Recombinant Growth Hormone and the Athlete

[Pinnacle]

Recombinant Growth Hormone and the Athlete
by Karl Hoffman


In last month’s issue of Mind and Muscle (M&M #14) we looked at how growth hormone has been used in a number of trials to successfully induce weight loss in obese humans.

In order to better understand how GH affects this weight loss we also discussed in some detail how growth hormone and fat cells interact with one another. In this review of the existing literature, I would like to look at another growing use of recombinant GH: its use to increase athletic performance and increase muscle mass. There are much less data to guide us here than was available in our discussion of GH treatment of obesity. Further, the scientific literature contrasts starkly with the vast number of anecdotal reports of dramatic improvement in athletic performance and muscle mass seen with GH use. The scientific literature paints a rather bleak picture of recombinant GH as an ergogenic aid.

The positive results of some of the obesity trials discussed in Mind & Muscle #14 do suggest that GH might be beneficial to athletes and bodybuilders for weight loss while maintaining lean body mass. In fact, the studies in which recombinant GH has been administered to athletes and healthy young adults have yielded mixed results in terms of changes in strength and body composition, with the data often being difficult to interpret. This will be evident upon looking in detail at the research. For example, Yarasheski et al (1) looked at the effect of 14 days of recombinant GH administration (40 mcg/kg/day) on muscle protein synthesis rates in experienced weight lifters. The authors concluded that short-term GH administration neither increased the fractional rate of skeletal muscle protein synthesis nor did it reduce the rate of whole body protein breakdown despite significantly elevated levels of circulating IGF-1. This is in contrast to research that has shown that GH administration in normal, healthy humans in the postabsorptive state increases net muscle amino acid balance during the period of GH infusion (2). This anabolic effect is evidently short lived, since as mentioned, long-term studies show no increase in muscle mass. Note that in the study by Yarasheski et al protein synthesis/breakdown rates were measured several hours after the last GH injection, not during an infusion as in (2). Nevertheless, IGF-1 levels were still elevated 2 fold above baseline when Yarasheski et al collected their data.

As an aside, in another interesting study (3) that looked at the short-term infusion of a combination of GH and insulin , GH once again appeared to increase protein synthesis, but it also blunted the normal antiproteolytic effects of insulin.

Yarasheski et al (4) conducted another study in which GH was administered to healthy young men in conjunction with a resistance training program. The authors measured a number of parameters: change in body composition; muscle strength improvement; whole body protein turnover; and fractional muscle protein synthesis rate. Compared to placebo, the GH treated group showed a significantly larger increase in fat free mass. However, due to the rapid gain in this mass and the rapid loss after treatment ended, the authors attributed this gain primarily to water retention. There was no difference in strength gains between the GH and placebo treated groups. The GH treated group showed an increase in whole body protein synthesis but no change in fractional skeletal muscle synthesis rate. From this, and the lack of strength gains and muscle circumference, the authors deduce that the net protein accretion was not in the form of skeletal muscle.

Deyssig et al (5) conducted a similar study in trained power athletes. One group was given rhGH at 0.09 U/kgBW day while another was given placebo. Both groups participated in a resistance training program for six weeks. At the end of the study period changes in strength and body composition were measured in both groups. Again there was no difference between the two groups in the parameters measured. The authors concluded that GH treatment had no effect on strength or body composition in highly trained strength athletes.

Crist et al (6) examined the effects of six weeks of rhGH administration (30 – 50 mcg/kg, 3 days per week) in a group of young, highly conditioned (resistance and aerobic trained) men and women. FFM increased more (2.7 kg) and body fat decreased more (1.5 kg) during the GH treatment period than during the six-week placebo treatment period. It is unclear however whether the increase in FFM was due to any accumulation of skeletal muscle (contractile) protein. The study did demonstrate a greater fat loss during the GH period. This is consistent with some of the research presented last issue of M&M showing that GH treatment is capable of promoting fat loss.

