Regulation of growth hormone action by oestrogen and selective oestrogen receptor modulators

生长激素(GH)是人体生长发育所必需的。在成人生活中，它在调节身体脂肪与肌肉的比例方面发挥着关键作用，从而影响健康。生长激素作用的中断会减少肌肉质量，增加身体脂肪。这些变化导致肌肉力量和体能下降，并增加糖尿病、高血压和心血管死亡的风险。我们的实验室报告说，口服雌激素会削弱生长激素的作用，并导致身体脂肪和肌肉的不利变化。这是如何发生的还不得而知。由于口服雌激素在我们的社会中被广泛使用，了解它们对生长激素作用的基础是很重要的。SERM，或选择性雌激素受体调节剂，是一组用于治疗乳腺癌和骨质疏松症的药物。这些物质在某些组织中模仿雌激素的作用，在另一些组织中阻断雌激素的作用。SERM是否像雌激素一样干扰GH的作用还没有研究，但由于它们的广泛和长期使用，这种知识将具有治疗意义。GH的作用是由位于靶组织表面的一种名为GH受体的蛋白质介导的。我们认为雌激素和SERM通过改变该蛋白的生产和功能来控制GH的作用。因此，该项目旨在测试在人类来源的培养细胞中，雌激素和SERM如何调节GH受体的丰度及其介导GH作用的能力。这项工作有望获得生长激素与雌激素和SERM相互作用的新见解。这些信息也可能有助于设计对生长激素作用没有不良影响的新药，因此对女性S的健康和疾病具有潜在的重大影响。

Growth hormone (GH) is essential for body growth and development. In adult life, it plays a key role in regulating the ratio of body fat to muscle, thus influencing health. Disruption of GH action decreases muscle mass and increases body fat. These changes lead to reduced muscle strength and fitness, and increase the risk of diabetes, hypertension and cardiovascular mortality. Our laboratory has reported that oestrogens taken orally blunt GH action and cause unfavourable changes in body fat and muscle. How this happens is not known. As oral oestrogens are widely used in our society, it is important to understand the basis of their impact on GH action. SERMs, or selective oestrogen receptor modulators, are a group of drugs used in the treatment of breast cancer and osteoporosis. These substances mimic oestrogen action in some tissues, and block oestrogen action in others. Whether SERMs interfere with GH action as oestrogens do have not been studied, but such knowledge would have therapeutic significance because of their widespread and long-term use. GH action is mediated by a protein, called the GH receptor, located on the surface of target tissues. We propose that oestrogens and SERMs alter the production and function of this protein to control GH action. Thereby, this project is designed to test, in cultured cells of human origin, how oestrogens and SERMs modulate abundance of the GH receptor and its ability to mediate GH action. This work is anticipated to gain novel insights into the interaction of GH with oestrogens and SERMs. This information may also be useful for the design of new drugs devoid of adverse effects on GH action, and hence would have potentially significant implications in women s health and disease.