DIFFERENTIAL EFFECTS OF GONADAL STEROIDS ON BONE

男性骨质疏松症是发病和死亡的重要原因，尤其是在老年人中。性腺功能减退是男性骨质疏松症的一个很好的危险因素，但性腺功能减退引起的骨丢失的机制还不完全清楚。在这一领域的一个基本的未解决的问题是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项拟议研究的第一项中，正常男性将被随机分配接受：1）单独的GnRH类似物12周（将内源性性腺类固醇抑制至青春期前水平），2）GnRH类似物加睾酮（T）（使循环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正常化但引起选择性雌激素缺乏）。每4周测量一次骨转换标志物。第1组的骨转换将增加，第2组应保持不变。如果需要雌激素来维持男性的正常骨转换，则第3组的骨转换也应增加。在第二项研究中，正常男性将被随机分配到相似的治疗组中，持续8周，并增加了一组接受GnRH类似物加生理雌二醇的治疗。每4周一次进行PTH输注，每次输注期间每6小时测量一次骨转换标志物。通过比较PTH输注期间这些标志物的变化率，将评估雄激素和雌激素对骨骼对PTH敏感性的选择性作用。在第三个方案中，将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，以评估其对骨保护素（OPG）和骨保护素配体（OPG-L）mRNA表达的差异效应。这些研究将有助于阐明性腺类固醇作用于骨的机制，并使候选人能够欣赏骨生物学的基本发展，以及开发和执行未来的转化研究项目。该提案的培训部分包括与Finkelstein和Bringhurst博士的定期指导，与内分泌部门教师的广泛互动，以及与GCRC生物统计学家的会议。候选人还将参加哈佛公共卫生学院的临床有效性计划，并参加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准备候选人实现他的长期目标，开发一个独立的研究计划，重点是性腺类固醇在骨代谢中的作用。

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.