In bodybuilders wishing to lower their body fat levels to what is humanly feasible, GH may be a viable option if one is willing to accept the possibility of some unhealthful side effects. In competitive endurance or strength athletes, as opposed to bodybuilders, the detrimental effects of GH use on performance may argue against its use. In a review of the topic (7) Rennie cites recent research conducted at the Danish Institute of Sports Medicine where GH administration to trained athletes actually impaired their performance (8). In these studies healthy endurance trained athletes were unable to complete accustomed cycling tasks after administration of exogenous hGH. The authors suggest that this could be a result of an observed increase in plasma lactate in the GH group compared to placebo. The significantly elevated lactate could result from the inhibition of the enzyme pyruvate dehydrogenase (PDH) by high levels of fatty acids released during GH-stimulated lipolysis. With PDH thus inhibited, pyruvate, produced from the glycolysis of glucose, is unable to enter the mitochondrial citric acid cycle and accumulates instead as lactate. One problem with this theory however, is that despite the increase in plasma free fatty acids observed by the authors, there was no apparent increase in lipid oxidation. The latter would be expected to be required to inhibit PDH. In any case, by whatever mechanism, GH administration clearly adversely affected cycling performance in this experiment.

Although the research described above looked at the acute effects of GH administration on athletic performance, there are chronic effects as well that could be detrimental to the athlete. Insulin resistance is a common side effect of GH use and would be expected to reduce glucose availability to muscle. GH administration also results in the impairment of muscle and liver glycogen storage. These latter effects, limited liver and muscle glycogen storage, could have a serious impact on recovery from strenuous exercise, as well as negatively impact performance itself as a result of decreased glycogen availability. The edema associated with GH administration could also impair athletic performance, as might the arthralgia experienced by many GH users. Rennie even cites the possibility that the fatty acidemia resulting from GH-induced lipolysis could promote cardiac arrhythmia during intense exercise. Although remarks such as this are reminiscent of some of the hyperbole from the medical community regarding anabolic steroids , there is probably some degree of legitimacy to the concerns of Rennie and others who have stressed the potential seriousness of GH related side effects. Athletes should at least be aware that concern exists over such things as potentially fatal as arrhythmia.

In addition to the potentially detrimental derangements in glucose metabolism mentioned above, GH administration in humans has been shown to induce a shift in muscle fiber type from type 2a to 2x (9, 10). The latter has been characterized as the “default” fiber type since the proportion of 2x fibers to type1 and type 2a is relatively high in “couch potatoes” compared to strength and power athletes. Resistance training induces a shift in the opposite direction from type 2x to 2a. During detraining, the muscle fiber type shifts back to 2x. The training induced shift is interpreted as an adaptive mechanism to the increased demands placed upon the muscle. If GH administration induces a shift in muscle fiber type away from the trained state, this could have negative implications for strength and power athletes.

Why, in light of all this negative evidence for any strength or muscle mass increase resulting from exogenous GH, is the bodybuilding literature replete with anecdotal reports of impressive gains in muscle mass and strength? And what motivates athletes to use GH in light of the negative research and side effects? One obvious possibility is that the research results are wrong or incomplete. But assuming they are not for the sake of furthering the discussion, another conceivable explanation for the reported gains in muscle mass are the lipolytic effects of GH discussed above. Bodybuilders could easily be mistaking enhanced definition for an increase in muscle. GH associated water retention could also add to the feeling that mass has increased. Certain anabolic steroids such as Dianabol and Deca Durabolin are notorious for causing water retention. These same drugs also have a reputation for increasing the resistance exercise induced muscle “pump”, contributing to a feeling of increased strength. The water retention from exogenous GH could have the same effect. Additionally, athletes and even researchers have noted that in elite athletes, studies would probably be unable to detect with statistical significance a 1 or 2 percent increase in performance that could result from GH use, and would make all the difference in the world to an elite athlete. Arguing against this is the observation that performances in a number of Olympic events such as shotput, discus, and javelin, particularly among women, have deteriorated since routine testing for anabolic steroids was implemented. It is very likely that these athletes who formerly were heavy users of anabolic steroids are now using rhGH, but it does not seem to be helping their performance. And perhaps the most obvious reason that many athletes and bodybuilders use GH is that the competition is using it.

