The Drug Files – Part 2

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The Drug Files – Part 2

Part 2 where we look at popular drugs in the world of bodybuilding.

By Anthony Roberts

Disclaimer: Muscle Evolution does not condone nor promote the use of performance enhancing drugs and steroids. This information is provided solely for the purpose of fostering a better understanding of these substances through education, to ensure that if they are used, it is done so responsibly.

Growth Hormone One

(a.k.a. hGH)

Synthetic Growth Hormone is the 22kDa isomer of the growth hormone found naturally within the human body (kDa denotes kilo dalton, a measure of mass on the atomic scale). It has increasingly been called “Growth Hormone 1″ in emerging scientific literature, out of respect for the characterisation of other isomers of GH. Each isomer of GH is a distinct chemical species comprised of both the same number and types of atoms as the other isomers, but possessing different properties. The products being sold by every pharmaceutical company in the world for the use of treating GH deficiency (the same stuff being used by athletes and bodybuilders) is the 22kDa isomer.

While it’s been making more headlines today than ever before, GH is not a new drug. It was first described in the 1920s and within a few decades, isolated as somatotropin. By 1956 it had been established that it increases nitrogen retention in humans (Lancet 1958; 1: 720–1.), an undisputed marker of the anabolic process.

GH is a protein-based 191-amino acid single-chain polypeptide hormone secreted by somatotroph cells found in the lateral wings of the anterior pituitary gland. It’s function is to stimulate cellular growth and reproduction. It is secreted in greater amounts earlier in life, but declines sharply from your 20s and continues to decline throughout the remainder of your life. Specifically, the term somatotropin refers to naturally occurring GH1, also known as hGH, and somatropin refers to GH produced by recombinant DNA (rDNA) technology, known as rhGH. In other words, the stuff that comes in vials, and is injected by athletes and bodybuilders is technically rhGH, but the terms GH and hGH, and even rhGH are often used interchangeably in the media. Because rhGH and hGH are identical down to the molecular level, detection of exogenous (outside) use of rhGH by chemical distinction is impossible.

However, rDNA molecules are synthesised through molecular cloning, but appear identical (in your body) to the molecule they’re replicating. The molecules from all organisms share the same chemical structure, but with differing nucleotide sequences. Think of these molecules as a paragraph from your favourite book. You could, theoretically, take another book and cut out various words and letters, and ultimately recreate a verbatim copy of that paragraph. That’s kind of how rDNA cloning works, and it’s how we arrive at end products like rhGH. When your body reads the paragraph, it reads it the same way you would have read the original paragraph from the book it was taken.

Growth hormone deficiency manifests in children as a variety of growth disorders and in adults as adult growth hormone deficiency. Currently, the treatment of these disorders is the only legal use for growth hormone in the United States. However, athletes and bodybuilders have been using it for decades to increase strength and lean body mass, while decreasing body fat. Only recently has the scientific community recognised the fact that they have been woefully behind the times when it comes to identifying anabolic agents. GH was recommended in “The Underground Steroid Handbook” in 1983 as “a new and exciting anabolic agent” approximately seven years before any publication suggesting that this effect occurred in adults appeared in scientific literature (Gibney et. al, Endocrinology Review. 2007 Oct;28(6):603-24.). The 1984 Olympics were known in the underground athletic community as “The Growth Hormone Games” because they not only featured numerous athletes who were rumoured to have been using the drug, but also because the games were held in Los Angeles. Back then LA was a mecca of body-conscious athletes and actors, punctuated by Venice Beach, the epicenter of 1980′s performance enhancing drug use, and it was also the birthplace of Arnold’s career, The Underground Steroid Handbook, The Anabolic Reference Guide, and the entire steroid subculture.

To say that performance enhancing drugs were readily available to the athletes attending the ’84 Olympics would be a vast understatement. GH was also becoming the drug of choice for some high profile football players in the area, and was starting to spread like wildfire. The anabolic (muscle building) effects of GH are generally thought to be in its ability to increase circulating insulin-like growth factor 1 (IGF-I), which is primarily of hepatic (liver-derived) origin, but is also expressed in muscle as a direct result of mechanical stress (i.e. weight training). Growth hormone also causes the synthesis of IGF-I in most non-hepatic (*muscular) tissues, which is also thought to be a major contributor to its anabolic effect.

