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IronLion2
Banned
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This article does very well to separate the use of GH for deficiency in clinical setting vs it's potential for use as a PED
Are scientists and doctors using too little hGH to see the effects that athletes achieve by using large doses? This is of course a possibility; by analogy, it was many years before scientists and doctors accepted that the anabolic effects of testosterone and its analogues were real—see, for example, the careful work of Forbes.65 Nevertheless, in my view the possibility is slight. Anecdotal evidence suggests that many hGH abusers, especially those taking the hormone without medical supervision, do inject supratherapeutic doses. However, in most of the studies in the literature, effects of hGH were also studied at greater than the therapeutic dose, and although these may well have been below the dosages used by abusers, they still resulted in serum concentrations of GH and IGF-I that were 3–6 times normal55,56 and that resulted in pronounced biological effects, such as increased lipolysis, altered carbohydrate metabolism, activation of the renin-angiotensin system, and water retention. It is difficult to believe that, even for effects that are not IGF-I mediated (such as the lipolytic effects), muscle tissue is IGF-I resistant to this extent.
Furthermore, when extremely large therapeutic doses of rhGH are used—for example, in the attempted treatment of wasting in HIV/AIDS—it appears to be much easier to induce diabetic symptoms than retention or recovery of lean body mass.29,66 This, of course, may be a feature of a GH resistant syndrome, but it is odd that there is such a separation between biological effects of the same substance.
Nevertheless, it is relatively easy to see effects of other biological agents that do have effects on muscle protein turnover at blood concentrations that are observed biologically, and without using massive pharmacological doses. For example, insulin has substantial effects on protein synthesis and breakdown in muscle67–69 at concentrations seen after meals. As a further illustration, a modest rise in blood amino acids such as is seen after feeding causes a near doubling of muscle protein synthesis.67,69 Why should a dose of rhGH, which can more than double serum IGF-I and cause considerable effects on body water, fat free mass, and nitrogen balance,50,51,56 be insufficient to have an effect through IGF-I on muscle protein metabolism? It would, arguably, be a very unbiological pattern of behaviour.
Does the increased nitrogen retention often reported to be observed with rhGH administration50 not argue for an effect on muscle, the largest component of the lean body mass? Not necessarily. Apart from anabolic effects in viscera and skin,70,71 rhGH has been reported to have anabolic effects on collagen metabolism,20,72 and even when bone is excluded from measurements of lean body mass using dual x ray absorptiometry, the epimysial, endomysial, and perimysial collagenous components of skeletal muscle and connective tissue elements of skin may all show up as new lean body mass. A modest increase in skin, visceral protein and tissue (including muscle) collagen would translate into a sizeable positive nitrogen balance.
Such an effect on connective tissue in muscle would make the muscle no more capable of force generation but may promote resistance to injury or faster repair, which would be an advantage to an athlete. This may explain the anecdotally reported predilection of baseball players for abuse of testosterone and rhGH together. Unfortunately this possible synergism has never been studied under control circumstances in young men. Certainly co-administration of testosterone and rhGH has only a minor effect on strength in elderly men.61
If there were a threshold in the supraphysiological range for an anabolic effect of rhGH on muscle, it would be expected that patients with acromegaly would show true muscle hypertrophy. In fact, the lack of appreciably greater muscle mass per height as well as associated pathological changes (see later) argues against this idea. This is reinforced by the finding that transgenic mice overexpressing GH show no relative increase in muscle mass as a fraction of total body weight, and what muscle they have develops less force than expected on a weight basis.73
Thus, the balance of evidence seems to be heavily against an anabolic effect of rhGH on human muscle. It may seem that the only way to settle the question in the minds of champions of the use of rhGH is to carry out a dose-response study with large amounts of the hormone. This is easier said than done: we need to discover what amounts abusing athletes inject (it will always be easy to say that what was used was insufficient) to target an appropriate dose range while staying within normal ethical limits given the cardiovascular and metabolic hazards involved.
