DOSE-RESPONSE OF SEX STEROIDS ON BONE METABOLISM IN MEN (SEE SPID 0665)

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。雄激素(或雌激素)缺乏在衰老的许多生理变化中的作用尚不清楚。血清睾酮(T)水平随着正常男性年龄的增长而下降，在60岁以上的男性中，有20%低于正常成年男性范围。许多伴随年龄增长的变化，包括骨质流失、肌肉萎缩、脂肪堆积、力量下降和性功能下降，可能与血清T水平随着年龄的增长而逐渐下降有关。由于严重的性腺功能减退会导致骨质丢失、身体成分改变、力量下降和各种症状，数百万男性可能会面临这些疾病的风险，因为随着年龄的增长，性类固醇水平会正常下降。然而，性腺类固醇激素缺乏的程度导致骨质丢失和其他疾病的程度仍然未知，因此我们不知道哪些男性随着年龄的增长而面临这些问题的风险。本研究的主要目的是确定性腺类固醇与成年男性骨转换之间的剂量-反应关系，然后剖析雄激素和雌激素对骨转换的不同剂量-反应关系。第二个目标是确定性腺类固醇与身体成分、力量、脂蛋白、性欲和生活质量指标之间的剂量-反应关系。为了实现这些目标，我们将招募3组男性(年龄20-50岁或60岁)。20-50岁的男性将接受GnRH激动剂的治疗(以抑制内源性T和E2的产生)，并：1)单独使用不同剂量的T凝胶(以产生从青春期前到中等正常水平的T和E2水平，目标1)或2)使用不同剂量的带有有效芳香化酶抑制剂的T凝胶(以产生类似范围的T水平，但E2水平非常低，目标3)。为了确定衰老本身对这些剂量-反应关系的影响，并直接确定改变老年男性靶组织功能的T和E2水平，目标1将在60岁的男性身上重复(目标2)。骨形成和吸收标志物、身体成分(通过DXA和CT)、强度、骨密度、血脂、PSA和症状将在16周内进行评估。这些剂量-反应研究将描绘T和/或E2水平在年轻人和老年人面临骨质丢失、血脂变化、性腺功能减退、力量丧失和身体成分变化的风险之前必须下降的程度。此外，通过比较目标1和目标3，这些研究将确定T本身和多个临床重要终点之间的精确剂量-反应关系，以及T的剂量-反应关系被芳构化为雌激素改变的程度。这些信息可能有助于临床医生决定何时治疗患有T的年轻人和老年人，以及在未来对老年男性进行雄激素替代的临床试验中合理选择男性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The role of androgen (or estrogen) deficiency in many of the physiologic changes of aging remains unclear. Serum testosterone (T) levels decline as normal men age and are below the normal adult male range in 20% of men over age 60. Many of the changes that accompany aging including bone loss, muscle wasting, fat accumulation, decreased strength, and decreased sexual function may be related to the gradual decline in serum T levels with age. Because severe hypogonadism leads to bone loss, changes in body composition, decreased strength and various symptoms, many millions of men may be at risk for these disorders due to the normal decline in sex steroids that occurs with aging. The degree of gonadal steroid deficiency at which bone loss and other disorders begins remains unknown, however, so that we do not know which men are at risk for these problems as they age. The overarching goal of this proposal is to determine the dose-response relationship between gonadal steroids and bone turnover in adult men and then to dissect the distinct dose-response relationships of androgens and estrogens on bone turnover in adult men. Secondary aims are to determine the dose-response relationships between gonadal steroids and body composition, strength, lipoproteins, libido, and quality of life measures. To accomplish these aims we will recruit 3 groups of men (ages 20-50 or > 60). Men age 20-50 will be treated with a GnRH agonist (to suppress endogenous T and E2 production) and: 1) various doses of a T gel alone (to create serum T and E2 levels that range from prepubertal to mid-normal, Aim 1) or 2) various doses of a T gel with a potent aromatase inhibitor (to create a similar range of T levels with very low E2 levels, Aim 3). To determine the effects of aging per se on these dose-response relationships and to determine directly the levels of T and E2 that alter target tissue function in aging men, Aim 1 will be repeated in men > age 60 (Aim 2). Bone formation and resorption markers, body composition (by DXA and CT), strength, BMD, lipids, PSA, and symptoms will be assessed over 16 wks. These dose-response studies will delineate the degree to which T and/or E2 levels must fall before young and old men are at risk for bone loss, changes in lipids, symptoms of hypogonandism, strength loss, and body composition changes. Moreover, by comparing aims 1 and 3, these studies will define the precise dose-response relationships between T itself and multiple clinically-important end points and the extent to which T dose-response relationships are modified by aromatization to estrogens. This information may help clinicians decide when to treat young and old men with T and in the rational selection of men for future clinical trials of androgen replacement in aging men.