I cant believe it, how could someone on T-Nation by the name of BBB not have thought of this many many months ago…oh wait
Intramuscular GH? New Research Suggests It Is Best
Written by Dan Gwartney, MD
Tuesday, 03 March 2009
Human growth hormone (hGH), despite all the news and sensationalism, is a hormone with a relatively short history. Early attempts to provide exogenous GH to humans failed, as the first material came from the pituitary glands of cows and human patients developed antibodies against the foreign protein. Strange as it sounds nowadays, the effort seemed reasonable at the time, as bovine (cow) extracts containing insulin were fairly successful in treating insulin-dependent diabetics.1
It was not until 1958 that an effective treatment for human GH deficiency was reported; pioneering endocrinologist M.S. Raben treated an adolescent suffering from dwarfism with purified GH extracted from the pituitary glands (a gland located at the base of the brain) of cadavers (dead people).2 This extract, called cadaveric GH, was the mainstay of treating children of short stature for decades until it was discovered that some of the cadaveric GH recipients were developing a degenerative and ultimately fatal brain disorder (Creutzfeldt-Jakob disease) that was found to be due to an infectious agent present in the extracted material used to produce cadaveric GHâ?? 405 cases were diagnosed between 1985 and 2006.3 In cattle, the infectious agent causes â??mad cow disease.â??
Fortunately, a series of events had occurred in the biotechnology sector that allowed for a rapid transition to a novel source of the hormone. On April 7, 1976, a new company was incorporated called Genentech, now worth in excess of $80 billion. Genentech recognized the commercial value of a new methodology developed in certain university laboratories, whereby protein-based hormones could be produced by bacteria that had been injected with human DNA, allowing for a virtually unlimited supply with near-zero risk of contamination. This could be accomplished by inserting the genes (DNA) for human hormones into bacteria, which then would continuously secrete the high-dollar material into collecting dishes like colonies of pharmaceutical Shmoo (a fictional character created by cartoonist Al Capp that existed merely to feed the hunger of humans). Genentechâ??s initial interests lay in capitalizing upon the insulin market, as diabetics were dependent upon insulin extracted from the pancreas glands of cows and pigs. As animal-based insulin is slightly different from human insulin, some patients failed to respond predictably to the drug or developed antibodies that destroyed the hormone before it could provide any therapeutic benefit. Fortuitously, one of the companyâ??s early employees arrived bearing technology and material that could produce hGH and by 1979, small batches of bacterial-derived GH were being produced.4
As clinicians recognized the link between cadaveric GH and Creutzfeldt-Jakob disease, the Food and Drug Administration quickly acted to ban the use or marketing of all such products, causing demand for the bioengineered GH to skyrocket.5 Of course, high demand and high production costs associated with a patented product dictated that Genentechâ??s product would be quite expensive and limited in availability. Thus, widespread use of GH outside of treating GH-deficient children of short stature did not occur for several years. Though a select few athletes and people of means were rumored to have been using GH, even cadaveric GH, during the 1960s through the 1980s, it was the publication of a 1990 study published in the New England Journal of Medicine that brought GH use into the mainstream.6 Since then, reports and allegations of GH use by athletes and the pre-elderly have become a frequent occurrence.
Of course, among athletes, the pioneering use of most performance-enhancing substances occurs among strength athletes and bodybuilders. For decades, the use of muscle-building and fat-reducing drugs has been rampant at the top tier of these sports, much as it has been in track and field events and professional cycling. Among bodybuilders, GH is desired for its combined effects, providing a potent anabolic effect to muscle while promoting fat loss and aiding in recovery and soft-tissue repair. Unfortunately, early users extrapolated their dosing based upon use in children, causing them to use excessively high doses and subsequently suffering disfiguring side effects and health issues, including: facial distortions, elongated fingers and toes, protruding bellies, fluid retention and problems with sugar control (glucose intolerance).7,8 An isolated case even suggests GH use as the cause of one manâ??s diabetes. Fortunately, the ultra-high dosing practices fell out of vogue just as many athletes realized the added muscle mass did not necessarily translate into increased strength. The bodybuilding organizations struggled to return some balance back into the judging standards.8 Undoubtedly, the high cost of GH detracted from its appeal, as well.
