Friday, June 17, 2016

TRT - How Healthy, Lean and Muscular Will Testosterone Replacement Make You? Data from Recent Meta-Analysis

TRT - What to expect in terms of its effects on a man's body composition?
If you hear people talk about "gear" (=performance enhancing drugs | PED), you get the impression that one injection of testosterone, nandrolone and co would turn a scrawny beginner into an Olympian. Reality, however, looks much different ... in fact, the number of people who ruin their health with (often oral) designer steroids without seeing any of the results they expect has been increasing continuously over the past years (Baker. 2006a,b; Graham. 2008; Rahnema. 2014) and that despite the fact that the "Anabolic Steroid Control Act" of 2004 was originally meant to prevent exactly that from happening (Herschthal. 2012).

In spite of the fact that the introduction of today's SuppVersity article focused on PED, the purpose of the meta-analysis and thus its summary was "systematically review [...] available observational and register studies reporting data on body composition in studies" in men with low or at least suboptimal testosterone levels.
This is what most studies were lacking: Exercise to shed fat and gain muscle.

Tri- or Multi-Set Training for Body Recomp.?

Alternating Squat & Blood Pressure - Productive?

Pre-Exhaustion Exhausts Your Growth Potential

Full ROM ➯ Full Gains - Form Counts!

Battle the Rope to Get Ripped & Strong

Hula Hooping to Spot Reduce in the Midsection
The original meta-analysis by Corona et al. (2016) was published in the Journal of Endocrine Investigation, only a few days ago. It involved "an extensive MEDLINE, Embase, and Cochrane search [that] was performed including the following words: testosterone and body composition. And is thus not focussing exclusively on testosterone as a "new anti-obesity medication", which is how the authors refer to it in the very first sentence of the abstract, because "all observational studies comparing the effect of TS on body weight and other body composition and metabolic endpoints were considered" (Corona. 2016) in the scientists' meta-analysis. Here's an overview of the studies, their design an results, as they were summarized by Corona et al.:
  • Suggested Read: Testosterone Gel Augments Increases in Lean Mass Gains (+3.9kg in 6 Months) in Older Intensely Training Men, but Testim Blocks Decrease in Marker of Heart Disease Risk | more
    Valdermasson et al. (1987) - no placebo group, 10 subjects, 9 months, late onset hypogonadism (LOH) w/ baseline T of 1.8 nmol/l receiving TE 250 mg/3–4 weeks
  • Rebuff√©-Scrive et al. - no placebo group, 11 subjects, 1.5 months, mean age 42y, overweight/obese subjects, mean baseline T 13.8nmol/l, receiving TU 120–160 mg/day
  • Forbes et al. (1991) - no placebo group, 7 subjects, 4 months, healthy, normal T levels, receiving TE 42 mg/kg/week
  • Marin and Krotkievski et al. (1992) - no placebo group, 11 subjects, 1.5 months, mean age 42y, obese subjects, low T at 13.8 nmol/l, receiving TU oral 160 mg/day
  • Marin and Krotkievski et al. (1996) - no placebo, 8 subjects, 3 months, mean age 42y, obese, low T at 14.1 nmol/l on T gel 250 mg/day
  • Brodsky et al. (1996) - no placebo, 5 subjects with late onset hypogonadism (LOH) and T-levels of only 3.7 nmol/l on TC 3 mg/kg/2 weeks
