HORMONE RECEPTORS AND MECHANISMS OF HORMONE ACTION

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Coronary heart, osteoporosis, and breast and uterine cancers have a significant impact on the health of women in their peri- and postmenopausal years. Heart disease is the leading cause of death among women, while osteoporosis is a debilitating disease affecting 30% to 50% of all postmenopausal women. Estrogen replacement in peri- and post- menopausal women reduces the risk of heart disease and osteoporosis by 50% or more. Unfortunately, estrogen replacement alone may increase the risk of endometrial and breast cancers. The addition of an opposing progestin reduces the risk of endometrial cancer without appearing to reduce the beneficial effects of estrogen on bone. However, the addition of a progestin may negate the heart-protective effect of estrogen and may have harmful effects on breast as well. The mechanism(s) behind these tissue- specific effects are not known. Estrogen, progesterone, and androgens modulate gene transcription through interaction with specific hormone receptors. Some of these hormone receptors have been identified in breast, uterus, artery and bone (as well as other tissues). We hypothesize that the tissue-specific effects of different hormone therapies are mediated primarily through differential modulation of the expression of the receptors for estrogen, progesterone, and androgens. Unfortunately, regulation of the expression of these hormone receptors is poorly understood in reproductive tissues and virtually unknown in arterial and skeletal tissues. We propose to determine steroid hormone receptor expression in breast, uterus, artery, and bone using a unique set of tissues available in our tissue bank. These tissues were derived from a set of ovariectomized female cynomolgus macaques that had been treated with 1) conjugated equine estrogens alone (CEE), 2) a progestin alone (medroxyprogesterone acetate, MPA), 3) the combination therapy (CEE + MPA), or 4) the anti-estrogen tamoxifen. The objectives are to determine hormone receptor expression, the location and types of receptor-positive cells, and the influences of individual hormone therapies on receptor expression in these tissues. Immunohistochemical analysis will be utilized to localize estrogen receptor, progesterone receptor, and androgen receptor positive cells in bone and artery sections, and to examine androgen receptor expression in mammary and uterine tissues. Hormone receptor mRNA expression will also be determined in each of these tissues. The results will provide valuable new information regarding the expression of individual receptors in these target tissues and the mechanisms of tissue-specific effects of different hormone regimens. These studies will have important implications for the health of postmenopausal women, and will further define the cynomolgus macaque as a model of women's health.