HGH: Supraphysiological Dose of GH & IGF-1 Does Not Cause Hypertrophy
Here are some background information. (please note, this is relevant to Chronic GH beyond natural levels as seen with bodybuilders and not usually in combination with anabolic steroids, as GH has healing properties and resolves some of the side effects seen with steroid use. Those who have GH deficiency who correct GH to be within range AND acute usage for post operative - are excluded.)
- Insulin counteracts GH
- GH causes insulin resistance by increasing the level of plasma free fatty acids
- GH causes insulin resistance by directly affecting insulin signalling
- IGF-1 has 3 variants. Only IGF-1ec (MGF) has been shown to have significant muscle hypertrophy effects. Administering exogenous IGF-1 increases whole body protein synthesis, but does NOT increase muscle protein synthesis. IGF-1ec is responsible for muscle protein synthesis. IGF-1ec is a gene spliced variant of IGF-1 and does not normally occur during exogenous IGF-1 administration.
   
Here is the big studies:
"Acute administration of either rhGH, or IGF-I, in normal healthy humans in the post-absorptive state, significantly increased forearm net balance of amino acids (Fryburg et al 1991). The effects are claimed to occur through the stimulation of protein synthesis rather than decreased protein breakdown.
However, increased LBM does not appear to have been translated into increased strength or power in young healthy individuals who have never previously used performance-enhancing drugs. For example, administration of rhGH appears to cause no further increase in muscle mass or strength than provided by resistance training in any healthy young athletes with a mean age of 23 years (Crist et al 1988; Yarasheki et al 1992, 1993; Deyssig 1993) or indeed in healthy elderly males with a mean age of 67 years (Taaffe et al 1994; Yarasheki et al 1995). There has been no substantial evidence that it can increase strength in healthy males and females greater than sixty years of age (Zachwieja and Yarasheki 1999)."
"RhGH administration did not enhance the muscle anabolism associated with heavy-resistance exercise in 16 males with a mean age of 27 years and a weight of 70.6 kg."
"A single rhGH dose (2.5 mg [7.5 IU]) in 7 highly trained males with a mean age of 26 years, body mass of 77 kg, and a V̇O2 peak of 65 ml.min−1.kg−1, who performed 90 min of cycling 4 hours after taking the rhGH, prevented two subjects from completing the exercise protocol. It significantly increased plasma lactate and glycerol as well as serum NEFA. This may compromise exercise performance. V̇O2 peak remained unaltered by drug effect until exhaustion (Lange et al 2002a). Plasma glucose was, on average, 9% higher during exercise after rhGH administration compared with placebo. Any benefit of exercise in terms of increased glucose tolerance appeared to be negated by rhGH in the subjects."
"The acclaim of the anabolic properties of growth hormone appeared in the underground doping literature as early as 1983 (Duchaine 1983). Its abuse has increased (Baker et al 2006) despite early research demonstrating its effect on functional abilities, is no greater than exercise alone in healthy young males (Yarasheki et al 1992) or elderly males (Yarasheki et al 1995) and the demonstration that supraphysiological dosages can have fatal consequences (Takala et al 1999)."
"Both hGH and rhGH are believed to stimulate production of class-1 isoforms of IGF-I locally in muscles and tendons. These may have a preventative effect on rupture of muscles and tendons in AAS-induced hypertrophy (Doessing and Kjaer 2005). The transmission of force from muscle fibres to bone, could be explained by the stimulating effect of hGH on collagen synthesis"
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" Supraphysiological GH in the young leads to pituitary gigantism, whereas adult-onset GH tumours result in a condition called acromegaly characterized by overgrowth of bony tissue (brow and lower jaw protrusion, enlargement of the extremities), osteoarthritis, carpal tunnel syndrome, headaches, cardiomyopathies, hyperglycaemia, hypertension and diabetes mellitus (Ayuk and Sheppard, 2006). In mice, enlargement of the heart and general increase in organ size are features of systemic GH overproduction or administration (Kopchick et al., 1999)."
