OVARIAN STEROIDS AND CALCIUM HOMEOSTASIS

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Recently completed work postmenopausal women with primary hyperparathyroidism showed that estrogen therapy was not only able to block bone resorption, but also was able to stimulate the PTH-1,25- (OH)2D axis, raise intestinal Ca absorption and thereby improve Ca balance and bone density. The mechanism by which estrogen stimulates renal 1,25-(OH)2D synthesis requires further elucidation. This action of estrogen may be due to a direct effect on the kidney, or it may be mediated by secondary hyperparathyroidism accompanying the inhibition of bone resorption, or another possibility is that estrogen may increase renal sensitivity to PTH. To approach these questions, the effect of estrogens on vitamin D metabolism and fractional intestinal 47Ca absorption will be examined in patients with PTH-deficient hypoparathyroidism before and after the administration of PTH. Chronic administration of the GnRH analogue leuprolide has been shown to suppress gonadotropins and ovarian steroids to castrate levels. This type of reversible "medical oophorectomy" may be of benefit to women with endometriosis, uterine fibroids, hirsutism or breast cancer. However, estrogen deprivation may be associated witH negative calcium balance and bone loss. Short-term studies in women with endometriosis or fibroids will examine the effect of leuprolide-induced hypoestrogenism on Ca homeostasis, and test the ability of medroxyprogesterone acetate, calcitonin or indomethacin to block bone resorption and/or improve intestinal Ca absorption. In studies in women with hirsutism or breast cancer, the effect of more long-term medical oophorectomy with leuprolide will be evaluated with respect to changes in Ca homeostasis and bone density. The potential ability of oral contraceptives (as an adjunctive agent in treating hirsutism) and the nonsteroidal estrogen antagonist tamoxifen (as an adjunctive agent in treating breast cancer) to protect bone will be evaluated.