The Most Effective Growth Hormone Protocol for Hypertrophy

Over the next few decades, many experiments demonstrated the wide variety of functions this family of sulfation factors possessed and the term “somatomedin” was proposed to include all of its family members [15]. Interestingly enough, the original hypothesis depicting the regulation of these sulfation factors by GH is still generally referred to as “the somatomedin hypothesis” to this very day [16]. The original hypothesis stated that somatic growth is caused by GH acting on the liver, where it stimulates IGF-1 synthesis which is subsequently released to target tissues in an endocrine model. The hypothesis remained the accepted model for decades until the autocrine roles of the IGFs were identified [17-18] along with the direct effects GH has in bone growth [19-20]. To reconcile these new discoveries, the original hypothesis was slightly modified to what most refer to now as the “Dual Effector Theory”, which defined both an autocrine and endocrine role of IGF-1 [21].

Going back a few years now, late in the 1970s, the chemical identity of these sulfation factors was more intimately recognized as being the manifestation of two peptides with a very high similarity to pro-insulin and thus they were renamed “insulin-like growth factors” (IGFs) [22-24]. It was around this same time when IGF binding proteins (IGFBPs) were also identified, and consequently the knowledge of the biology of IGF-1 took off at an exponential rate [25].

Meanwhile, human pituitary extracts became available via cadavers and early experiments using them on humans and animals showed just how complex the actions of human GH really were [26-33]. The practice of using these human pituitary extracts was stopped by clinicians when cases of Creutzfeldt-Jakob disease (CJD) were discovered in patients who had previously been administered cadaver GH [34]. CJD is a particularly nasty and universally fatal brain disorder, with the vast majority of infected cases dying shortly after diagnosis.

Fortunately, in 1985 around the same time these CJD cases began to make headlines, the FDA approved the first synthetic recombinant growth hormone (rHGH) for use on human growth-hormone deficient subjects. This version of rHGH was produced by Genentech and named Protropin [35-36]. Worth noting, for those going through some of the older synthetic GH references in this article, it was not uncommon for the first synthetic GH lines to be 192 amino acids (met-hGH) as opposed to rHGH which consists of 191 [37]. In any event, with rHGH now being readily available, it ushered in a whole new era, with much safer clinical conditions, for the ever-expanding group of human patients now relying upon it.

Growth Hormone’s Effects on Protein Synthesis

Earlier in the article, I defined anabolism and also stated that growth hormone is anabolic in nature. So let’s take a moment to review what actually makes growth hormone anabolic as well as dive into some of the literature that exists on the topic.

Over the years, GH has been widely studied in just about every way imaginable. Most lines of evidence, when looked at as a whole, suggest that GH is anabolic. More specifically, GH is anabolic because it stimulates whole-body protein synthesis with either no effect, or a suppressive effect, on rates of protein breakdown [38]. However, when you dig deeper into the topic, things tend to get a bit cloudier as trial results over the years tend to be all over the place. The differing results are a direct reflection of the immense complexities of GH.

GH elicits its effects on protein synthesis by first binding with the GH receptor (GHR) and subsequently increasing muscle gene transcription via downstream signaling paths, ultimately activating mTOR signaling [39-40]. These effects are acute, often happening within minutes, and are insulin-like in nature using many of the same anabolic pathways [41-44]. The rapid onset of these protein-related metabolic changes suggest they are directly caused by GH and not secondarily mediated via IGF-1 [45]. GH’s impacts on proteolysis, on the other hand, are very likely indirect in nature. By all accounts, they have more to do with its inhibitory effects upon insulin, which has been seen to have direct effects upon proteolysis [46].

Now, since readers of this article are primarily interested in muscle growth, let’s focus this effort for a moment on how GH impacts muscle protein synthesis rates (MPS) specifically. There are numerous studies in the literature where GH was administered to healthy adult subjects and was found to have no impact on MPS rates [45,47-52]. What is intriguing about these findings is that a couple of the trials even included a resistance training element, yet still found no increase in local MPS rates. Conversely, there are a handful of studies which did result in increase MPS rates without any significant changes to whole body protein synthesis rates [53-55].

There are many reasons why these results may not be entirely consistent within the body of literature. One of the primary reasons would be how the trials were designed with regard to GH administration type (e.g. dosing concentration, whether it was locally or systemically administered, as well as whether the hormone was pulsed or constantly injected). Some of the other reasons include how protein synthesis was measured, whether subjects were fasted or fed, what type of skeletal muscle was examined, or even how long the trial lasted. Many of the effects GH has on protein metabolism are acute in nature, as mentioned earlier.

Although we are primarily concerned with hypertrophy, I still feel it is worth discussing the differences GH has on protein metabolism in the fasted and fed states. Doing so will help paint a clear picture of how its behavior is often the direct result of the environment it is introduced in. As I covered thoroughly in part one in this article series, GH secretion is increased during prolonged periods of fasting. This is a built in survival mechanism, with a primary goal being to conserve valuable stored amino pools via preventing protein breakdown [56]. This same protein-sparing behavior can be seen, to a lesser extent, in subjects provided GH and undergoing severe dietary restriction [57], obese subjects undergoing various types of hypocaloric dieting [58-61], and subjects being deprived of dietary protein [62].

IGF-1 has been shown to similarly inhibit whole-body protein breakdown [63], which would make sense due to the close relationship it has with GH. When amino acids and insulin are provided to test subjects alongside IGF-1, it has been demonstrated in both humans and animals that whole-body protein synthesis rates increase [64-65]. It is worth noting that IGF-1 is biphasic in the sense that how high it is dosed, and conversely how high serum IGF-1 levels are, changes its behavior more from “GH-like” to “insulin-like”. I will get much deeper into this topic a little later in the article.

To sum things up, GH is very well suited to prevent protein breakdown, and does so under a vast array of dietary-restricted conditions. However, in the presence of sufficient energy intake, its behavior changes. GH’s primary effect on protein metabolism is by first creating an environment with reduced amino acid oxidation [47,66] and second by increasing whole-body protein synthesis [67].

The Role of GH and IGF-1 in Postnatal Growth

It is well-established that GH regulates postnatal growth and that these growth promoting effects are primarily mediated via IGF-1 [68-69]. To reiterate though, it needs to be clarified that these growth promoting effects are not exclusive to hypertrophy. Linear growth of an organism includes changes to skeletal, organ, as well as muscle tissues.