  • Katznelson et al. (1996) - no placebo, 29 subjects, 13 months, mean age 57, LOH w/ testosterone levels of 6.4 nmol/L on TE or TC 100 mg/week
  • Wang et al. (1996) - no placebo, 67 subjects, for 6 months, LOH w/ starting T levels of 4.1 nmol/l taking T sublingually at 15 mg/day
  • Zgliczynski et al. (1996) - no placebo, 22 subjects, 12 months, mean age 58.5y, normal elderly men with very low T (4.3 nmol/l) taking TE 200 mg/2 weeks
  • Bhasin et al. (1997) - no placbeo, 7 subjects, 2.5 months, mean age 34.7y, LOH at initially 2.5 nmol/l receiving TE at a dosage of 100 mg/week
  • Tan et al. (1998) - no placebo, 11 subjects, 4 months, mean age 33.3y, LOH w/ initially 5.5 nmol/l receiving TE at a dosage of  250 mg/4 weeks
  • Brill et al. (2002) - no placebo, 10 subjects, 1 month, mean age 68.1y, but T-levels of 15 nmol/l treated with T patches at 5 mg/day
  • Minnemann et al. (2007) - no placebo 25 subjects, mean age 57y w/ LOH and initial T levels of pretty high 14.3 nmol/l receiving TU 1000 mg/12 weeks from week 6
  • Suggested Read: Tribulus Boosts Testosterone (+12%), IGF-1 (+20%), Sheds 2kg (7%) Body Fat and Maintains Lean Mass in 12 Wk RCT | more
    Naharci et al. (2007) - no placebo, 24 subjects, 6 months, mean age 20.7y, low T at 5.7 nmol/l treated with mixed ester at 250 mg/3 weeks
  • Saad et al. (2007) - no placebo, 28 subjects, 13 months, LOH with erectile dysfunction (ED), low  T at initially 7.5 nmol/l treated with  TU at 1000 mg/12 weeks from week 6
  • Saad et al. (2008) - 27 subjects, 9 months, mean age 60y LOH with ED and initial T levels of 7.5 nmol/l treated with TU 1000 mg/12 weeks from week 6 or T gel 50mg/day
  • La Vignera et al. (2009) - no placebo, 7 subjects, 3 months, mean age 58y, LOH with MetS and unknown baseline T levels treated with T gel 50 mg/day
  • Moon et al. (2010) - no placebo, 133 subjects, 6 months, mean age 54y baseline T of 8.6 nmol/l treated with TU at 1000 mg/12 weeks from week 6
  • Permpongkosol et al. (2010) - no placebo, 161 subjects, 13.5 months, mean age of 60.4y and LOH consulting urological center w/ T at 9.4 nmol/l on TU 1000 mg/12 weeks from week 6
  • Garcia et al. (2011) - no placebo, 29 subjects, treated for 25.5 months,  mean age 55.5y, LOH and diabetes, no baseline T available, treated with TU 1000 mg/12 weeks from week 6
  • Schwarz &Willix (2011) - no placebo, 56 subjects, 18 months, mean age 52.3y, overweight or obese with baseline T of 15 nmol/l receiving TC 80–200 mg/week + diet + training
  • Arafa et al. (2012) - no placebo, 56 subjects, 12 months, mean age 55.5y w/ T2DM and unknown baseline T treated w/ TU 1000 mg/12 weeks from week 6
  • Schroeder et al. (2012) - no plaebo 29 subjects, 4 months, mean age 71y, baseline T of 13.1 nmol/l treated with T patch 5 or 10 mg/day
  • Jo et al. (2013) - no placebo, 18, 26.8 months, mean age 35.9y and suffering from Klinefelter syndrome, with low T at 3.1 nmol/l at baseline treated w/ TU 1000 mg/12 weeks from week 6
What is the Klinfelter syndrome? That's a genetic disorder that affects males. Klinefelter syndrome occurs when a boy is born with one or more extra X chromosomes. Most males have one Y and one X chromosome. Having extra X chromosomes can cause a male to have some physical traits unusual for males.
