Arginine Blunts Growth Hormone Response to Resistance Training: Will the -41% Reduction in Post-Workout Growth Hormone Release Hamper Your Strength & Size Gains?

Arginine-based pre-workout products are more popular with guys than with girls. Could this be the reason that only women complain about unlovedly rapid muscle gains? ;-)

No, this is not a typo! The verb in the headline of today's SuppVersity article really is "to blunt", as in "to neutralize partially" (OED Online 2013). I have to admit that I was also surprised, when I spotted the study over in the "ahead of print" section of the International Journal of Sports Nutrition and Exercise Metabolism. Unless Forbes, Harber and Bell, of whom you will learn later that they've already conducted another 'arginine study', messed up, the results of their most recent experiment do yet leave little doubt: Arginine, an amino acid that is used to test the function of the GH-releasing somatotropic cells within the lateral wings of the anterior pituitary, does - when it is administered at a dosage of 0.075 g·kg-1 body mass right before an acute bout of resistance exercise (3 sets of 8 exercises, 10 repetitions at ~75% 1RM) attenuate the post-workout growth hormone surge in strength trained individuals (Forbes. Nov 2013).

You want more details? Here you go...

With ~5-6g of arginine being taken before a workout that consists of 3 sets of 8 classic strength training exercises that are performed for 10 repetitions and at an intensity ~75% of the personal 1RM of the 14 strength trained men [age: 25±4 y; body mass: 81.4±9.0 kg; height: 179.4±6.9 cm; and training experience: 6.3±3.4 y], the researchers from the Faculty of Physical Education & Recreation at the University of Alberta in Edmonton, Alberta, Canada designed an experimental setup which comes "shockingly" close to what the average and extraordinaire gymrat is doing, when he or she is hitting the grind.

Figure 1: Level of arginine, GHRH and IGF-1 at T = 0, 15, 30, 60 min of rest-recovery + integrated area under the curve for growth hormone (iAUC GH); all values expressed relative to placebo control (Forbes. Nov 2013)

Against that background the question whether you and the rest of the millions of hobby athletes who spend hundreds of bucks on pre-workout products every year have been hampering their own progress is, as hilarious as it may sound, not a totally unwarranted one. I mean, we can hardly ignore the statistically highly significant -41% reduction in total growth hormone secretion in the one hour "anabolic window" after the workout, Forbes and his colleagues measured - can we?

What do we make of these results?

Most of you will probably remember the often referenced results of West & Phillips, whose 12-week resistance training intervention in the course of which the researchers from the Exercise Metabolism Research Group at the Department of Kinesiology of the McMaster University in Hamilton, Ontario,  made the following observations (West. 2012):

• 

  Suggested Read: "Anabolic Workouts Revisited!" | more

  No correlations between GH, testosterone or IGF-1 and the lean mass gains of their 56 recreationally active young men, who were not actively participating in any weightlifting
  activities <8 months before the study.
• Significant correlations between GH and the increase in type I (slow twitch, oxidative) muscle fibers, but no correlation between testosterone, IGF-1 and cortisol.
• Significant correlations between GH, as well as cortisol and the increase in type II (fast twitch, gylcolytic) muscle fibers, but no correlation between testosterone and IGF-1.

Unlike Forbes, Harber and Bell in the study at hand, West and Phillips measured the hormone levels for up to 2h after the workout. It is thus possible, but in view of the progression of the GH levels in the Forbes study relatively unlikely, that we'd see a rapid increase in the 2nd hour of the rest period and thus an increase in the total amount of GH that's released in response to the combination protocol (arginine + exercise).

Is the decrease the result of a previous GH "overload"?

With respect to the possible involvement of an auto-negative feedback, which is another, previously suggested explanation for this phenomenon, of which I had to realize during my research for this article that it has been covered in the literature before (Kanalay. 2008), Forbes et al. remark that their data would basically exclude the possibility that "the GH suppression was not due to a GH or IGF-1 induced autonegative feedback loop." (Forbes. Nov 2013)

It may not be the perfect muscle builder and maybe not even something you want to take in the vicinity of a workout, but there is still promising data on the metabolic effects of arginine esp. for (pre-)diabetics | more

In other words, Forbes et al. exclude the possibility that the subjects experienced a rapid increase in growth hormone as we would see it in response to the intravenous injection of arginine (10x increase with 20g/m² surface area of the 12 normal men in a 1996 study by Rahim et al.) that would then have shut down the GH production just as the exogenous administration of steroids would shut down your natural testosterone production.

If we focus on the available data, the conclusion of the researchers from the University of Alberta is certainly right. If we do take into account that we are talking about post workout supplementation and remind outselves that "the somatotrope is also known to have a refractory period" (Kanaley. 2008), it should be obvious that post-workout measurements, alone, cannot exclude the possibility that the GH spike that's responsible for the auto-negative feedback occurred during, not after the workout.

