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hGH + Metformin: A Good Thing. (Metformin does not lower, but rather increases IGF-1)

Type-IIx

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hGH + Metformin: A Good Thing. (Metformin does not lower, but rather increases IGF-1)

by Type-IIx (Apr. 2021)

Does Metformin reduce IGF-1 levels?

No, Metformin actually increases IGF-1 levels in adults. This data comes from The influence of metformin on IGF-1 levels in humans: A systematic review and meta-analysis (2020) (Yang, et. al.), and may come as a surprise to many bodybuilders and athletes that have been told otherwise as the paper is still in pre-publication.

To hone in on the effects of Metformin + hGH and IGF-1 levels, this author selected two similar placebo-controlled, long-term studies with groups that were selected based on similar dosage of administered hGH (2.85iU daily for 100kg bodyweight; 0.20 IU/kg BW / week), and sex (male), controlling for variables:

Herrmann, et. al.: Administered 9.5mcgxbodyweight daily (0.20 IU/kg bw weekly), i.e. 2.85iU hGH for 100kg male, daily:

Met + GH: IGF-1 increased from 146 (S.D. 56mcg/L) => 357 at 6 weeks, and stabilized around 373 (S.D. 111 mcg/l) by the third month. (E.S. 4.05).

Johannsson, et. al.: Administered 9.5mcgxbodyweight daily (0.20 IU/kg bw weekly) [same as above]:

GH: IGF-1 increased from 134 (S.D. 8 mcg/L) => 338 (S.D. 16 mcg/L). After 6 weeks rhGH treatment, the GH group's IGF-1 levels were 3.30 above the expected mean; calculated from predicted IGF-1 values, adjusted for age and sex, obtained from the normal population. However, by the 9 month mark, the mean serum IGF-1 concentration had dropped to 1.89 above the predicted mean.

As we can see, this is consistent with the recent research review that shows that Metformin does not decrease IGF-1 in adults, but rather increases it. More importantly, here, we see that Metformin does not attenuate rhGH's concomitant increase in IGF-1.

Is IGF-1 responsible for fat loss associated with rhGH?

hGH exerts direct effects on human adipocytes (fat cells) independently of IGF-1. In fact, human fat cells do not contain IGF-1 binding sites but contain specific hGH binding sites that are primary targets of physiological hGH. (DiGirolamo, et. al.). hGH enhances the oxidation of fatty acids relative to glucose (or amino acids). This is achieved by increasing adipose tissue lipolysis and/or reducing triglyceride storage in a nonuniform manner such as to redistribute adipose tissue from intra-abdominal to peripheral depots in addition to decreasing body fat mass. (Shadid, et. al.).

Still, practically IGF-1 is responsible for much of rhGH's downstream effects on fat loss. IGF-1 functions in part by increasing free fatty acid utilization, and enhancing insulin sensitivity upon receptor binding and subsequent intracellular signaling and glucose metabolism. (Kraemer, et. al.).

Still a good idea to take Metformin + rhGH?

Yes. Metformin in addition to rhGH controls the hyperglycemic effects and ameliorates insulin resistance in addition to reducing cancer risk that increasing systemic-liver IGF-1 introduces.

hGH (directly or indirectly) increases endogenous glucose production and inhibits cellular glucose uptake, thus raising plasma glucose concentrations. (Kraemer, et. al.). Prolonged excess GH can lead to pancreatic B-cell failure such that insulin secretion cannot overcome the insulin resistance, resulting in hyperglycemia and eventually diabetes. (Id.).

Conversely, IGF-1 ameliorates this diabetogenic (tendency to cause diabetes) effect of hGH. In many ways having supraphysiological exogenous hGH levels without a concomitant rise in IGF-1 could be a Bad Thing. So while Metformin does not apparently reduce IGF-1 levels (at least serum or systemic-liver), the desire to reduce the rise in IGF-1 from hGH administration is misguided. If one decides to embark on hGH for its myriad benefits for performance and bodybuilding, then one should embrace the principal functions of hGH - growth and nutrient partitioning. If one intends to burn fat, there are better lipolytic compounds.

In light of the recent research showing that Metformin actually increases IGF-1 levels significantly in adults, it seems advisable to take Metformin with hGH. Not for the purpose of lowering IGF-1, but rather for the purpose of increasing it as well as ameliorating insulin resistance and reduction of hyperglycemia, potentially preventing onset of diabetes for long-term hGH users on high caloric diets. It is likely that Metformin and rhGH work synergistically to regulate glucose metabolism.

Further, the use of Metformin has been found to be associated with a decreased incidence and mortality of various cancers (Yang, et. al). Metformin achieves its anti-hyperglycemic and anti-cancer effects through highly complex mechanisms, which include suppressing the hepatic fatty acid oxidation, increasing insulin sensitivity, reducing intestinal absorption of glucose, and decreasing inflammation. (Yang, et. al.).

