The Most Effective Growth Hormone Protocol for Hypertrophy

Human myocyte studies show that GH increases IGF-1 mRNA expression within 30-60 minutes and it peaks much quicker than it does in animal trials, within 1-2 hours, using the JAK/STAT5b signaling pathway [365]. These elevated levels of mRNA have been shown to last for as long as 48 hours following a single GH exposure. The amount of GH required to maximally stimulate IGF-1 mRNA expression was found to be at a dose somewhere between 7.5 ng/mL and 30 ng/mL [366], with an effective median dose occurring at 3ng/mL. These numbers fall well in line with the physiological dose ranges seen in animals, which are effectively between 2-100 ng/mL [367]. They also fall right in line with what is seen endogenously in humans, with normal peak concentrations falling between 22.4-32.4 ng/mL [368-369,436]. There have been cases where humans have shown slightly higher peak concentrations but these are to be considered outliers [370]. In any event, what this data tends to suggest is that the human body is very well suited to deal with the expected natural levels of endogenous GH peak secretions. Trying to further hack the system by elevating GH beyond these endogenous levels, solely for the sake of increased hypertrophy potential, may not actually translate into the expected or desired behavior.

Studies comparing local infusions to systemic infusions of either GH or IGF-1 are a bit harder to come by than I wish they were. The few animal trials I’ve found do indicate that direct infusion of either GH or IGF-1 into target tissues results in increased mass. This increased hypertrophy occurs, even without the presence of activity in target muscle groups [371-372]. The trials also consistently show that local GH injections result in substantially higher levels of local IGF-1 mRNA expression than local IGF-1 injections do, by a factor of more than twenty [127]. I was also able to find one trial which actually did compare exercised rats that were locally infused with IGF-1. The IGF-1 plus training group experienced an increase in both local muscle mass and strength as compared to either treatment in isolation [373]. So, albeit limited, the literature which is available does seemingly provide evidence that locally injecting GH or IGF-1 has merit.

I’ve mentioned this quite a few times already but, in an attempt to further drive this point home, autocrine levels of IGF-1 appear to be far more important than endocrine levels of IGF-1 as it relates to muscle mass regulation. Further to this point, overexpression of autocrine IGF-1 within muscle causes fiber hypertrophy [374]. Overexpression of autocrine IGF-1 has also shown anti-catabolic effects, with animal models tending to demonstrate an overall resistance to the muscle atrophy normally observed with aging [375]. Localized IGF-1 also provides age-independent regenerative capacity in skeletal muscle cells [376].

There is also some compelling evidence that suggests endocrine IGF-1 acts directly as a negative feedback regulator on autocrine IGF-1 production. This negative feedback mechanism is PI3K/Akt pathway dependent [377-378]. In addition, elevated endocrine IGF-1 levels may also act indirectly to stifle autocrine IGF-1 production. So, in other words, not only does endocrine IGF-1 have minor direct impacts on skeletal muscle mass regulation itself, but it also possibly suppresses the autocrine IGF-1 that has major impacts on hypertrophy.

Elevated levels of circulating IGF-1, and specifically elevated free IGF-1, act in a negative regulatory manner on GH ultimately resulting in a suppressed rate of downstream autocrine IGF-1 production [379]. It is not entirely clear, however, if IGF-1 negative regulation changes the half-life of IGF-1 mRNA or directly affects IGF-1 gene expression. Further to this, it has also been demonstrated that autocrine IGF-1 expression is downregulated in muscle cells following IGF-1 treatment [366]. Hepatic expression of IGF-1 mRNA has also been shown to be downregulated by acute IGF-1 exposure [127]. So ensuring we keep endocrine levels as suppressed as possible for a respective rHGH dose, while simultaneously elevating autocrine levels, is going to be a priority for the stack design.

GH is pulsatile by nature in all species. So it would stand to reason that many of the body’s built in processes are going to thereby be designed in a manner which will be optimized to exposure to GH in a similar manner. In accordance with this statement it has been shown that only pulsatile GH administration, and not continuous infusion, has the ability to maximally stimulate IGF-1 mRNA expression in skeletal muscle [366,380-381]. Pulsatile delivery has also been shown to lead to increased overall postnatal growth potential, as compared to continuous delivery [89,382]. Pulsatile administration may also lead to comparable, or even decreased, serum endocrine IGF-1 levels [383] which is advantageous due to the potential negative regulatory capabilities it possesses on autocrine IGF-1 expression which were discussed earlier. Evidence also suggests that the peak itself, and not necessarily the number of peaks, may be of utmost importance to target tissues [384]. For maximal growth and hypertrophy potential the evidence tends to suggest that getting GH elevated, and then back to baseline multiple times per day, may be preferable as compared to keeping them elevated for longer periods of time. This behavior just so happens to mimic in vivo secretory patterns.

The GH pathways involved in anabolism are also susceptible to desensitization, which is by design as part of endogenous GH physiology [385]. Due to the inherently pulsatile nature of GH in vivo, receptors and pathways expect a pulse followed by a period of inactivity [386]. Continuous, or repeated, exposure to subsequent GH without proper refractory time will result in heavily suppressed activity levels. In fact, numerous studies have shown this to be the case over the years. Skeletal muscle cells and tissues require a somewhat lengthy refractory period before their full response to GH is recovered. After exposure to GH, muscle cells are unable to even respond to subsequent GH doses at all. In fact, it takes a full two hours just to partially regain responsiveness in cell models, with a total of 6-8 hours of GH abstinence required for full sensitivity to be restored [366]. Conversely, when GH is micro-dosed in ten minute pulses, followed by eight hour intervals, it was shown to progressively increase IGF-1 mRNA with each subsequent pulse [386].

This phenomenon is potentially a result of an overall desensitization within the JAK-STAT5 pathway, as exposure to GH in hepatic cell studies has been shown to cause resistance to subsequent activation of the STAT5 pathway for 4-8 hours [387-388]. This timeframe just so happens to sync up quite nicely with what has been seen in the myocyte cell models mentioned previously. In the hepatic cell models, GH stimulated a significant increase in SOCS3 expression, which is a potent inhibitor of GH action [389]. Because GH had no effect on the expression of SOCS3 in muscle cells, it must be another mechanism causing this refractory period. This mechanism may be GHR downregulation, inhibition mediated via another SOCS protein, or induction of a tyrosine phosphatase that simply inactivates the JAK/STAT pathway [390]. The JAK-STAT5b pathway, which as you recall is intimately associated with skeletal muscle and IGF-1 expression, is transient in nature – with maximal activation achieved within 10-30 minutes followed by a prolonged period of inactivation.

A rather novel finding by Xu and team [391] demonstrated that even spacing GH exposures five hours apart still left both the downstream MEK1/2 and ERK1/2 pathways significantly suppressed as compared to all upstream pathways, due to a potential disconnect in signal transduction. This is of particular interest as these same two downstream pathways just so happen to be significantly involved in both growth and proliferation [392-393]. It was also discovered that GH-induced activation of both STAT1 and STAT3 were desensitized, but insulin exposure reverses the desensitization observed in all impacted pathways. Although I’m not going to be deep-diving on insulin, there are a couple of important take-away points to be had here. Understand first that there are many downstream targets of the GH receptor, and many of these have the potential to become desensitized after exposure to GH. Also understand that insulin possesses the somewhat unique ability to resensitize many of these pathways. This would tend to make sense though based upon the yin-yang-like relationship they have with one another. It is well-known that GH and insulin possess a synergistic anabolic relationship due to many effects they have on one another, which I will be covering in more depth in the next installment of this series. This just so happens to be a sneak peek into one of them.