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Anthony
Anthony Roberts holds a BA in both English and Philosophy, is the author of Anabolic Steroids: Ultimate Research Guide and Beyond Steroids, and is a staff writer for Muscle Evolution and a contributor to Muscle Insider. He’s a certified trainer and coach as well as having worked as a formulator in the nutritional industry. He is a member in good standing of the Society for Professional Journalists.

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IGF1, Growth Hormone, Peptides, and Sprinting: What do we really know?

by: Anthony Roberts

This past summer (July of 2012) a study was published titled:

“A quantitative approach for assessing significant improvements in elite sprint performance: Has IGF-1 entered the arena?”(1)

The answer, of course, is yes. Without a doubt, we already know that IGF-1 has become a favorite drug among athletes of every flavor, from sprinters to BJJ players, and especially bodybuilders. Everyone in the underground athletic community is talking about IGF-1 and has been for over a decade. So why am I so excited that a study has come out that simply confirms what we already know? More importantly, why do I agree with the conclusion of the study, while disagreeing with nearly every premise that leads to the conclusion? First, let's take a look at the abstract and talk about why the conclusion is correct while the premises are not:

"The introduction of doping substances and methods in sports triggers noticeable effects on physical performance in metric sports. Here, we use time series analysis to investigate the recent development in male and female elite sprinting performance. Time series displaying the average of the world's top 20 athletes were analyzed employing polynomial spline functions and moving averages. Outstanding changes in performance over time were statistically analyzed by Welch's t-test and by Cohen's measurements of effect. For validation we exemplarily show that our analysis is capable of indicating the effect of the introduction of in- and out-of-competition doping testing on women's shot put as well as the effects of the market introduction of erythropoietin (EPO) and the introduction of EPO and continuous erythropoiesis receptor activator (CERA) testing on 5000 m top 20 male performances. Time series analysis for 100m men reveals a highly significant (p < 0.001) drop by more than 0.1 s from 2006 to 2011 with a large effect size of 0.952. This is roughly half of the effect size that can be found for the development of the 5000m performance during the introduction of EPO between 1991 and 1996. While the men's 200m sprinting performance shows a similar development, the women's 100m and 200m sprinting performances only show some minor abnormalities. We will discuss here why the striking sex-specific improvement in sprinting performance is indicative for a novel, very effective doping procedure with insulin-like growth factor-1 (IGF-1) being the primary candidate explaining the observed effects. "

What we have here is a published, peer-reviewed, article stating that IGF-1 is likely being used by sprinters at the highest level of competition (which is something that we already knew). This is good stuff because it forces the issue of yet another undetectable drug into WADA's face, and holds them accountable for the very likely probability that most (read: all) of the world's top sprinters are doping. Of course, there's also the “told you so” factor, which works on multiple levels.

Unfortunately, although the conclusion of the article is true, the argument being made by the authors is weak – but probably strong enough to support their conclusion (or at least something in the neighborhood of the conclusion). Their article rests on two main premises: the first being the statistical probability that top men's 100m and 200m times are improving too rapidly, therefore making chemical assistance likely. The second being that the women's times are not improving as rapidly, thereby pointing towards a compound that would give women less of an advantage than men. Therefore, IGF-1 (which women produce in naturally greater amounts than men) appears to be a likely candidate.

I see nothing wrong with the first premise, i.e. that men's 100m and 200m times are improving at a rate that would suggest doping to be a high probability (and let's not forget that I'm somewhat clued into this world and know for a fact that sprinters are doped up). However, just because doping is highly probable doesn't make IGF-1 the primary candidate. Therefore, they include some information on gender disparity in circulating IGF-1 levels and the gender disparity in decreasing times; novel but not conclusive. The second premise, therefore, requires a couple of logical leaps that aren't unwarranted, but push us dangerously close to the edge of a slippery slope. I think I could make at least as strong of a case for numerous other drugs.

What the authors are proposing is that androgens give men less of an advantage than women (testosterone, for example, at any given dose, will produce greater results in a woman than a man) – this has been established in the official literature as well as the mountains of data provided by the East Germans (who kept records of all of their elite athletes and their respective doping programs). This is most likely because men already produce more testosterone naturally.

