Cross-sectional studies suggest that the menopause is associated with changes in endocrine-metabolic function and body composition that may accelerate the development of osteoporosis and cardiovascular disease. The hypotheses of this longitudinal study are that the menopausal transition is associated with change before the cessation of menses as described: 1) decreases in nocturnal secretory profile of growth hormone that, in combination with the decreases in ovarian sex hormones, contribute to changes in body composition, specifically decreases in bone mass and increases in fat mass; 2) increases in biochemical markers of bone turnover that are measured in blood and urine that predict decreases in bone mass; and 3) increases in body fat mass and fat distribution to the intra-abdominal area that are associated with adverse changes in lipid and lipoprotein profiles. The women are 110 healthy, nonsmoking female participants of the Baltimore Longitudinal Study of Aging (BLSA), ages 45-55 years who are experiencing monthly menses at enrollment. They receive quarterly GCRC outpatient visits until menses have ceased for 2 years. The visits include a menopausal symptom questionnaire, endocrine and blood lipid profiles, anthropometry, dual energy x-ray absorptiometry (DEXA), bone biochemistries, and dietary assessments. To date, 1092 outpatient visits have been compeleted. We have performed preliminary analyses of longitudinal data of bone mineral density (BMD) at the lumbar spine and hip. We found that in women who remained premenopausal, without elevations in plasma FSH levels measured during the midfollicular phase of the menstrual cycle, the group has a significant increase in BMD in the spine (1.7+/- 0.7%, *p<.05 vs baseline), while the group who became perimenopausal with plasma FSH >30mU/mL had a significant decrease (-2.7+/- 1.1%, p<.05 vs baseline). The two groups were significantly different in their rates of change in BMD (p<.002). Both the premenopausal women and the perimenopausal women were significantly losing bone at the femoral neck (-4.3+/- 1.2%, -6.5+/- 1.4% respectively) and trochanteric region (-4.0+/- 1.1%, -6.9+/- 1.6%, p<.002 vs baseline). There was no significant difference between the premeonpausal and perimenopausal women in any hip site. These data reveal the expected accelerated vertebral bone loss during the perimenopausal transition, whereas the similar losses of hip BMD in pre- and perimenopausal women appear not to be distinguishable by the reproductive hormone milieu. The preliminary data also suggest that the serial changes in biochemical markers of bone turnover correlate with changes in bone density. Body composition is measured by DEXA and anthropometrics. None of the parameters of body composition measured (weight, body mass index (BMI), waist circumference, waist-hip ratio (WHR), total fat mass by DEXA scan, or % fat) differed by ANOVA comparing premenopausal and perimenopausal groups at baseline. Perimenopausal women, in contrast to the premenopausal group, exhibit significant increases in the estimates of fatness (total fat and % fat by DEXA, p<0.03 by ANOVA comparing premenopausal and perimenopausal deltas), in fat distribution (waist circumference and WHR, p<0.05), and in serum leptin levels (p<0.03), but not in weight or BMI. These data suggest that changes in body composition may occur early in the menopausal transition as defined by a serum FSH level >+/- 30mU/mL. Of the 15 women who have compeleted the first of three pairs of overnight vists for study of growth hormone by frequent blood sampling, two have begun the menopausal transition based on elevation of plasma FSH level and irregularity of menses, and one has been two years without menstrual periods. These three women have completed the second set of overnight visits, and the postmenopausal woman has compeletd a final overnight visit. A preliminary analysis of the longitudinal data will be performed when plasma FSH levels are greater than 30 mU/mL in 6 of the women. Future plans include the continued characterization of the biological antecedents and sequelae of the menopausal transition. Biochemical markers of bone and cardiovascular disease risk will be studied so as to target hormone replacement therapy to those women who are most likely to benefit. Moreover, the continued longitudinal assessment of the BLSA cohort beyond that provided in this proposal will permit an evaluation of the effects of the menopausal transition on age-related disease in women.
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