Gonadal steroids and body composition, strength, and sexual function in men

Abstract

Background: Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both account for clinical manifestations.

Methods: We provided 198 healthy men 20 to 50 years of age with goserelin acetate (to suppress endogenous testosterone and estradiol) and randomly assigned them to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Changes in the percentage of body fat and in lean mass were the primary outcomes. Subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function were also assessed.

Results: The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced.

Conclusions: The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00114114.).

Figure 1. Recruitment of Participants and Study Completion

Participants were recruited by sending letters to men in the local area who were identified with the use of commercially available mailing lists or by advertising in newspapers or on the Internet. A computerized program was used to randomly assign participants in permuted blocks. The block sizes were also randomly determined. Participants in cohort 1 (Panel A) were assigned to receive goserelin acetate plus placebo (group 1), 1.25 g of testosterone (group 2), 2.5 g of testosterone (group 3), 5 g of testosterone (group 4), or 10 g of testosterone (group 5) daily for 16 weeks. Participants in cohort 2 (Panel B) received the same study medications plus anastrozole at a dose of 1 mg per day. Participants who discontinued participation at week 8 or 12 were permitted to undergo repeat body-composition and strength testing that was planned for week 16. In cohort 1, eight men in group 1, five men in group 2, two men in group 3, and one man in group 4 underwent repeat body-composition and strength testing at week 8 or 12. In cohort 2, five men in group 1, two men in group 2, four men in group 3, one man in group 4, and one man in group 5 underwent repeat body-composition and strength testing at week 8 or 12.

Figure 2. Mean Serum Testosterone and Estradiol Levels from Weeks 4 to 16, According to Testosterone Dose and Cohort

I bars indicate standard errors.

Figure 3. Mean Percent Change from Baseline in Percentage of Body Fat, Lean Body Mass, Subcutaneous- and Intra-abdominal-Fat Area, Thigh-Muscle Area, and Leg-Press Strength, According to Testosterone Dose and Cohort

T bars indicate standard errors. Within each cohort, bars with the same number indicate no significant difference between dose groups. For example, the change in the percentage of body fat (Panel A) did not differ significantly among the groups that received 0 g, 1.25 g, or 2.5 g of testosterone daily in cohort 1 (all labeled “1”). The change in each of those three groups differed significantly from the change in the group that received 5 g per day (labeled “2”) and the change in the group that received 10 g per day (labeled “3”), and the change also differed significantly between these latter two groups. P values are for the cohort–testosterone dose interaction terms in analyses of variance comparing changes in each outcome measure between cohorts 1 and 2.

Figure 4. Mean Absolute Change from Baseline in Sexual Desire and Erectile Function, According to Testosterone Dose and Cohort

Sexual desire (Panel A) was assessed at each visit by asking participants to rate their sex drive as compared with their sex drive before the study began (−2 indicates much less, −1 somewhat less, 0 the same, 1 somewhat more, and 2 much more). Erectile function (Panel B) was evaluated by asking each man to consider the prior month and rate the degree to which each of the following three statements most closely applied to himself: “I had difficulty becoming sexually aroused,” “I had difficulty getting or maintaining an erection,” and “I had difficulty reaching orgasm,” with 1 indicating not at all, 2 a little, 3 some, 4 quite a bit, and 5 a great deal. For each man, the mean value at the final visit was then subtracted from the mean value at the baseline visit. T bars indicate standard errors. Within each cohort, bars with the same number indicate no significant difference between dose groups. P values are for the cohort–testosterone dose interaction terms in analyses of variance comparing changes in each outcome measure between cohorts 1 and 2.