So the leap they're making here, is that since women produce more IGF-1 naturally, this drug becomes the likely candidate, because it would logically produce lesser results in women (which is what we see with testosterone use in women versus men, but in reverse). As further supporting evidence, they also cite a reference that shows that women receiving a larger dose of growth hormone will respond with a lower increase in IGF-1 than men (2). The conversion of GH to IGF-1 is irrelevant when directly injecting the latter itself. Ergo, a seemingly important piece of their supporting references is rendered wholly inapplicable. However, even if it wasn't completely and embarrassingly irrelevant, it is still a leap as there have been no studies, or even anecdotal reports, suggesting that women receiving less of an anabolic or performance enhancing effect from IGF-1.

Still, if this holds true, and women do get less results from IGF-1, we'd be able to infer that not only IGF-1, but also hGH, and the GH releasing peptides (GHRP-2, GHRP-6, hGRF1, CJC-1295, Hexarelin, etc...) on the market would probably cause greater results in men as opposed to women. This puts any of those candidates in play as explaining the gender disparity in falling sprint times. I posit the theory that these peptides are minimally as responsible for the falling sprint times in men, especially since they also show potential for masking the use of Growth Hormone.

Would this apply to Selective Androgen Receptor Modulators? We could (perhaps) logically infer that stimulating the androgen receptor would prove to be more anabolic in women as opposed to men (as we see with traditional androgens)? Probably, but maybe not – this is pure speculation, as no studies or anecdotal evidence exists to confirm or invalidate these hypothesis.

Of course, any mentioning of the reckless (record-shattering) use of undetectable performance enhancing drugs should mention Myostatin inhibitors, like ACE-031. Young males were shown in a study to have higher levels of myostatin (a hormone that curtails muscle growth), but they experienced a greater drop after resistance training (along with greater results).(3) With regards to gender differences in myostatin, it appears that the myostatin genotype can not explain why men respond to strength training more robustly than women. However, intergender differences among women reveals that those possessing the less common myostatin allele exhibit a 68% larger increase in muscle volume as a response to strength training.(4)

Are we still sure IGF-1 is the only candidate that fits the bill here?

Myostatin inhibition seems very likely to increase sprint performance, if the canine data applies to humans. Whippets (a type of dog, not the thing that gets you high for three seconds) that were heterozygous for a 2 base pair deletion in the myostatin gene (which inactivates it) were shown to place significantly higher and more consistently in dog races.

The authors of the study even suggest that this particular myostatin mutation may not be desirable in greyhounds because the latter run races that are 300% the distance of Whippets (5). Could Myostatin inhibitors explain why men are getting faster more rapidly than women, and furthermore, why there seems to be less of a pronounced effect as the distance increases? ACE-031, which has been widely available for several years now on the research chemical market, looks to be a winner:

A rodent study revealed that  mice were treated ACE-031 versus control for 28 days had a mean body weight 16% greater than that of the control group, and wet weights of soleus, plantaris, gastrocnemius, and extensor digitorum longus muscles increased by 33, 44, 46 and 26%, respectively, while mean fiber cross-sectional area increased by 22 and 28% in type I and II fibers, respectively. In the plantaris (which is mainly comprised of type II muscle fibers, the fast twitch type used in sprinting) mean fiber cross-sectional area increased by 57% with ACE-031. (6)



ACE-031 has been around for many years, and we began seeing information emerging online by around 2006 or so, right before we see a precipitous drop in 100m sprint times.

I'm left wondering if we shouldn't put some chips on S107 also, as it enhances the ability of muscles to continuously and repeatedly contract as well as reducing muscle damage (measured by creatine kinase). Who knows if it works differently in men versus woman? We know that WADA isn't testing for it, and we know that it has shown to improve athletic performance in rodents, so as long as we're speculating... My point here is that if the authors of this paper want to say "it's probably IGF-1" they need to rule out a lot of other candidates more conclusively.

To their credit, the authors recognize that they are leaving out a myriad of potential doping candidates, some of which they mention (undetectable steroids, Insulin, hGH, estrogen receptor antagonists) and some of which they do not (Mechano Growth Factor, S107, MK-2866, GH2, SARMs like S4 etc.).

However, the most damning counterargument emerges when we look at some of the established reference ranges for IGF-1 in women, we find that the applicable range (age-adjusted for competing in international athletics) is between 110-420ng/ml and men are 160-390ng/ml.

