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Lessons from KEEPS: the Kronos Early Estrogen Prevention Study

Miller, V M; Taylor, H S; Naftolin, F; Manson, J E; Gleason, C E; Brinton, E A; Kling, J M; Cedars, M I; Dowling, N M; Kantarci, K; Harman, S M
The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of hormone treatments (menopausal hormone treatments [MHTs]) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (0.45 mg/day) or transdermal 17β-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. Although MHT did not decrease the age-related increase in CIMT, KEEPS provided other important insights about MHT effects. Both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of β-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes.
PMID: 32880220
ISSN: 1473-0804
CID: 4614622

Heart fat and carotid artery atherosclerosis progression in recently menopausal women: impact of menopausal hormone therapy: The KEEPS trial

El Khoudary, Samar R; Venugopal, Vidya; Manson, JoAnn E; Brooks, Maria M; Santoro, Nanette; Black, Dennis M; Harman, Mitchell; Naftolin, Frederick; Hodis, Howard N; Brinton, Eliot A; Miller, Virginia M; Taylor, Hugh S; Budoff, Matthew J
OBJECTIVE:Heart fat deposition has been linked to atherosclerosis, and both accelerate after menopause. Hormone therapy (HT) may differentially slow heart fat deposition and progression of atherosclerosis, depending on the specific HT agent or its route of administration. Our objective was to evaluate the effects of different HT agents, oral and transdermal, on associations between heart fat accumulation and atherosclerosis progression, measured by carotid intima-media thickness (CIMT), in recently menopausal women from the Kronos Early Estrogen Prevention Study (KEEPS) trial. METHODS:KEEPS was a randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens (o-CEE) or 50 mcg/d transdermal 17β-estradiol (t-E2), compared with placebo, on 48 months progression of CIMT. Epicardial adipose tissue (EAT) and paracardial adipose tissue (PAT) volumes were quantified by computed tomography. RESULTS:In all, 467 women (mean age [SD] 52.7 [2.5]; 78.2% White; 30% on o-CEE, 30.8% t-E2, 39.2% placebo) with heart fat volumes and CIMT at baseline and 48 months were included. EAT and PAT changes were not associated with CIMT progression; however, the assigned treatment significantly modified the association between PAT (but not EAT) change and CIMT progression. In the o-CEE group, adjusted CIMT progression was 12.66 μm (95% confidence interval [CI] 1.80, 23.52) lower than in t-E2 group (P = 0.02), and 10.09 μm (95% CI 0.79, 19.39) lower than in placebo group (P = 0.03), as per 1-SD increase in PAT. CONCLUSION:Compared with t-E2, o-CEE appears to slow down the adverse effect of increasing PAT on progression of atherosclerosis. Whether this beneficial association is specific to CEE or to the oral route of CEE administration is unclear and should be assessed further.
PMID: 32015261
ISSN: 1530-0374
CID: 4879602

Electrical inhibitor for tocolysis

Chapter by: RajKumar, Ashwin; Karsdon, Jeffrey; Naftolin, Frederick; Kapila, Vikram
in: Frontiers in Biomedical Devices, BIOMED - 2020 Design of Medical Devices Conference, DMD 2020 by
[S.l.] : American Society of Mechanical Engineers (ASME)infocentral@asme.org, 2020
pp. ?-?
ISBN: 9780791883549
CID: 4612982

Higher blood pressure is associated with loss of white matter integrity and higher Alzheimer's Tau biomarkers in postmenopausal women of the KEEPS continuation study [Meeting Abstract]

Kara, F; Lowe, V J; Reid, R I; Schwarz, C G; Tosakulwong, N; Lesnick, T G; Zuk, S M; Kendall-Thomas, J; Thostenson, K B; Reyes, D A; Fields, J A; Senjem, M M; Min, H -K; Jack, C R; Bailey, K R; James, T; Lobo, R A; Manson, J E; Pal, L; Hammers, D B; Malek-Ahmadi, M; Cedars, M; Naftolin, F; Miller, V M; Harman, S M; Dowling, N M; Gleason, C E; Kantarci, K
Objective: Elevated blood pressure (BP) is a risk factor for white matter injury associated with cerebrovascular disease, cognitive decline, and dementia. White matter hyperintensities (WMH) on MRI, a marker of white matter injury, increases with aging and are more common in women than in men after the age of 60. We examined BP in relation to WMH volume, diffusion MRI biomarkers of white matter microstructure and PET biomarkers of Alzheimer's disease (AD) in postmenopausal women.
Design(s): Women (mean age 67 +/- 2, n=75), who had previously enrolled in the multi-site Kronos Early Estrogen Prevention Study (KEEPS), were invited to participate in the present KEEPS Continuation Study. BP, MRI, and PET data were collected 9 years after the end of KEEPS menopausal hormone therapies. White matter integrity was assessed with WMH volume measurements on structural MRI and with measures of white matter microstructure on diffusion MRI. AD biomarkers were measured by Florbetapir amyloid-beta PET and Flortaucipir tau PET which were performed in a subset of participants from the Mayo Clinic site (n=25). Multiple linear regression analysis was used to assess the association between imaging measures and measured BP. All models were adjusted for age and p<0.05 was considered statistically significant.
Result(s): Higher systolic BP (SBP) and diastolic BP (
EMBASE:634461904
ISSN: 1530-0374
CID: 4824782