There is no longer any lingering question in the scientific community about IGF-1’s ability to increase muscle size and strength while decreasing body fat. IGF-I has a profound anabolic effect on protein metabolism – it inhibits whole body protein breakdown and simultaneously stimulates protein synthesis (PMID: 8074213). IGF-1 use is typically cited as one of the major anabolics being used by top bodybuilders, and among top competitors it is considered a must-have compound for competition at the highest levels.

Although anti-doping officials denied that growth hormone did anything to enhance athletic performance, they quickly banned the substance. It wasn’t until a 1990 study published in the New England Journal of Medicine (N Engl J Med 1990; 323:1-6) that growth hormone entered the public consciousness. In that study it was revealed that increases in muscle tissue and concomitant decreases in fat were experienced by elderly men taking the drug.

Still, as was the case with anabolic steroids, scientists denied that the drug could improve athletic performance. This led to a rapid deterioration of scientific credibility within the athletic and bodybuilding community, similar to what was seen with anabolic steroids (the Physicians Desk Reference still fails to acknowledge that they enhance athletic ability). A Stanford University metastudy, published in the Annals of Internal Medicine (PMID: 18347346) attempted to figure out if GH could improve performance. They analysed previously published studies comparing participants receiving the hormone to those who didn’t. 27 studies involving 440 participants were examined and the researchers concluded, apparently not understanding that muscle is good for athletes, that GH use may hinder performance:

Claims that growth hormone enhances physical performance are not supported by the scientific literature. Although the limited available evidence suggests that growth hormone increases lean body mass, it may not improve strength. In addition, it may worsen exercise capacity and increase adverse events. More research is needed to conclusively determine the effects of growth hormone on athletic performance.

Later, speaking to MSNBC, the lead researcher repeated her absurd claims. “It doesn’t look like it helps and there’s a hint of evidence it may worsen athletic performance,” said Dr. Hau Liu,

However, in 2010, in the Annals of Internal Medicine (May 4, 2010, Vol. 152 no. 9 568-577) GH administration was conclusively shown to increase athletic performance in sprinters, who got substantially faster in their 100m times. “…significantly reduced fat mass, increased lean body mass & significantly increased sprint capacity…”

GH was therefore finally validated by the World Anti-Doping Agency (WADA) as being a genuine performance enhancing drug, after several decades of various scientists saying it may increase muscle and burn fat, but do nothing for performance (hint: a more muscular sprinter, wing or shot putter, with less fat is better than a less muscular athlete with more fat). In metabolic terms, GH use causes a marked increase in lipolysis (fat burning) and free fatty acid levels. After a meal, GH affects protein metabolism, causing increased protein synthesis and decreased whole-body and local-muscular protein breakdown, while decreasing the rate of amino acid oxidation, and activating the mTOR pathway of anabolism (PMID: 19773097). It also prevents carbohydrates from being stored in fat tissue (PMID: 19800274), potentially because GH preferentially down-regulates the glucose transporter in adipose tissue. GH administration also has beneficial effects on tendon and joint repair (PMID: 21403984).

Dosing strategies vary between athletes and sports, with a low end of 1-2iu/day being used by women or as an adjunct/anabolic enhancer (that takes advantage of GH’s synergy with testosterone). However, 4-8iu/day is closer to what we see with athletes and bodybuilders, with a dosing schedule of 1/1 (one day on, one day off), 5/2 or continuous (every day) use. Regardless of how it’s being used, it has been well established that growth hormone will build muscle and burn fat in athletes, as well as enhance performance, period.

Growth Hormone Two

(a.k.a GH2)

There is now another form of synthetic growth hormone available, known as GH2 or Growth Hormone Two, which is comprised of the 20kDa isomer of Growth Hormone (there are numerous other isoforms of the GH protein as well). The 20,000 dalton human GH (20kDa-hGH) is a naturally occurring isoform of the 22,000 dalton hGH (22K-hGH) and constitutes roughly 5–10% of pituitary hGH. Both arise from the same gene, albeit by alternative mRNA splicing, and the 20-version differs from the 22 in its deleted amino acid region (E32-Q46). Interestingly, GH2 (the 20k version) appears to show a greater absorption rate in some cells when compared to regular GH.