- this indicates that in disorders where there is elevated GH (acromegaly), it has detrimental effects on health. The levels seen in acromegaly is actually on par or less than the amount used by chonic administration of GH by bodybuilders
"Care must be taken in extrapolating animal studies to humans, as species differences do exist, but the data seem to indicate similar roles for GH and IGF-I in the regulation of postnatal growth. In humans, GH deficiency results in a similar growth pattern to primary IGF-I deficiency, underlining the role of GH-dependent IGF-I production (Walenkamp and Wit, 2007). It is also interesting to note that the growth response following treatment of GH-deficient patients with GH is better than that observed after treating patients suffering from GH insensitivity with IGF-I (Savage et al., 2006; Walenkamp and Wit, 2007). This may be due to the IGF-I-independent effects of GH as discussed in the previous section. Alternatively, the low levels of IGFBP3 found in GH-insensitive patients may result in shorter IGF-I half-life and thus the diminished effects of the infused protein."
"Observations in people with acromegaly suggest that chronic high levels of circulating GH and IGF-I may actually be detrimental to muscle function. Although people with acromegaly have large muscles, they have less specific force (force per CSA) than expected and they often present histological signs of myopathy (Nagulesparen et al., 1976; Woodhouse et al., 2006). Furthermore, people with acromegaly tend to have smaller type II than type I fibre CSAs. This is in contrast to the general population. As type II fibres are important for power generation, this could account for their relative weakness. Overexpression of human GH in transgenic mice has been reported to increase the percentage of type I fibres (Dudley and Portanova, 1987) and in GH receptor knockout mice there are fewer type I fibres and more type II fibres relative to the wild-type animals (Sotiropoulos et al., 2006). Taken together, these observations argue for a negative rather than positive effect of long-term supraphysiological circulating GH (or IGF-I) on power output and strength. It is important to remember, however, that people with acromegaly have had the disease for many years and often present other hormonal abnormalities. Therefore, they are not the best model for assessing the effects of supraphysiological GH in otherwise healthy people."
- Given the last part of the above, they have now looked at healthy people with supraphysiological levels of GH
"Taaffe et al. (1994, 1996) showed that in healthy elderly men (mean age 70.3 years) myofibre CSA and strength gains were not different between those following a resistance training programme in combination with recombinant human GH (rhGH) or placebo. In two other studies, both on 31 elderly males (mean age >70 years), GH plus exercise had no effect over placebo plus exercise on strength, power or hypertrophy gains following 12 weeks (Lange et al., 2002) or 6 months (Hennessey et al., 2001) administration and training."
"Superior increases in whole body protein synthesis have been observed in both young (mean age 23 years; Yarasheski et al., 1992) and old (mean age 67 years; Yarasheski et al., 1995) untrained subjects undertaking resistance exercise in combination with GH relative to those on placebo, but interestingly, this effect was not mirrored in quadriceps protein synthesis rates, suggesting that the GH effects are not on muscle tissue. Yarasheski et al. (1993) also demonstrated that there was no effect of 2 weeks GH administration on quadriceps protein synthesis rates or whole body protein breakdown in young experienced weight lifters (mean age 23 years). The data suggest that there is no beneficial effect of administering GH in combination with an exercise programme for muscle mass gains."
"Administration of IGF-I acutely activates muscle protein synthesis (Fryburg et al., 1995), but similarly to GH a 1-year administration did not result in increased lean body mass (Friedlander et al., 2001). The effects of GH on fat-free mass may be due to water retention, which is a known side effect of GH administration, or to an increase in soft tissue due to the stimulatory effects of GH on collagen synthesis."
- Weight gain attributed to GH is related to water retention and increase in collagen synthesis.
