The Role of Testosterone and Estradiol in Changes Attributed to Male Hypogonadism
Introduction: The study was designed to investigate the level of testosterone deficiency or estradiol deficiency (or both) at which unwanted changes in body composition, strength, and sexual function begin to occur.
Methods: The study involved two cohorts of healthy men age 20 to 50 years. The first cohort (n=198) received 3.6 mg goserelin acetate (to suppress endogenous testosterone and estradiol) at 0, 4, 8, and 12 weeks and were randomized to a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of 1% testosterone gel daily for 16 weeks. Men in the second cohort (n=202) also received goserelin acetate and were randomized to placebo gel or testosterone gel (same dosage as cohort 1), with the addition of 1 mg anastrozole daily (to block conversion of testosterone to estradiol).
The primary outcome measure was change in the percentage of body fat and lean mass. Secondary outcomes included subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function.
Results: In the first cohort, significant increases in body fat were seen in the placebo group and men who received 1.5 g or 2.5 g of testosterone daily; the corresponding testosterone levels in these group showed mild testosterone deficiency (ie, 44, 191, 337 ng per deciliter). In contrast, body fat was significantly increased in men who received 10 g testosterone daily. Significant decreases in lean body mass and the size of the thigh muscle were found in men who received placebo or 1.5 g of testosterone daily and significant decreases in leg strength were found in men who received placebo. Sexual desire decreased progressively with each drop in testosterone dose, and problems with erectile function were mainly found in men who received placebo or 1.5 g testosterone.
In the second cohort, which had suppressed estradiol production, increases in body fat were seen at all testosterone dose levels, suggesting that estradiol plays a key role in fat accumulation. However, estradiol suppression had no apparent effect on lean mass, muscle size, or leg strength. Adverse effects on sexual function were more marked when estradiol synthesis was suppressed regardless of participants’ testosterone levels.
Conclusion: Testosterone levels appear to regulate lean body mass, muscle size and strength, while estradiol levels regulate fat accumulation. Both testosterone and estradiol regulate sexual function (ie, desire and erectile function).
The work by Finkelstein and colleagues focuses on healthy men age 20 to 50 years, providing insight into the role of estradiol as well as testosterone on clinical signs and symptoms attributed to testosterone, as well as into the level of testosterone deficiency at which signs and symptoms may occur. Over the course of the study period, cohort 1 demonstrated dose-dependent testosterone and estradiol levels, and cohort 2 demonstrated dose-dependent testosterone levels and flat estradiol levels, as intended.
Comparison between the cohorts provides insight into the contribution of estradiol. The findings suggest that estradiol has an independent effect (separate from testosterone) in percentage body fat, subcutaneous and intraabdominal fat, sexual desire and function; in measures of fat accumulation, estradiol played the predominant role. For example, percentage of body fat increased in cohort 1 men on placebo or the two lowest doses of testosterone, but all men in cohort 2 had increased in body fat percentage—indicating estradiol’s effect. This is in contrast to lean body mass, which decreased in all placebo versus testosterone-treated groups, suggesting this effect is indeed due to testosterone and not estradiol. Lean mass and thigh muscle area and strength did not differ based on estradiol level. The role of estradiol has implications for management of symptomatic hypogonadism, suggesting that estradiol levels be monitored in certain clinical manifestations of hypogonadism, and pointing to the utility of an aromatizable androgen in treating patients.
This study design also allowed analysis of the level of testosterone at which certain functions are affected. Clinical manifestations were seen at different testosterone levels. Increases in percentage of body fat began with mild gonadal deficiency, but lean mass and thigh muscle area and strength were affected only with more severe gonadal deficiency (serum level <200 ng/dL). (The committee that wrote The Endocrine Society guidelines on testosterone therapy was, of note, divided as to whether testosterone treatment in symptomatic individuals is warranted below 200 ng/dL or 300 ng/dL.) Different tissues display different threshold sensitivities to testosterone before symptoms are noted. For example, thigh muscle strength decreased significantly only in those men in cohort 1 on placebo, but thigh muscle area decreased in men on placebo or the lowest testosterone dose. This suggests that less testosterone is needed to sustain functional strength than to sustain thigh mass area, at least during time period studied.
Limitations in study design include the time course of 16 weeks, and the sudden loss of gonadotropins, the effect of which may differ from the gradual decline that may more often accompany disease states (or aging).
The approach allows not only insight into the role of estradiol versus testosterone, but the level of testosterone necessary to support various functions. This is highly relevant as we struggle to understand the risk-benefit profile for testosterone replacement, and at which testosterone level replacement becomes beneficial. While this study was conducted in healthy men age 20 to 50 years, the findings have implications for older men. The variability of testosterone levels at which different symptoms were noted highlights the importance of considering testosterone replacement in older men in the context of testosterone level and symptoms—and certainly not treating without knowledge of both. Additional study in an older population is needed, as discussed in the Introduction section of this issue of EndoScan.