In summary, despite numerous anecdotal reports to the contrary, to quote from (7),

The results of studies of muscle protein synthesis, body composition, and strength in healthy young to middle aged humans tell a different tale: so far no robust, credible study has been able to show clear effects of either medium to long term rhGH administration, alone or in combination with a variety of training protocols or anabolic steroids, on muscle protein synthesis, mass or strength.

These results, coupled with the possibility that GH use could significantly compromise training and performance, as described in (8), make a fairly strong argument against the use of GH in sport.


References

(1) Yarasheski KE, Zachweija JJ, Angelopoulos TJ, Bier DM Short-term growth hormone treatment does not increase muscle protein synthesis in experienced weight lifters. J Appl Physiol. 1993 Jun;74(6):3073-6.

(2) Fryburg DA, Gelfand RA, Barrett EJ. Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans. Am J Physiol. 1991 Mar;260(3 Pt 1):E499-504

(3) Fryburg DA, Louard RJ, Gerow KE, Gelfand RA, Barrett EJ. Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin's antiproteolytic action in humans. Diabetes. 1992 Apr;41(4):424-9

(4) Yarasheski KE, Campbell JA, Smith K, Rennie MJ, Holloszy JO, Bier DM. Effect of growth hormone and resistance exercise on muscle growth in young men. Am J Physiol. 1992 Mar;262(3 Pt 1):E261-7

(5) Deyssig R, Frisch H, Blum WF, Waldhor T. Effect of growth hormone treatment on hormonal parameters, body composition and strength in athletes. Acta Endocrinol (Copenh). 1993 Apr;128(4):313-8.

(6) Crist DM, Peake GT, Egan PA, Waters DL. Body composition response to exogenous GH during training in highly conditioned adults. J Appl Physiol. 1988 Aug;65(2):579-84.

(7) Rennie MJ.Claims for the anabolic effects of growth hormone: a case of the emperor's new clothes? Br J Sports Med. 2003 Apr;37(2):100-5.

(8) Lange KH, Larsson B, Flyvbjerg A, Dall R, Bennekou M, Rasmussen MH, Orskov H, Kjaer M. Acute growth hormone administration causes exaggerated increases in plasma lactate and glycerol during moderate to high intensity bicycling in trained young men. J Clin Endocrinol Metab. 2002 Nov;87(11):4966-75.

(9) Hennessey JV, Chromiak JA, DellaVentura S, Reinert SE, Puhl J, Kiel DP, Rosen CJ, Vandenburgh H, MacLean DB. Growth hormone administration and exercise effects on muscle fiber type and diameter in moderately frail older people. J Am Geriatr Soc. 2001 Jul;49(7):852-8.

(10) Lange KH, Andersen JL, Beyer N, Isaksson F, Larsson B, Rasmussen MH, Juul A, Bulow J, Kjaer M. GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. J Clin Endocrinol Metab. 2002 Feb;87(2):513-23

[goose]

GH and Obesity
by Karl Hoffman



INTRODUCTION


The observation that growth hormone (GH) secretion is impaired in obesity, and is reversible upon weight loss, has prompted a great deal of research that has helped us understand how GH acts on adipocytes to regulate lipolysis and lipogenesis. Reciprocally, we are beginning to understand how adipocytes, as secretory organs, contribute to the regulation of GH secretion. The impaired secretion of GH in obesity, as well as the predominantly lipolytic effects of GH has prompted a number of studies where GH has been successfully used to induce significant weight loss in obese patients.

In this brief overview, I’d like to first look at the effects of GH on adipocyte function, then address the converse subject of adipocyte regulation of GH secretion, with particular emphasis on how obesity impairs GH secretion. Finally, we will look at how GH has been used therapeutically to treat obesity.



