27 HORMONES AND SPORT Proof of the effect of testosterone on skeletal muscle S Bhasin, L Woodhouse and T W Storer1 Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, California 90059, USA 1Laboratory for Exercise Sciences, El Camino College, Torrance, California, USA (Requests for offprints should be addressed to S Bhasin, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, California 90059, USA) Abstract In spite of the widespread abuse of androgenic steroids improve physical function and health-related quality of by athletes and recreational body-builders, the effects of life, and reduce the risk of falls and disability in older men these agents on athletic performance and physical func- or those with chronic illness. Testosterone increases maxi- tion remain poorly understood. Experimentally induced mal voluntary strength in a dose-dependent manner and androgen deficiency is associated with a loss of fat-free thus might improve performance in power-lifting events. mass; conversely, physiologic testosterone replacement of However, testosterone has not been shown to improve healthy, androgen-deficient men increases fat-free mass performance in endurance events. The mechanisms by and muscle protein synthesis. Testosterone supplemen- which testosterone increases muscle mass are not known, tation of HIV-infected men with low testosterone levels but probably involve alterations in the expression of and of older men with normally low testosterone concen- multiple muscle growth regulators. trations also increases muscle mass. However, we do not Journal of Endocrinology (2001) 170, 27–38 know whether physiologic testosterone replacement can The abuse of androgenic steroids by athletes and the increase muscle mass and strength; however, the academic proposed anabolic applications of these agents in sarco- community decried their use, citing lack of verifiable penia (loss of muscle mass and strength) associated with evidence (Wilson 1988, Bardin 1996, Casaburi et al. aging or chronic illness is based on the premise that these 1996b). The historical aspects of the use of androgenic/ agents increase muscle mass and improve measures of anabolic steroids have been extensively reviewed (Wilson skeletal muscle performance, and that androgen-induced 1988, Bardin 1996). Although their use is most common changes in skeletal muscle performance translate into among weight-lifters and heavy throwers, almost all types improvements in athletic performance and health-related of athletes whose event requires explosive strength, in- outcomes (Fig. 1). The premise remains unsubstantiated. cluding football players, swimmers and track and field There is agreement that testosterone supplementation athletes, have been known to use steroids. Their use has increases muscle mass and maximal voluntary strength in a spread to high-school athletes and to amateur body- variety of clinical and experimental paradigms (Tenover builders. Disqualification of highly celebrated athletes 1992, Urban et al. 1995, Bhasin et al. 1996, 1997, Brodsky in recent years has focused substantial media attention on et al. 1996, Katznelson et al. 1996, Wang et al. 1996, 2000, this issue. Synder et al. 2000), but we do not know whether Considerable debate has raged in the academic com- testosterone improves athletic performance or health- munity for five decades on whether androgenic steroids related outcomes, and whether beneficial effects of andro- had anabolic effects on the muscle, due in part to the gens can be achieved without significant long-term shortcomings of previous studies; several reviews have adverse effects. discussed these study design issues (Wilson 1988, Bardin Opinion as to the effects of testosterone on the muscle 1996). For instance, many of the studies that examined the in healthy eugonadal men has been enormously contro- effect of androgenic steroids were neither blinded nor versial for more than five decades (Wilson 1988, Bardin randomized. Some studies included competitive athletes, 1996, Casaburi et al. 1996b). The athletes who abuse whose desire to win at any cost prevent them from androgenic steroids believe fervently that these drugs complying with a standardized regimen of diet and Journal of Endocrinology (2001) 170, 27–38 Online version via http://www.endocrinology.org 0022–0795/01/0170–027 2001 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 10:22:26PM via free access 28 S BHASIN and others · Effect of testosterone on skeletal muscle Figure 1 Rationale for the abuse of androgenic steroids by athletes and their potential application as anabolic therapy for sarcopenia associated with old age and chronic illness. This is based on the premise that these agents induce alterations in muscle gene expression that result in increased muscle mass and improved muscle performance. It is further assumed that increased muscle mass and performance will translate into improved physical function, athletic performance and health-related outcomes. Although androgenic steroids have been shown to increase muscle