Effects of Chronic Estrogen on TIDA Neurons: Role of Cytokines and NO

围绝经期是女性生活中最复杂、最不为人所知的状态之一。许多人 与这种状态相关的健康风险被认为是由于雌激素水平的下降和 雌激素可以预防围绝经期妇女面临的健康风险。然而，雌激素会波动。 在围绝经期，如果有的话，在月经前和卵泡期会增加。近期临床 试验表明，对绝经后妇女长期服用雌激素化合物可能会 增加了几种疾病的风险。因此，研究雌激素的作用非常重要。 暴露在各种器官系统上。到目前为止的研究表明，雌激素对大脑的影响是 有益的。然而，这些报道的影响涉及大脑的非下丘脑区域。的影响 调节几个关键身体功能的下丘脑慢性雌激素暴露尚未见报道 调查过了。这一点很关键，因为女性长期使用雌激素制剂，而且 在整个成年期都暴露在内源性雌激素之下。该提案侧重于以下方面的影响 慢性雌激素暴露在下丘脑对雌激素敏感的神经系统之一，即， 结节漏斗多巴胺能(TIDA)系统。从TIDA神经元释放的多巴胺(DA)抑制 垂体腺分泌催乳素(PRL)。与年龄相关的TIDA活动减少与 动物模型中高催乳素血症与乳腺和垂体肿瘤的出现。其作用机制 TIDA神经元功能丧失的原因尚不清楚。在这项申请中，我们提出了一种小说 研究雌激素如何影响TIDA神经元和增加催乳素的假设和有趣的模型 级别。 这一系列研究很重要，因为女性不仅在激素替代疗法中长期使用雌激素，而且 也暴露在环境雌激素之下。长期接触雌激素和催乳素水平升高 可能会增加患乳腺癌的风险。

Perimenopause is one of the most complex and least understood states of a woman's life. Many of the health risks associated with this state were believed to be due to decreases in estrogen levels and that estrogen could protect against health risks faced by perimenopausal women. However, estrogen fluctuates during perimenopause and if at all increases during the premenstrual and follicular phases. Recent clinical trials have shown that chronic administration of estrogenic compounds in postmenopausal women may increase the risk for several diseases. Therefore, it is important to investigate the effects of estrogen exposure on various organ systems. Studies so far indicate that estrogen's effects in the brain are beneficial. These reported effects, however, deal with non-hypothalamic regions of the brain. The effects of chronic estrogen exposure on the hypothalamus which regulates several key body functions have not been investigated. This is critical because women use estrogenic preparations on a prolonged basis and are exposed to endogenous estrogen throughout their adulthood. This proposal focuses on the effects of chronic estrogen exposure on one of the estrogen sensitive neuronal systems of the hypothalamus, namely, the tuberoinfundibular dopaminergic (TIDA) system. Dopamine (DA) released from TIDA neurons inhibits prolactin (PRL) secretion from the anterior pituitary. Age-related reductions in TIDA activity is associated with hyperprolactinemia and appearance of mammary and pitutiary tumors in animal models. The mechanisms behind the loss of TIDA neuronal function is not clear. In this application, we are proposing a novel hypothesis and an interesting model to study how estrogen could affect TIDA neurons and increase PRL levels. This series of studies is important because women not only use estrogen on a long-term basis in HRT but are also exposed to environmental estrogens. Prolonged exposure to estrogen and elevated levels of PRL may promote the risk for breast cancer.