GH â??replacementâ?? therapy remains one of the foundational treatments in anti-aging medicine. One upside to the growing clinical use of GH is ongoing interest from the academic research community. Recently, two discoveries were reported of great interest to any person considering therapeutic or illicit use of GH. Typically, GH is injected just under the skin (subcutaneously), using the same size and type of needles that diabetics use to inject insulin. Initially, GH was administered by intramuscular injection, but studies demonstrated that children experienced similar growth when given subcutaneous injections, experiencing far less pain. GH was less bioavailable when injected by the subcutaneous route, however.9,10 But physicians saw similar clinical response, reduced risk of striking a nerve or blood vessel and the patients greatly preferred the easier subcutaneous injections. Bodybuilders were happy with this route and did not question subcutaneous injecting as the best method for using GH, especially as many of them suffer twice-weekly or more frequent intramuscular injections of anabolic steroids. The development of abscesses, formation of oil-filled cysts and bruising are not uncommon problems among users of anabolic steroids.11 So, for years, subcutaneous injections remained the norm and went unquestionedâ?? until a recent study published in the European Journal of Endocrinology revisited the issue, looking at adult recipients of GH.12
Just as the early adult users often suffered side effects due to excessive doses when they tried to extrapolate the childrenâ??s therapeutic dosage (by weight), the idea of injecting subcutaneously is an example of adults not receiving the full benefits of GH by mimicking the pediatric experience. German endocrinologists and researchers teamed up to investigate the effects of gender, dose and route of administration (subcutaneous versus intramuscular) on the availability and effectiveness of GH. Ten male and 10 female subjects were recruited; subjects were healthy and athletic young adultsâ?? the doses provided were three to five times the recommended adult replacement dose, roughly nine to 20 units for the males. The subjects received three separate injections: ~9 units subcutaneously, ~9 units intramuscularly and ~20 units subcutaneously. Data obtained by analyzing the subjectsâ?? blood over the next 36 hours revealed interesting results that might offer insight to users of GH.
Comparing the ~9 unit doses, it was clear that intramuscular injections provided significantly higher peaks in GH concentration and greater total-delivered dose.12 In fact, the male subjects received nearly 50 percent more total GH from the same dose when the hormone was injected into muscle as opposed to subcutaneous fat. While GH delivery was vastly improved with intramuscular injections, IGF-1 concentrations were no different between subcutaneous versus intramuscular injections following the same (single) dose. Thus, it is unclear at this time whether intramuscular administration would provide any anabolic or tissue repair benefits. Hopefully, further research will clarify this point with long-term studies.
As most preschoolers learn, boys are different from girls. In the above study, men cleared GH from their system more quickly. At first, this might seem a disadvantage, but in fact, it appears to be the basis for some of the physical advantages males display. Intramuscular GH not only peaked higher, but also earlierâ?? so, despite being cleared more rapidly, a greater total amount of GH is delivered when injected into muscle.12 Not only does the body benefit from receiving more total drug/hormone, the cells of the body are able to prime themselves to respond to the next dose of GH more quickly as the drug is cleared. GH triggers responses in cells by binding to receptors on the surface, which activate a series of enzymes inside the cell.13 Ultimately, the reactions send chemical factors to the DNA to turn on growth-promoting processes.
The GH response sequence doesnâ??t always happen in a linear relationship; in other words, a little GH does not produce a little response in some reactions (GH is involved in over 400 metabolic processes).14 There appears to be a threshold concentration (when the cell is fully primed) that triggers the biochemical cascade in gender-specific reactions and once that level is passed, higher doses cause greater response.15 However, uncontrolled or continuous growth, enticing as that sounds, is neither healthy nor beneficial. To prevent the cell from being stressed with responding to another growth signal too soon, feedback suppressors are generated inside the cell at the same time the cell is building protein and burning fat.13 By clearing out GH more quickly, males also clear out the suppressor blockade, allowing the cells to respond to the next pulse of GH more quickly.
