Intermittent Thoughts on Building Muscle: Quantifying "The Big T" - Do Testosterone Increases Within the Physiological Range Really Matter? And How Much is too Much?

Image 1: As it turns out, changes within the broad physiological range, have only negligible effects on muscle mass. Their potential negative impact on body fat is yet startlingly pronounced (see also fig. 2)
Welcome back! I am not going back on yesterday's promise and won't let "the Big T" slip out of chokehold of science ;-) So, where was I? Ah, yes... we have seen that out of the >11,000 published studies where the authors used the words "testosterone administration" (numbers according to Google Scholar), there appears to be exactly one (this is "1" as in only one ;-), in which the researchers dared to "proof" that testosterone alone, i.e. in the absence of exercise or dietary interventions, "builds muscle" - and that in otherwise completely healthy young men. We have also seen that there is a clear cut dose-response relationship with the largest increases in lean muscle mass and the most profound decreases in body fat in the high dose (600mg test enanthate) group.

More is more, but is more better?

If you took a scrutinizing look at figure 1 from yesterday's installment, you probably will have noticed that quadrupling the amount of testosterone enanthate from 125mg /week to 600mg /week did not quadruple the the amount of lean muscle the subjects gained - or, as an economist would immediately realize, the marginal utility is diminishing!
Figure 1: Dose response relationship of muscle gain (in kg) per mg of testosterone enanthate; the white line indicates a dose that would probably have produce testosterone levels identical to baseline (calculated based on Bhasin. 2001)
To make that a little more comprehensible, I have plotted the respective ratio of the amount of free mass the subjects gained to the amount of testosterone enanthate that was necessary to induce this changes in figure 1. In view of the fact that the different ways of administration / natural ways to boost testosterone will all have different effects on the actual levels of serum testosterone, I will however leave the interpretation of this muscle gains / test-enanthate ratio to those of you, who have a vested interest in this topic ;-) I, for my part, will focus on the changes in total testosterone (which correlated almost perfectly - r = 0.996, as of my own calculation - with the free testosterone levels in this study) and the associated increases in lean muscle mass. In that, it should be noted that the testosterone levels were measured at the end of each week meaning that right after the injection of the given dose of testosterone enanthate, which has a half-life of 4-5 days, the levels will have been markedly higher.

Surprise, surprise! Slightly below the "natural range" you get the most bang for your... T!

If we take into consideration that the "normal range" for testosterone levels ranges from 300 to 1000 ng/dl and that the subjects in the Bhasin study had baseline levels of ~600 ng/dl, all changes between -50% and +66% would be within what the medical orthodoxy considers "normal" (note: if the subjects already had "low" levels, even changes of +200% would still be within the normal range, please keep that in mind, when you read about the latest and greatest test-boosters ;-):
Figure 2: Relative change in lean and fat mass in response to changes in serum testosterone levels; the green area indicates "normal" = physiological testosterone levels; the asterisks (*) denote statistically significant (p < 0.05) changes vs. baseline (calculated based on Bhasin. 2001)
If we look at the data and acknowledge that only those data points I tagged with an asterisk (*) represent statistically significant changes from baseline (p < 0.05), it is quite obvious that elevations and even reductions of testosterone levels within the normal physiological range do not have any significant effects on skeletal muscle mass. As far as "building muscle" in the absence of exercise and nutritional interventions is concerned, the magic does not begin before we reach super-physiological concentrations of testosterone.
A brief note on the effect size: If you look at figure 2 without using your brain, it may seem that by just using enough test you would in no time become Mr. O. If, however, you take a closer look at the slope within the supraphysiological range, the latter signifies that for each +1% in lean mass you would have to increase your testosterone level by >27% - and maintain that over a time-course of 20 weeks! And as if that was not enough, even if you would survive boosting your levels into the >+400% zone, you should be aware that the slope will level out and you will probably need another +100% to make the +1% addition in lean mass. If, on the other hand you are not using injectable, but a natty test booster, or test or measure your levels right after or shortly after injections, chances are that you would have to have +60-80% increases in serum testosterone for 1% increases in total lean mass and that within 20 weeks! After all, 7 days after the injection (which is when the testosterone levels of the subjects were measured) the serum levels should actually be <50% of what we see in the hours immediately after the testosterone enanthate injection, which has, as I have already mentioned, a half-life of about 4-5 days.
What is almost frightening, though, is the tremendous (and statistically highly significant) detrimental effect reductions of testosterone within the "normal range had on the fat mass of the subjects (-47% testosterone = +17% fat mass; -57% testosterone = +36% fat mass). These obesogenic effects of low testosterone levels may be related to the direct anti-adipogenic effect of testosterone (Singh. 2006) and fits perfectly into the emerging (yet still not canonical) image of low testosterone levels as result of and contributing factors to the obesity epidemic (Corona. 2011).

