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

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

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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
• Rebuffé-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-Tolrà 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

References:

• 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.

Tribulus Boosts Testosterone (+12%), IGF-1 (+20%), Sheds 2kg (7%) Body Fat and Maintains Lean Mass in 12 Wk RCT

Tribulus Boosts Testosterone (+12%), IGF-1 (+20%), Sheds 2kg (7%) Body Fat and Maintains Lean Mass in 12 Wk RCT

andropause build muscle gains lose fat male health testosterone testosterone booster tribulus tribulus terrestris TRT

Could a high dose of purified saponin tribulus extract as it was obviously used in the study at hand actually be a valid TRT alternative or even option? 

No, this is not the 2015 study in trained boxers that found similarly surprising, because impressive benefits from tribulus terrestris (TT) supplementation (read it). It's a new study from the Jerzy Kukuczka Academy of Physical Education in Katowice, Poland (Wilk. 2016) that has no direct link to the previously discussed study from the  Shanghai University of Sport Affiliated School of Sports in China.

And even though, the aim, i.e. to determine the effects of steriodal saponins from tribulus terrestris on the blood concentration of testosterone (T), GH and IGF-1 was similar, the overall design of the study was significantly different.

Don't forget to work out - Without exercise you're not going to get lean and jacked, bro!

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While the previously discussed study by Ma et al. (2015) was conducted with young athletic individuals, Wilk et al. deliberately chose 14 men between the age of 45 and 60 years, i.e. exactly those years in a man's life over the course of which the natural hormone production starts to decline significantly.

Table 1: How to recognize your T-levels are declining (from Matsumoto. 2002).

Over twelve weeks, the subjects who were normal-to-overweight with a body mass index of 25–33, and body fat content between 23–30%, received either...

• experimental group: steroidal saponins (TT) - for the first six weeks three capsules (900 mg) per day in split doses (2x capsules were ingested in the morning on an empty stomach, 600 mg, and one at bedtime, 300 mg) and twice the dose, i.e. 6 capsules (1,800 mg) were ingested per day in split doses (4x capsules in the morning on an empty stomach, 1,200 mg, and 2x capsules at bedtime, 600 mg), or 

What's the use of the "front load", i.e. taking more in the AM vs. PM? That's a question I just received from Peter via Facebook. Good question, but one the scientists do not answer. So I'd have to speculate that they may have intended to mirror the natural 24h (=circadian) rhythm of testosterone which peaks in the AM and declines over the day to re-increase over night and peak again in the AM. What is particularly interesting about this rhythm, by the way, is that it - or rather the peaks in the AM, are lost as you age (see Figure on the left | Bremner. 1983).

• control group: placebo (CON) - in the form of gelatin capsules using the same supplementation protocol as it was prescribed in the experimental group 

And even though all subjects participated in a physical activity program over the 12 week study period, the workouts the scientists describe as follows,...

"Get leaner, more muscular and hornier than ever before" - That's probably the promise on the T-booster someone will release after reading this SuppVersity Classic article and sourcing an inferior Shilajit extract on Alibaba. Is that going to be a waste of time - just as the majority of the tribulus products on the market, which are lightyears away from providing grams of pure saponines on a multiple serving per day basis | learn more.

"4 training sessions per week, with 2 sessions directed at the improvemnt of anaerobic power (resistance exercise), while 2 consisted of aerobic endurance exercise. Aerobic training was performed on a stationary cycle ergometer, starting with 30 minutes of continuous exercise at an intensity of 70–75% of maximum heart rate (HR max). Every two weeks, the work volume was increased by 5 minutes in order to reach 60 minutes in the last two weeks of the experiment. Strength training had a holistic aproach, involving all major muscle groups (the back, chest, abdomen, arms and lower limbs). For the first four weeks, exercises were performed in 3 sets of 8–12 reps with the resistance equal to 60–70% of 1RM and 2 min rest periods between sets. During the experiment, the number of sets of each exercise increased from 3 to 4 sets in weeks 5–8, and respectively to 5 sets in weeks 9–12 for each exercise," (Wilk. 2016)

was of course not the same as the one in the previously discussed Chinese study. In conjunction with the standardized isocaloric (same energy content) mixed diet containing 55% carbohydrate, 20% protein, 25% fat, the workouts are still an important means of standardizing / reducing inter-group differences that could otherwise arise due to personal exercise and / or diet preferences.