PHYSIOLOGICAL EFFECTS OF GH ON ADIPOCYTES


Two enzymes active in adipocytes which are of paramount importance in regulating lipogenesis (fat accumulation) and lipolysis (the breakdown of stored triglycerides into free fatty acids [FFA]) are lipoprotein lipase (LPL) and Hormone Sensitive Lipase (HSL); both are affected by GH. The accumulation of triglycerides in adipose tissue is controlled primarily by LPL. Triglycerides are transported to fat cells for storage in the form of very low-density lipoproteins (VLDL) and chylomicrons. LPL is synthesized by adipocytes and then secreted to the intracellular space, after which it attaches to the luminal portion of the vascular endothelium of the vessels supplying the adipocytes. There it hydrolyzes the triglyceride fraction of the VLDL and chylomicron particles, releasing FFA that are taken up by adipocytes. GH has been shown to have an inhibitory effect on adipose LPL (1,2), with a more pronounced reduction of LPL activity in intra-abdominal fat deposits than in subcutaneous fat (3). Exactly how GH inhibits LPL is unclear. GH treatment does not seem to affect LPL gene expression or mRNA levels, so it is assumed that the effect is post-translational, with GH somehow interfering with the activity of the enzyme (1). In any case, the net effect is that GH reduces the uptake of free fatty acids by fat cells, a clear antiadipogenic effect.

It should be noted that a number of other hormones affect LPL activity in significant ways. Insulin is the hormone with the greatest ability to stimulate LPL activity, contributing to the well-known lipogenic effect of this hormone. Conversely catecholamines (e.g. epinephrine) are strong downregulators of LPL, contributing to their ability to block fat accumulation. Testosterone and estrogen both inhibit LPL, contributing to their fat burning properties (4).

The second enzyme that dominates adipocyte metabolism is Hormone Sensitive Lipase (HSL). HSL is responsible for the hydrolysis of stored triglycerides to glycerol and free fatty acids. Thus hydrolyzed, the FFA can leave the adipocyte and travel in the blood to other tissues where they can be used as fuel, primarily in working muscle (As with fats entering adipocytes, the glycerol portion of the triglyceride must be removed in order for free fatty acids to leave the fat cell). GH amplifies the action of HSL in two ways. First, HSL is activated by catecholamines that act as agonists at beta 1, beta 2, and possibly beta 3 receptors in adipocytes. This is how sympathomimetic drugs like ephedrine and clenbuterol stimulate fat burning: they act as beta agonists to stimulate HSL. GH has been shown to be capable of inducing beta 2 receptors in adipocytes; more beta 2 receptors mean more HSL activity (5). As an aside, this is one way androgens promote lipolysis as well, via the upregulation of beta adrenoreceptors. Beta receptors employ the “second messenger” cyclic AMP (cAMP) to relay their signal within the cell that ultimately activates HSL. The signal is terminated by the enzyme phosphodiesterase. GH has been shown to have the ability to block phosphodiesterase, prolonging the activity of HSL (5). So we see GH promotes lipolysis via HSL by two routes: it upregulates the receptors that activate HSL, and it prolongs the sign****g that keeps HSL functioning.

Besides affecting the metabolic functioning of adipocytes, GH controls adipocyte differentiation and proliferation. Differentiation refers to the process whereby immature preadipocytes activate the genes that direct them onto the path to becoming fully functioning mature adipocytes capable of carrying out the metabolic and secretory processes described above, as well as storing lipids. Proliferation refers to the increase in cell number via repeated cell division. The actions of GH are mixed here. We know that GH stimulates the hepatic production of Insulin-like Growth Factor 1 (IGF-1), which is responsible for many of the metabolic and perhaps anabolic actions of GH. It has been shown that IGF-1 is capable of stimulating the proliferation of preadipocytes, increasing the pool of potential adult fat cells (6). On the other hand, GH itself inhibits the differentiation of these precursor cells into adult adipocytes. Despite these contradictory effects of GH/IGF-1 on adipocyte proliferation and differentiation, the net effect of GH treatment in obese subjects in a number of studies is one of reduced adiposity.



