Psychosomatic Medicine, Vol 58, Issue 6 598-611, Copyright © 1996 by American Psychosomatic Society

ORIGINAL ARTICLES

Psychosocial factors, sex differences, and atherosclerosis: lessons from animal models

JR Kaplan, MR Adams, TB Clarkson, SB Manuck, CA Shively and JK Williams
Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1040, USA.

OBJECTIVE: Premenopausal women, compared with men, are relatively spared from coronary heart disease and the underlying atherosclerosis. Our purpose has been to elucidate the reason for this difference and to explore the role of behavioral factors in this phenomenon. METHODS: Studies employed socially housed cynomolgus macaques (Macaca fascicularis) fed an atherogenic diet and subjected to behavioral observations. Ovariectomy, with or without hormone replacement, was used to test specific hypotheses about estrogen's role in the protection of females from atherosclerosis and coronary heart disease. RESULTS: Female macaques, like women, are resistant to atherosclerosis. However, this resistance is modified by social status-dominant monkeys develop little atherosclerosis, whereas subordinates resemble males in the amount of lesion that occurs. Subordinate females also are characterized by hypercortisolemia, behavioral dysfunction, and impaired ovarian function; the resulting low concentrations of circulating estrogen perhaps explain their accelerated atherosclerosis. Notably, atherosclerosis is exacerbated in ovariectomized monkeys but is suppressed in association with pregnancy, a hyperestrogenic state. Moreover, exogenous estrogen (an oral contraceptive) inhibits atherosclerosis in premenopausal social subordinates. CONCLUSIONS: To the extent that our results apply to women, they highlight the potential importance of behavioral stressors and their effects on estrogen activity in the premenopausal development of atherosclerosis. The triad of hypercortisolism, ovarian impairment, and psychiatric morbidity found in monkeys also occurs in women and may represent a high-risk state for disorders of the cardiovascular system and perhaps, other estrogen-sensitive tissues.

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