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

描述(申请人提供)：围绝经期是女性生活中最复杂和最不被理解的状态之一。与这种状态相关的许多健康风险被认为是由于雌激素水平的下降，以及雌激素可以预防围绝经期妇女面临的健康风险。然而，雌激素在围绝经期波动，如果在经前期和卵泡期增加的话。最近的临床试验表明，绝经后妇女长期服用雌激素化合物可能会增加几种疾病的风险。因此，研究雌激素暴露对各种器官系统的影响是很重要的。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。长期雌激素暴露对调节几个关键身体功能的下丘脑的影响尚未被研究。这一点至关重要，因为女性长期使用雌激素制剂，并在整个成年期暴露于内源性雌激素。本研究旨在探讨慢性雌激素暴露对下丘脑对雌激素敏感的神经系统之一，即结节漏斗状多巴胺能系统的影响。TIDA神经元释放的多巴胺(DA)抑制垂体前叶催乳素(PRL)的分泌。年龄相关的TIDA活动减少与高血压症相关 动物模型中催乳素血症与乳腺和垂体肿瘤的出现。TIDA神经元功能丧失的机制尚不清楚。在这个应用中，我们提出了一个新的假设和一个有趣的模型来研究雌激素如何影响TIDA神经元和增加PRL水平。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，而且还暴露在环境雌激素之下。长期接触雌激素和PRL水平升高可能会增加患乳腺癌的风险。

DESCRIPTION (provided by applicant): 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 hyper prolactinemia and appearance of mammary and pituitary tumors in animal models. The mechanisms behind the loss of TIDA neuronal function are 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.