What will be included within this article are pieces to the puzzle of how one may use growth hormone to maximize their overall hypertrophy potential. For those that do not care about how I ultimately arrived at my final recommendations, please feel free to skip straight ahead to the “practical application” section located at the very end of the article. Okay, let’s begin…
How would you like to be equipped with a highly effective method to get bodybuilders to look at you first with confusion, followed shortly afterward by utter irritation? It’s quite simple really; just use any variation of the following statement:
Growth hormone causes lean body mass to significantly increase, is also highly anabolic, yet it won’t grow skeletal muscle tissue…
Over the course of this article, I’ll explain how this comment is 100% accurate despite seeming to be a bit nonsensical at first glance. To set some of the parameters up front, there will be talk about AAS as well as its synergistic relationship alongside GH, but there will only be a few mentions of insulin. The article was an enormous undertaking in its current format. I feel that in order to give the topic its just due, GH + insulin deserves its own article because of the immense complexities that exist in their relationship. I’m also not going to touch on GH secretagogues, exotic research peptides, or other analogs so that we can focus primarily on the core fundamentals. Unless otherwise stated in the article, assume we are talking about either endogenous or recombinant FDA-grade growth hormone.
And finally, this article is geared exclusively towards men. Sorry ladies, but males are far more responsive to the anabolic effects of GH supplementation than women, and GH is highly sexually dimorphic in nature [1]. So unless I clearly state otherwise, this will be male-oriented and I will have to save save a more female-friendly article for another time.
I. Introduction to Anabolism and Muscle Growth
The first thing we need to do is set ourselves up with some concise definitions of what things like anabolism, hypertrophy, and hyperplasia mean. I see them frequently used almost interchangeably, but there are quite a few key differences. For instance, just because something is anabolic does not automatically mean it will cause skeletal muscle tissue growth. Conversely just because something is catabolic does not automatically mean it cannot contribute to skeletal muscle tissue growth in a positive fashion.
Anabolism may be defined as any state in which nitrogen is positively retained in lean body mass, either via stimulation of protein synthesis or suppressed rates of proteolysis, which is just a fancy term for protein breakdown [2]. The first caveat to our earlier statement is that lean body mass measurements include both total body and free water in their calculations [3], which growth hormone is very adept at increasing. So, just because you read a study which claims lean body mass was increased by GH treatment, don’t automatically assume this is the same thing as concluding skeletal muscle tissue increased.
Skeletal muscle is a highly complex and plastic tissue able to adapt to the ever-changing functional demands being placed upon it. And when we talk about skeletal muscle increasing its mass, we are primarily talking about it doing so via one of two primary mechanisms – hypertrophy or hyperplasia.
Hypertrophy is the process by which an increase in skeletal muscle mass occurs via the increased size of an existing muscle fiber’s cross-sectional area (CSA). The hypertrophy process is mediated by many factors with exercise-induced hypertrophy, of special interest to bodybuilders, being mediated by a combination of mechanical tension, muscle damage, and metabolic stress [4].
Conversely, hyperplasia is the process by which an increase in skeletal muscle mass is achieved via an increase in the actual number of muscle fibers. It is generally accepted that, in humans, the number of fibers within skeletal muscle is genetically predetermined and fixed during the perinatal period [5]. There have been a handful of animal studies that have demonstrated that hyperplasia can occur [6-7], often under unique test conditions, but trying to infer from this that it occurs in humans [8-9] is highly speculative at best. Even if hyperplasia does occur in human muscle, it is very likely only a minor factor in the overall mass gaining picture and I’m not planning on spending a lot of time on it here. However, due to how often definitive claims are made that GH causes hyperplasia, it is worth reiterating that these types of statements should be seen as nothing more than speculative.
II. The Discovery of the “Hormone of Growth”
It has been well over 100 years since Harvey Cushing first proposed the existence of a “hormone of growth” [10] and growth hormone was later isolated, identified, and extracted from the human pituitary in the 1940s [11]. In the decade following, a pivotal hypothesis first proposed that it wasn’t this newly isolated GH peptide which was causing growth but rather a group of serum factors under the control of GH [12]. These serum factors were later referred to as sulfation factors, to indicate substances controlled by GH which stimulated sulfate uptake into cartilage and tissue. This hypothesis tried to help researchers better reconcile how somatic growth was being regulated by a substance secreted by the pituitary gland, while simultaneously reinforcing the fact that this pituitary-secreted substance did not act directly on its target tissues to promote growth [13-14].
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.