In other words: Instead of focusing exclusively on the post-workout GH levels, Forbes, Harber and Bell would actually have had to measure the pre & intra-workout GH response, as well. The GH spike that would cause the auto-negative feedback could after all have been caused by a sudden drop in blood glucose in response to the insulin sensitizing effects of arginine and the 'glucose hungry' strength training session.

Auto-negative feedback is still possible, but isn't there something else?

An alternative explanation for the lowered growth hormone response may come from a closer reading of the 'prequel' to this study. In January, Forbes et al. published a paper with the same supplement, but a different exercise protocol. Instead of hitting the weights, their 15 aerobically trained male subjects cycled for 60 min at 80% of their personal VO2_max - again, immediately after ingesting 5-6g of l-arginine (0.075g/kg body weight).

Is there anything arginine is good for, if it's not a muscle builder and it's effects on nitric oxide are overblown? There is a previous SuppVersity article that would suggest so: "Arginine a BAT Building WAT Killer & Repartitioning Agent?" | more

Contrary to the strength training routine, the (relatively) high intensity cycling had identical effects on the hormonal, metabolic and cardio-respiratory markers of the subjects, the two things that differed, though, were

• the rate of fatty acid oxidation at the onset of the workout, which was reduced in the l-arginine group, and
• the levels of the sugar alcohol glycerol at the 45-min time point, which were slightly, but significantly increased

These observations stand in line with the effects McConell et al.  observed in a 2006 study in response to the infusion of l-arginine.

The arginine infusion increased the glucose uptake and blunted the increase in nonesterified fatty acid and glycerol concentrations during 120min of cycling at 72% of the VO2max which were followed immediately by a 15-min "all-out" cycling performance bout (McConell. 2013). Whether it also changed the GH response is however something I can't tell you, because reseachers from the The University of Melbourne did not measure the effect the arginine infusion had on the growth hormone levels of their study participants. I would yet guess that it will have been similar to the one on the cycling study Forbes did. This, in turn, would suggest that the effect depends on (a) duration and energy expenditure, or (b) the substrate utilization during the workout (lifting weights = glycolytic; cycling = rather oxidative). In the end both of these are related to the reliance on fat, not glucose / glycogen to fuel the energetic demands of your workout and as you all know the acute provision of  glucose is the prerogative of glucocorticoids (i.e. cortisol), not GH.

There may be another reason arginine does not make you "big": It's one out of three amino acids that have an especially pronounced satiety effect | learn about the others!

I can't exactly tell you why, but I can tell you that... I openly admit that I was surprised by the results of the study at hand. I  surprised that I missed this (side) effect of arginine, before, but I am not worried that the arginine supplements you may be or may have been taking are / were  hampering your training success.

 If that was the case one of the many "real-world" arginine supplementation studies, where the study outcome wasn't some funky hormonal marker of which we still don't know whether / to which extent it actually affects skeletal muscle hypertrophy, would have shown a trend for decreasing performance, lean mass and strength gains with arginine supplementation - this, I can assure you was not the case.

In fact, those of you who remember one of my posts on the 'arginine powered' VPX preworkout products (learn more), will remember that the scientists observed, if anything, opposing, i.e. beneficial effects from complex preworkout products as most of you will be using. A somewhat different picture emerges for the 'arginine only studies' where "only" three out of five acute supplementation and four out of eight chronic supplementation studies showed measurable, but in many cases negligible performance gains (Alvares. 2011). And the null-effect the authors of the other papers observed is no reason to be concerned, either.

References:

• Álvares TS, Meirelles CM, Bhambhani YN, Paschoalin VM, Gomes PS. L-Arginine as a potential ergogenic aid in healthy subjects. Sports Med. 2011 Mar 1;41(3):233-48.
• "blunt, v.". OED Online. September 2013. Oxford University Press. http://www.oed.com/view/Entry/20664?rskey=iZQVcA&result=3&isAdvanced=false (accessed November 19, 2013).
• Forbes SC, Harber V, Bell GJ. The acute effects of L-arginine on hormonal and metabolic responses during submaximal exercise in trained cyclists. Int J Sport Nutr Exerc Metab. 2013 Aug;23(4):369-77. Epub 2013 Jan 8.
• Forbes SC, Harber V, Bell GJ. Oral L-Arginine Prior To Resistance Exercise Blunts Growth Hormone in Strength Trained Males. Int J Sport Nutr Exerc Metab. 2013 Nov 13. [Epub ahead of print]
• Kanaley JA. Growth hormone, arginine and exercise. Curr Opin Clin Nutr Metab Care. 2008 Jan;11(1):50-4. Review.
• McConell GK, Huynh NN, Lee-Young RS, Canny BJ, Wadley GD. L-Arginine infusion increases glucose clearance during prolonged exercise in humans. Am J Physiol Endocrinol Metab. 2006
• Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol (Oxf). 1996 Nov;45(5):557-62.
• West DW, Phillips SM. Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training. Eur J Appl Physiol. 2012 Jul;112(7):2693-702.