The growth hormone doping test currently available and used by WADA relies on the ratio of 20:22kDa. The use of standard rhGH will elevate an athlete’s 22kDa levels while lowering the 20kDa level. This depressed state of the latter isoform compared to the elevated state of the former is the litmus test by which a sample is said to be positive for GH use. However, GH2 use can elevate this isoform, thereby manipulating the ratio, and can therefore be used as a fool-proof masking agent for GH against the current WADA test.

Additionally, it appears that GH2 is less prone to being bound up by hGH-binding proteins, and is therefore able to exert a stronger effect than regular hGH on tissues that release hGH-BP. For example, human abdominal fat tissue has a high hGH-BP level in healthy non-obese adults, so it may be possible that GH2 is more potent for fat loss in this area. Additionally, GH2 seems to have a longer clearance time (PMID: 19467614), perhaps due to its lower affinity to binding proteins, or through a lowered impact on the GH-axis negative feedback loop.

GH exerts some of its direct actions through stimulating site-specific cell surface receptors (Nature 1987; 330: 537–43), but most of its anabolic actions are mediated through the generation of IGF-1 (Endocrinology 1988; 123: 433–7), which has highly pronounced anabolic effects and is responsible for profound metabolic changes in numerous cell types (Endocr Rev 1995; 16: 3–34). Therefore, the anabolic effects of GH1 are thought to be mediated, if not caused outright or strongly attributable to, IGF-1. It’s important to remember that the effects of GH are largely reliant on IGF-1 expression, because GH2 has shown a similar, if not greater, ability to stimulate the production of IGF-1. In addition, the lipolytic (fat burning) effects are also thought to be largely as a result of increased IGF-1 levels, and not as a direct result of GH elevation, per se.

In a study published by The Journal of Clinical Endocrinology & Metabolism (Feb. 1, 2000, vol. 85 no. 2, pg 601-606), GH2 was administered to normal men (20–31 years of age, n= 6–8 per group), achieving an elevation in 20kDa-hGH levels that increased in a dose-dependent manner while suppressing 22kDa-hGH secretion [administration of regular rhGH (GH1) has the opposite effect, i.e. it lowers the natural secretion of 20kDa-hGH]. Moreover, this study also demonstrated that GH2 significantly elevates IGF-1 levels. According to the scientists, these results suggested that regulation of 20K-hGH secretion is physiologically the same as that of 22K-hGH, as well as the fact that pharmacokinetics after SC injection of 20K-hGH are comparable with those of 22K-hGH. They also showed that 20K-hGH regulates hGH secretion through ‘GH-induced negative feedback mechanisms’ and that administration of 20K-hGH is expected to exert GH actions (growth-promoting activity and lipolytic activity).

As you can see from the chart, the highest dose of GH2 corresponded to an IGF-1 elevation several orders of magnitude greater than the placebo. Free fatty acids also increased, and these increases in the main hGH-dependent substances (i.e. FFA and IGF-I) suggested that 20K-hGH has direct GH actions on adipose tissue or the liver through hGH receptors that appear very similar, if not exactly similar, to 22K-hGH (GH1). However, some of the available literature would indicate that lower concentrations of 20kDa-hGH more strongly induces muscular IGF-I (mIGF-1) gene expression as compared to the 22kDa-hGH isomer (at least in mice) (PMID: 10890180). Furthermore, if we compare the elevation in IGF-1 levels seen in the previous charts it starts to become apparent that GH2 may actually be more anabolic than regular rhGH, although it needs to be noted that the stronger effect of 20K hGH, when compared to that of 22K hGH in enhancing the IGF-I gene expression, may be correlated with a yet-undescribed 20K hGH specific receptor dimerisation process (PMID: 10890180). So, although the previous chart is from a rodent model, it would give us good reason to think that there is strong potential for GH2 to be more anabolic than regular GH, or at least equal at a lower dose.

Summarily reviewing the currently available data, GH2 has a longer active life in the human body than currently available rhGH. It also has a stronger impact on IGF-1 levels and therefore has a potentially higher anabolic effect, or at least the same anabolic effect at a considerably lower dose. Oh, and it’s not too expensive, either.

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