Welcome from Tamara L. Wexler, MD, PhD
Prescriptions for testosterone supplementation have increased strikingly over past decades, with a nearly 5-fold increase in prescriptions for testosterone therapy between 1993 and 20001 and 4-fold increase in testosterone use in men in the United States (US) between 2000 and 2011.2
Testosterone helps to support not only sexual function, but also body composition, bone and muscle strength, and quality of life.3-7 Use of testosterone in older men has been shown to increase lean body mass and decrease fat mass,3,4 and improve strength;3 this has been demonstrated in randomized clinical trials as well as observational trials, though the particulars of the inclusion criteria differ and are likely relevant to the outcomes. Recent observational studies also have reported an association between low testosterone levels and higher rates of mortality.8,9
Building on existing evidence of testosterone’s positive impact on body composition and strength in healthy older men,3,4 the Testosterone in Older Men with Mobility Limitations (TOM) trial5 looked at the safety and efficacy of testosterone supplementation in men ≥65 years with lower testosterone levels (100-350 ng/dL) and limited mobility in a 6-month randomized clinical trial (RCT). However, the study was terminated early after a higher rate of cardiovascular adverse events was noted in the testosterone group (23 subjects on testosterone gel vs. 5 subjects on placebo out of 209 enrolled). Applicability of the findings for the general population is uncertain given the specific study population (ie, mobility limitations, comorbidities, average age 74 years), relatively small sample size, and that cardiovascular events were not among the primary or secondary outcomes in study design. Nevertheless, the adverse event signal prompted two large retrospective observational studies reviewed here, and underscored the need for larger and longer RCTs.
In addition, the criteria supporting testosterone use in older men are less clear. The normal range for testosterone is best established in young and middle-aged men, and the benefits of testosterone replacement are clearer in hypogonadism caused by disturbances to the hypothalamic-pituitary-testicular axis. A decline in testosterone levels does occur with aging, but there is debate over whether this physiologic phenomenon should be considered pathologic, and whether it warrants testosterone replacement. A consistent reference range in older men has yet to be established. Body fat, smoking, and certain diseases also impact testosterone levels.10
In this publication, we review: The Endocrine Society guidelines for testosterone replacement; the rise in use of testosterone treatment in individuals who do not meet those criteria as described in a study of prescription patterns in the US and United Kingdom (Layton et al, 2014); a recent study examining the level of testosterone at which symptoms occur, as well as evidence that symptoms attributed to testosterone deficiency may in fact be due to low estradiol (Finklestein et al, 2013); and the two large observational studies investigating increased cardiovascular risk in men on testosterone therapy (Vigen et al, 2013 and Finkle et al, 2014).
Implications of these Studies
Awareness and further study of both the benefits and the potential risks of testosterone use become increasingly urgent as testosterone therapy is increasingly prescribed in older men and in those who may not meet guidelines or even have had hormone levels tested. A testosterone value in the lower range may not be sufficient reason to initiate treatment, given the lack of information on the value of testosterone replacement in aging under different conditions, and particularly the lack of reliable safety data. Specific subject inclusion criteria and subject and patient characteristics are important in determining whether study results are relevant to a given individual.
Existing evidence to date—both the randomized controlled trials demonstrating benefits of testosterone levels in the “normal” range, and observational studies suggesting enhanced cardiovascular risk in some patients, and improved mortality in others—highlights the need for randomized trials on the effects of testosterone replacement. There are two large ongoing randomized controlled trials (RCTs), the results of which are eagerly awaited. The Testosterone Trial is a multicenter randomized trial looking at the effects of 1 year of testosterone therapy vs placebo on men >65 years with baseline testosterone levels <250 ng/dL; physical and cognitive outcomes include cardiovascular measurements (lead investigator Peter J. Snyder, MD, of the University of Pennsylvania Perelman School of Medicine). The Testosterone Supplementation and Exercise in Elderly Men (TEAM) trial is looking at the effects of various levels of testosterone gel supplementation for 1 year with and without progressive exercise resistance in men >60 years (lead investigator Robert S. Schwartz, MD, of University of Colorado School of Medicine, Denver).
- Testosterone is important not only for sexual function, but also to support body composition, strength, and other functions.
- The correct level of testosterone levels in normal aging is still unclear. Low testosterone from dysfunction in the hypothalamic-pituitary-testicular axis may act differently than declining levels in healthy aging men.
- There are few randomized controlled trials looking at testosterone replacement in older men. Existing evidence demonstrates some benefits, but suggests potential risks in certain populations.
- The results of two ongoing large RCTs are eagerly awaited.
1. Liverman CT, Blazer DG. Testosterone and aging: clinical research directions. Washington, DC: National Academy of Sciences, 2004.
2. Layton JB, Li D, Meier CR, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000-2011. J Clin Endocrinol Metab. 2014 Jan 1:jc20133570. [Epub ahead of print]
3. Sattler FR, Castaneda-Sceppa C, Binder EF, et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab. 2009;94:1991–2001.
4. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. 1999;84:2647-2653.
5. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363:109-122.
6. Ho CC, Tong SF, Low WY, et al. A randomized, double-blind, placebo-controlled trial on the effect of long-acting testosterone treatment as assessed by the Aging Male Symptoms scale. BJU Int. 2012;110(2):260-265.
7. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;21;169(6):725-733.
8. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050-2058.
9. Seidman SN, Weiser M. Testosterone and mood in aging men. Psychiatr Clin North Am. 2013;36(1):177-182.
10. Camacho EM, Huhtaniemi IT, O'Neill TW, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol. 2013;168(3):445-455.