The Most Effective Growth Hormone Protocol for Hypertrophy

Androgens have demonstrated the ability to increase local IGF-1 mRNA expression in skeletal muscle. We can therefore speculate that androgens, particularly in higher doses, create an environment within skeletal muscle which is going to be rather adept at handling the higher levels of IGF-1 that will be present with supraphysiological rHGH administration. There have even been human trials which have shown reduced levels of local IGFBP-4 in skeletal muscle samples, in addition to the increased levels of IGF-1 mRNA. This would infer changes have taken place in those muscles to liberate more local IGF-1 for binding to its receptors [277,295]. We haven’t gone too deeply into the individual binding proteins but IGFBP-4 is an inhibitor of IGF-1 so, at a high level, low levels correlate with higher IGF-1 [149,296].

Testosterone has even been shown to promote hypertrophy in GH/IGF deficient states [297-298]. This is intriguing as it demonstrates that testosterone possesses both IGF-mediated and IGF-independent anabolic pathways in muscle tissues [299]. To this point, cell models have shown that testosterone can upregulate the expression of various IGF isoforms in skeletal muscle, even in the absence of GH/IGF-1 [298]. And, although this was demonstrated in fibroblasts, testosterone was shown to increase IGFBP-3 expression – an effect that was further enhanced by IGF-1 administration [300]. It is pretty clear, anyway you slice things, that testosterone has both synergistic and additive effects upon GH/IGF mediated anabolism.

We’ve focused on testosterone up to this point, however there have been slightly different behaviors observed as it relates to androgen variants and their impacts on systemic and local IGF-1 expression. I wanted to touch on a couple specific compounds that are frequently seen in growth stacks before moving on; trenbolone and nandrolone. Unless otherwise noted, please understand these trials are all animal based.

Nandrolone administration has consistently shown to cause no changes in endocrine IGF-1 levels, despite simultaneously producing significantly higher local muscle IGF-1 expression and increased muscle fiber CSA [286,301-302]. In addition, local IGFBP-3 levels have been reported to be significantly higher and IGFBP-4 levels have also been shown to be significantly suppressed, which if you recall from earlier suggests more local free IGF-1 is available. Again, in all trials, nandrolone administration directly led to increased hypertrophy despite not having any impact on systemic IGF-1 levels. This further strengthens the hypothesis that endocrine IGF-1 is not a primary factor in skeletal muscle hypertrophy and therefore elevated levels are not a prerequisite for increased muscle mass [303-305].

Trenbolone has also been universally shown to increase rates of skeletal muscle growth in all the various species tested. Unlike testosterone and nandrolone though, it does not convert to estrogen and it has been suggested as far back as the 1970s that adding estradiol with trenbolone seemingly enhances the anabolic effects of the compound [306-307]. There have also been enhanced effects on hypertrophy when trenbolone is administered alongside a growth hormone releasing factor (GHRF) [308]. As I mentioned earlier, the GH/IGF access requires estrogen to maximally stimulate the GH/IGF axis, primarily that which is derived via aromatization. Because the administration of trenbolone inherently decreases estradiol levels, by negative feedback inhibition of testosterone via the hypothalamic-pituitary-gonadal (HPG) axis [309], administration of estradiol should technically enhance the GH/IGF axis. This should therefore further the anabolic synergy it would possess with the androgen. This hypothesis is in line with what various trials have demonstrated to be the case over the years.

In cell cultures, estrogen has also been shown to directly alter the MPS and MPB rates of trenbolone via mechanisms involving both the estrogen receptor and IGF-1 receptor [310-311]. In fact, by and large, solo treatments with trenbolone do not significantly increase either endocrine or autocrine IGF-1 levels. However, co-treatment with estradiol has traditionally shown similar increases of autocrine IGF-1 levels as has been seen with testosterone [312-314]. This is just further evidence suggesting estrogen, both systemic and aromatase-derived, is a key component to both the maximal stimulation of the GH/IGF axis as well as the maximal anabolic capabilities of androgens.

Much like its 19-nor cousin, trenbolone has also shown increased growth factor expression in skeletal muscle tissues, as well as evidence of increased responsiveness of skeletal muscle to such growth factors [315]. Trenbolone has also shown increased satellite cell activation and proliferation in various species, to a similar degree as testosterone [316-317]. Knowing what we do now about GH, you can see why both of these effects would be advantageous in a stack design which includes both compounds.

Moving back to testosterone now, both GH and testosterone increase collagen synthesis markers such as PIIINP. Furthermore, testosterone has also been shown to potentiate GH’s abilities to increase collagen synthesis in both muscle and tendons [318]. In support of this, coadministration of GH and testosterone in recreationally trained human subjects caused significant increases in both IGF and collagen markers [319]. And a bit of a fun fact, some of these very same collagen markers being discussed here are the exact indicators that are examined as part of GH doping tests [320-321].

We have only briefly touched on the JAK-STAT pathway, but a slightly deeper dive is warranted here so please bear with me. The JAK-STAT pathway is a critical component of GH and it relates to both IGF-1 gene transcription and postnatal growth. One of the STAT proteins in particular, STAT5, appears to be intimately involved in the regulation of skeletal muscle as well [322]. There are two sub-proteins in the STAT5 family, and they are referred to as STAT5a and STAT5b. Although they are 96% identical, it is the STAT5b variant which is abundant in muscle and liver tissues and thus the specific protein we’ll be focusing on from this point forward [323-324].

A full-on signaling pathway review would make this already bloated article a novel, but I do feel it is important that we understand the JAK/STAT5b pathway has continuously been shown in both humans and animals to have a direct relationship with local IGF-1 expression in skeletal muscle tissues as well as hypertrophy [248,325-332]. Because of this, if there were ways to enhance or optimize this specific pathway, then it would seemingly translate to not only increased IGF-1 gene activation [333-335] but greater hypertrophy potential as well.

Fortunately, some novel animal studies have already done the work to show us how the AR and JAK-STAT pathways are intimately related [248,336]. To be precise, the STAT5a/b pathway is upstream and the AR is a direct downstream target via regulation of AR gene expression. Human studies have also demonstrated that this translates to us as well, with STAT5 activity being positively correlated with AR expression in prostate cancer cell lines [337]. In the next section, I am going to discuss ways we can attempt to ensure the JAK-STAT5b-AR pathway is maximally sensitized thereby ensuring that hypertrophy potential is maximized when androgens and GH are being used with one another.