GH/IGF Axis – Relationship with Other Hormones
Before wrapping this up and heading to my concluding remarks, I want to briefly go over some other hormones that need to be addressed. First, I want to touch on the thyroidal axis because this is a topic I see coming up quite often as to whether it should be run alongside GH during periods of growth.
Skeletal muscle is a principal target of thyroid hormone signaling, with both thyroid hormone transporters and converting enzymes expressed locally . It is pretty well-known that GH enhances the peripheral deiodination of T4 to T3, thus lowering T4 and reverse T3, while simultaneously increasing T3 [395-398]. What a lot of people fail to realize however is that this is a transitory effect, and longer-term studies seem to indicate that the GH-mediated effects on peripheral conversion stabilize with time [399-402].
Instead, I’d rather focus on a few thyroid-related items I don’t see discussed quite as often. Thyroid, by nature, is a catabolic compound as it stimulates whole-body protein breakdown to a greater degree than it does protein synthesis . Locally, in skeletal muscle it stimulates an increase in activity within the ubiquitin/proteasome pathway, which is largely involved in proteolysis [404-406]. The result of this is an accelerated rate of protein turnover and an overall net loss in aminos located within valuable skeletal muscle stores.
In addition, in humans, both hyper- and hypothyroid states have been associated with suppressed IGF levels with a tendency towards normalizing when getting back to more of a euthyroid state. Hyperthyroidism is also associated with low GH-binding activity, which is speculated to be a result of reduced GH receptor processing abilities . Hyperthyroidism has also been hypothesized to accelerate urinary GH clearance . Furthermore, animal studies have shown that thyroid hormones can have major suppressive effects upon GH-stimulated IGF-1 synthesis . Of course, due to the complex relationship the thyroidal axis has with the GH axis, capturing all interactions they have with one another into just a few paragraphs is doing the topic a bit of a disservice. However, when the body of literature is examined in its entirety, there is a lot of evidence suggesting that exogenous thyroid supplementation might not be ideal when the goal of an individual is hypertrophy. For those interested in exploring this topic deeper, I’d recommend starting with the review here .
I’d also like to touch on myostatin, which also gets talked about a lot on Internet message boards. It was arguably made most famous as a result of those muscle bound cattle lines possessing a genetic myostatin mutation, carrying significantly more muscle mass than their non-mutated cousins . Myostatin, a growth and differentiation factor belonging to the TGF-beta superfamily, has been shown to selectively inhibit myogenesis, largely via its suppression on myoblast proliferation . It is expressed and secreted predominantly by skeletal muscle. As the story goes, if you can suppress or inhibit myostatin, the potential for increased hypertrophy comes as a result.
Myostatin mutations have been seen in both animals as well as humans. These mutations of the myostatin gene lead to a hypertrophic phenotype in animals, as mentioned earlier [413-415]. The GH/IGF axis and myostatin do appear to have a direct regulatory relationship with one another, as seen in both GHD and HIV patients who show marked increases in myostatin mRNA expression . Although this can be corrected with rHGH supplementation, is this something that translates to real-world applicability when talking about supraphysiological doses [209,417-419]? Unfortunately, despite a few select case studies, I just don’t believe we have enough data at this time to know one way or another.
What we do know is that increased muscle IGF-1 mRNA expression and circulating concentrations of IGF-1 have been seen following myostatin inhibition [419-421]. We also know that myostatin inhibition tends to cause hypertrophy via many of the same methods that autocrine IGF-1 does, namely increasing protein synthesis and satellite cell activation [422-425]. And we also know that hypertrophy induced by either IGF-1 overexpression or myostatin inhibition uses the exact same same pathway – PI3K/Akt/mTOR [426-428]. However, IGF-1 is also not a requirement for follistatin-induced hypertrophy except in the case of extremely low insulin levels – follistatin is a myostatin inhibitor . And chronic exposure to GH may actually lead to upregulated expression of myostatin and its receptor .
So what we can say, with certainty, is that the expression of myostatin is not going to be a singular or straight-forward factor with regard to hypertrophy potential, nor contractile activity, in human skeletal muscles . For this very reason, I do not feel it is something folks should necessarily be hyperfocused on.
Okay, let’s try and condense all that we’ve learned into some practical suggestions for those that simply want to maximize their ability to grow skeletal muscle without stressing over the minutia.
It is now clear that GH possesses very little, if any, direct effects on hypertrophy. So any proper growth stack design is going to need to account for this by including AAS, which also just so happens to have a fantastic synergy with GH. Both the scientific literature and in-the-trenches data clearly demonstrate that using both together has a significantly higher hypertrophy ceiling than using either of them by themselves. Personally, I think that folks should always considering using either testosterone or nandrolone as their growth anchor compound. Trenbolone may be considered as part of a growth stack design, but it should be used in an accessory compound role due to its inherent strength as an anabolic substance. It should be used sparingly and with caution as, along with its many strengths as a growth compound, it comes with quite a few inherent weaknesses. Most of these weaknesses are a result of how harsh this compound is on most individuals. So, if trenbolone is used, it should be strategically implemented in and out of a stack as opposed to being continuously left in for long periods of time.
After a sustained period of supraphysiological AAS usage, a break should occur. This break can be either complete abstinence from AAS, or a transition to TRT for those that employ the blast and cruise methodology. If one decides to come off, there is no need for a PCT. The growth stack design should always follow minimum effective dose principles and the amount of AAS should be increased only when growth plateaus have been reached, assuming that all other lifestyle variables are in place. Using this approach not only limits the risk of unwanted side-effects, but it also helps limit the rate at which desensitization to these external hormones occurs.