardial and intra-thoracic fat volumes by CT using a semi-automated software has excellent intra-observer and inter-observer reliability. Cardiac fat volumes can be obtained easily and reproducibly from routine calcium scoring scans and may help in assessing cardiovascular risk.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00154180; Keywords: Epicardial fat volume; intra-thoracic fat volume; computed tomography; intra-observer; inter-observer.

Project description:ObjectiveThe objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years.MethodsA total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 μg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling.ResultsModerate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity.ConclusionsRecently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

Dataset Information

The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

Objective

Method

Results

Conclusions

Publications

The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

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