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.
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