FREE FATTY ACIDS AND GH SECRETION


GH and FFA function together in a regulatory feedback fashion. We have seen above how GH stimulates lipolysis, resulting in elevated levels of FFA. FFA in turn act back in a negative feedback manner to inhibit GH secretion. Circulating free fatty acids, elevated in obesity, are thought to be partly responsible for the suppression of GH seen in this condition (Plasma levels of FFA are elevated in obesity primarily because a greater than normal amount of FFA is released from the expanded adipose tissue mass even though the rate of lipolysis from individual fat cells appears to be normal).

It is generally accepted that circulating FFA rapidly partition into the plasma membranes of pituitary cells which secrete GH. This is believed to alter the function of proteins embedded in the plasma membrane, perturbing intracellular sign****g and inhibiting GH release (9). Animal studies have shown that FFA are also capable of acting directly on the hypothalamus to increase the release of somatostatin, with a resulting inhibitory effect on GH release. It is controversial whether this hypothalamic effect exists in humans (10). No known stimulus for GH release seems to be able to escape the suppressive effects of elevated FFA. As just one example of relevance to athletes, exercise is a well-known stimulus for GH release. Seemingly paradoxically, exercise also elevates FFA acid levels, as lipolysis increases in order to supply FFA to muscle to serve as a fuel source. However, when nicotinic acid, a potent inhibitor of FFA release from adipocytes is administered during exercise, the low FFA levels resulting from nicotinic acid feeding were associated with a 3- to 6-fold increase in concentrations of human growth hormone throughout exercise. Exercise performance was also negatively impacted by the lack of availability of FFA as a fuel substrate (11). This could have practical implications for anyone using nicotinic acid to elevate HDL cholesterol levels, as many anabolic steroid using athletes are known to do (Anabolic steroids in general, and oral 17 alpha alkylated steroids in particular, are known to significantly lower HDL, or “good” cholesterol).

Somewhat surprisingly, in light of the evidence discussed above that FFA inhibit GH release, GH secretion is increased during fasting both in obese and normal subjects after administration of GHRH, despite an increase in fasting related FFA levels. This has been cited as contradictory to the theory that FFA impair GH secretion in obesity (12). However, as mentioned above, ghrelin may be more important than GHRH in stimulating GH release during fasting. While FFA do reduce the ability of ghrelin to stimulate GH release, ghrelin is partially refractory to this inhibitory effect of FFA. So it is possible that the results described in (12) were confounded by the effects of ghrelin on GH during fasting.

In any case, GH is generally low in obesity, and as a consequence there is a loss of the usual lipolytic effect of GH seen in normal individuals. This has prompted the experimental use of GH to attempt to reverse obesity in a number of studies.



INCREASED GH CLEARANCE RATE IN OBESITY


Studies have shown besides decreased production of GH in obesity, GH clearance rates are increased as well. While not necessarily being an effect directly attributable to the action of adipocytes on GH, it does contribute to lower overall GH plasma levels (13). Not well understood, this phenomenon has been attributed to either increased glomerular filtration of GH, changes in liver metabolism, or accelerated processing by excessive body fat stores.



