PROGESTOGEN EFFECT ON BONE AND COGNITION IN MENOPAUSE

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Clinicians have recognized that the use of a progestogen in menopausal women on estrogen hormone replacement can prevent endometrial hyperplasia and carcinoma. However, the addition of progestational agents may have a significant impact on bone metabolism. Recent in vitro and in vivo data suggest that progestogens are potent bone cell mitogens and may promote bone formation whereas estrogens may act only to inhibit bone resorption. For these reasons, we proposed to examine the metabolic effects of progestogens on bone mineral content, bone histomorphometry, and on emotional-cognitive function in an estrogen-progesterone deficient, early menopausal population. We will compare 3 types of progestogens; micronized progesterone, norethindrone (NET), and medroxyprogesterone acetate (MPA). Thy hypotheses to be tested in this proposal are: 1) progestogen's induce depressive mood changes and reduce cognitive function independent of estrogen. We propose to carry out a longitudinal, double-blinded study in which six groups of menopausal women between the ages of 45-60 years, (n=44/group) will be randomized to receive either placebo, micronized progesterone (400 mg/day), NET (2.5 mg/day), MPA (20 mg/day), micronized estradiol (1 mg/day), and micronized estradiol (1 mg) + MPA (10 mg/day) during a two year study duration. Each group will receive an adjusted calcium intake (1500 mg/day) and vitamin D (400 IU/day) to reduce experimental variance related to diet and vitamin D. Primary variables that will be examined include: 1) changes in bone mineral content at the lumbar spine and proximal femur as determined by dual energy x-ray absorptiometry; 2) bone histomorphometry by bone biopsy; 3) changes in markers of bone metabolism (serum osteocalcin, bone alkaline phosphatase, urinary pyridinium crosslinks); 4) changes in calciotropic hormones (serum parathyroid hormone, calcitonin, vitamin D metabolites); and 5) psychometric, tolerance and lipid profile and covariates such as race, physical activity, and calcium intake also will be evaluated. These studies will provide significant new information on the mechanism of action of sex steroids on bone metabolism and will guide clinicians in the selection and dosing of progestogens for treatment and prevention of postmenopausal osteoporosis.