Figure 1: Relative changes in blood lipids, GH, IGF-1 and testosterone (Wilk. 2016).

The results of the scientists' two series of laboratory tests (independent tests were conducted at the beginning and after 12 weeks of the intervention), revealed a statistically significant effect of the intervention on the following variables: T-Ch (η2 = 0.542), HDL-Ch (η2 = 0.522), LDL-Ch (η2 = 0.587), T (η2 = 0.603), IGF-1 (η2 = 0.512) and GH (η2 = 0.621).

Figure 2: Relative changes in body composition; effect sizes and p-values (Wilk. 2016).

Effects of which you will probably pleased to hear that they went hand in hand with significant decreases in total body fat (TBF) total body mass (BM) and borderline significant effects on the fat-free mass (muscle, organ and bone mass) of the subjects - an observation of which the scientists say that it "indicate[s] that treatment or supplementation of individual hormone deficiencies can be a successful form of counteracting the aging process" - an aging process that is evidenced by increasing body fat levels, decreasing amounts of fat-free mass and concomitant deterioration of blood lipids and blood glucose (the latter was unfortunately not measured in the study at hand).

Wtf!? What kind of tribulus was that? I wish I could tell you that, but a brand name or other specifics are not mentioned in the publicly financed study from Poland.

Make no mistake about it, the impressive increases in free T in Brown's often miscited 2001 study from which I took this figure were due to a combination of the prohormone androstenediol with tribulus and other herbs. To ascribe the T-increase to TT is idiotic.

What I can tell you is that the results are in line with a 2009 study by Milasius, et al. who used food a commercial supplement Tribulus from Optimum Nutrition, USA, and observed positive effects on the acid-base equilibrium after short-term, high intensity anaerobic exercise in competitive athletes. The study at hand apparently used a more pruified steroidal saponin supplement, however, and observed similar effects as Brown et al. (2001), who supplemented tribulus alongside 300mg of the prohormone androstenediol and found - not to anyone's surprise, probably a significant effect on serum testosterone concentration in both young and older men (see Figure to the right).

Since no such effects were observed in the often cited study by Neychev, et al.  (2005) in allegedly much younger subjects, the question future studies will have to answer is whether that's due to an (subject-)age- or dosage / otherwise supplement-related difference between the high dose of (probably) pure saponins used in the study at hand and the relatively low dose of Bulgaria TT (200mg/day) with 60% saponins that was used by Neychev, et al. in 2005 | Comment!

References:

• Bremner, William J., Michael V. Vitiello, and Patricia N. Prinz. "Loss of Circadian Rhythmicity in Blood Testosterone Levels with Aging in Normal Men*." The Journal of Clinical Endocrinology & Metabolism 56.6 (1983): 1278-1281.
• Brown, Gregory A., et al. "Endocrine and lipid responses to chronic androstenediol-herbal supplementation in 30 to 58 year old men." Journal of the American College of Nutrition 20.5 (2001): 520-528.
• Matsumoto, Alvin M. "Andropause clinical implications of the decline in serum testosterone levels with aging in men." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57.2 (2002): M76-M99.
• Milasius, K., R. Dadeliene, and Ju Skernevicius. "The influence of the Tribulus terrestris extract on the parameters of the functional preparedness and athletes’ organism homeostasis." Fiziol Zh 55.5 (2009): 89-96.
• Neychev, Vladimir Kostadinov, and Vanyo Ivano Mitev. "The aphrodisiac herb Tribulus terrestris does not influence the androgen production in young men." Journal of ethnopharmacology 101.1 (2005): 319-323.
• Wilk, Michał, et al. "Endocrine Responses to Physical Training and Tribulus Terrestris Supplememtation in Middle-Age Men." Central European Journal of Sport Sciences and Medicine 13.1 (2016): 65-71.