  • Ko et al. (2013) - no placebo, 246 subjects, 14.7 months, mean age 58.5y  treated w/ TU 1000 mg/12 weeks from week 6
  • Rodriguez-Tolr√† et al. (2013) - no placebo, 50 subjects, 12 months, mean age 59.1y, LOH, mean T at baseline 10.2 noml/l treated w/ T gel 25–100 mg/day
  • Suggested Read: Hormonal Response to Exercise, Revisited: A Consequence, not a Determinant of Your Mood, Effort & Performance | more
    Saad et al. (2013) - no placebo, 255 subjects, 60 months, mean age 58y, mixed urological population, low T at 10.0 nmol/l treated with TU 1000 mg/12 weeks from week 6
  • Tirabassi et al. (2013) - no placebo, 15 subjects, 18.5 months, mean age of 55.7y, LOH w/ baseline T levels of 5.2 nmol/l on TU 1000 mg/12 weeks from week 6
  • Zitzmann et al. (2013) - no placebo, 1438 subjects, 10.5 months, mean age 49.2y, LOH w/ baseline T levels of 9.6 nmol/l on TU 1000 mg/12 weeks from week 6
  • Francomano et al. (2014) - no placebo, 20 subjects, 60 monhts, mean age 57.5y, MetS and basline T of 8.3 nmol/l on TU 1000 mg/12 weeks from week 6
  • Pexman-Fieth et al. (2014) - 669 subjects, 6 months, 53y, LOH on  T gel 50, 75 or 100 mg/day
  • Yassin et al. (2014) - no placebo, 261 subjects, 54 months, mean age 59.5y, LOH w/ baseline T levels of 7.7 nmol/l treated w/ TU 1000 mg/12 weeks from week 6
  • Zitzmann et al. (2014) - no placebo, 381 subjects, treated for 60 months, mean age 42.6y w/ LOH and low T at 5.2 nmol/l on TU 1000 mg/12 weeks from week 6
Figure 1: Influence of trial duration (a, b), age (c, d) and testosterone levels at enrollment (e, f) on weighted mean differences (with 95 % CI) of body weight (a, c, e) and waist circumference (b, d, f) at endpoint after testosterone supplementation. The size of the circles reflects the sample dimension (Corona. 2016).
Why did the scientists prefer observational trials over RCTs? "The peculiar study design of these RCTs might, as the authors point out justify the lack of efficacy of testosterone supplementation on weight parameters in previous meta-analyses. In fact, RCTs are performed under idealized and rigorously controlled conditions, which are different from everyday clinical practice. Hence, results of RCTs offer an indication of the efficacy of an intervention rather than its effectiveness in everyday practice. [...] In contrast, observational and register studies maintain the integrity of the context in which medical care is provided. As a result, whereas RCTs provide an indication of the minimal effect of an intervention, observational studies offer an estimate of the maximal one," Corona et al. write.
Table 1: Number and proportion (%) men reporting use of AAS, life-time, past 12 months and past 30 days, in different subgroups (Leifman. 2011).
All in all, we are talking about 32 out of 824 initially retrieved articles and 4513 patients whose mean age of 51.7 ± 6.1 years is yet far above that of the average PED (ab-)user whose age appears to be somewhere between 25 and 29, likely to have visited only "compulsory school" and a friend of alcohol and dietary supplements (Leifman. 2011 | see Table 1) and a very obvious result, i.e. that the supplementation of testosterone "was associated with a time-dependent reduction in body weight and waist circumference (WC).

