The major objective of the KEEPS (Kronos Early Estrogen Prevention Study) Cognitive and Affective Study is to evaluate the potential differential efficacy of oral conjugated equine estrogen (CEE or Premarin) and transdermal 17 ?-estradiol (tE2) on mood and cognitive function of healthy perimenopausal women over an extended therapy of 4 years. Recent findings from the Women's Health Initiative (WHI) and the Women's Health Initiative Memory Study (WHIMS) have raised serious concerns about the long-term safety of both the unopposed and opposed CEE. Additionally, these studies have raised several issues related to HT that need to be systematically evaluated in well-designed clinical studies. These issues include the following: 1) which is the best period in a woman's reproductive history to initiate hormone therapy (perimenopausal versus postmenopausal), 2) what is the preferred form of estrogen therapy (CEE versus estradiol), 3) which is the most effective route of administration of estrogen (oral vs. transdermal), 4) which is the best progestin for opposed hormone therapy (natural progesterone vs. medroxyprogesterone), 5) what are the most sensitive psychometric measures to characterize potential effects of estrogen on cognition and mood, and 6) which hormone therapy regimen is physiologically most relevant and mimics the menstrual cycle hormonal milieu (continuous vs. cyclic). The KEEPS Cognitive and Affective (C/A) Study is the first multisite, randomized, placebo-controlled, double-blind, parallel-group design clinical study that will address major HT-related issues raised by WHI and WHIMS. Specifically, the C/A Study will involve perimenopausal women and evaluate the differential efficacy of CEE and tE2 on comprehensive measures of cognition and mood in perimenopausal women over an extended therapy of four years. The present study will employ cyclic administration of micronized progesterone to counteract proliferative effects of HT on the endometrium, and accomplish the following objectives: 1) to characterize the potential differential efficacy and adverse effect profile of extended therapy with CEE and tE2 on cognitive function of perimenopausal women, 2) to identify the effects of micronized progesterone on the proposed battery of cognitive and affective tests in perimenopausal women, 3) to establish the relationship between estrogen-induced changes in markers of atherosclerosis, heart disease, and measures of mood and cognition, 4) to characterize the relationship between estrogen-related changes in proposed markers of inflammation, blood hypercoagulability, and tests of cognition and mood, and 5) to determine if ApoE genotype will influence cognitive responsitivity to HT.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG029624-05S1
Application #
8700821
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Wagster, Molly V
Project Start
2007-04-15
Project End
2014-03-31
Budget Start
2013-08-15
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$138,802
Indirect Cost
$46,574
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Messina, Mark; Gleason, Carey (2016) Evaluation of the potential antidepressant effects of soybean isoflavones. Menopause 23:1348-1360
Kantarci, Kejal; Lowe, Val J; Lesnick, Timothy G et al. (2016) Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. J Alzheimers Dis 53:547-56
Santoro, Nanette; Allshouse, Amanda; Neal-Perry, Genevieve et al. (2016) Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause :
Raz, L; Hunter, L V; Dowling, N M et al. (2016) Differential effects of hormone therapy on serotonin, vascular function and mood in the KEEPS. Climacteric 19:49-59
Gleason, Carey E; Dowling, N Maritza; Wharton, Whitney et al. (2015) Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med 12:e1001833; discussion e1001833
Fischer, Barbara; Gleason, Carey; Asthana, Sanjay (2014) Effects of hormone therapy on cognition and mood. Fertil Steril 101:898-904
Wharton, Whitney; Gleason, Carey E; Dowling, N Maritza et al. (2014) The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition. J Alzheimers Dis 40:331-41
Dowling, N Maritza; Gleason, Carey E; Manson, Joann E et al. (2013) Characterization of vascular disease risk in postmenopausal women and its association with cognitive performance. PLoS One 8:e68741
Carlsson, Cynthia M; Xu, Guofan; Wen, Zhifei et al. (2012) Effects of atorvastatin on cerebral blood flow in middle-aged adults at risk for Alzheimer's disease: a pilot study. Curr Alzheimer Res 9:990-7
Gleason, Carey E; Dowling, N Maritza; Friedman, Elliot et al. (2012) Using predictors of hormone therapy use to model the healthy user bias: how does healthy user status influence cognitive effects of hormone therapy? Menopause 19:524-33

Showing the most recent 10 out of 14 publications