Perhaps the time is overdue in this article to remind the reader that GH is most effective when released in pulses, not as a steady, continuous signal. So although it was not seen with the single-dose study, it is likely that intramuscular GH would offer a more â??lifelikeâ?? signal and possibly greater physiologic benefits over time.
The concepts of suppressor factors and pulsatile GH-release patterns appear to explain some of the differences seen between men and women relative to GH therapy. Typically, men respond much more robustly to GH therapy than women. Additionally, men have higher IGF-1 levels despite the sexes (male and female) releasing the same amount of GH.16,17
In a paper submitted to the journal Endocrinology, researchers at the University of Pennsylvania investigated the effect of â??maleâ?? pattern (pulsatile) and â??femaleâ?? pattern (continuous) release of GH on the liver cells of rats.18 Similar to humans, rats display sex-based differences in GH release, with males generating sharp peaks and valleys in hormone concentrationâ?¦females generally maintain a continuous release with little change in hormone concentration. As a result, females (rat and human) generate less IGF-1 and have a blunted effect to GH treatment. The researchers attempted to discover why this is so.
As mentioned above, when GH triggers its receptor, it generates biochemical signals that stimulate cell growth; it also stimulates suppressor signals to reduce the cellâ??s response to further GH signaling. While the growth signals require fairly high levels of GH, the suppressor proteins are generated by relatively low concentrations of the hormone.18 Thus, while women secrete the same or possibly greater total amounts of GH throughout the day, they benefit less due to the ongoing production of the suppressor proteins which block cells from reacting to GH. Even the male rat cells did not respond vigorously to GH when it was present continuously.18 Compared to the â??maleâ?? pattern of GH pulses, a continuous â??femaleâ?? GH presence only generated about 10 percent to 15 percent of the response at the same dose.
Not only do females secrete GH in a pattern that is much less effective, they are also less capable of responding to the more optimal â??maleâ?? pulsatile pattern. When exposed to pulses of GH, male cells responded twice as well. Further, certain genes in female cells are not activated by the GH cascade, even when a pulsatile pattern is presented, suggesting that sex-specific responses to the hormone have developed over the eons due to natural selection, evolution, intelligent design, God or whatever guiding force actually determines human existence.
Perhaps it is all scientific mumbo-jumbo as described above. What does it boil down to for the person considering GH treatment or use? Men have significant physiologic advantages in responding to GH, natural or pharmaceutical. In addition to secreting GH in a pattern that promotes, rather than suppresses, growth and positive changes, male cells are also programmed to respond to GH bursts more vigorously and certain enzymes are turned on that are not activated in female cells. In contrast, females secrete GH in a continuous fashion that causes cells to block any response or positive changes and when presented with a burst of GH, such as might occur during exercise, they experience a lower level of response and have different cellular effects. So, on the face of things, it appears that there is less justification for the use of GH, therapeutically or illicitly, in women. In practice, women do experience similar benefits from GH therapy but to a lesser degree than men, further emphasizing the need to consult with a qualified and experienced clinician when considering GH therapy or use.
Also, the standard method of administering GH, via a subcutaneous injection, may not be the best method. A higher peak, greater total amount and faster clearance occurred when GH was injected intramuscularly. The downside to this is a greater risk of injury (striking a nerve, injecting into a blood vessel, suffering a deep tissue infection), more pain and potential interference with anabolic steroid injections in those who use the two drugs during the same period.
