Furions Qualifications
MPharm MPS ND BScHlthSci (Comp Med & Nutr)
Furions Summary from James Dries
HGH is a peptide hormone produced and secreted in the brain and is expressed in 4 similar forms, acting on all tissues in the body to promote tissue repair. In response to exercise, one particular type is primarily attributed to enhancing muscle growth (it is this specific type that synthetic forms attempt to replicate). HGH produced in the brain stimulates the release of IGF-1 from the liver, which plays a significant role in signalling muscle growth. When produced naturally, both hormones may work by themselves, or together, amplifying the effects of each other. For this reason, people mistakenly believe that administering synthetic versions of HGH and IGF-1 will promote muscle growth.
The way in which HGH is produced in laboratories leads to a slightly different shape and stability of the synthetic HGH molecule. Therefore, its ability to communicate with muscle cells and signal muscle growth is altered (remember the lock and key analogy). Even if measures are taken to make the purest form of HGH, not all of the product will be effective in its intended role due to manufacturing constraints.
In relation to Brads post, this would make sense as synthetic HGH may be very effective at signalling heart and gut growth, but much less effective in enhancing muscle growth due to its reduced ability to signal IGF-1 release within muscles (less compatible). A lesser quality synthetic HGH will most likely compound this problem. As Brad also mentioned, high circulating levels of IGF-1 are not desirable and may have detrimental effects on brain and lung tissue. Therefore, it appears that the optimal levels of HGH and IGF-1 in relation to building muscle, occurs naturally and is optimally stimulated by resistance training (and diet).
Furions Report
I will follow on from Brads article- through a neutral perspective to dissect this contentious and quantitatively negative finding of myogenic/hypertrophic activity as it pertains to applicable pharmacological qualitative analyses.
I will preface this by indicating that it the information presented here is in fact casted through substantiated hypothetical molecular targeting and effector downstream cascades. It is thus collectively theorized- however does indeed form congruence with the comprehensive quantitative results Brad has described.
As a sort of add-on bonus to the topic- I will describe a potential reason for the widely noted (and consequently accepted) discrepancies of approved GH as somatotropin pharmaceuticals vs. unapproved generically labelled GH- as it pertains to the manufacturing processes.
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To examine the pharmacological activity of supraphysiological growth hormone administration for the physique athlete- it would seem most suitable to establish the endogenous fluxes and bioactivity during resistance exercise and then model these against the (then deduced) molecular targets and downstream effectors that may be conducive to myogenesis when using a pharmaceutical.
In doing this, it is pertinent to stipulate that GH, as a pituitary hormone, occurs as a “superfamily” of (now currently identified) 4 different molecular isoforms, these categorized by the weight (20 kDa, non-22 kDa, 44 kDa, and 66 kDa (1). Each isoform appears to bear role in mediating physiological activity during recovery in response to exercise stress (1-4). The pharmaceutical preparations of GH (as somatotropin) occur as only the monomeric 22kDa peptide, hence it is important to make this distinction when scrutinizing the endogenous patterns against exogenous administrations in exercise models and to consider that the complexity is such that no finites or absolutes can yet be made as to the complete pharmacological myogenic activity.
In saying this, associated evidence does suggest that in non-aged, non-obese subjects the more rapid-response patterns and greatest fluxes of endogenous GH associated with anaerobic resistance exercise are actually related to this 22-kDa (immunoreactive GH) isoform (5-8) see figure 1. It is also worth noting that there does appear to be aged and body compositional implications to the magnitude of the responses (7,8).
It is now understood that the growth hormone receptor (GHR) is ubiquitious and through signal transduction can have effect on all tissues (9,10). From a broad analytical examinations, any likely anabolic activity associated with exogenous GH will be confounded by anabolic activity of GH stimulated, hepatic secreted systemically circulating IGF-1. It has been recently identified that the anabolic activities between these two hormones may be in fact independent of each other, potentially additive and in respect to the endogenous patterns; synergistic as it pertains to myogenesis and tissue repair (11). Henceforth for the purposes of distinguishing these two hormones as exogenous preparations, this report will focus on that unique to GH alone.
