Within a decade one of every seven Americans will be a postmenopausal woman. Cardiovascular disease will be the largest single cause of death within this group, up to half will suffer an osteoporosis-related fracture, and one in ten will develop breast cancer. The relationship between stage of reproductive life and the onset of these menopause-associated diseases has not been explored adequately, in large part, because of the lack of a suitable animal model of natural menopause in women. We propose to extend to cynomolgus monkeys (Macaca fascicularis) a technique developed in mice that uses exposure to 4-vinylcyclohexene diepoxide (VCD) to selectively target primordial and primary follicles, thereby inducing ovarian failure and modeling the menopause as it occurs in women. We hypothesize that monkeys with a hormone-producing, follicle-depleted ovary (a condition that we refer to as """"""""residual ovary menopause"""""""" [ROM]) will mimic the disease vulnerability of naturally postmenopausal women. The overall objective is to use ROM and ovariectomized (OVX) monkeys to determine the development of chronic disease processes during the perimenopausal transition compared to the postmenopausal period.
The aims are:
Specific Aim 1. To compare and contrast the hormonal characteristics of monkeys with follicle-depleted ovaries with those observed in their ovariectomized counterparts.
Specific Aim 2. To determine the extent to which vulnerability to atherosclerosis is increased during the perimenopausal transition and how any such increase in vulnerability is related to changes in cardiovascular risk factors or ovarian hormones observed among animals in the ROM and OVX treatment conditions.
Specific Aim 3. To determine the extent to which vulnerability to bone loss is increased during the perimenopausal transition and how any such increase is related to the pituitary and ovarian hormonal changes observed among ROM and OVX animals.
Specific Aim 4. To determine if and to what extent plasma androgen concentrations modulate estradiol-stimulated breast cell proliferation in ROM monkeys in comparison to their OVX counterparts. Relevance: It has been speculated that there is a perimenopausal increase in vulnerability to the diseases that prominently affect postmenopausal women, especially cardiovascular disease and osteoporosis;such an increase (which the proposed research is designed to detect) implies the need for vigorous early intervention. Further, it has been speculated that the ovarian stroma of naturally menopausal women produces a significant -though variable- amount of testosterone, which in turn may moderate the progression of bone loss, atherosclerosis, and perhaps the occurrence of breast cancer. By determining the extent to which the residual hormones of peri- and postmenopausal women influence these disease processes, the proposed research will facilitate the development of targeted, individualized therapies for improving the postmenopausal quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG027847-04
Application #
7664976
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Sherman, Sherry
Project Start
2006-09-01
Project End
2010-07-31
Budget Start
2009-08-15
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$391,885
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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Eyster, K; Appt, S; Chalpe, A et al. (2014) Effects of equol on gene expression in female cynomolgus monkey iliac arteries. Nutr Metab Cardiovasc Dis 24:423-7
Eyster, Kathleen M; Appt, Susan; Chalpe, Abha et al. (2014) Effects of estradiol on transcriptional profiles in atherosclerotic iliac arteries in ovariectomized cynomolgus macaques. Menopause 21:143-52
Clarkson, Thomas B; Ethun, Kelly F; Pajewski, Nicholas M et al. (2014) Effects of bazedoxifene, conjugated equine estrogens, and a tissue-selective estrogen complex containing both bazedoxifene and conjugated equine estrogens on cerebral artery atherosclerosis in postmenopausal monkeys. Menopause 21:8-14
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Clarkson, Thomas B; Ethun, Kelly F; Chen, Haiying et al. (2012) Effects of bazedoxifene alone and with conjugated equine estrogens on coronary and peripheral artery atherosclerosis in postmenopausal monkeys. Menopause :
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Schnatz, Peter F; Vila-Wright, Sharon; Jiang, Xuezhi et al. (2012) The association between plasma 25-hydroxyvitamin D3 concentrations, C-reactive protein levels, and coronary artery atherosclerosis in postmenopausal monkeys. Menopause 19:1074-80
Appt, Susan E; Chen, Haiying; Clarkson, Thomas B et al. (2012) Premenopausal antimullerian hormone concentration is associated with subsequent atherosclerosis. Menopause 19:1353-9

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