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

描述（由申请人提供）：围绝经期是妇女生命中最复杂和最不了解的状态之一。许多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，雌激素可以保护围绝经期妇女免受健康风险。然而，雌激素在围绝经期波动，如果在月经前期和卵泡期增加。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患几种疾病的风险。因此，研究雌激素暴露对各器官系统的影响具有重要意义。迄今为止的研究表明，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。慢性雌激素暴露对调节几种关键身体功能的下丘脑的影响尚未研究。这是至关重要的，因为妇女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。该建议侧重于慢性雌激素暴露对下丘脑的雌激素敏感神经元系统之一，即结节漏斗多巴胺能（TIDA）系统的影响。从TIDA神经元释放的多巴胺（DA）抑制垂体前叶的催乳素（PRL）分泌。TIDA活性的降低与高胰岛素血症有关。 催乳素血症以及动物模型中乳腺和垂体肿瘤的出现。TIDA神经元功能丧失背后的机制尚不清楚。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。这一系列的研究是重要的，因为女性不仅在HRT中长期使用雌激素，而且还暴露于环境雌激素。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.