EFFECT OF ADIPOSE TISSUE ON IGF-1


Despite the fact that GH levels are typically depressed in obesity, total serum IGF-1 levels are normal or high, and free IGF-1 levels are consistently elevated (5). This may seem surprising since—as discussed above—IGF-1 is normally produced in the liver under the stimulus of GH. One might expect the opposite to be observed: low GH in obesity leading to low circulating IGF-1. However, the observation that IGF-1 mRNA levels in fat cells are nearly as high as those found in the liver has led to the suggestion that adipocytes could contribute significantly to circulating levels of IGF-1 (5). If this is the case, then the normal negative feedback of IGF-1 on GH secretion could contribute in part to the depressed levels of GH seen in obesity. Adipocytes seem to secrete IGF-1 in response to GH, and in obesity, individual fat cells may secrete less IGF-1 than in normal subjects. The net overall effect of the increased number of fat cells in obese subjects would offset this, leading to the observed elevation in IGF-1. The depressed GH due to elevated IGF-1 in obesity provides another rationale for the use of GH to treat obesity.



INHIBITION OF GH SECRETION AND SIGN****G BY INSULIN


Insulin resistance and hyperinsulinemia are often associated with obesity. Research has shown that both normal physiological levels of insulin (14) as well as obesity-associated hyperinsulinemia blunt the GH response to GHRH and may contribute to the GH deficiency seen in obesity (15). Although the exact mechanism by which insulin regulates GH secretion is not known, a number of possibilities exist. Specific insulin binding sites have been found in both rat and human anterior pituitary adenoma cells. Inhibition of GH synthesis and release, and suppression of GH mRNA content, has also been observed when pituitary cells are exposed to insulin. So insulin could have a direct inhibitory effect on the pituitary. Insulin receptors are also present in the hypothalamus, so it is possible insulin is acting there. It has also been suggested that insulin could inhibit GH release by lowering plasma amino acid levels, since amino acids stimulate GH release. It has also been observed that insulin lowers circulating levels of the potent GH secretagogue ghrelin (16).

In vitro, insulin has also been shown in nonhepatic tissue to block the translocation of the GH receptor from the cytosol to the cell surface, with the effect of inhibiting binding of GH to its receptor. This may be another way hyperinsulinemia associated with obesity disrupts GH sign****g (17)



GROWTH HORMONE THERAPY TO TREAT OBESITY


We have discussed a number of reasons why GH might potentially be of therapeutic use in the treatment of obesity due to its lipolytic action. Nevertheless, the results of trials have been inconsistent. This inconsistency, coupled with side effects of treatment which include insulin resistance, edema, arthralgia, and carpel tunnel syndrome to name a few, has prompted some critics to take a strong stand against the use of GH to treat obesity:



OBJECTIVE: To summarize the reports in the literature regarding the effect of growth hormone (GH) treatment of obesity. RESEARCH METHODS AND PROCEDURES: Clinical trials of GH treatment of obese adults were reviewed and summarized. Specifically, information regarding the effects of GH on body fat and body fat distribution, glucose tolerance/insulin resistance, and adverse consequences of treatment were recorded. RESULTS: GH administered together with hypocaloric diets did not enhance fat loss or preserve lean tissue mass. No studies provided strong evidence for an independent beneficial effect of GH on visceral adiposity. In all but one study, glucose tolerance during GH treatment suffered relative to placebo. CONCLUSION: The bulk of studies indicate little or no beneficial effects of GH treatment of obesity despite the low serum GH concentrations associated with obesity (18).


Despite the harsh tone of these investigators, a number of studies have shown a positive effect of GH on fat loss, with the abovementioned side effects being reversible upon termination of treatment. Additionally, countless anecdotal reports by bodybuilders and athletes contribute to the evidence that GH can be efficacious for fat loss.

In stark contrast to the assessment of the GH trials in (18) are reports by Lucidi et al (19) and Nam et al (20) that cite a number of studies where “GH is effective in reducing fat mass, especially visceral fat” (20). Nam et al discuss why some studies may have shown negative results. In their paper, the authors reported significantly enhanced fat loss (1.6 fold) compared to placebo, with a greater loss in visceral fat and an increase in lean body mass (20). Kim et al used low dosages of GH (0.18 U/kg Ideal Body Weight/week) and a hypocaloric diet, and believed this accounted for at least part of the success of their trial. They point out that one of the well known and dose dependent side effects of GH administration is insulin resistance and hyperinsulinemia. Insulin is well known to be an adipogenic hormone, and the hyperinsulinemia that often accompanies GH treatment could offset the lipolytic effect of the administered GH. To quote from the authors,