It's important to note that I'm relying on one set of reference ranges, of which there are many, but according to this one, men actually have a higher average, and a higher floor, but a lower top natural limit. Sadly, there are a bunch of different reference ranges for men and women (University of Iowa actually has them combined for adults and seperated by sex per year for children), and after the teen years we find that the values are identical throughout the 20s according to the Mayo Clinic. For growth hormone, the charts also fluctuate wildly, but according to the University of Iowa, women produce significantly more growth hormone than men:

Growth Hormone Reference Ranges

  1. Male: 0-6 years: 0.10-8.80 ng/mL
  2. 7-17 years: 0.03-14.90 ng/mL
  3. 18 years and older: 0.01-1.00 ng/mL
  1. Female: 0-6 years: 0.10-8.80 ng/mL
  2. 7-17 years: 0.06-23.80 ng/mL
  3. 18 years and older: 0.03-10.00 ng/mL

The Mayo Clinic doesn't put women quite so far ahead of men, respectively placing the range for adult males at 0.01-0.97 ng/mL and adult females at 0.01-3.61 ng/mL. Still, the gulf is far greater than that of IGF-1.

So why can't the culprit be - and you might call me old fashioned fir this:  Growth Hormone (*which has an incredibly small chance of actually being detected by the anti-doping dopes)? Is it just because of the timeline with the more recent drops in times corresponding with the more recent availability of IGF-1? Of course, that's rhetorical – it's highly probable that both are being used by elite sprinters. In fact, if we accept that IGF-1 is responsible for the majority of Growth Hormone's anabolic and performance enhancing effects, I believe that the authors of this paper have actually made a much stronger case for GH (perhaps more likely, a GH releasing peptide that remains undetectable) as the drug of choice here.

Therefore, because women have naturally higher levels of IGF as well as GH, it seems likely that GH would also be less anabolic in women. However, this same reasoning leads me to believe that GH would be far less anabolic in women as compared to IGF, respectively (making GH perhaps seem to be a more credible candidate to explain the disparate differences in dropping sprint times by gender). And what we're looking for here, to fit their timelines and graphs of the improvements in short distance sprint times, is a drug that works better in men than women.
 
It seems to me that GH is a much better fit...since we get less of the highly anabolic IGF-1 conversion in women. Additionally, GHRPs, and their ability to not only increase GH and IGF-1, along with their ability to mask GH use, makes them a far (far) more likely candidate than IGF-1.

Confounding the issue is the fact that women also have higher levels of MGF (mechano growth factor) a peptide hormone released in response to mechanical loading (weight training) - though their levels don't rise in response to training as well as mens do.

But then there's the “timeline” issue to contend with – what about the drop in times corresponding more closely to IGF-1 availability?

To this end, the authors of the paper conduct a virtual seminar of disinformation, blundering their way through an almost entirely inaccurate timeline of IGF-1 use, making the occasional pitstop to incorrectly explain the workings of the doping subculture.

First of all, they've got pretty credible information (by way of a snitch who worked as an informant) that Maurice Greene had been using IGF-1 as early as 2003. This same snitch is a journeyman in the track scene, and has worked with (among others) Tim Mongomery, Justin Gatlin, and Marion Jones (who passed 160 drug tests, en route to winning five Olympic medals, prior to getting caught using performance enhancing drugs). Oh, and he also worked with Usain Bolt and a dozen lesser known (but elite) track stars. So while I'm not saying anything that I'm not saying, it's important to note that the fastest man in the world has worked with an admitted drug expert who has experience dealing in undetectable compounds.



The way drug use trends in elite athletics, it's highly unlikely that IGF-1 was only being used by any of the top 20 sprinters in the world and remain an unknown quantity to the rest (which is how the authors of this paper determined the mathmatical average of the top sprint times in the world, by year - which they consent, is only possible in retrospect and by assumption with regards to doping).

By my reckoning, once I can show you that one of the top sprinters in the world has used a drug, and show that there's a solid connection between his dealer and other top flight sprinters, there's not much room left for a counterargument. It's an arms race with these guys and if one person has a new weapon in their arsenal, you can bet everyone else has it (or is trying to get it) too. To this end, I feel the authors of the paper (1) have proven their point, at least inductively.

But by 2003, we're literally a decade into the emergence of IGF-1 in the bodybuilding subculture, as we can find the first mention of it in print by 1995, in an interview published by the now defunct Hardcore Muscle, where Dan Duchaine talks about the abundance of counterfeit IGF-1 on the market. The January 1996 issue of Muscle Media 2000 followed shortly thereafter with the now-infamous “Bodybuilder X” interview, where IGF-1 is again mentioned, and we see it appearing regularly in MM2K and more underground publications from that point on.