Two Weeks on 2.5g Betaine Increase Performance, IGF1 & Growth Hormone by Antagonizing Corticotropin-Releasing Hormone at the Hypothalamic Level

Image 1: You can probably get some cheap betaine (TMG) from your local fishing (not vitamin) shop.

Sometimes, the thing we have been looking for has been there all along. And, no, I am not talking about the love of your life, but the cheap, effective and side-effect free anti-catabolic ergogenic every hard training athlete and fitness fanatic could benefit from. It turns out, Betaine, or trimethyl-gylcine (TMG), the methylated version of the relatively unknown amino acid glycine could be just that: a readily available, cheap ergogenic with the ability to safely modulate your hormonal training response in a way that will actually translate into real world performance increments.

It is not without reason that I underline the importance of real world performance increments against impressive figures on a (oftentimes unrealiable) lab report. What's the use of the 40% increase in testosterone supplement X has been shown to provide, when the latter simply does not translate into practical performance, let alone muscle gains?

Figure 1: The decreases in cortisol and increases in IGF1 and GH compared to the control groups may not bee too impressive, yet they did produce statistically significant increases in two of the four measured markers of exercise performance (data calculated based on Apicella. 2011)

Compared to 40% more testosterone, the effects the supplementation of 1.25g betaine twice a day had on the IGF (+12.4%), GH (+4%) and cortisol (-4.7%) levels of the 12 male, previously resistance trained subjects (age, 19.7 years; height, 172.6 cm; weight, 84.27 kg; body fat, 18.7 %; BMI, 28.2 m²/kg) of the experiment in Jenna M. Appicella's Master thesis appear mediocre, at best, in contrast to the overwhelming majority of expensive "testosterone boosters" supplementation with N-N-N-methyl-glycine (the chemical name of betaine) delivered measurable real world results in form of increments in isometric squat force production and the number of boxes lifted during a box lift test (subjects had to lift as many 18.14 kg metal boxes onto a 1.32 m high platform in 10min, as possible).

Quinoa	630 mg
Spinach	577 mg
Wheat bran	360 mg
Lamb's quarters	332 mg
Beet	256 mg
Table 1: Amount of TMG in common foodstuff per 100g

Next to these immediate (14 days is a short time span) performance increments, both, the small, but measurable increase in total muscle Akt (+1% total Akt), a serine/threonine protein kinase that plays a key role in multiple cellular processes, as well as the compensation of training induced decreases in the phosphorylation of of Akt at S473 and p70 S6k at T389, both enzymes that are intricately involved in cell- and in this case muscle growth, it can be expected that long(er) term supplementation with betaine would also improve the hypertrophy response to resistance training.

With regard to the underlying mechanism of action, the author speculates that

since cortisol has been shown to inhibit GH release, specifically by blunting GH release
in response to GHRH [and] CRH [which is the hypothalamic messenger telling your body to release cortisol] has also been shown to inhibit GH release stimulated by GHRH [and] cortisol may increase somatostatin as another point of inhibition to GH [...] [i]t could be suggested that the decrease in cortisol during the post betaine supplementation trial would decrease the
inhibitory effects to allow the increase in GH release that was observed in our study.

In that, Appicella refers to the results of Yan et al. (2001; incomplete reference given, article not trackable) who observed that betaine deposition in the hypothalamus of pigs increased GHRH [growth hormone releasing hormone] gene transcription and thus elevated GH secrection and speculates

that the decrease in cortisol decreased somatostatin to allow the overall stimulus to the
anterior pituitary to be more positive and allow increased GH secretion.

Personally, I would be interested to see follow up studies with a) longer durations b) different dosing protocols and c) more sophisticated exercise regimens. In fact, Appicella is part of the Volek group from Department of Kinesiology at the University of Connecticut with whom she published her results in the March issue of the Journal of Strength and Conditioning Research, already and who have published similar findings on the effects of trimethylglycine on exercise performance (e.g. Lee. 2010) in the past.

Attention! There seems to be some confusion about betaine (tri-methyl-glycine, TMG) and betaine hcl, the former is the one used in the study, whereas the latter is what you would take (in smaller amounts!) if you had low stomach acid.

This means you can be pretty sure that we will hear more on this remarkable N-trimethylated amino acid and its potential application as an ergogenic, soon. And where is the place you will read about these news first? Correct! Right here at the SuppVersity ;-)