In addition, as the product of GH-induced lipolysis, FFA has been considered to be the principle factor in peripheral insulin resistance. These findings suggest that GH-induced hyperinsulinemia may antagonize the lipolytic effect of GH. In our study, GH treatment did not induce a further increase in insulin levels. [This] suggest[s] that although GH might induce insulin insensitivity and hyperinsulinemia, low-dose GH therapy with diet restriction in obesity could overwhelm the antilipolytic action of insulin.

The frequency of side effects depends on the dose of GH. We observed only minor side effects which spontaneously subsided, indicating that the dose of GH in this study was lower in comparison with other studies (20).


So it may very well be that many of the studies that failed to demonstrate weight loss after GH administration employed excessively high doses, which either aggravated pre-existing hyperinsulinemia or subsequently induced hyperinsulinemia, which offset any lipolytic effects of GH.

We have discussed a number of ways by which GH promotes lipolysis, the main effect being to stimulate Hormone Sensitive Lipase in adipocytes. But lipolysis, the term used to describe the mobilization of fatty acids so that they can potentially be used as fuel, is not the same thing as the actual oxidation of those fatty acids for energy in muscle tissue. Perhaps the failure of some trials to show fat loss during GH treatment is a result of a failure to oxidize the lipids that GH makes available as a potential fuel source. This seems not to be the case however, as research has shown that GH actually increases lipid oxidation at the expense of glucose oxidation by activating the so called glucose-fatty acid cycle where the preferential use of fat as a fuel substrate inhibits the use of glucose as fuel (21) (This process actually provides a mechanistic explanation of how GH administration induces insulin resistance: when more fatty acids are used as fuel, cells take up less glucose for use as a fuel substrate, leading to glucose intolerance). In addition to promoting the preferential use of fat as a fuel substrate by increasing its availability through enhanced lipolysis, GH also appears to directly stimulate the oxidation of lipids, perhaps by upregulating key mitochondrial enzymes involved in lipid oxidation (22).

Moreover, another well-known effect of growth hormone is to slow skeletal muscle breakdown during fasting (23). Teleologically speaking, the body secretes GH during periods of caloric restriction in an attempt to preserve skeletal muscle at the expense of increased fat oxidation for fuel. So during periods of caloric restriction, GH is responsible for less reliance on glucose and protein for energy, with fat being preferentially oxidized.



References

(1) J Endocrinol Invest. 1999;22(5 Suppl):10-5 Effect of growth hormone on adipose tissue and skeletal muscle lipoprotein lipase activity in humans. Richelsen B

(2) J Endocrinol Invest. 1999;22(5 Suppl):2-9 Effects of growth hormone on lipoprotein lipase and hepatic lipase. Oscarsson J, Ottosson M, Eden S.

(3) J Endocrinol. 1993 May;137(2):203-11. Influence of growth hormone deficiency on growth and body composition in rats: site-specific effects upon adipose tissue development. Flint DJ, Gardner MJ.

(4) Hum Reprod. 1997 Oct;12 Suppl 1:21-5. Hormonal control of regional fat distribution.Bjorntorp P.

(5) Horm Res. 2000;53 Suppl 1:87-97. Growth hormone and adipocyte function in obesity Nam SY, Marcus C.

(6) Pediatr Res 1996 Sep;40(3):450-6 Mitogenic and antiadipogenic properties of human growth hormone in differentiating human adipocyte precursor cells in primary culture. Wabitsch M, Braun S, Hauner H, Heinze E, Ilondo MM, Shymko R, De Meyts P, Teller WM

(7) Endocrinology. 2003 Mar;144(3):967-74. Interrelationship between the novel peptide ghrelin and somatostatin/growth hormone-releasing hormone in regulation of pulsatile growth hormone secretion. Tannenbaum GS, Epelbaum J, Bowers CY.