III. 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].
IV. 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.
To provide dramatic examples of the importance that GH and IGF-1 have on postnatal growth, look no further than individuals with either mutations or disorders related to the GH/IGF axis. A detailed review is beyond the scope of this article but, generally speaking, disorders that suppress/inhibit the GH/IGF axis at a young age result in short stature while those that stimulate the GH/IGF axis result in gigantism [70-71].
The vast majority of GH’s growth promoting effects are mediated via IGF-1, however there are a handful of things that are GH-mediated, or IGF-independent. The most telling example of this would be present in animal models where double GH/IGF “knockout” mutants are more severely growth retarded than with either GH or IGF “knockout” alone [72]. But let’s instead look at some of the more specific effects that have been identified in human models.
The first is hepatic steatosis, also known as “fatty liver disease” [73]. It has been demonstrated in both humans with Laron Syndrome and animals with GHR suppression that this condition can still occur in the presence of suppressed IGF-1 [74]. Laron Syndrome provides some rather unique insights on the GH/IGF system due to the fact it is caused by a mutation in the GHR which results in significantly low levels of endocrine IGF-1, as GH has effectively been prevented from stimulating IGF-1 production.
Another GH-specific action is related to its ability to enhance ovarian preantral follicle development. In fact, GH has even been under investigation recently for its potential enhancements on female fertility. Results indicate that some groups using in vitro fertilization (IVF) do appear to benefit from the administration of GH [75-76]. GHR deficient animal models have also consistently shown lower numbers of primary preantral and antral follicles than their control littermates.
One of the more interesting, and earliest discovered, GH-specific actions is its ability to promote longitudinal bone growth via its effects on chondrocyte (cartilage cell) generation in the epiphyseal growth plate region [19-20,77-80]. GH actually has dual roles in its promotion of longitudinal bone growth; both the aforementioned effects on chondrocyte generation in the growth plate but also an IGF-1 mediated role in promoting chondrocyte hypertrophy [81]. It is worth noting that fully intact endocrine IGF-1 levels aren’t even a necessity when it comes to postnatal bone growth. In fact, as long as there are at least 10-20% levels of circulating endocrine IGF-1 present, the combination of autocrine IGF-1 and GH can still ensure normal postnatal bone growth is achieved [82]. This is likely due to the overlapping roles autocrine and endocrine IGF-1 have as it relates to this longitudinal bone growth [83].
And last, but not least, is likely going to be the most relevant GH-mediated effect to readers of this article. GH promotes increased rates of late-stage muscle cell fusion which may have the ability to increase muscle fiber size in a manner completely independent of IGF-1 upregulation [84]. Using a novel animal cell technique, researchers were able to demonstrate that GH promoted fusion of myoblasts with nascent myotubes without an increase in actual IGF-1 mRNA expression. Nascent myotubes are present in the later stages of muscle cell fusion [85] and GH was shown to increase the number of nuclei per myotube. This will be something we’ll go into further, and discuss why this can be particularly advantageous, as we dive deeper into GH and hypertrophy later in the article.
V. The Relationship Between GH Secretion and IGF-1
Growth hormone is well-known to increase levels of circulating IGF-1 as well as the synthesis of IGF-1 locally, in an autocrine manner. Both of these play critical roles in muscle mass regulation, so let’s take a moment to better understand how GH secretion leads to increased endocrine and autocrine levels of IGF-1.
The vast majority of growth hormone in healthy adults is secreted from the pituitary gland and, more specifically, by the somatotroph cells in the anterior lobe as mediated by the transcription factor Prophet of Pit-1 (PROP1) [86-87]. GH can also be synthesized locally in many tissues such as the brain, immune cells, mammary tissues, teeth, and placenta which are all outside the regulation of the pituitary [88]. This supports the idea that GH has autocrine roles in addition to its already well established endocrine roles.
GH is natively pulsatile in all species [89-90] and this secretory pattern plays a major physiological role in everything from its sexual dimorphic characteristics to IGF-1 mRNA expression, which we will discover more about as we move forward. Healthy young adult males secrete between 0.4mg – 0.5mg every 24 hours, and many of these secretions occur as “pulses within pulses” [91]. Normally, there are around 10-12 secretory bursts each day with men having a significantly more regular pulse pattern than women. In males, GH is secreted episodically, with the well-known large evening surge occurring near the onset of slow-wave sleep. Males also have less dramatic secretions which occur a few hours after consuming meals [92-94]. Females have higher inter-secretory trough levels, particularly in the follicular phase of menstruation, with more frequent GH pulses during the day and a significantly lower nocturnal pulse than males [95-96]. It is not entirely clear why this sexually dimorphic secretory pattern exists.