Impact of menopausal hormone formulations on pituitary-ovarian regulatory feedback

Kling, Juliana M; Dowling, N Maritza; Bimonte-Nelson, Heather A; Gleason, Carey E; Kantarci, Kejal; Manson, JoAnn E; Taylor, Hugh S; Brinton, Eliot A; Lobo, Rogerio A; Cedars, Marcelle I; Pal, Lubna; Neal-Perry, Genevieve; Naftolin, Frederick; Harman, S Mitchell; Miller, Virginia M
Changes in pituitary-ovarian hormones across the menopausal transition have multiple physiological consequences. However, little is known about how the major types of postmenopausal hormone therapy (HT) affect pituitary-ovarian hormonal relationships. This study evaluated these relationships in recently menopausal women (52.45 ± 2.49 yr of age) in the Kronos Early Estrogen Prevention Study (KEEPS) who were compliant to randomized, double-blinded treatment with oral conjugated equine estrogen (o-CEE; n = 109), transdermal 17β-estradiol (t-E2; n = 107), or placebo (n = 146). Androstenedione, testosterone, 17β-estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum before (baseline) and 48 mo after randomization to treatment. Descriptive summaries of hormone levels were performed, and multiple regression analyses were used to examine the effects of o-CEE, t-E2, and placebo on these hormone levels at 48 mo, adjusting for baseline levels. A network analysis examined the covariance of changes in hormone levels over the 48 mo within treatment groups. As expected, at 48 mo of treatment, hormone levels differed between women in the two active treatment groups compared with placebo, and network analysis indicated stronger relationships among hormone levels in the t-E2 and o-CEE groups compared with placebo. Associations among testosterone, 17β-estradiol, FSH, and LH differed between the o-CEE group compared with t-E2 and placebo groups. Thus, two common HT regimens differentially alter pituitary-ovarian hormone levels, altering feedback cycles and interhormonal associations in recently menopausal women. These interactions provide the basis for future studies investigating the impact of hormonal modulation of aging, including cognitive decline in women.
PMCID:6957372
PMID: 31663769
ISSN: 1522-1490
CID: 4271542

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

Miller, Virginia M; Naftolin, Fredrick; Asthana, Sanjay; Black, Dennis M; Brinton, Eliot A; Budoff, Matthew J; Cedars, Marcelle I; Dowling, N Maritza; Gleason, Carey E; Hodis, Howard N; Jayachandran, Muthuvel; Kantarci, Kejal; Lobo, Rogerio A; Manson, JoAnn E; Pal, Lubna; Santoro, Nanette F; Taylor, Hugh S; Harman, S Mitchell
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/METHODS: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.
PMID: 31453973
ISSN: 1530-0374
CID: 4054382

Cardiovascular health and the menopausal woman: the role of estrogen and when to begin and end hormone treatment

