Muscular responses to testosterone therapy vary by administration route - meta-analysis of injectable vs. transdermal testosterone preparations
STUDY: 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.
Reduced muscle mass and strength, commonly accompanied by increased body fat, are common signs in all forms of hypogonadism (primary, secondary, classical or functional).1,2 One of the best documented effects of testosterone therapy is an increase in lean body mass3-6, which is mostly attributed to gain in muscle mass.7 The increased lean body (muscle) mass seen during testosterone therapy is often accompanied by gains in muscle strength.5,6,8
However, inconsistent gains in lean mass and muscle strength have been observed in double-blind, placebo-controlled randomized clinical trials (RCTs) that investigated the muscular effects of testosterone therapy in middle-aged and older men.9-11
Here we summarize the results of a meta-analysis which investigated the magnitude of the increases in lean body mass and muscle strength when giving middle-aged and older men testosterone therapy, and whether these muscular responses to testosterone therapy vary by administration route (i.e. injection vs. gel).12
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, hypertriglyceridemia, low HDL cholesterol, hypertension, 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 (intramuscular, transdermal, oral, nasal).9,10
Short-acting intramuscular testosterone preparations – 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 intramuscular 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, transdermal testosterone preparations such as gels, while producing a steady physiologic elevation in testosterone levels if applied daily, typically do not elevate testosterone levels as high as intramuscular testosterone preparations do.20,28
What this study adds
The present systematic review and meta-analysis included double-blind randomized controlled trials (RCTs) that compared intramuscular or transdermal testosterone preparations vs. placebo and reported effects on lean body mass or leg strength or arm strength.12 Studies of oral testosterone preparations were excluded because a previous meta-analysis showed that oral testosterone preparations did not increase lean body mass when compared to injectable testosterone preparations10, and oral testosterone preparations are not as popular as injectable and transdermal testosterone preparations.29
31 RCTs reporting lean body mass (sample size: n = 1213 testosterone treated, n = 1168 placebo) and 17 reporting leg or arm strength (n = 2572 testosterone treated, n = 2523 placebo) were included in this meta-analysis.
Results showed that when all testosterone preparations were collectively assessed, testosterone therapy significantly increases lean body mass, overall strength, leg strength and arm strength.
When administration routes were evaluated separately, the effect sizes were larger and the per cent changes were 3–5 times greater for intramuscular testosterone preparations than for transdermal preparation vs. respective placebos, for all outcomes.
As illustrated in figure 1, intramuscular testosterone preparations 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, transdermal testosterone preparations were associated with only a 1.7% increase in lean body mass and only 2–5% increases in total body and arm strength. Notably, transdermal testosterone preparations did not increase leg strength. Sub-analyses limited to men aged 60 years and older showed similar results.
It was concluded that testosterone therapy with intramuscular testosterone preparations is more effective than testosterone therapy with transdermal testosterone preparations 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 intramuscular testosterone preparations increase leg strength, and that for all studied outcomes, the effect sizes for intramuscular testosterone preparations are larger and the percentage improvements 3-5 times greater than those achieved with transdermal testosterone preparations.12 For example, intramuscular testosterone preparations resulted in a 5.7% increase in lean body mass, while the increase in lean body mass with transdermal testosterone preparations was only 1.7%.
From a clinical perspective, for a 90 kg man, these differences would translate into a 5.1 kg increase in lean body mass with intramuscular testosterone preparations, compared to a 1.5 kg increase in lean body mass with transdermal testosterone preparations. 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 as glycogen after meals, and therefore plays an important role in glucose disposal and regulation of blood glucose levels.30-36 In line with this, a lower muscle mass is associated with higher fasting and postprandial 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 ≥60 years of age 12, 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
Most RCTs included in this meta-analysis evaluated body composition using DEXA (dual-energy X-ray absorptiometry), which partitions body weight into three components: fat, lean soft tissue and bone mineral.42 While DEXA is the most accurate body composition assessment technology available in clinical practice, it should be pointed out that it makes the assumption that the water content of lean soft tissue compartment or the fat-free mass compartment (which is the sum of lean soft tissue and bone mineral mass) is relatively stable across subjects.43,44 However, in reality fluctuations in hydration status do occur43, which can impact the accuracy of body composition assessments with DEXA (as well as other common technologies). Of relevance to the present meta-analysis, testosterone therapy significantly increases extracellular water in hypogonadal men.45 Nevertheless, intramuscular testosterone therapy also increases muscle fiber cross-sectional area in older men.46 Hence, the gain in lean body mass during testosterone therapy is comprised of a combined increase in muscle growth and fluid volume. In fact, 65% of the increase in lean body mass during testosterone therapy has been shown to be attributed to accretion of muscle mass.7
As for lean body mass, increases in strength were larger after treatment with intramuscular testosterone preparations compared to transdermal testosterone preparations. Testosterone therapy with intramuscular testosterone preparations resulted in a significant 10.4% increased leg strength, while testosterone therapy with transdermal testosterone preparations had no significant effect on leg strength. Arm strength increased by 12.9% with intramuscular testosterone preparations but only by 4.5% with transdermal testosterone preparations. Likewise, total body strength increased by 11.2% with intramuscular testosterone preparations but only by 2.1% with transdermal testosterone preparations.
Notably, the strength gains conferred by testosterone therapy are, at least partly, independent of exercise.9 Thus, testosterone therapy with intramuscular testosterone preparations 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 to follow an exercise program.47 Androgens, by improving mitochondrial function, control the sense of energy and vitality, and the “pick-up-and-go” mentality.47 In addition, experimental data shows that testosterone stimulates physical activity behavior by acting on central dopamine pathways.48
The pace of population aging around the world is increasing dramatically. 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%.49 A hallmark of aging is progressive loss of muscle mass and reduction in strength, known as sarcopenia.50 Muscle mass progressively decreases by as much as 40% from 20 to 70 years of age.51 The prevalence of low muscle mass, also called “muscle mass depletion”51, commonly ranges from 10 to 40%52,53, but can be as high as 98% in some populations.54
Sarcopenia is associated with the metabolic syndrome even in non-obese middle-aged and older adults.55 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 persons56, and is a consistent predictor of chronic disease progression, all-cause mortality, poorer functional outcomes, and postoperative complications.53 Sarcopenia increases risk of hospitalization by nearly 60% and confers a 2-fold increased risk of all-cause mortality.57
Given the rising prevalence of people over 60 years, 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.58 As shown in the present meta-analysis, testosterone therapy with intramuscular testosterone preparations holds great potential for the growing population of older hypogonadal men with muscle depletion and weakness.