The secretion of GH is regulated in a very complex manner involving the participation of several neurotransmitters, as well as both hormonal and metabolic feedbacks. It is principally positively regulated by GHRH, aptly named growth hormone releasing hormone [97], and negatively regulated by SRIF, or Somatostatin. Both of these peptides are produced within the hypothalamus. In fact, in addition to its base role in hormone production, the hypothalamus is also consistently monitoring the GHRH/SRIF ratio and consequently controlling secretion by the pituitary [98].
In addition to its primary function of stimulating GH secretion, GHRH also plays an essential role in the proliferation and development of the aforementioned somatotroph cells. In fact, in environments with impaired or absent GHRH, anterior pituitary hypoplasia has been observed which is likely a result of somatotroph maldevelopment [99-100]. Humans who had GHRH suppressed by an antagonist demonstrated severely impaired pulsatile GH release as well as suppressed GH response to GHRH [101], so it is clearly a vital component within the GH/IGF axis.
SRIF, the main negative regulator of GH secretion, suppresses TSH. In addition, to a lesser degree, it also suppresses both prolactin and the adrenocorticotropic hormone [97]. All of these are well-known to have close relationships with the GH/IGF axis, so this is not entirely surprising. SRIF has a short half-life of around 2-3 minutes in serum and is then rapidly inactivated by tissue peptidases. During its active time, it suppresses not only spontaneous GH release but also GH response to all external stimuli including GHRH, hypoglycemia, arginine, and exercise just to name a few. Its suppressive effects seemingly are limited to both the magnitude of basal and pulsatile GH release, as it has not been shown to alter GH pulse frequency [102].
Circulating GH is largely bound with carrier proteins referred to as GHBPs, or growth hormone binding proteins. These carrier proteins are essentially a soluble and truncated form of the extracellular domain of the GHR – mobile circulating GHRs which are not located within cellular membranes, if you will [103]. GH in circulation can also exist as free or unbound and the ratio of bound versus unbound is dependent upon the pulsatile pattern of its secretion [104]. Circulating GH complexes in humans can be comprised of one of two distinct GH molecules (22-kDa and 20-kDa), with roughly 90% being the 22-kDa molecule despite early estimates putting that number much lower [105-106]. Fun fact, modern indirect GH doping test methodologies can actually leverage the real-time ratios of circulating GH molecules within an athlete’s system to determine if someone has used rHGH in the past 24-36 hours prior to the test. The growth hormone molecule, in its correct 22-kDa form, is pictured below [107]:
Ultimately, this circulating GH binds with GHRs, which are class one cytokine receptors expressed in numerous cell-type membranes throughout the body [108-110]. The cellular surface levels, or receptor density, of these GHRs are the primary determinant of GH’s binding affinity to cells. GHR translocation, or the receptor relocating from a cell’s nucleus to its external membrane, is directly inhibited by IGF-1 – which is one of many feedback mechanisms that exist between these tightly related hormones. By inhibiting GHR translocation, IGF-1 directly contributes to lower the responsiveness of these cells to an external GH stimulus [111].
A deep-dive into tyrosine kinase activation, downstream signaling pathways, and gene expression is a bit beyond the scope of this article. So instead we’ll just stick our toes in the water and get them a little wet. I feel that we must touch on some of the high points of intracellular signaling to truly understand the underpinnings of the hypertrophy process, and why there are both compound synergies and potential optimized strategies for maximizing the process.
As mentioned already, GHRs exist on cellular membranes and they exist as preformed and inactive homodimers. This is really just a fancy way of saying the GHR has two identical protein receptor dimers, and these homodimers are always going to be coupled to JAK2 when devoid of enzymatic activity. This coupling to JAK2 causes an overall inhibitory action on the receptor [112-113]. In other words, the GHR lays dormant until it is activated as part of the GH/GHR binding process. When a GH molecule binds to the GHR, a structural change occurs within the GHR that results in actual movement of the receptor’s intracellular domains apart from one another. This relieves that inhibitory action of the JAK2 molecules and allows them to activate one another [114-116].