The findings of the last two decades are very exciting and as the knowledge base expands regarding GH therapy, safer and more appropriate use of the drug is likely to expand, unless political hurdles occur. Research has shown that adults can benefit from very low doses of GH (0.5 to 3.0 units daily), avoiding most adverse side effects associated with the initial high-dose attempts.19 Further, ********** research has shown that GH may be beneficial to anabolic steroid users during post-cycle recovery by maintaining lean mass and lowering body fat while reducing systemic inflammation; certain parameters of cardiovascular function are also improved though greater work is done by the heart as measured by heart rate and blood pressure.20
The era of GH is still relatively new, as safe and reliable sources have been accessible to clinicians for less than 20 years and widespread use is still in its infancy. Sadly, the ethical and political drama relating to sports doping and Internet trafficking will curtail research in this area, much as it has for anabolic steroids. Hopefully, for those who use GH within the confines of approved uses, further research will be published, allowing clinicians and patients to approach decisions relating to GH therapy in an informed and educated manner. Further, though illicit use is not advocated, it is equally important to minimize the burden of unnecessary or suboptimal use by athletes or those seeking to avoid the perils of age or a sedentary lifestyle.
References:
- Devlin JG, Brien T, et al. Effect of alteration of species source of insulin on insulin-antibody levels. Lancet, 1966;2:883-4.
- Raben MS. Treatment of a pituitary dwarf with human growth hormone. J Clin Endocrinol Metab, 1958;18:901-3.
- Brown P, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob disease: the waning of an era. Neurology, 2006;67:389-93.
- Cronin MJ. Pioneering recombinant growth hormone manufacturing: pounds produced per mile of height. J Pediat, 1997;131(1 Pt 2):S5-7.
- Centers for Disease Control and Prevention. Fatal degenerative neurologic disease in patients who received pituitary-derived human growth hormone. MMWR, 1985 June 21;34:359-60,365-6.
- Rudman D, Feller AG, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med, 1990;323:1-6.
- Lehmann S, Cerra FB. Growth hormone and nutritional support: adverse metabolic effects. Nutr Clin Pract, 1992;7:27-30.
- Nelson AE, Ken KY Ho. Abuse of growth hormone by athletes. Nature Clin Pract Endocrinol Metab, 2007;3:198-9.
- Russo L, Moore WV. A comparison of subcutaneous and intramuscular administration of human growth hormone in the therapy of growth hormone deficiency. J Clin Endocrinol Metab, 1982;55:1003-6.
- Jorgensen JO, Moller J, et al. Pharmacological aspects of growth hormone replacement therapy: route, frequency and timing of administration. Horm Res, 1990;33; Suppl, 4:77-82.
- Rich JD, Dickinson BP, et al. Abscess related to anabolic-androgenic steroid injection. Med Sci Sports Exerc, 1999;31:207-9.
- Keller A, Wu Z, et al. Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration. Eur J Endocrinol, 2007;156:647-53.
- Le Roith D, Nissley P. Knock your SOCS off! J Clin Invest, 2005;115:233-6.
- Waters MJ, Hoang HN, et al. New insights into growth hormone action. J Mol Endocrinol, 2006;36:1-7.
- Verma AS, Dhir RN, et al. Inadequacy of the Janus kinase 2/signal transducer and activator of transcription signal transduction pathway to mediate episodic growth hormone-dependent regulation of hepatic CYP2C11. Mol Pharmacol, 2005;67;891-901.
- Koranyi J, Bosaeus I, et al. Body composition during GH replacement in adults - methodological variations with respect to gender. Eur J Endocrinol, 2006;154:545-53.
- Johannsson G, Bjarnason R, et al. The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender. J Clin Endocrinol Metab, 1996;81:1575-81.
- Thangavel C, Shapiro BH. A molecular basis for the sexually dimorphic response to growth hormone. Endocrinology, 2007;148:2894-***.
- Abrahamsen B, Nielsen TL, et al. Dose-, IGF-I- and sex-dependent changes in lipid profile and body composition during GH replacement therapy in adult onset GH deficiency. Eur J Endocrinol, 2004;150:671-9.
- Graham MR, Baker JS, et al. Evidence for a decrease in cardiovascular risk factors following recombinant growth hormone administration in abstinent anabolic-androgenic steroid users. Growth Horm IGF Res, 2007;17:201-9.
-bron: Muscular Development Online Magazine - Intramuscular GH? New Research Suggests It Is Best