So although one particular drug dealer had been using it with his guys since 2003, it's highly likely that it had appeared on the scene previously, perhaps through a sprinter who's connected with the bodybuilding world. As the BALCO case showed, through its inclusion of Milos Sarcev, et al. as well as the Greg Anderson/Barry Bonds connection, bodybuilders are frequently employed as personal trainers (and drug dealers) to high-profile athletes who ought to know better. Interestingly, professional sports organizations very rarely employ “bodybuilders” any longer, while half a century ago, you could get a job as a strength coach in the NFL with no real credentials as long as you had a few bodybuilding trophies and titles to your name (I'm thinking here of Alvin Roy, who provided steroids to the 1963 San Diego Chargers – the team who took the AFL championship by routing the Patriots 53-10, taking a meager 15mgs/day of Dianabol).

I mention this because although the authors seem to note that many of the improvements in short distance running have not occurred by chance shortly after the market introduction of IGF-1. They posit that 2005 represents a watershed year for the use of IGF-1, simply because the drug has finally been released (officially) to the legitimate market. Who cares? We're talking years and years since it was available as a research chemical online (where it can still be found cheaply, quickly, and anonymously).

They claim that the effect of EPO on long distance running was noted 3 years after market introduction, and this would plot a very similar course to the improvements seen after IGF-1's mainstream market introduction in 2005 (again, over a decade after it was available on the blackmarket and two years since its recorded use by a world class sprinter). However, EPO is not only available, but the methods used to beat the test are widely available: we can look at EPO levels in athletes from 2003-2006, where a study actually revealed that 17% of the tested athletes (3050 samples) contained no EPO.(7) That's zero. Meaning 17% of these athletes had no detectable levels of EPO, something that is naturally present in 100% of the population. Gosh, do you think perhaps these athletes went a little overboard on their masking agents? If 17% of these athletes went overboard on their masking agents, and we speculate that's about half the number who got the dose wrong (or whatever) that means over a third of the tested athletes were doping. Even at a lower percentage, it's a huge embarrassment to the anti-dopingistas.

But again, athletes are not waiting for masking agents or FDA approval for their doping compounds. We've seen drugs that never (ever) had FDA approval (Trenbolone sound familiar to anyone?) become widely used and even the synthesis of completely new drugs for the explicit purpose of doping (again, let's reference BALCO and the GDR doping programs). We're literally seeing things like PPARδ agonists (AICAR, GW1516, and GW501516) hitting the market within months of rodent data being published (the first has been shown in rodents to improve endurance by 44% while the second is good for 77%)(8). These drugs, although not yet on the legitimate market, are literally exercise mimetics - they act on the body in the same manner as exercise.(9) So I can't think that officially releasing a drug or gaining FDA approval is going to matter greatly to the chemical athlete.

However, although I believe 2005 to be of little consequence in the case of IGF-1 distribution, that year marks the first that we saw published research (indexed by the National Institute of Health) on CJC-1295, a highly potent Growth Hormone releasing peptide. Could this be the real culprit? The 2005 paper (10) mentions successful rodent testing and gives some pretty strong data indicating both safety and efficacy.



Also mentioned in the 2005 research are several compounds that worked to elevate GH, but not as well (CJC-1288, CJC-1293). Here's a hot tip: WADA doesn't develop tests for discarded compounds. That's right, boys and girls, WADA usually waits until a drug is in Phase 2-3 of the FDA approval process (phase 2 trials), thereby giving a nice window of opportunity to dopers. [That's actually an improvement over ten years ago, when they normally screened for drugs already for sale on the legitimate market.] This means we could likely be using one of the other CJCs and test clean forever (unless there are shared metabolites with the other ones and WADA comes up with a worthwhile test -  two very big ifs).

CJC-1295 at a 60-μg/kg dose injected sc shows an increase of GH levels of 125% and IGF-1 levels of 80%.(11) A follow up study showed a mean IGF-1 increase of 44% and a GH increase of 46%.(12) In this particular study (done only in men, unfortunately), the pituitary continued to secrete Growth Hormone in its usual pulses. Ergo, I believe CJC-1295 (along with GH, or even GH2, and IGF-1) would be a winning cocktail for sprinters - certainly even without the IGF-1, it would be a better explanation than the authors of this paper have put forth.