Cumulative data suggests that the molecular patterns specific with growth hormone administration (or secretion) in combination with resistant exercise are hallmarked by an up regulation of a tissue specific mechanosensitive isoforms of IGF-1 (12,13). These are IGF-1 isoforms literally produced by skeletal muscle, to act locally within the skeletal muscle; a paracrine response (13,14). Skeletal muscle induced IGF undergoes alternative splicing and generates 3 isoforms; IGF1Ea, IGF1Eb and IGF1Ec (15,16). The IGF1Ec isoform, colloquially known as mechano growth factor (MGF) appears the most active and also has recently been implicated as the likely main driver behind the paracrine activity that may have the terminal responsibility for the downstream myogenesis associated with resistance training and subjectively augmented by growth hormone (17,18).
MGF (as IGF-1Ec) has been shown to activate muscle satellite cells, promote myonuclei accumulation and expand myofiber diameter (17,19) whilst growth hormone has independently been shown to rapidly induce expression of MGF in muscle satellite cells in varying models, and may in fact do so in an additive manner with MGF when combined with resistance training (12,13,20).
So to apply this as a theoretical basis, it may be postulated that the MGF response, as induced by the combination of mechanical loading and exogenous GH administration, may activate muscle satellite cells and accrue extra myonuclei as a repair response in greater amplitude than what can occur in normal physiological conditions. This induced state may therefore somewhat override the negative regulators of satellite cells maturation, such as myostatin, that normally halt and shift the satellite cell activation back into the quiescient state and potentially remove a limitation to the mitotic and subsequent myogenesis (21-23).
**Working off this premise- there may be further pharmaceutical methods to exploit this mode of action when considering the systemic IGF-1 implications. This would include the use of insulin and other anabolic compounds- however may need a separate article in itself**
Although it may seem as though this could explain the anecdotally claimed skeletal muscle hypertrophic capacity of growth hormone, these actions alone may not account for any measurable degree of muscle strength increase or performance enhancement- hence may provide some degree of rationale for the consistently negative results observed in the quantitative analyses Brad has cited. This has certainly been comprehensively concluded in related qualitative research (24-26). Additionally as this molecular pathway has not been comprehensively researched so I am really at a stretch here to conclusively say that this is the unique pharmacological property of growth hormone that distinguishes it from all performance and image enhancing drugs.
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Peptide syntheses can be performed via two main methods. The distinction between the methods may account for the discrepancies of subjective quality of approved GH preparation against those unapproved generically labelled.
Peptide synthesis can be performed via amino acid binding- known simply as chemical synthesis. This is generally the cheapest and simplest method for peptide syntheses. It is usually performed with apparatus that literally link the individual amino acid together in a linear manner using catalytic enzymes and chemicals. This permits manufacture of perfectly functional short chain peptides (such as melanotan, GHRPs, ect). For synthesizing long chain peptides with 3 dimensional complex binding this method is limited in creating the tertiary and quaternary conformation patterns often associated with these.
So although the peptide sequence may be correct, it is likely that the shape formed by the extra-sequence binding might not be consistently present, if at all.
Recombinant peptide synthesis differs completely. This involves a live in-cell model usually using strains of bacterial or fungi, whereby the DNA and ribosomal transcriptional activity is stimulated so as to produce and then harvest the desired peptide. The peptide will therefore contain the bioidentical, 3 dimensional structure owing to the presence of the tertiary and quaternary peptide bonding. This is often necessary to the exploit the complete activity of the hormone and given research has not completely elucidated the binding properties of the GH receptor at the skeletal muscle, we must assume that the structural homogeneity is necessary for this binding. This therefore may serve as plausible explanation for the biological activity discrepancies between GH preparations.
As completed synthetic preparations, the stability of each peptide between these manufacturing procedures can also give reason as to the variance in the bioactivity. A peptide synthesized by chemical means tends to be more flexible and therefore more stable in shorter chains (i.e less than 100 residues). This decreases linearly in concert with the increasing number of residues. The reciprocal applies for recombinantly synthesized peptides. As the growth hormone isomer consists of 191 residues- it could be inferred that subsequent manufacturing procedures, including the lyophilisation (freeze drying), could pose detriment to the integrity of the peptide. A lyoprotectant should be used in GH manufacturing to maintain the structural integrity during this process. As result of the presence of tertiary and quaternary bonds, the recombinantly synthesized peptide is much more stable in the presence of a lyoprotectant. The same can be guaranteed for a chemically synthesized peptide, thus it could be well-assumed a percentage may become damaged as result this process.
Hence it may also seem plausible that a greater percentage of the peptide would be damaged using a chemical synthesis process.
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