"**In summary, normal GH/IGF-I function does have a role in the development and maintenance of muscle mass, as gathered from evidence in GH-deficient patients, burn patients, hypophysectomized animals, and animal models in which GH receptor and IGF-IR activity are lacking. GH or IGF-I administration have, however, no proven benefits for muscle mass in healthy subjects in whom GH function is normal (Figure 3). In most animal studies, GH is administered while the animals are still growing and this may confound the results in comparison to administration in fully grown animals. **"
" In another model where IGF-I expression is controlled by a muscle-specific promoter, but the construct contains a somatostatin signal peptide to ensure secretion, increased circulating and muscle IGF-I levels are observed, but muscle hypertrophy is not (Shavlakadze et al., 2006). This contrasts sharply with animals in which IGF-I is expressed in muscle without leading to concomitant increases in serum IGF-I (Coleman et al., 1995; Musaro et al., 2001). It is possible that increased circulating IGF-I affects GH and thus has consequences for the synthesis of autocrine/paracrine levels of IGF-I. Alternatively, increased circulating IGF-I may directly inhibit either muscle IGF-I synthesis or the effects of locally produced IGF-I. Indeed, it has been reported that IGF-I mRNA is downregulated in cultured muscle cells following IGF-I treatment (Frost et al., 2002)."
"Recently, we observed that GH administration does not upregulate IGF-IEa in skeletal muscles of young men (M Aperghis et al., 2004) whereas in older men, GH resulted in increased skeletal muscle IGF-IEa (Hameed et al., 2004). In the young men, GH administration led to serum IGF-I levels that were supraphysiological, whereas in older men serum IGF-I levels after treatment were equivalent to the pretreatment levels observed in young men. The effects of supraphysiological versus normal circulating IGF-I on muscle hypertrophy and local IGF-I production remain to be investigated in detail."
"In adult humans, GH administration is lipolytic and causes increase in serum-free fatty acids. In turn, this inhibits glucose uptake to the heart, adipose tissue and muscle and may underlie the hyperglycaemia and insulin resistance associated with acromegaly. GH also causes an increase in water absorption by the gut and sodium retention leading to extracellular fluid accumulation, carpal tunnel syndrome and hypertension. "
"The use of GH in amateur and professional sports seems to be widespread, although the evidence is quite strong that supraphysiological GH administration does not potentiate the effects of exercise on muscle mass and strength in healthy individuals. IGF-I use is probably more limited as it is less readily available than GH."
"Exercise performance (maximal oxygen uptake, ventilatory threshold and muscle strength) is lower than predicted for age, gender and height in GHD patients and these improve with GH replacement (Woodhouse et al., 2006). These improvements are in proportion to increased lean body mass. This suggests that body composition and metabolic adaptations rather than increased muscle mass may be responsible for performance gains. The effects on fuel metabolism, VO2max and ventilatory threshold may be of consequence to athletes seeking to improve endurance (Woodhouse et al., 2006; Gibney et al., 2007). A combination of testosterone and GH led to improved body composition and VO2max in elderly men, suggesting that GH does have a performance-enhancing effect (Giannoulis et al., 2006). GH also improves aerobic performance in those who have a history of androgenic anabolic steroid use (Graham et al., 2007)."
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"Growth Hormone Induces Cellular Insulin Resistance by Uncoupling Phosphatidylinositol 3-Kinase and Its Downstream Signals in 3T3-L1 Adipocytes"
"Growth hormone therapy and its relationship to insulin resistance, glucose intolerance and diabetes mellitus: a review of recent evidence."
"Growth Hormone Replacement Therapy Induces Insulin Resistance by Activating the Glucose-Fatty Acid Cycle"
- "In conclusion, replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH, resulting in enhanced oxidation of lipid substrates. Also, a shift toward more insulin-resistant type II X fibers is seen in muscle. Glucose metabolism should be carefully monitored during long-term GH replacement therapy."
"Insulin-Like Growth Factor I (IGF-1) Ec/Mechano Growth Factor – A Splice Variant of IGF-1 within the Growth Plate"
- "Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle."
"The role of the IGF-1 Ec in myoskeletal system and osteosarcoma pathophysiology"
"AAS, growth hormone, and insulin abuse: psychological and neuroendocrine effects"
"Regulation of muscle mass by growth hormone and IGF-I"