HORMONE RECEPTORS AND MECHANISMS OF HORMONE ACTION

冠心病、骨质疏松症、乳腺癌和子宫癌 对围产期妇女的健康有重大影响 绝经后的岁月。心脏病是最主要的死亡原因。 女性，而骨质疏松症是一种影响30%至50%的衰弱疾病 在所有绝经后女性中。雌激素替代疗法在围术期和术后的应用 更年期妇女患心脏病和骨质疏松症的风险降低50% 或者更多。不幸的是，单靠雌激素替代可能会增加这种风险。 子宫内膜癌和乳腺癌。添加一种相反的孕激素 降低子宫内膜癌的风险，但似乎并没有减少 雌激素对骨骼的有益作用。但是，添加一个 孕激素可能会抵消雌激素的心脏保护作用，并可能具有 对乳房也有有害影响。这些组织背后的机制(S)- 具体效果尚不清楚。 雌激素、孕激素和雄激素通过 与特定激素受体的相互作用。其中一些荷尔蒙 已在乳腺、子宫、动脉和骨骼(以及 和其他组织一样)。我们假设，组织特异性效应 不同的激素治疗主要通过不同的 调节雌激素、孕激素受体的表达 和雄激素。不幸的是，对这些基因表达的调控 激素受体在生殖组织中知之甚少， 在动脉和骨骼组织中几乎是未知的。 我们建议测定乳腺中类固醇激素受体的表达， 子宫、动脉和骨骼使用一套独特的组织在我们的 组织银行。这些组织是从一组卵巢切除术中提取的 曾用结合马处理过的雌性食蟹猴 单独雌激素(CEE)，2)单独孕激素(甲羟孕酮醋酸酯， 3)联合治疗(CEE+MPA)，或4)抗雌激素治疗 他莫昔芬。目的是确定荷尔蒙受体的表达， 受体阳性细胞的位置、类型及其对细胞的影响 个体化激素治疗对这些组织中受体表达的影响。 免疫组织化学分析将被用来定位雌激素 受体、孕激素受体和雄激素受体阳性细胞 骨和动脉切片，并检测雄激素受体在 乳腺和子宫组织。激素受体mRNA的表达也将 在这些组织中的每一个组织中被确定。结果将提供有价值的 关于单个受体在这些细胞中表达的新信息 不同靶向组织及其组织特异性作用机制的不同 激素疗法。这些研究将对以下方面产生重要影响 绝经后妇女的健康，并将进一步定义食蟹猴 猕猴是女性健康的典范。

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.