To be more specific, "[t]he estimated weight loss and WC reduction at 24 months were −3.50 [−5.21; −1.80] kg and −6.23 [−7.94; −4.76] cm, respectively" (Corona. 2016). In addition, the provision of testosterone was, as you would probably have guessed based on previous SuppVersity articles, "also associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction in fasting glycemia and insulin resistance" that were accompanied by reductions in fasting glycemia and insulin resistance (IR), as detected by HOMA-IR index - especially in studies enrolling a diabetic subject clientele at baseline (Corona. 2016).
Figure 2: Effects of TRT on blood pressure, lipids and glucose metabolism (Corona. 2016).
But isn't testosterone supplementation (TS) bad for your cholesterol and blood pressure? Even though nobody really appears to care about cholesterol on the interwebs, these days, the claim that testosterone would ruin your blood lipids and, maybe more importantly, one's blood pressure, is still propagated on "the boards". In the studies Corona et al. reviewed for their latest meta-analysis, however, the provision of exogenous testosterone (albeit in not necessarily superphysiological levels) triggered sign. improvements of the subjects' lipid profiles (reduction in total cholesterol as well as of triglyceride levels and an improvement in HDL cholesterol levels) and in both systolic and diastolic blood pressure was observed.
You're scratching your head, I see... Are you disappointed of the effect sizes? Well, you should take a closer look at the full spectrum of the results. Let's take the reduction in waist circumference, for example (Figure 3):
Figure 3: Effect of TS on waist circumference (cm) in the studies that were part of the meta-analysis (Corona. 2016).
As you can see, the latter ranged from ZERO in La Vignera (2009), who didn't even measure the waist circumference ;-) to HERO,... ah, I mean -19.6 cm in Zitzmann (2014), who studied the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. With a baseline waist circumference of relatively moderate 99.5 +/ - 15.25 cm, we are talking about a ~20% reduction in waist circumference, here!
Figure 4: Zitzmann et al. also found sign. improvements in mood (left) and the ability to concentrate (right) in their previously (mostly) hypogonodal subjects (Zitzmann, 2014).
Physical changes that were accompanied by significant improvements in the subjects' mood (Figure 4, right) and ability to concentrate (Figure 4, right) - results that had the authors conclude that their "study corroborates and strengthens the modern view on the desirability and efficacy of substitution therapy in men with proven hypogonadism, also in a “real-life” setting" (Zitzmann. 2014).
You to know more about superphysiological doses?
If that's not "good enough" for you, let me remind you of my previous review of a seminal paper by Bhasin et al.  who conducted (to my knowledge) the only "dose-escalation" study that comes remotely close to being a "PED"-RCT, i.e. a controlled trial that may give us some insights into the effects T at dosages that are used by performance enhancing drug users would have.
Figure 5: Dose response relationship of muscle gain (in kg) per mg of testosterone enanthate (left) , the white line indicates a dose that would probably have produce testosterone levels identical to baseline; and relative change in lean and fat mass in response to changes in serum testosterone levels (right | Bhasin. 2001)
While I've reprinted the most important data in Figure 5, I'd still suggest you take a closer look at the corresponding SuppVersity Classic article, if you want to learn more - especially about the interpretation of the graph on the right hand side that shows the relative change in lean and fat mass in response to changes in serum testosterone levels.
Overview of factors controlling muscle gains (Moussa. 2012)
If you want to know what's possible in healthier people, I suggest you go back to my articles in the "Intermittent Thoughts on Building Muscle" series. More specifically, the articles "Zoning in on "The Big T" - Does Testosterone (Alone) Build Muscle?" (read it), "Quan-tifying "The Big T" - Do Testosterone Increases Within the Physiological Range Really Matter? And How Much is too Much?" (read it) and the conclusion "Exercise, mTOR/AKT/MAPK, IGF-1, Testosterone, Estrogen, DHT, Nutrition, Supps & Sleep" (read it) from which I have copied the overview of different mechanism that contribute to / control muscle growth on the right | Comment
  • Baker, Julien S., Michael Graham, and Bruce Davies. "Gym users and abuse of prescription drugs." Journal of the Royal Society of Medicine 99.7 (2006a): 331-332.
  • Baker, J. S., M. R. Graham, and B. Davies. "Steroid and prescription medicine abuse in the health and fitness community: A regional study." European journal of internal medicine 17.7 (2006b): 479-484.
  • Bhasin, Shalender, et al. "Testosterone dose-response relationships in healthy young men." American Journal of Physiology-Endocrinology And Metabolism 281.6 (2001): E1172-E1181.
  • Corona, G., et al. "Testosterone supplementation and body composition: results from a meta-analysis of observational studies." Journal of Endocrinological Investigation (2016): 1-15.
  • Graham, Michael R., et al. "Anabolic steroid use." Sports medicine 38.6 (2008): 505-525.
  • Herschthal, Adam. "From Rats to Riches: How the Anabolic Steroid Control Act of 2004 Unjustly Punished the Gym Rat and How a New Prescription Is the Road to Salvation." Syracuse L. Rev. 63 (2012): 437.
  • La Vignera, S., et al. "Andrological characterization of the patient with diabetes mellitus." Minerva endocrinologica 34.1 (2009): 1-9.
  • Rahnema, Cyrus D., et al. "Anabolic steroid–induced hypogonadism: diagnosis and treatment." Fertility and sterility 101.5 (2014): 1271-1279.
  • Zitzmann, Michael, et al. "IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men." The journal of sexual medicine 10.2 (2013): 579-588.