STRESS, ESTROGEN, OPIOIDS AND ATHEROGENESIS IN WOMEN

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DESCRIPTION: Coronary heart disease is the number one killer of women. Women enjoy less risk for coronary disease than men throughout their reproductive years, but around the age of menopause the relative risk for coronary heart disease in women increases, suggesting that reproductive hormones may provide some degree of protection from cardiovascular pathophysiology of coronary heart disease. This is further supported by reports suggesting that estrogen replacement therapy may prevent the postmenopausal surge in coronary heart disease risk. At present the precise role of estrogens in the pathophysiology of cardiovascular disease is unclear, but greater understanding of these interactions can provide concrete strategies for coronary heart disease risk reduction. Previous work by the principal investigator has identified endogenous opioid peptide mechanisms that may buffer the pathophysiological effects of psychological stress. Previous work by others has shown that estrogen deprivation of menopause disrupts opioid control of pituitary function, and estrogen replacement can restore this function. These findings suggest that opioid mechanisms may be involved in the cardioprotective role of estrogens. The purpose of the proposed research is to examine the interaction between estrogen and opioids in risk for coronary heart disease. This will be accomplished by comparison of the effects of the opioid antagonist naltrexone on cardiovascular reactivity in postmenopausal women with and without estrogen replacement therapy. A combined cross- sectional and longitudinal study is proposed. The cross-sectional study will utilize intact groups of women on hormone replacement and women not previously on hormone replacement therapy in the longitudinal study, women not previously on hormone replacement therapy will be randomly assigned to one of three groups: estrogen replacement, estrogen plus progestin, or placebo. Naltrexone stress testing will take place before and after three months of therapy. If estrogens reduce cardiovascular risk by reduction of stress reactivity, then postmenopausal women on estrogen replacement therapy will show smaller blood pressure and heart rate changes during psychological stress than women not on estrogen replacement therapy. If the reduction in stress reactivity is mediated via estrogen facilitation of opioid inhibitory mechanisms, then pretreatment with naltrexone should increase reactivity in the estrogen replacement groups, thereby antagonizing the cardiovascular benefits of estrogen.