IGF-1: The Upside

The effects of IGF-1 include satellite cell activation, proliferation, survival, and differentiation, increasing myotube size and number of nuclei per myotube, stimulating amino acid uptake and protein systesis and muscle hypertrophy*, neuronal myelinization, axonal sprouting and repairing damage, reducing chronic inflammatory response, increasing free fatty acid utilization and enhancing insulin sensitivity upon receptor binding and subsequent intracellular signaling and glucose metabolism. (Kraemer, et. al.).

*: While upregulation in the muscle isoform of IGF-1, that is, locally produced (autocrine) IGF-1 is linked to hypertrophy, elevated systemic-liver IGF-1 a la administered supraphysiological doses of rHGH have not been shown to directly increase hypertrophy in muscle cells. (Id.). Resistance exercise potently stimulates the muscle isoform of IGF-1 and its interaction with IGF receptor, with moderate to high intensity training stimulating IGF-1R mRNA two hours post-workout. (Id.).

Cancer Risk: Interplay Between hGH & IGF-1

High systemic IGF-1 levels increase risk for several common cancers. Multiple metanalyses have shown a link between elevated IGF-1 levels and prostate, colorectal, and other types of cancer. (Pollak; Yang). Human growth hormone's direct effects are predominantly mediated through the mitogen-activated protein kinase/extracellular-signal–regulated kinase (MAPK/ERK)4 and janus kinase signal transducer and activator of transcription (JAK-STAT)5 pathways. IGF-1 directly upregulates the MAPK/ERK6 and phosphoinositide 3-kinase (PI3K)7 pathways. Given that overstimulation of these pathways has been implicated in the pathogenesis of melanoma, there may be indication to closely monitor patients using exogenous hGH for development of malignant disease.

Conclusion:

Metformin is a well-tolerated drug with few side-effects that should be used in combination with rhGH (that is, administered GH) by bodybuilders and athletes that use rhGH either year-round or for multiple "cycles" during the course of a year: unless the goal is maximal mass. Metformin does not reduce IGF-1 levels; quite the opposite. If the bodybuilder or athlete is using rHGH for accruing maximal muscle via hyperplasia, sarcoplasmic and myofibrillar hypertrophy, then the bodybuilder or athlete should instead opt for shorter-duration hGH + Insulin or very high hGH protocols (research appropriately). Due to Metformin's appetite suppressant effects and its link to weight loss it should not be used for this purpose. Metformin and IGF-1 synergistically improve glucose metabolism and increase insulin sensitivity in muscle. Metformin additionally ameliorates the cancer risk of prolonged elevated systemic IGF-1 levels.

Citations:

Yang X, Kord-Varkaneh H, Talaei S, Clark CCT, Zanghelini F, Tan SC, Zarezadeh M, Mousavi SM, Rahmani J, Zhang Y. The influence of metformin on IGF-1 levels in humans: A systematic review and meta-analysis. Pharmacol Res. 2020 Jan;151:104588. doi: 10.1016/j.phrs.2019.104588. Epub 2019 Dec 6. PMID: 31816435.

Kraemer WJ, Ratamess NA, Hymer WC, Nindl BC, Fragala MS. Growth Hormone(s), Testosterone, Insulin-Like Growth Factors, and Cortisol: Roles and Integration for Cellular Development and Growth With Exercise. Front Endocrinol (Lausanne). 2020 Feb 25;11:33. doi: 10.3389/fendo.2020.00033. PMID: 32158429; PMCID: PMC7052063.

Johannsson G, Mårin P, Lönn L, Ottosson M, Stenlöf K, Björntorp P, Sjöström L, Bengtsson BA. Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J Clin Endocrinol Metab. 1997 Mar;82(3):727-34. doi: 10.1210/jcem.82.3.3809. PMID: 9062473.

Herrmann BL, Berg C, Vogel E, Nowak T, Renzing-Koehler K, Mann K, Saller B. Effects of a combination of recombinant human growth hormone with metformin on glucose metabolism and body composition in patients with metabolic syndrome. Horm Metab Res. 2004 Jan;36(1):54-61. doi: 10.1055/s-2004-814199. PMID: 14983408.

DiGirolamo M, Edén S, Enberg G, Isaksson O, Lönnroth P, Hall K, Smith U. Specific binding of human growth hormone but not insulin-like growth factors by human adipocytes. FEBS Lett. 1986 Sep 1;205(1):15-9. doi: 10.1016/0014-5793(86)80856-0. PMID: 3017755. Shadid S, Jensen MD. Effects of growth hormone administration in human obesity. Obes Res. 2003 Feb;11(2):170-5. doi: 10.1038/oby.2003.27. PMID: 12582210.

Jørgensen JO, Møller L, Krag M, Billestrup N, Christiansen JS. Effects of growth hormone on glucose and fat metabolism in human subjects. Endocrinol Metab Clin North Am. 2007 Mar;36(1):75-87. doi: 10.1016/j.ecl.2006.11.005. PMID: 17336735.

Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8, 915–928 (2008).
 
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