Dose-Response Relationships Between Gonadal Steroids and Bone, Body Composition, and Sexual Function in Aging Men

Abstract

Context: Most labs set the lower limit of normal for testosterone at the 2.5th percentile of values in young or age-matched men, an approach that does not consider the physiologic changes associated with various testosterone concentrations.

Objective: To characterize the dose-response relationships between gonadal steroid concentrations and measures regulated by gonadal steroids in older men.

Design, participants, and intervention: 177 men aged 60 to 80 were randomly assigned to receive goserelin acetate plus either 0 (placebo), 1.25, 2.5, 5, or 10 grams of a 1% testosterone gel daily for 16 weeks or placebos for both medications (controls).

Primary outcomes: Changes in serum C-telopeptide (CTX), total body fat by dual energy X-ray absorptiometry, and self-reported sexual desire.

Results: Clear relationships between the testosterone dosage (or the resulting testosterone levels) and a variety of outcome measures were observed. Changes in serum CTX exceeded changes in the controls in men whose testosterone levels were 0 to 99, 100 to 199, 200 to 299, or 300 to 499 ng/dL, whereas increases in total body fat, subcutaneous fat, and thigh fat exceeded controls when testosterone levels were 0 to 99 or 100 to 199 ng/dL. Sexual desire and erectile function were indistinguishable from controls until testosterone levels were <100 ng/dL.

Conclusion: Changes in measures of bone resorption, body fat, and sexual function begin at a variety of testosterone concentrations with many outcome measures remaining stable until testosterone levels are well below the stated normal ranges. In light of this variation, novel approaches for establishing the normal range for testosterone are needed.

Trial registration: ClinicalTrials.gov NCT00114114.

Keywords: aging; bone turnover markers; hypogonadism; testosterone.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Recruitment of subjects and number of men completing baseline, week 8, week 16, and early termination visits.

Figure 2.

Mean ± SE serum testosterone (left panel) and estradiol (right panel) concentrations in men who received goserelin acetate plus 0 g/day (Group 1), 1.25 g/day (Group 2), 2.5 g/day (Group 3), 5 g/day (Group 4), or 7.5/10 g/day (Group 5), of a 1% testosterone gel or placebos for both drugs (PBO/PBO; Group 6). The shaded area represents the current reference range of the laboratory. Men in Group 5 received either 7.5 or 10 g/day.

Figure 3.

Mean ± SE percentage change from baseline in serum C-telopeptide concentrations, L4 trabecular BMD by quantitative CT, lumbar spine BMD by DXA, and femoral neck BMD by DXA according to testosterone dose (A, C, E, and G) and testosterone levels (B, D, F, and H). P values for tests of dose-dependent linear trends for each measure are at the top of each panel. Men in Group 5 received either 7.5 or 10 g/day. *Denotes groups that are significantly different from the control group using Duncan’s multiple range test.

Figure 4.

Mean ± SE percentage change from baseline in total body fat mass by DXA, total body lean mass by DXA, subcutaneous fat area by CT, and thigh fat area by CT according to testosterone dose (A, C, E, and G) and testosterone levels (B, D, F, and H). P values for tests of dose-dependent linear trends for each measure are at the top of each panel. Men in Group 5 received either 7.5 or 10 g/day. *Denotes groups that are significantly different from the Control group using Duncan’s multiple range test.

Figure 5.

Mean ± SE change in scores for sexual desire and erectile function according to testosterone dose (A and C) and testosterone levels (B and D). The International Index of Erectile Function (IIEF) was used to assess sexual desire (IIEF items 11 and 12; score ranges from 2 to 10) and erectile function (IIEF item 15; score ranges from 1 to 5). Higher IIEF scores indicate better sexual function. P values for tests of dose-dependent linear trends of each measure are at the top of each panel. Men in Group 5 received either 7.5 or 10 g/day. *Denotes groups that are significantly different from the Control group using Duncan’s multiple range test.