DIFFERENTIAL EFFECTS OF GONADAL STEROIDS ON BONE

男性骨质疏松症是发病率和死亡率的重要原因，尤其是在老年人中。性腺功能减退是男性骨质疏松症的危险因素，但性腺功能减退导致骨丢失的机制尚不完全清楚。这一领域的一个根本悬而未决的问题涉及雄激素和雌激素对男性骨骼的不同影响。为了解决这个问题，在3项拟议研究中的第一项，正常男性将被随机分配到：1)单用GnRH类似物12周(将内源性性腺类固醇抑制到青春期前的水平)，2)GnRH类似物加睾酮(T)(使循环中的T和雌二醇水平正常化)，或3)GnRH类似物加T加芳香酶抑制剂(使T正常化，但导致选择性雌激素缺乏)。每4周测量一次骨转换指标。第一组骨转换增加，第二组不变。如果需要雌激素来维持男性的正常骨转换，第三组也应该增加骨转换。在第二项研究中，正常男性将被随机分成类似的治疗组，为期8周，并增加一组将接受GnRH类似物加生理雌二醇组。甲状旁腺素输注每4周进行一次，每次输注期间每6小时测量一次骨转换标志物。通过比较甲状旁腺素输注过程中这些标志物的变化率，可以评估雄激素和雌激素对甲状旁腺素骨骼敏感性的选择性影响。在第三种方案中，将小鼠基质细胞系和原代小鼠成骨细胞暴露于雌激素和雄激素，以评估它们对骨保护素和骨保护素配体(OPG-L)基因表达的不同影响。这些研究将有助于阐明性腺类固醇作用于骨骼的机制，并使应聘者能够欣赏骨骼生物学的基本发展，以及开发和执行未来的翻译研究项目。该提案的培训部分包括与芬克尔斯坦和布林赫斯特博士的定期指导，与内分泌科教职员工的广泛互动，以及与GCRC生物统计学家的会议。候选人还将报名参加哈佛大学公共卫生学院的临床有效性计划，并参加由MGH临床研究计划提供的课程。这些结合的研究和教学努力将为候选人实现他的长期目标做好准备，即开发一个专注于性腺类固醇在骨骼代谢中的作用的独立研究计划。

Osteoporosis in men is an important cause of morbidity and mortality, especially in the elderly. Hypogonadism is a well described risk factor for osteoporosis in men, but the mechanisms underlying hypogonadism-induced bone loss are incompletely understood. A fundamental unresolved question in this area concerns the differential effects of androgens and estrogens on the male skeleton. To address this question, in the first of 3 proposed studies, normal men will be randomly assigned to receive: 1) a GnRH analog alone for 12 weeks (suppressing endogenous gonadal steroids to pre-pubertal levels), 2) a GnRH analog plus testosterone (T) (normalizing circulating T and estradiol levels), or 3) a GnRH analog plus T plus an aromatase inhibitor (normalizing T but causing selective estrogen deficiency). Bone turnover markers will be measured every 4 weeks. Bone turnover will increase in Group 1 and should remain unchanged in Group 2. If estrogens are required to maintain normal bone turnover in men, bone turnover should also increase in Group 3. In the second study, normal men will be randomized into similar treatment groups for 8 weeks with the addition of a group that will receive a GnRH analog plus physiologic estradiol. PTH infusions will be performed every 4 weeks and bone turnover markers will be measured every 6 hours during each infusion. By comparing the rates of change in these markers during PTH infusion, the selective effects of androgens and estrogens on the skeletal sensitivity to PTH will be assessed. In the third protocol, murine stromal cell lines and primary mouse osteoblasts will be exposed to estrogens and androgens to assess their differential effects on osteoprotegerin (OPG) and osteoprotegerin-ligand (OPG-L) mRNA expression. These studies will help elucidate the mechanisms by which gonadal steroids act on bone and enable the candidate to appreciate basic developments in bone biology as well as develop and perform future translational research projects. The training portion of the proposal includes regular mentoring with Drs. Finkelstein and Bringhurst, extensive interaction with the Endocrine Unit faculty, and meetings with the GCRC biostatistician. The candidate will also enroll in the Harvard School of Public Health's Clinical Effectiveness Program and participate in courses offered by the MGH Clinical Research Program. These combined research and didactic endeavors will prepare the candidate to achieve his long-term goal to develop an independent research program focusing on the role of gonadal steroids in bone metabolism.