Declines in testosterone regulate decreases in men's muscle mass and strength, declines in estrogen regulate increases in men’s fat mass and abdominal fat, and declines in both hormones regulate decreases in men’s libido and erectile function, according to a report published online Sept. 11 in the New England Journal of Medicine.
These are the key findings from a dose-ranging study designed to tease out the complex roles played by both testosterone and estrogen in so-called androgen deficiency. They indicate that a simple, straightforward decline in testosterone doesn’t account for the myriad changes in body composition, strength, and sexual factors experienced by men with "low T."
This in turn suggests that the current approach to assessing and managing the condition – a one-time measurement of serum testosterone only, an across-the-board designation of a "low" level, and simple replenishment with endogenous testosterone only – should be replaced by more rational, nuanced approaches, said Dr. Joel S. Finkelstein of the endocrine unit and his associates at Massachusetts General Hospital, Boston.
They examined a wide spectrum of testosterone levels, and the adverse effects of different levels, by temporarily suppressing the normal endogenous gonadal steroids of healthy men aged 20-50 years using subcutaneous goserelin. In one cohort, 198 men then were randomly assigned to receive placebo, 1.25 g, 2.5 g, 5 g, or 10 g of a topical testosterone gel daily for 16 weeks. In another cohort, 202 men were randomly assigned to receive these same doses of topical testosterone plus 1 mg daily of anastrozole to block the aromatization of testosterone to estrogen.
All the study subjects, who were blinded to their medication assignments, were assessed every 4 weeks for the duration of the study for gonadal steroid levels, physical function, health status, vitality, and sexual function. Dual-energy x-ray absorptiometry (DXA) was used to measure body fat and lean mass, and CT was used to measure the areas of subcutaneous fat, intra-abdominal fat, and thigh muscle. Thigh-muscle strength was assessed using leg presses.
"By administering a variety of testosterone doses, with and without concomitant aromatase inhibition, we found that changes in lean mass, thigh-muscle area, and leg-press strength were attributable to changes in testosterone levels, whereas changes in fat measures were primarily related to changes in estradiol levels. Both androgens and estrogens contributed to the maintenance of normal libido and erectile function," Dr. Finkelstein and his associates said (N. Engl. J. Med. 2013 Sept. 11 [doi:10.1056/NEJMoa1206168]).
As important, the level of testosterone needed to maintain lean mass, fat mass, strength, and sexual function was found to vary considerably among these study subjects.
Most men showed reduced lean mass, muscle area, and erectile function at a mean serum testosterone level of 200 ng/dL, so testosterone supplementation appears to be justified at this level. However, many men showed impairment in these outcomes at lower or higher testosterone levels. In addition, the testosterone levels at which body fat increased and sexual desire decreased varied widely.
"Thus, each person’s specific clinical scenario should be considered when interpreting the clinical significance of the circulating testosterone level," Dr. Finkelstein and his colleagues said.
Also important was the finding that deficiency of estrogen, not testosterone, "is largely responsible for some of the key consequences of male hypogonadism." This indicates that measuring men’s estradiol levels may help in assessing their risk for sexual dysfunction, bone loss, or fat accumulation, the researchers added.
This study was limited in that the duration was restricted to 16 weeks, so as to avoid inducing clinically significant changes in the healthy men who participated. "Because changes in body composition may progress over time, greater changes might have been seen at higher testosterone and estradiol levels if gonadal steroids had been suppressed over a longer period," the investigators noted.
This study was supported by the National Institutes of Health and Abbott Laboratories. Abbott also supplied the testosterone gel at no cost, and Astra Zeneca provided goserelin and anastrozole at no cost, but neither company played a role in study design, data analysis, data interpretation, or manuscript preparation.