Would women, who convert GH to IGF-1 at a lower rate than men, also see a lower increase with this drug? I think so. I think, in fact, CJC-1295 emerges as an even more likely candidate than straight IGF-1 (though I insist on repeating they're both probably part of a much larger drug cocktail being used at the international level). Or maybe MGF is the answer, since women respond with lower levels, post-training, compared to men. The point here is that for every argument that we have pointing towards IGF-1 being responsible for descending sprint times in men, I can point to half a dozen other drugs that fit the criteria.

I'll also note that the first recorded instance of IGF-1 use, allegedly by Maurice Greene, is still two years prior to its being released on the legitimate market, while the initial data on CJC-1295 begins being published right around the same time as we see a significant improvement in sprint times – just enough time to read the study and find a source in China...

By the mid to late 2000s we began seeing scholarly papers appearing in the literature, mostly speculative in nature, talking about the potential for IGF-1 to be used for doping purposes. Rewind the tape for a minute and you'll kindly note that the underground subculture has been talking about this for nearly two decades at this point. So while the authors do their best in reconstructing a plausible timeline, they're ignoring the underground use of the drug and keeping their noses a bit too “above ground” in their research.

So although their argument is weak, I think it crosses the threshold of providing some evidence that IGF-1 is being used in elite sprinting. I think I can make stronger cases for about a dozen other drugs, however. It's not perfect and there are some missteps, but I think that the authors of the "sprint paper" at very least put it in play. Unfortunately, they didn't quit while they were ahead and they attempted to piece together a timeline that consistently followed the doping narrative supported by dropping sprint times, and they came up woefully short. This is egregious because the additional data that would have made their timeline correct was widely available (I can forgive being wrong when data is incomplete or unavailable or simply has not yet been studied - I've been guilty of that myself).

I was slightly embarrassed to see how prominently they displayed their ignorance of the doping world, the black market, and the underground community at large. Their argument regarding IGF-1 being used in elite sprinting was, to my thinking, stronger without their absurd attempt at post-facto construction of a timeline that mixed their (inadequate & incorrect) suppositions about the drug's availability with the statistical work they provided with regards to falling times.

I still think (know) that IGF-1 is being used by elite sprinters. I would argue that GHRPs are being used heavily as well, as they probably represent a better fit for the criteria that the authors of this paper have presented (they also show the potential to mask GH use). Myostatin inhibitors like ACE-031 and PPARδ agonists seem likely also. I'll still argue that Growth Hormone isn't off the table and that furthermore, SARMs are probably in there somewhere.

The doping world is and always has been far, far ahead of the people who write for scientific journals, and usually maintains a comfortable lead on the people who purport to have the latest and greatest test to catch the so-called cheaters. The blackmarket is called that for a reason - it's obscured from the light; it's not called the underground because it's found in an Ivory Tower. Papers like the one I mentioned at the outset of this article simply serve to reinforce just how large the gap between scientists and sports doping really is.




References
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Am J Physiol Endocrinol Metab. 2005 Jun;288(6):E1110-9. Epub 2005 Jan 11. Impact of resistance loading on myostatin expression and cell cycle regulation in young and older men and women.Kim JS, Cross JM, Bamman MM.

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Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, Parker HG, Ostrander EA (May 2007). "A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs". PLoS Genet. 3 (5): e79. doi:10.1371/journal.pgen.0030079. PMC 1877876. PMID 17530926.

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Clin Chim Acta. 2007 Oct;385(1-2):61-6. Epub 2007 Jul 10.Possible origins of undetectable EPO in urine samples.
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Warning to Beijing Olympics over pills that mimic exercise. The Independent. By Jeremy Laurance and Amol Rajan, Friday 01 August 2008.

Vihang A. Narkar, Michael Downes, Ruth T. Yu, Emi Embler, Yong-Xu Wang, Ester Banayo, Maria M. Mihaylova, Michael C. Nelson, Yuhua Zou, Henry Juguilon, Heonjoong Kang, Reuben J. Shaw, Ronald M. Evans, AMPK and PPARδ Agonists Are Exercise Mimetics, Cell, Volume 134, Issue 3, 8 August 2008, Pages 405-415, ISSN 0092-8674, 10.1016/j.cell.2008.06.051

Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne J-P, Frohman LA 2006 Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analogue of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab 91:799–805

J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. Epub 2006 Oct 3.Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog.Ionescu M, Frohman LA.

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