The worldwide population of postmenopausal women is increasing (expected to be 1.1 billion by 2025) and these women are surviving longer than their predecessors. Coronary heart disease (CHD), osteoporosis, and the metabolic syndrome comprise a substantial part of the health burden affecting this population. However, despite considerable epidemiological and clinical research, the initiation and trajectory of these chronic and degenerative conditions remain unclear. Two specific gaps in knowledge are: 1) whether or to what extent the perimenopause is a time of accelerated disease progression;and 2) whether the pathobiological changes that have accumulated by the time of menopause establish the trajectory of postmenopausal disease outcomes. Accordingly, this application seeks support to continue a study of peri- and post-menopausal monkeys. The study in progress takes advantage of a nonhuman primate model of the menopausal transition developed recently at our institution. This model was adapted from a mouse model of perimenopause which uses a chemical (4-vinylcyclohexene diepoxide -VCD) to destroy primordial follicles via apoptosis and atresia. The model recapitulates the physiological changes experienced by women during the perimenopausal transition, including decreased numbers and ultimate depletion of primordial follicles and subsequent decreases in antimullerian hormone (AMH). Further, the stroma of the resulting follicle-depleted ovary has similar biologic activity (e.g. androgen production) to that of naturally postmenopausal women. As summarized, this model has several advantages over ovariectomized animals, a research platform that does not yield hormonal characteristics or risk factors (e.g., serum lipids) comparable to those observed in naturally postmenopausal women. The existing gaps in knowledge surrounding the perimenopausal transition and postmenopause prompted us to propose the following four Specific Aims: 1) Determine the extent to which diet induced atherosclerosis progression, as measured directly through biopsy, differs among ovariectomized (OVX), perimenopausal (VCD treated) and premenopausal monkeys, whether perimenopausal atherosclerosis extent determines the extent of postmenopausal atherosclerosis development, and finally, whether the trajectories of atherosclerosis progression differ between the peri and postmenopausal phases;2) Determine whether bone loss occurs during the perimenopausal transition and to compare the magnitude of any bone loss that does occur with that observed during the postmenopausal phase;3) Determine if and to what extent, elements of the metabolic syndrome appear during the perimenopausal transition, and whether the increases are greater in peri or postmenopausal phase;and 4) To compare and contrast the hormonal characteristics of VCD-treated monkeys both peri- and postmenopausally, with those observed in their OVX and premenopausal counterparts, and to determine whether changes in ovarian hormones in these reproductive phases are associated with changes in atherosclerosis extent and cardiovascular, skeletal, and metabolic risk biomarkers.

Public Health Relevance

The information gained through this investigation will provide women and their physicians with urgently required evidence on which to base decisions concerning peri- and postmenopausal treatment options. In addition, the outcomes observed in this study might well extend beyond the vascular and musculoskeletal systems to include other tissues that are sensitive to the effects of ovarian hormones, such as the brain.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Sherman, Sherry
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Schools of Medicine
United States
Zip Code
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
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
Atkins, Hannah M; Willson, Cynthia J; Silverstein, Marnie et al. (2014) Characterization of ovarian aging and reproductive senescence in vervet monkeys (Chlorocebus aethiops sabaeus). Comp Med 64:55-62
Ulu, A; Appt, Se; Morisseau, C et al. (2012) Pharmacokinetics and in vivo potency of soluble epoxide hydrolase inhibitors in cynomolgus monkeys. Br J Pharmacol 165:1401-12
Ethun, K F; Wood, C E; Parker Jr, C R et al. (2012) Effect of ovarian aging on androgen biosynthesis in a cynomolgus macaque model. Climacteric 15:82-92
Schnatz, Peter F; Nudy, Matthew; O'Sullivan, David M et al. (2011) Identification of a mechanism for increased cardiovascular risk among individuals with low vitamin D concentrations. Menopause 18:994-1000
Appt, Susan E; Ethun, Kelly F (2010) Reproductive aging and risk for chronic disease: Insights from studies of nonhuman primates. Maturitas 67:7-14
Appt, Susan E; Chen, Haiying; Goode, Amanda K et al. (2010) The effect of diet and cardiovascular risk on ovarian aging in cynomolgus monkeys (Macaca fascicularis). Menopause 17:741-8
Muhammad, F Salih; Goode, Amanda K; Kock, Nancy D et al. (2009) Effects of 4-vinylcyclohexene diepoxide on peripubertal and adult Sprague-Dawley rats: ovarian, clinical, and pathologic outcomes. Comp Med 59:46-59

Showing the most recent 10 out of 13 publications