Although there is little information available regarding age-dependent altered tissue responses to natural hormones, several lines of evidence strongly suggest that the biologic response of the vascular wall to hormones may differ in younger and older postmenopausal women. The Women's Health Initiative showed that women randomized to hormone therapy within 10 years of menopause had a relative risk less than 1 for coronary heart disease (CHD) compared with women more than 10 years postmenopausal who had a relative risk for CHD greater than 1. Nurse's Health Study data indicate that women who initiated hormone therapy within 6 years of menopause had a significantly lower CHD risk than did women who initiated therapy 6 or more years after menopause. Estrogen in the Prevention of Atherosclerosis Trial results show that estrogen therapy more effectively reduced the progression of subclinical atherosclerosis in women who were randomized within 6 years of menopause relative to those women who were 10 years or more postmenopausal. Non-human primate studies provide pathobiological evidence that the optimal time for intervention with estrogen therapy is within 6 years of menopause. With the rapidly growing number of women entering menopause and introduction of new hormonal products into the marketplace, postmenopausal hormone therapy is likely to increase. Understanding the effects of estrogen on the progression of subclinical atherosclerosis continues to be an important and timely public health issue since young postmenopausal women who have climacteric symptoms, predominantly flushing, are the women who are most likely to initiate hormone therapy. Since there are no trials designed to directly test the hypothesis that the effect of exogenous estrogen on the progression of atherosclerosis will vary by time since menopause, we propose a double-blind, placebo-controlled trial with a 2x2 factorial design (treatment x time since menopause) in which 504 healthy postmenopausal women without clinical evidence of cardiovascular disease will be randomized to 1713-estradiol 1 mg/day versus placebo according to their number of years since menopause, <6 years or >10 years. Treatment duration will average 3 years (,range, 2 to 5 years) and the rate of change _ carotid artery intima-media thickness, a well-established measure of subclinical atherosclerosis, will be the primary trial end point. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024154-04
Application #
7255399
Study Section
Special Emphasis Panel (ZRG1-ASG (01))
Program Officer
Badinelli, Joanna
Project Start
2004-09-30
Project End
2009-06-30
Budget Start
2007-08-15
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$1,978,297
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Herrera, Alexandra Ycaza; Hodis, Howard N; Mack, Wendy J et al. (2017) Estradiol Therapy After Menopause Mitigates Effects of Stress on Cortisol and Working Memory. J Clin Endocrinol Metab 102:4457-4466
Kurita, Keiko; Henderson, Victor W; Gatz, Margaret et al. (2016) Association of bilateral oophorectomy with cognitive function in healthy, postmenopausal women. Fertil Steril 106:749-756.e2
Rettberg, Jamaica R; Dang, Ha; Hodis, Howard N et al. (2016) Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer's risk metabolic phenotype. Neurobiol Aging 40:155-163
Karim, Roksana; Dang, Ha; Henderson, Victor W et al. (2016) Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life. J Am Geriatr Soc 64:2448-2456
Hodis, Howard N; Mack, Wendy J; Henderson, Victor W et al. (2016) Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med 374:1221-31
Karim, Roksana; Stanczyk, Frank Z; Brinton, Roberta D et al. (2015) Association of endogenous sex hormones with adipokines and ghrelin in postmenopausal women. J Clin Endocrinol Metab 100:508-15
Hodis, Howard N; Mack, Wendy J; Shoupe, Donna et al. (2015) Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause 22:391-401
Hodis, Howard N; Mack, Wendy J (2014) Hormone replacement therapy and the association with coronary heart disease and overall mortality: clinical application of the timing hypothesis. J Steroid Biochem Mol Biol 142:68-75
Gatto, Nicole M; Henderson, Victor W; Hodis, Howard N et al. (2014) Components of air pollution and cognitive function in middle-aged and older adults in Los Angeles. Neurotoxicology 40:1-7
Hodis, Howard N; Mack, Wendy J (2013) The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 2: comparative risks. J Am Geriatr Soc 61:1011-8

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