Is it Low T’ or Low E’ or Both?
Abstract &COMMENTARY
By Rahul Gupta, MD, MPH, FACP
Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV
Dr. Gupta reports no financial relationships relevant to this field of study.
Synopsis: In men 20-50 years of age, testosterone deficiency accounted for decreases in lean muscle mass, size, and strength while estrogen deficiency primarily accounted for increases in body fat, and both contributed to the decline in sexual function.
Source: Finkelstein JS, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013;369:1011-1022.
It is well documented that serum testosterone levels decline modestly with age in men. A variety of age-related changes are considered to be related to the physiologic lowering of testosterone. Existing evidence suggests that based on free testosterone levels, up to 20% of men > age 60, 30% > age 70, and 50% > 80 years of age may be hypogonadal.1 Aging in men is associated with declines in bone mineral density and consequent increase in risk for fractures, lean muscle mass and strength decline with fat mass increases, reduced sexual function, anemia, mood, and cognitive changes. As a result, declining levels of testosterone are often blamed as the culprit and millions of American men are prescribed testosterone therapy each year. Coupled with widespread marketing for conditions named as "Low T," there has been a recent rapid expansion in the market for demand of testosterone replacement therapy. It is common for the clinician to prescribe this type of therapy when a patient presents with nonspecific symptoms, such as fatigue or decline in libido, coupled with laboratory findings of serum testosterone levels below the reference range. However, unlike the case for menopause in women, there still remains a certain degree of uncertainty in establishing a link between the physiological decline of androgens in males and the symptoms of late-stage hypogonadism. Therefore, it is unclear if increasing the serum testosterone concentrations of elderly men to those of young men will prevent or reverse these changes. Nonetheless, this has not halted the use of testosterone replacement as an anti-aging or sexual tonic among aging men. While the consequences of male hypogonadism are routinely attributed solely to testosterone deficiency, there are two additional active metabolites in males, dihydrotestosterone and estradiol, that are also significant in the metabolic processes. Through 5 alpha reductase, testosterone is converted into its more potent form, dihydrotestosterone. Estradiol is also produced as an active metabolic product of testosterone through aromatization. There is evidence to suggest that men require some locally synthesized estradiol in tissues.2 While the potential role of this type of estrogen deficiency in certain processes such as bone loss are clear, that is not the case for others such as sexual function, muscle, and fat mass.
In their study, Finkelstein et al recruited 400 healthy men between the ages of 20 and 50 years who were given monthly shots of goserelin acetate to suppress endogenous testosterone and estradiol production to pre-puberty levels. At this time, one cohort (198 men) was randomly assigned to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. The other cohort (202 men) additionally received anastrozole (to suppress the conversion of testosterone to estradiol). Primary study outcomes measured were percentage change in body fat and lean muscle mass. Sexual function, physical function, vitality, and overall health status were also assessed with a self-administered questionnaire at each visit. The researchers found that the percentage of body fat increased in groups receiving placebo or low-dose daily testosterone (1.25 g or 2.5 g) without anastrozole. Lean mass and thigh-muscle area was found to be decreased in men receiving placebo and the lowest daily testosterone dose of 1.25 g (eliciting a mean serum level of approximately 200 ng/dL) without anastrozole. Leg-press strength fell only with placebo administration. Overall, the sexual desire declined as the testosterone dose was reduced. The researchers also found that in the cohort of men in whom the aromatization of testosterone to estradiol was inhibited with anastrozole, the percentage of body fat increased in all groups. The magnitudes of these increases were similar with all doses of testosterone, suggesting a predominantly estrogenic effect. In further comparison analysis conducted between the two cohorts, researchers found that the group receiving testosterone with inhibition of estrogen synthesis, as compared with intact estrogen synthesis, was associated with significant increases in the percentage of body fat (P < 0.001), subcutaneous-fat area (P < 0.001), and intra-abdominal-fat area (P = 0.002), as well as significant decreases in sexual desire (P < 0.001) and erectile function (P = 0.022).
COMMENTARY
In this remarkable study, the authors conducted what I consider groundbreaking research on a significant issue related to male aging. By employing an ingenious study design, they found that testosterone levels regulate lean body mass, muscle size, and strength, while estrogen levels regulate fat accumulation in healthy men 20-50 years of age. On the other hand, sexual function, including the desire and erectile function, seems to be regulated by both hormones. So, it seems that both "Low T" and "Low E" may be an issue in the aging male patient.
There are several contributions and implications of this study to our current understanding of the concept of male menopause. First and most obvious is the fact that estrogens have a fundamental role in the regulation of body fat and sexual function. Second, since muscle loss and erectile dysfunction were not seen until serum testosterone dropped to approximately 200 ng/dL in the study, not everyone with levels between 200-300 may require testosterone replacement. This is especially significant since the impact of testosterone replacement in older men with low serum testosterone and hypogonadal symptoms remains unclear. Finally, when prescribing testosterone replacement, it may be worthwhile to ensure that the particular supplement should be capable of being aromatized into estrogen. However, while there is no compelling need to taper patients off from existing testosterone replacement regimens or start prescribing estrogen to men, I would anxiously await further research on this issue since it seems we are heading for a new era — one of better understanding the complicated physiology in male menopause!
References
- Harman SM, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724-731.
- Vanderschueren D, et al. Androgens and bone. Endocr Rev 2004;25:389-425.