THE DOWNSIDE OF rhGH ABUSE
The acute administration of rhGH may have appreciably detrimental effects on performance. In fact, there is good evidence that acute administration of rhGH actually results in a decrease in exercise performance according to recent results obtained by Dr Kai Lange of the Danish Institute of Sports Medicine (personal communication). In these studies, healthy endurance trained athletes were unable to complete accustomed cycling tasks after administration of exogenous hGH. There is good evidence that hGH administration exacerbates the pronounced increase in lipolysis that occurs during exercise and, in addition, increases the production of lactate and protons by working muscles. The inevitable metabolic acidaemia and consequent reduction in the rate of glycogenolysis in muscle and liver could explain the acutely decreased performance. Furthermore, because of the effect of rhGH in decreasing glycogen storage in muscle and liver, it will make recovery from exercise more difficult. However, a bigger danger is probably the unphysiologically high fatty acidaemia, which could promote cardiac arrhythmia.
Chronic rhGH abuse is more dangerous. As most athletes are likely to be using suprapharmacological amounts, the correct model in which to look for such deleterious effects is not the adult GH deficient patient given replacement therapy, but patients suffering from acromegaly—that is, with an excess of GH secretion, often 100 times normal. These patients have poor exercise tolerance, which improves after treatment to decrease GH secretion.74 However, they show little evidence of true muscle hypertrophy in terms of creatinine to height ratios or muscle cross sectional areas, but often exhibit a number of myopathic features such as increased plasma creatine kinase, raised type 2 to type 1 muscle fibre areas, type 2 fibre atrophy, and myofilament loss as well as myopathic electrophysiological changes.75 Furthermore, patients with acromegaly have considerably increased rates of cardiovascular disease, diabetes, abnormal lipid metabolism, osteoarthritis, and breast and colorectal cancer.63 The concentrations of free fatty acids stimulated by exercise in these patients76 is in the range suggested by Opie77 to be a possible cause of sudden death from arrhythmia.
TL; DR GH likely effects anabolism minimally, even at high doses primarily through nitrogen retention rather than IGF pathways. While it can aid in body composition it fails to be the end all be all some want it to be.
.
Are scientists and doctors using too little hGH to see the effects that athletes achieve by using large doses? This is of course a possibility; by analogy, it was many years before scientists and doctors accepted that the anabolic effects of testosterone and its analogues were real—see, for example, the careful work of Forbes.65 Nevertheless, in my view the possibility is slight. Anecdotal evidence suggests that many hGH abusers, especially those taking the hormone without medical supervision, do inject supratherapeutic doses. However, in most of the studies in the literature, effects of hGH were also studied at greater than the therapeutic dose, and although these may well have been below the dosages used by abusers, they still resulted in serum concentrations of GH and IGF-I that were 3–6 times normal55,56 and that resulted in pronounced biological effects, such as increased lipolysis, altered carbohydrate metabolism, activation of the renin-angiotensin system, and water retention. It is difficult to believe that, even for effects that are not IGF-I mediated (such as the lipolytic effects), muscle tissue is IGF-I resistant to this extent.
Furthermore, when extremely large therapeutic doses of rhGH are used—for example, in the attempted treatment of wasting in HIV/AIDS—it appears to be much easier to induce diabetic symptoms than retention or recovery of lean body mass.29,66 This, of course, may be a feature of a GH resistant syndrome, but it is odd that there is such a separation between biological effects of the same substance.
Nevertheless, it is relatively easy to see effects of other biological agents that do have effects on muscle protein turnover at blood concentrations that are observed biologically, and without using massive pharmacological doses. For example, insulin has substantial effects on protein synthesis and breakdown in muscle67–69 at concentrations seen after meals. As a further illustration, a modest rise in blood amino acids such as is seen after feeding causes a near doubling of muscle protein synthesis.67,69 Why should a dose of rhGH, which can more than double serum IGF-I and cause considerable effects on body water, fat free mass, and nitrogen balance,50,51,56 be insufficient to have an effect through IGF-I on muscle protein metabolism? It would, arguably, be a very unbiological pattern of behaviour.
