Physiologic effects of androgen and estrogen deficiency in young and old men

描述(由申请人提供)：性腺类固醇缺乏在男性衰老的许多生理变化中的作用尚不清楚。血清睾酮(T)水平随着男性年龄的增长而下降，在60岁以上的男性中，20%的人低于正常的成年男性范围。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。因此，数百万男性可能面临着随着年龄增长而出现的性类固醇正常下降的后果的风险。然而，这些不良变化开始时性腺类固醇激素缺乏的程度尚不清楚。因此，我们不知道哪些男性面临这些衰老后果的风险，或者哪些男性可能从T管理中受益。这项研究的总体目标是1)确定T与年轻和老年男性的骨转换、身体成分和其他因素之间的剂量-反应关系，2)确定雌激素产生的抑制是否改变这些剂量-反应关系，以及3)确定这些关系是否随着年龄的变化而改变。为了实现这些目标，我们将招募三组男性(目标1和目标2的年龄为20-50岁，或者目标3的年龄为60岁)。男性将接受GnRH激动剂(以抑制内源性T和E2的产生)的治疗，以及：1)不同剂量的T凝胶(以产生从青春期前到高正常水平的血清T水平)持续16周(目标1和3)或2)不同剂量的T凝胶加有效的芳香化酶抑制剂(以产生类似范围的T水平，且EJ水平非常低)16周(目标2)。骨吸收标记物和身体成分的变化(通过DXA和CT)将是关键的终点。还将评估力量、肌肉大小、骨密度、性功能、血脂、PSA、红细胞压积和症状的变化。这些研究将勾勒出T水平在年轻人和老年人面临不良生理变化风险之前必须下降的程度，以及防止这些变化所需的最低剂量的T凝胶。通过比较AIMS 1和2或1和3的剂量-反应关系，这些研究将证明T的剂量-反应关系被芳构化为雌激素和老化所改变的程度。这些研究将提供与性腺类固醇对男性影响有关的基本生理学信息。此外，这些研究的结果将有助于确定男性性腺功能减退综合征，帮助临床医生决定何时使用睾酮治疗年轻和老年男性，并为未来雄激素替代治疗老年男性的临床试验合理选择男性提供必要的信息。

DESCRIPTION (provided by applicant): The role of gonadal steroid deficiency in many of the physiologic changes of aging in men remains unclear. Serum testosterone (T) levels decline as 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. Thus, many millions of men may be at risk for consequences of the normal decline in sex steroids that occurs with aging. The degree of gonadal steroid deficiency at which these undesirable changes begins is unknown, however. Thus we do not know which men are at risk for these consequences of aging, or which men might benefit from T administration. The over-arching goals of the study are 1) to determine the dose-response relationships between T and bone turnover, body composition, and other factors in young and old men, 2) to determine whether inhibition of estrogen production alters these dose-response relationships, and 3) to determine whether these relationships change with aging. To accomplish these aims we will recruit 3 groups of men (ages 20-50 in Aim 1 and 2 or > 60 in Aim 3). Men 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 levels that range from prepubertal to high-normal) for 16 weeks (Aims 1 and 3) or 2) various doses of a T gel plus a potent aromatase inhibitor (to create a similar range of T levels with very low Ej levels) for 16 weeks (Aim 2). Changes in bone resorption markers and body composition (by DXA and CT) will be the key end points. Changes in strength, muscle size, BMD, sexual function, lipids, PSA, hematocrit, and symptoms will also be assessed. These studies will delineate the degree to which T levels must fall before young and old men are at risk for undesirable physiologic changes and the minimum dose of T gel needed to prevent those changes. By comparing dose-response relationships from aims 1 and 2 or 1 and 3, these studies will demonstrate the extent to which T dose-response relationships are modified by aromatization to estrogens and by aging. These studies will provide fundamental physiologic information related to effects of gonadal steroids in men. Moreover, results from these studies will help define the syndrome of male hypogonadism, assist clinicians in deciding when to treat young and old men with testosterone, and provide essential information for the rational selection of men for future clinical trials of androgen replacement in aging men