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

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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