Androgens primarily mediate their effects via the androgen receptor (AR) gene which is expressed in myoblasts, myofibers, and satellite cells [247-248]. ARs have also been detected in muscle-supporting cells, such as fibroblasts and endothelial cells. AR density appears to be muscle-group-specific, with both resistance training and AAS usage having the ability to affect the number of ARs present in these muscle groups. In addition to its effects on AR density, AAS use has also demonstrated the ability to affect AR activity levels in both an acute and long-term manner [249-250]. These are pretty important factors to consider when coming across individuals who claim that former AAS usage does not necessarily give someone a permanent competitive advantage.
Due to the overall complexity of the topic, there have been several hypotheses generated on the mechanisms by which AAS exerts its anabolic actions on skeletal muscle . Testosterone treatments have been shown to increase muscle protein synthesis (MPS) rates , decrease protein breakdown rates , and even cause the body to more efficiently utilize readily-available stored amino acids. So again, this is a fairly complex system that can just as well be simplified by remembering that AAS promote muscle anabolism via their ability to positively impact amino acid balance.
It is generally accepted that AAS exert their anabolic effects via binding with, and activating, the AR which subsequently activates downstream signaling cascades involving the Wnt-beta-catenin pathway [254-256]. Wingless/Int (Wnt) are a family of secreted glycoproteins that regulate cellular proliferation and differentiation [257-258]. Cell models have shown us that the AR forms a complex with beta-catenin which becomes enhanced in the presence of AAS [259-260]. Once this complex is activated, it translocates into the nuclei where it regulates the expression of target genes and the differentiation of satellite cells [261-262]. This also happens to be the AAS pathway largely responsible for myogenesis, the formation of muscular tissues [263-265].
It is worth noting that AAS also possess non-genomic characteristics which can rapidly affect numerous hormonal and metabolic processes outside of classical receptor binding. There have actually been reports in the literature of adult males with androgen insensitivity disorders, caused by AR mutations, who responded very similarly to healthy subjects in their response to testosterone. These case studies do reinforce the hypothesis that the anabolic effects of AAS can be mediated independent of the AR . The non-genomic actions of androgens can actually be quite a fascinating topic, yet a little beyond the intended scope of this article. For those that want to dive deeper into it, I would recommend starting with the reviews referenced here [267-268].
AAS – Potential for Synergy with the GH/IGF Axis
We’ve laid a lot of groundwork, but this is where things really start to get interesting. A logical question at this point would be are there any human trials on healthy subjects comparing the differences between single treatments of GH or androgens and combined treatments? Fortunately for us, the answer is “yes” as there have been a handful of trials, primarily using elderly subjects, including both male and female subjects. The results from each and every one of these trials clearly demonstrates that GH has an additive effect upon the well-established benefits that sex hormone therapy provides – namely hypertrophy, lipolysis, collagen synthesis, physical function, quality of life, and other various performance markers [187-188,269-270]. Since it is pretty clear an additive effect does exist, let’s see if we can dig deeper to uncover some of the underlying mechanisms working to achieve this androgen and GH synergy.
It must be understood that testosterone, in and of itself, has an additive effect on the entire GH/IGF axis. This has been seen in both human and animal subjects, with testosterone administration leading to increased circulating GH and IGF-1 levels [241,271-276]. Conversely, testosterone deficiency is commonly associated with significantly reduced levels of IGF-1 . The stimulatory effect testosterone has on the GH/IGF axis appears to be mediated at the hypothalamic level and a result of promoted GHRH functionality .
Furthermore, and this is a critical point to drive home, non-aromatizing androgens do not seem to possess this same stimulatory effect on the GH/IGF axis . Aromatase inhibitors (AIs), designed to suppress the aromatization process, have been shown to directly attenuate the stimulation of GH by testosterone administration. These clues provide pretty compelling evidence that local estrogens, via aromatization, play a pivotal role in the regulation of GH secretion in males [280-281]. Because aromatase is not expressed in the liver, AIs do not impact the hepatic action of GH but instead affect the GH system centrally [282-283], however selective estrogen receptor modulators (SERMs) are even more suppressive in that they act in almost a double negative manner due to their mechanism of action [284-285].
Even androgens that increase serum estrogen levels, such as nandrolone, show little-to-no effect on systemic GH and IGF levels as compared to testosterone . I speculate this is due to the fact that nandrolone does not aromatize via the aromatase enzyme like testosterone , which appears to be the most crucial step in androgen-mediated hypothalamic stimulation. Now please understand that someone using exogenous rHGH probably doesn’t have to worry about this as much as someone not using rHGH, considering hormone levels are almost exclusively being controlled by exogenous means. With that said, it is still something important to understand, when looking at the big picture, especially if maximizing hypertrophy is the goal.
Another potential reason that increased GH and IGF levels have been seen with testosterone treatments is due to its direct effects upon GHRs. Both human and animal studies have provided evidence that testosterone modifies GHRs in both the liver and peripheral tissues, enhancing GHR expression [288-289]. In addition, hypopituitary and hypogonadal human subjects undergoing GH treatments have shown augmented response to both local IGF-1 and androgen receptor gene expression when also administered testosterone [187,290-291]. Further to this, hypopituitary males provided with testosterone treatments only showed notable effects on protein anabolism in the presence of GH, with the primary site of hormonal interaction being the liver . So even when hormone levels are deficient, there is still a very important interplay going on between testosterone and the GH/IGF axis.
As I mentioned earlier, the GHR is expressed in just about all major tissue types. It is worth pointing out though that the GHR is expressed in very low amount in skeletal muscle – only around 4-33% of the levels seen in other tissues. On the other hand, the IGF receptor is expressed much higher in skeletal muscle, just as it is in hepatic tissues [293-294]. Even with that said, having increased GHR sensitivity to the supraphysiological amounts of available serum GH is only going to serve to benefit the bodybuilder. Bodybuilders continuously look to use high amounts of rHGH in their quest for maximal hypertrophy, and whether the GH is being used directly or subsequently converted to IGF-1 and used by skeletal muscle tissues, having an enhanced GH/IGF axis is going to be beneficial.