Naftolin, Frederick; Friedenthal, Jenna; Nachtigall, Richard; Nachtigall, Lila
Reports have correlated the use of estrogen for the treatment of menopausal symptoms with beneficial effects on the cardiovascular system. Molecular, biochemical, preclinical, and clinical studies have furnished a wealth of evidence in support of this outcome of estrogen action. The prospective randomized Women's Health Initiative (WHI) and the Early Versus Late Intervention Trial (ELITE) showed that starting menopausal hormone treatment (MHT) within 5 to 10 years of menopause is fundamental to the success of estrogen's cardioprotection in post-menopausal women without adverse effects. Age stratification of the WHI data has shown that starting hormone treatment within the first decade after menopause is both safe and effective, and the long-term WHI follow-up studies are supportive of cardioprotection. This is especially true in estrogen-treated women who underwent surgical menopause. A critique of the WHI and other relevant studies is presented, supporting that the timely use of estrogens protects against age- and hormone-related cardiovascular complications. Salutary long-term hormone treatment for menopausal symptoms and prevention of complications has been widely reported, but there are no prospective trials defining the correct length to continue MHT. At present, women undergoing premature menopause receive estrogen treatment (ET) until evidence of hormone-related complications intervenes. Normal women started on MHT who receive treatment for decades without hormone-related complications have been reported, and the WHI follow-up studies are promising of long-term post-treatment cardioprotection. A prevention-based holistic approach is proposed for timely and continuing MHT/ET administration as part of the general management of the menopausal woman. But this should be undertaken only with scheduled, annual patient visits including evaluations of cardiovascular status. Because of the continued occurrence of reproductive cancers well into older ages, these visits should include genital and breast cancer screening.
PMCID:6733383
PMID: 31543950
ISSN: 2046-1402
CID: 4105312

Contemporary Hormonal Contraception and the Risk of Breast Cancer [Comment]

Nachtigall, Lila; Naftolin, Frederick; Keefe, David L
PMID: 29595938
ISSN: 1533-4406
CID: 3025942

Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS)

Cintron, Dahima; Lahr, Brian D; Bailey, Kent R; Santoro, Nanette; Lloyd, Robin; Manson, JoAnn E; Neal-Perry, Genevieve; Pal, Lubna; Taylor, Hugh S; Wharton, Whitney; Naftolin, Fredrick; Harman, S Mitchell; Miller, Virginia M
OBJECTIVE:This study determined whether two different formulations of hormone therapy (HT): oral conjugated equine estrogens (o-CEE; 0.45 mg/d, n = 209), transdermal 17β-estradiol (t-E2; 50 μg/d, n = 201) plus cyclic progesterone (Prometrium, 200 mg) or placebo (PBO, n = 243) affected sleep domains in participants of the Kronos Early Estrogen Prevention Study. METHODS:Participants completed the Pittsburgh Sleep Quality Index at baseline and during the intervention at 6, 18, 36, and 48 months. Global sleep quality and individual sleep domain scores were compared between treatments using analysis of covariance, and correlated with vasomotor symptom (VMS) scores using Spearman correlation coefficients. RESULTS:Global Pittsburgh Sleep Quality Index scores (mean 6.3; 24% with score >8) were similar across groups at baseline and were reduced (improved sleep quality) by both HT (average change -1.27 [o-CEE] and -1.32 [t-E2]) when compared with PBO (-0.60; P = 0.001 [o-CEE vs PBO] and P = 0.002 [t-E2 vs PBO]). Domain scores for sleep satisfaction and latency improved with both HT. The domain score for sleep disturbances improved more with t-E2 than o-CEE or PBO. Global sleep scores significantly correlated with VMS severity (rs = 0.170, P < 0.001 for hot flashes; rs = 0.177, P < 0.001 for night sweats). Change in scores for all domains except sleep latency and sleep efficiency correlated with change in severity of VMS. CONCLUSIONS:Poor sleep quality is common in recently menopausal women. Sleep quality improved with both HT formulations. The relationship of VMS with domains of sleep suggests that assessing severity of symptoms and domains of sleep may help direct therapy to improve sleep for postmenopausal women.
PMCID:5771895
PMID: 28832429
ISSN: 1530-0374
CID: 2915842

Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS)

Taylor, Hugh S; Tal, Aya; Pal, Lubna; Li, Fangyong; Black, Dennis M; Brinton, Eliot A; Budoff, Matthew J; Cedars, Marcelle I; Du, Wei; Hodis, Howard N; Lobo, Rogerio A; Manson, JoAnn E; Merriam, George R; Miller, Virginia M; Naftolin, Frederick; Neal-Perry, Genevieve; Santoro, Nanette F; Harman, Sherman M
Importance: Sexual dysfunction, an important determinant of women's health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition. Objective: To determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women. Design, Setting, and Participants: Ancillary 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. Interventions: Women were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 microg/d transdermal 17beta-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 Measures: Aspects 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. Results: The 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 Relevance: Treatment with t-E2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known. Trial Registration: clinicaltrials.gov Identifier: NCT00154180.
PMCID:5710212
PMID: 28846767
ISSN: 2168-6114
CID: 2679862