DIFFERENTIAL EFFECTS OF GONADAL STEROIDS ON BONE

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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.