An analysis of the complex interrelations between your beer belly and that which is hidden from your view beneath the former would yet go way beyond the scope of this installment of the Intermittent Thoughts, where testosterone's effects on skeletal muscle, not adipose tissue, are at the center of our attention. And that these effects should obviously not be restricted to increases in "lean mass", but should also be measurable in terms of "size", i.e. muscle circumference / cross-sectional area (CSA), and strength gains, is self-evident.

Does testosterone make you bigger, leaner and stronger?

As those of you who are familiar with the results of any of the 11,000-1 studies on hypogonodal, old or sick patients, where HRT-induced increases in total skeletal muscle mass are oftentimes similarly "statistically insignificant", will probably have expected the researchers would nevertheless not actually have needed an expensive DEXA scanner to see that the muscle mass of their subjects had increased - as the data in figure 3 shows, a simple measuring tape would have been sufficient:
Figure 3: Relative changes in thigh and quadriceps circumference and maximal leg press strength and power (measured on a Nottingham leg extensor power rig) in response to 20 weeks on different dosages of testosterone enanthate (calculated based on Bhasin. 2001)
For the muscle volume, just as for the the previously discussed changes in total muscle mass, the marginal utility is again maximal within the upper "physiological range", which corresponds to the use of 125mg of testosterone enanthate per week (figure 3, green).

For both the leg press strength, as well as the total leg power, though, a different picture emerges: Contrary to the weight and size gains, the gains in strength and power in the 125mg were not statistically significant (p = 0.42 and p = 0.59). Moreover, the aforementioned effect of "diminishing returns" with doses of testosterone >300mg /week is way more pronounced for leg strength and power than it is for the gains in total muscle mass and leg muscle volume. And as if that was not already confusing enough, in contrast to the +7% increase in the 125mg group, the + 6% increase in leg press power in the "low testosterone" group (50 mg) did reach statistical significance (p = 0.02).

Testosterone, myostatin and IGF-1 - tying the knots together

In order to explain this "strength anomaly", we will have to resort to what we have learned in previous installments of this series about the differential effects of myostatin and IGF-1 on muscle size and composition. Assuming that you have read all the installments of the Intermittent Thoughts, you will be familar with the results from the Quaisar study, I discussed in "What is Hypertrophy". You will also remember that Quaisar et al.'s observations showed quite clearly that the "uncontrolled" muscular hypertrophy in the myostatin negative mice left them with huge, yet dysfunctional muscles. The over-expression of IGF-1 on the other hand, facilitated a profound restructuring process within the skeletal muscle in the course of which the recruitement of satellite cells and the subsequent addition of myonuclei allowed for "healthy" growth that would not burst the maximally allowed myonuclear domain sizes (cf. "Getting Big Means Growing Beyond Temporary Physiological Limits").
Figure 4: Correlation (R²) of muscle volume and performance with testosterone and IGF 1 (left); testosterone / IGF-1 ratio before and after 20 weeks on different amounts of testosterone enanthate (right; data calculated based on Bhasin. 2001)
Against that background the testosterone to IGF-1 ratios on the right hand side of figure 2 in yesterday's installment of the Intermittent Thoughts (the graph on the right hand side of figure 4 is an identical copy in figure 4) should get a whole new meaning: If IGF-1 is required to keep rapidly growing muscles functional, the reason for the stalled power and reduced strength gains in the 600 mg testosterone enanthate group could well be a relative lack of IGF-1 (>3.5x elevated testosterone / IGF-1 ratio). The superior correlation (R²) between performance measures and IGF-1 values of the study participants (cf. figure 4, left) would does not only support this hypothesis it also underlines the vital importance adequate insulin-like growth factor levels (and its splice variants, which have unfortunately not been measured in this study) may have for "chemical athletes", in particular.

How all this is (or at least researchers believe it is) eventually in fact related to myostatin, how testosterone affects the fast- to slow-twitch fiber ratio (which could explain the anomalous increase in leg strength in the 50mg test E group), mitochondrial biogenesis and satellite cell function, are yet topics that will have to wait until Sunday, when - just as every week - I will sacrifice my free time and write down more Intermittent Thoughts Building Muscle.
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