Does the increased nitrogen retention often reported to be observed with rhGH administration50 not argue for an effect on muscle, the largest component of the lean body mass? Not necessarily. Apart from anabolic effects in viscera and skin,70,71 rhGH has been reported to have anabolic effects on collagen metabolism,20,72 and even when bone is excluded from measurements of lean body mass using dual x ray absorptiometry, the epimysial, endomysial, and perimysial collagenous components of skeletal muscle and connective tissue elements of skin may all show up as new lean body mass. A modest increase in skin, visceral protein and tissue (including muscle) collagen would translate into a sizeable positive nitrogen balance.
Such an effect on connective tissue in muscle would make the muscle no more capable of force generation but may promote resistance to injury or faster repair, which would be an advantage to an athlete. This may explain the anecdotally reported predilection of baseball players for abuse of testosterone and rhGH together. Unfortunately this possible synergism has never been studied under control circumstances in young men. Certainly co-administration of testosterone and rhGH has only a minor effect on strength in elderly men.61
If there were a threshold in the supraphysiological range for an anabolic effect of rhGH on muscle, it would be expected that patients with acromegaly would show true muscle hypertrophy. In fact, the lack of appreciably greater muscle mass per height as well as associated pathological changes (see later) argues against this idea. This is reinforced by the finding that transgenic mice overexpressing GH show no relative increase in muscle mass as a fraction of total body weight, and what muscle they have develops less force than expected on a weight basis.73
Thus, the balance of evidence seems to be heavily against an anabolic effect of rhGH on human muscle. It may seem that the only way to settle the question in the minds of champions of the use of rhGH is to carry out a dose-response study with large amounts of the hormone. This is easier said than done: we need to discover what amounts abusing athletes inject (it will always be easy to say that what was used was insufficient) to target an appropriate dose range while staying within normal ethical limits given the cardiovascular and metabolic hazards involved.
THE DOWNSIDE OF rhGH ABUSE
The acute administration of rhGH may have appreciably detrimental effects on performance. In fact, there is good evidence that acute administration of rhGH actually results in a decrease in exercise performance according to recent results obtained by Dr Kai Lange of the Danish Institute of Sports Medicine (personal communication). In these studies, healthy endurance trained athletes were unable to complete accustomed cycling tasks after administration of exogenous hGH. There is good evidence that hGH administration exacerbates the pronounced increase in lipolysis that occurs during exercise and, in addition, increases the production of lactate and protons by working muscles. The inevitable metabolic acidaemia and consequent reduction in the rate of glycogenolysis in muscle and liver could explain the acutely decreased performance. Furthermore, because of the effect of rhGH in decreasing glycogen storage in muscle and liver, it will make recovery from exercise more difficult. However, a bigger danger is probably the unphysiologically high fatty acidaemia, which could promote cardiac arrhythmia.
Chronic rhGH abuse is more dangerous. As most athletes are likely to be using suprapharmacological amounts, the correct model in which to look for such deleterious effects is not the adult GH deficient patient given replacement therapy, but patients suffering from acromegaly—that is, with an excess of GH secretion, often 100 times normal. These patients have poor exercise tolerance, which improves after treatment to decrease GH secretion.74 However, they show little evidence of true muscle hypertrophy in terms of creatinine to height ratios or muscle cross sectional areas, but often exhibit a number of myopathic features such as increased plasma creatine kinase, raised type 2 to type 1 muscle fibre areas, type 2 fibre atrophy, and myofilament loss as well as myopathic electrophysiological changes.75 Furthermore, patients with acromegaly have considerably increased rates of cardiovascular disease, diabetes, abnormal lipid metabolism, osteoarthritis, and breast and colorectal cancer.63 The concentrations of free fatty acids stimulated by exercise in these patients76 is in the range suggested by Opie77 to be a possible cause of sudden death from arrhythmia.
TL; DR GH likely effects anabolism minimally, even at high doses primarily through nitrogen retention rather than IGF pathways. While it can aid in body composition it fails to be the end all be all some want it to be.
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