(8) Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E163-E170. Epub 2003 Apr 01. Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin. Dimaraki EV, Jaffe CA, Bowers CY, Marbach P, Barkan AL.

(9) Pombo M, Pombo CM, Astorga R, Cordido F, Popovic V, Garcia-Mayor RV, Dieguez C, Casanueva FF. Regulation of growth hormone secretion by signals produced by the adipose tissue. J Endocrinol Invest 22(5 Suppl):22-6 1999

(10) Endocrinology. 1998 Dec;139(12):4811-9. Hypothalamic mediated action of free fatty acid on growth hormone secretion in sheep. Briard N, Rico-Gomez M, Guillaume V, Sauze N, Vuaroqueaux V, Dadoun F, Le Bouc Y, Oliver C, Dutour A.

(11) Med Sci Sports Exerc. 1995 Jul;27(7):1057-62. Physiological and performance responses to nicotinic-acid ingestion during exercise. Murray R, Bartoli WP, Eddy DE, Horn MK

(12) J Clin Endocrinol Metab. 1988 Mar;66(3):489-94. Enhanced growth hormone (GH) responsiveness to GH-releasing hormone after dietary manipulation in obese and nonobese subjects. Kelijman M, Frohman LA.

(13) Am J Physiol. 1999 Nov;277(5 Pt 1):E824-9. Influence of obesity and body fat distribution on growth hormone kinetics in humans. Langendonk JG, Meinders AE, Burggraaf J, Frolich M, Roelen CA, Schoemaker RC, Cohen AF, Pijl H.

(14) J Clin Endocrinol Metab. 1997 Jul;82(7):2239-43. Evidence for an inhibitory effect of physiological levels of insulin on the growth hormone (GH) response to GH-releasing hormone in healthy subjects. Lanzi R, Manzoni MF, Andreotti AC, Malighetti ME, Bianchi E, Sereni LP, Caumo A, Luzi L, Pontiroli AE.

(15) Metabolism 1999 Sep;48(9):1152-6 Elevated insulin levels contribute to the reduced growth hormone (GH) response to GH-releasing hormone in obese subjects. Lanzi R, Luzi L, Caumo A, Andreotti AC, Manzoni MF, Malighetti ME, Sereni LP, Pontiroli AE.

(16) Am J Physiol Endocrinol Metab. 2003 Feb;284(2):E313-6. The influence of insulin on circulating ghrelin. Flanagan DE, Evans ML, Monsod TP, Rife F, Heptulla RA, Tamborlane WV, Sherwin RS.

(17) Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11381-6. Insulin and insulin-like growth factor-I acutely inhibit surface translocation of growth hormone receptors in osteoblasts: a novel mechanism of growth hormone receptor regulation. Leung KC, Waters MJ, Markus I, Baumbach WR, Ho KK.

(18) Obes Res. 2003 Feb;11(2):170-5. Effects of growth hormone administration in human obesity. Shadid S, Jensen MD.

(19) J Clin Endocrinol Metab. 2002 Jul;87(7):3105-9. Short-term treatment with low doses of recombinant human GH stimulates lipolysis in visceral obese men. Lucidi P, Parlanti N, Piccioni F, Santeusanio F, De Feo P

(20) Int J Obes Relat Metab Disord. 2001 Aug;25(8):1101-7. Low-dose growth hormone treatment combined with diet restriction decreases insulin resistance by reducing visceral fat and increasing muscle mass in obese type 2 diabetic patients. Nam SY, Kim KR, Cha BS, Song YD, Lim SK, Lee HC, Huh KB.

(21) J Clin Endocrinol Metab. 2003 Apr;88(4):1455-63. Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L.

(22) J Clin Endocrinol Metab. 1997 Dec;82(12):4208-13. Stimulation of mitochondrial fatty acid oxidation by growth hormone in human fibroblasts. Leung KC, Ho KK.