What is known about testosterone, lean body (muscle) mass and strength
Regardless of age, hypogonadism is associated with loss of lean body mass13,14 and reduced muscle strength.15 Muscle weakness in turn is strongly associated with obesity (BMI ≥30 kg/m2), elevated waist circumference >102 cm, high levels of blood fats (triglycerides), low HDL “good cholesterol”, blood pressure, diabetes, cardiovascular disease and depression.16
Several meta-analyses show that testosterone therapy increases lean body mass (sometimes incorrectly used synonymously with the term fat-free mass)10,17,18 and muscle strength in middle-aged and older men.18,19 However, the magnitude of the gains in lean body mass and strength varies widely between studies. For example, in one meta-analysis the increase in lean body mass ranged from 1.65 to 6.20 kg.17 Similarly, the gains in strength have varied between studies.18,19
The studies included in these meta-analyses used different testosterone preparations with different pharmacokinetics and achieved varying elevations in testosterone levels for varying duration20-23, which may affect muscle-related outcomes. Therefore, one explanation for the different gains in lean body mass and strength could be that the muscular effects of testosterone therapy may be dependent on the particular testosterone preparation used (such as injections, gels or pills).9,10
Short-acting testosterone injections – such as testosterone enanthate and cypionate - produce a supraphysiologic spike in testosterone levels for several days following injection, and then decline into the physiologic range during the 10-12 days before the next injection.21-24 Unless a new injection is given, testosterone will drop to hypogonadal levels after 2-3 weeks.23,24 In contrast, long-acting testosterone injections of testosterone undecanoate produces a more physiologic and steady elevation in testosterone levels which stay within the physiological range between injections, which are needed only every 12 weeks.25-27 In comparison, testosterone gels, while producing a steady physiologic elevation in testosterone levels if applied daily, typically do not elevate testosterone levels as high as testosterone injections do.20,28
What this study adds
The present meta-analysis included high quality studies that compared testosterone injections or testosterone gel vs. placebo and reported effects on lean body mass or leg strength or arm strength.12 Studies of testosterone pills were excluded because a previous meta-analysis showed that testosterone pills did not increase lean body mass when compared to injectable testosterone preparations10, and testosterone pills are not as popular as injections and gels.29
Results showed that when effects of testosterone injections and gels were collectively assessed, testosterone therapy significantly increases lean body mass, overall strength, leg strength and arm strength. When evaluated separately, the effect sizes were larger and the per cent changes 3–5 times greater for testosterone injections than for testosterone gels vs. respective placebos, for all outcomes.
Specifically, testosterone injections were associated with a 5.7% increase in lean body mass and 10–13% increases in total body strength, leg strength and arm strength. In comparison, testosterone gels were associated with only a 1.7% increase in lean body mass and only 2–5% increases in total body and arm strength. Notably, testosterone gels did not increase strength. Sub-analyses limited to men aged 60 years and older showed similar results.
As illustrated in figure 1, treatment with testosterone injections were associated with a 5.7% increase in lean body mass and 10–13% increases in total body strength, leg strength and arm strength. In comparison, treatment with testosterone gels were associated with only a 1.7% increase in lean body mass and only 2–5% increases in total body and arm strength. Notably, testosterone gels did not increase leg strength. Sub-analyses limited to men aged 60 years and older showed similar results.
Figure 1: Changes in lean body mass and strength after testosterone therapy with injections vs. gels.
Data from: Skinner JW, Otzel DM, Bowser A, et al. Muscular responses to testosterone replacement vary by administration route: a systematic review and meta-analysis. Journal of cachexia, sarcopenia and muscle. 2018;9(3):465-481.
It was concluded that testosterone therapy with testosterone injections is more effective than testosterone therapy with testosterone gels for increasing lean body mass and improving muscle strength in middle-aged and older men, particularly in the legs.
The main results from this meta-analysis are that only testosterone injections increase leg strength, and that the effect sizes for intramuscular testosterone preparations are larger and the percentage improvements 3-5 times greater than those achieved with testosterone gels.12 For example, testosterone injections resulted in a 5.7% increase in lean body mass, while the increase in lean body mass with testosterone gels was only 1.7%.
To put this in perspective, for a 90 kg man, these differences would translate into a 5.1 kg increase in lean body mass with testosterone injections, compared to a 1.5 kg increase in lean body mass with testosterone gels. Consequently, testosterone therapy with testosterone injections results in significantly greater muscular benefits than testosterone therapy with testosterone gels and can be expected to help prevent sarcopenia and physical disability. Muscle tissue, together with the liver, is also the main place for storage of glucose (from ingested carbohydrates) as glycogen after meals, and therefore plays an important role in regulation of blood glucose levels.30-36 In line with this, a lower muscle mass is associated with higher fasting and after-meal blood glucose levels, as well as elevated insulin levels.37 Higher levels of glucose and/or insulin reflect some degree of insulin resistance. This suggests that the association of higher glucose and insulin levels with reduced muscle strength38-40 is mediated, at least in part, by reduced muscle mass.
Similar lean body mass and muscle strength improvements were seen in analyses confined to men aged 60 years of age or older12, which is the age range most likely to experience hypogonadism. The finding that older men benefit from testosterone therapy as much as younger men is in agreement with data from other studies which found that older men over 65 years of age with hypogonadism benefit as much from testosterone treatment as do younger men.41
As for lean body mass, increases in strength were larger after treatment with testosterone injections compared to testosterone gels. Testosterone therapy with testosterone injections resulted in a significant 10.4% increased leg strength, while testosterone therapy with testosterone gels had no significant effect on leg strength. Arm strength increased by 12.9% with testosterone injections but only by 4.5% with testosterone gels. Likewise, total body strength increased by 11.2% with testosterone injections but only by 2.1% with testosterone gels.
Notably, the strength gains conferred by testosterone therapy are, at least partly, independent of exercise.9 Thus, testosterone therapy with testosterone injections significantly increases muscle strength in men with hypogonadism, including those who do not have the means or ability to exercise. Among men who do have the ability to exercise, testosterone therapy can increase motivation, sense of energy and vitality, and the “pick-up-and-go” mentality to follow an exercise program.42,43
The proportion of older people is increasing dramatically around the world. In Japan 30% of the population is already over 60 years old, and between 2015 and 2050, the proportion of the world's population over 60 years will nearly double from 12% to 22%.44 A hallmark of aging is progressive loss of muscle mass and reduction in strength, known as sarcopenia.45 Muscle mass progressively decreases by as much as 40% from 20 to 70 years of age.46 The prevalence of low muscle mass, also called “muscle mass depletion”46, commonly ranges from 10 to 40%47,48, but can be as high as 98% in some populations.49
Sarcopenia is associated with the metabolic syndrome even in non-obese middle-aged and older adults.50 If left untreated, this age-related reduction in muscle mass and strength may lead to functional impairment and physical disability. Sarcopenia is a major cause of falls and functional deterioration in older persons51, and is a consistent predictor of chronic disease progression and death.48,52
Given the rising prevalence of people who are 60 years old or older, and the serious and costly public health problems associated with sarcopenia, there is considerable interest in the development and evaluation of therapeutic strategies to attenuate, prevent, or ultimately reverse age-related muscle loss and weakness.53 As shown in the present meta-analysis, testosterone therapy with testosterone around the world holds great potential for the growing population of older hypogonadal men with muscle depletion and weakness.