mass and maximal voluntary strength, their effects on physical function, health-related outcomes and athletic performance have not been rigorously studied. The heavy arrow indicates areas of certainty, and lighter arrows indicate areas of uncertainty. exercise. Nutritional intake was not controlled in many of eugonadal men (Katznelson et al. 1996, 1998). Mauras the studies; changes in energy and protein intake might et al. (1998) have reported that experimental suppression of have had independent effects on nitrogen balance. Exer- serum testosterone by administration of a gonadotropin- cise stimulus was not standardized and, in some studies, the releasing hormone (GnRH) agonist analog in healthy participants were allowed to exercise ad libitum. Therefore, young men is associated with a significant reduction in the effects of androgen administration could not be fat-free mass, an increase in fat mass, and a decrease separated from the effects of resistance exercise training. in fractional muscle protein synthesis. An age-associated Most of the studies performed before the 1980s used decline in serum testosterone concentrations correlates relatively small doses of androgenic steroids, equivalent with decreased appendicular muscle mass and reduced to or less than the replacement dose of testosterone used lower extremity strength in white and in African- for the treatment of androgen-deficient men. In con- American men (Morley et al. 1993, 1997). trast, athletes use supraphysiological doses of androgenic steroids. Because of these problems of study design, the results of these previous studies were inconclusive. With Effects of physiologic testosterone replacement in the advent of magnetic resonance imaging and more healthy, young hypogonadal men refined methods for the assessment of body composition, it has become possible to detect small changes in muscle Testosterone replacement increases nitrogen retention in volume and fat-free mass with a greater degree of precision castrated males of several animal species (Kochakian et al. and accuracy than was feasible before. Consequently, 1950), eunuchoidal men, boys before puberty, and women studies published in the past 6 years by a number of groups (Kenyon et al. 1940). Several recent studies have re- have now established that testosterone supplementation examined the effects of testosterone on body composition does increase muscle mass and strength (Bhasin et al. 1996, and muscle mass in hypogonadal men in more detail. We Brodsky et al. 1996, Katznelson et al. 1996, Wang et al. administered 100 mg testosterone enanthate intramuscu- 1996, 2000, Snyder et al. 2000). larly weekly for 10 weeks to seven hypogonadal men after a10–12 week period of androgen withdrawal (Bhasin et al. 1997). Testosterone replacement was associated with a A reduction in serum testosterone is associated 4·50·6kg(P=0·005) increase in body weight because with decreased fat-free mass ofa5·00·8kg(P=0·004) increase in fat-free mass, estimated from underwater weight, whereas body fat Healthy, hypogonadal men have lower fat-free mass and did not change. Similar increases in fat-free mass were higher fat mass compared with those of age-matched observed using the deuterium water dilution method. Arm Journal of Endocrinology (2001) 170, 27–38 www.endocrinology.org Downloaded from Bioscientifica.com at 09/26/2021 10:22:26PM via free access Effect of testosterone on skeletal muscle · S BHASIN and others 29 Table 1 Effects of testosterone replacement on body composition in hypogonadal men Age Testosterone Change in Change in Change in (years) regimen fat-free mass fat mass muscle strength Study Bhasin et al. 19–47 Testosterone enanthate 5·00·7kg No change in fat mass +223% (1997) 100 mg weekly for (9·91·4%) by underwater weight 10 weeks increase by underwater and D2O weight and D2O Katznelson 22–69 Testosterone enanthate 72% increase by 144% decrease in Not measured et al. (1996) or cypionate 100 mg bioelectrical impedance percent body fat, weekly for 18 months 134% decrease in subcutaneous fat Brodsky et al. 33–57 Testosterone cypionate 15% increase by DXA 11% decrease in fat Not measured (1996) 3 mg/kg every 2 weeks scan mass for 6 months Wang et al. 19–60 Sublingual testosterone 0·9 kg (2%) increase by No change in fat mass No change in arm press, (1996) 5 mg three times a day DXA scan 8·7 kg increase in for 6 months leg-press Snyder et al. 22–78 Transdermal 3·13·3 kg increase by No change in fat mass No change in isokinetic (2000) testosterone patch for DXA scan strength of knee 12–36 months extension Wang et al. 19–68 Testosterone gel 2·70·3 kg increase by 1 kg decrease in fat Leg-press strength (2000) (50–100 mg/day) DXA scan mass increased by 11–13 kg 180 days D2O, deuterium water. and leg muscle cross-sectional areas, assessed by magnetic Bardin 1996, Casaburi et al. 1996b). We conducted a resonance imaging, increased significantly. Substantial in- placebo-controlled, double-blind, randomized clinical trial creases in muscle strength were also noted after treatment.