In this proposal, the interactions of PTH and ovarian hormones in the regulation of bone metabolism will be investigated. Women with endometriosis will be treated with a long-acting GnRH analog (Synarel) to produce a reversible state of severe estrogen deficiency that mimics the menopause. Although Synarel is highly effective as a therapy for endometriosis, its clinical usage is limited because of estrogen deficiency bone loss. In pilot study of 20 women, hPTH-(l-34) administration prevented trabecular bone loss from the spine in women treated with Synarel for 6 mo. No cortical bone loss was observed in either group. However, some prior data have suggested that cortical bone loss in elderly osteoporotic women might be accelerated after 9 mo of PTH therapy. Therefore, an additional l2 young women were treated with Synarel +/- hPTH-(l-34) for l2 mo. Trabecular bone loss was again prevented by PTH. More important, cortical bone mass was completely stable in both groups. A principal aim of this proposal is to determine whether hPTH-(l- 34) administration can prevent both cortical and trabecular bone loss in young, estrogen-deficient women. To do so, the study group must be sufficiently large and the study of sufficient duration to produce cortical bone loss in the women who receive Synarel alone. Other principal aims of this proposal are to investigate the mechanisms of PTH action on bone and of hypogonadal bone loss. 48 ovulatory women with endometriosis will be randomly assigned to treatment with Synarel alone or Synarel plus daily hPTH-(l-34) for l yr. Bone density of the lumbar spine (AP and lateral), femoral neck, trochanter, 1/3 radius, and total body bone mineral will be measured every 3 mo by DEXA to assess both cortical and trabecuLar bone. Serial measurements of calcium regulatory hormones, biochemical markers of bone turnover, and calcium absorption will be made to assess the mechanism of PTH action on bone. The patients who receive Synarel alone will be further randomized to undergo either l) iv calcium and citrate infusions before and at the end of Synarel therapy to assess the effects of chronic estrogen deficiency on the regulation of PTH secretion by calcium, or 2) 24 hr iv PTH infusions before and at the end of Synarel therapy to assess the effects of chronic estrogen deficiency on the ability of PTH to stimulate bone resorption and l ,25-(OH)2 vitamin D secretion. These investigations should help determine whether alterations in the secretion of PTH, skeletal sensitivity to PTH, or the ability of PTH to stimulate 1,25-(OH)2 vitamin D secretion and calcium absorption are involved in the mechanism of hypogonadal bone loss. Similar studies in a group of 24 normal women with regular menstrual cycles will be performed to document that women with endometriosis have normal baseline bone densities, biochemical markers of bone turnover, and regulation of PTH and l ,25-(OH)2 vitamin D secretion.
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