BALTIMORE LONGITUDINAL STUDY OF AGING (BLSA)--PERIMENOPAUSAL INITIATIVE

横断面研究表明，更年期与内分泌代谢功能和身体成分的变化有关，这可能会加速骨质疏松症和心血管疾病的发展。这项纵向研究的假设是更年期转变与月经停止前的变化有关：1)夜间生长激素分泌减少，与卵巢性激素的减少一起，导致身体成分的变化，特别是骨量的减少和脂肪质量的增加；2)在血液和尿液中测量的预测骨量减少的骨转换生化标记物的增加；以及3)身体脂肪质量和腹部脂肪分布的增加，这与脂类和脂蛋白谱的不利变化有关。这些女性是巴尔的摩老龄化纵向研究(BLSA)的110名健康、不吸烟的女性参与者，年龄在45-55岁之间，注册时每月都会有月经。他们每季度接受GCRC门诊就诊，直到月经停止2年。这些访问包括更年期症状问卷、内分泌和血脂谱、人体测量、双能X射线吸收测量仪(DEXA)、骨生化和饮食评估。到目前为止，已完成1092次门诊。我们对腰椎和髋部骨密度(BMD)的纵向数据进行了初步分析。我们发现，在绝经前，在月经周期的卵泡中期没有测量到血浆FSH水平升高的女性中，脊柱骨密度显著增加(1.7+/-0.7%，与基线相比p&lt；0.05)，而围绝经期血浆FSH&Gt；30mU/m l组显著降低(-2.7+/-1.1%，p&lt；0.05与基线相比)。两组的骨密度变化率有显著差异(p&lt；.002)。绝经前妇女和围绝经期妇女的股骨颈(分别为-4.3+/-1.2%，-6.5+/-1.4%)和粗隆部位(-4.0+/-1.1%，-6.9+/-1.6%，与基线相比，p&lt；.002)均有明显的骨质丢失。绝经前妇女和围绝经期妇女在任何髋关节部位均无显著差异。这些数据揭示了在围绝经期过渡期间预期的椎骨加速丢失，而绝经前和围绝经期妇女髋部骨密度的类似损失似乎不能通过生殖激素环境来区分。初步数据还表明，骨转换生化标志物的一系列变化与骨密度的变化有关。身体成分是由DEXA和人体测量学测量的。所有测量的身体成分参数(体重、身体质量指数(BMI)、腰围、腰臀比(WHR)、DEXA扫描总脂肪质量或脂肪百分比)在基线水平上与绝经前组和围绝经组比较，经方差分析均无差异。与绝经前组相比，围绝经期妇女在肥胖(DEXA，p&lt；0.03经方差分析比较绝经前和围绝经期增量)、脂肪分布(腰围和腰围比，p&lt；0.05)和血清瘦素水平(p&lt；0.03)以及血清瘦素水平(p&lt；0.03)方面显著增加，但体重和BMI并不显著。这些数据表明，身体成分的变化可能发生在绝经过渡的早期，如血清FSH水平&GT；+/-30mU/mL所定义的那样。在通过频繁采血完成三次过夜生长激素研究的15名妇女中，有两名因血浆FSH水平升高和月经不规律而开始绝经过渡，一名已有两年没有月经。这三名妇女已经完成了第二组过夜访问，而这名绝经后妇女已经完成了最后一次过夜访问。当其中6名女性的血浆FSH水平大于30mU/ml时，将对纵向数据进行初步分析。未来的计划包括继续描述更年期转变的生物学前兆和后遗症。将研究骨骼和心血管疾病风险的生化标记物，以便将激素替代疗法瞄准最有可能受益的女性。此外，在本提案规定的基础上继续对BLSA队列进行纵向评估，将能够评估绝经过渡对妇女年龄相关疾病的影响。

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.