Next, one GH molecule binds sequentially to one of the two GHR homodimers, and the completion of this binding process facilitates interactions with the second homodimer. After this occurs, the intracellular domains of this newly formed GHR dimer undergo an actual rotation. Rotating the new GHR dimer allows the kinase domains of JAK2 to be in contact with one another, allowing them to transactivate and each subsequently binds to one JAK2 molecule [117-118]. Each JAK2 molecule will then perform cross-phosphorylation (activation) of tyrosine residues, and it is these residues which form “docking sites” for many of the different signaling molecules that make up the downstream signaling pathways, and ultimately lead to gene expression [114,118-120]. One of the more important downstream pathways for our purposes is the JAK-STAT pathway. This pathway is vital for both the hepatic transcription of IGF-1 by GH as well as many of the GH-mediated anabolic processes within skeletal muscle tissue. The vast majority of this complicated section was largely just background, so we could simply get to this last point.
Okay, my apologies, as I suppose it was our entire leg that just got wet and not only our toes. In any event, let’s take time to exhale for a moment while we move away from signaling pathways and go back to some higher level information for a bit…
VI. A Primer on IGF-1
We’ve previously gone over both the history and timeline by which GH and IGF-1 were discovered. However, I’d still like to cover some additional ground on the insulin-like growth factor family members to more firmly establish what they are, in addition to their roles in the hypertrophy process. The IGFs are a family of peptides, largely GH-dependent, who mediate many of the growth promoting actions that GH has [121]. The liver is chiefly responsible for all endocrine IGF-1 production, with around 75% being hepatically produced under the regulation of GH [83,122-123]. This assumes there are both sufficient dietary intake and elevated portal insulin levels [124-125]. Autocrine IGF-1 synthesis is also regulated by GH, in addition to other tissue-dependent autocrine factors [126-128].
The IGF family of peptides belong to a large family of over ten structurally similar proteins including IGF-1, IGF-2, insulin, relaxin, and pro-insulin [129]. They are all highly homologous in both structure and function and the metabolic effects of IGF-1 have even been characterized as “insulin-like” due to the similarities, and pathways, they share with one another. IGF-1 has over a 50% amino acid sequence homology with insulin and the IGF-1 receptor has a 60% amino acid sequence homology with the insulin receptor [121,130-131]. The similarities in structure are due to the fact that these peptides evolved from a single precursor molecule found in vertebrates over 60 million years ago [132]. Both IGF-1 and insulin secretion is stimulated by food intake, while being inhibited by fasting [83].
Due to these structural similarities, IGF family members can often bind with one another’s native receptor types [133]. To briefly summarize these cross-binding relationships, the IGF-1 molecule binds with the IGF-1 receptor with the highest affinity, however the IGF-1 receptor also binds with IGF-2 and insulin, but with significantly lower affinities. The IGF-2 receptor binds the IGF-2 molecule with the highest affinity but it also binds IGF-1 with a lower affinity, and it will not ever bind with insulin.
The family of IGF receptors have densities which vary significantly based upon the cell types in which they are present [132]. This is one of the reasons why insulin and IGF-1 can possess differing metabolic actions despite being so structurally similar. Cells such as hepatocytes and adipocytes have many more insulin receptors than IGF-1 receptors. Conversely, vascular smooth muscle cells located in blood vessels have significantly more IGF-1 receptors than insulin receptors.
Since we already did a deep-dive earlier on the chemical underpinnings which occur during GHR activation, I won’t do it again here. But please understand that the IGF family of receptors are also tyrosine kinase activated which, as we now know, leads to phosphorylation of substrates, activation of cellular pathways, and ultimately gene expression and protein synthesis [121]. IGF-1 receptor activation seems to be independent of the isoform from which IGF-1 was produced. Also, please note that both IGF receptor types have been found in human skeletal muscle cells [134].
Serum levels of IGF-1 are stable in healthy adults and there is little variation from day-to-day, or even week-to-week. In fact, looking at an individual’s serum IGF-1 levels can be a pretty decent indicator that one has GH sensitivity issues when compared against well-defined ranges, as corrected for their age and sex [135]. Of course, things like the individual’s overall nutritional state, as well as liver health, must also be considered when trying to decide if actual sensitivity issues exist.
In circulation, IGF-1 exists primarily in a bound state with IGF binding proteins (IGFBPs). The IGFBP superfamily includes six high-affinity proteins dubbed IGFBP-1 through IGFBP-6, as well as a number of lower affinity proteins referred to as IGFBP-related proteins [136]. Nearly 95% of all circulating IGF-1 exists in a bound state, with roughly 75% bound specifically with IGFBP-3 [137]. A small fraction of IGF-1 (normally under 5%) may also exist in the free state, and these unbound molecules importantly act as a negative regulator of GH secretion [104]. The IGFBPs can bind with either IGF-1 and IGF-2, but not insulin [138]
Going a bit further, bound IGF-1 most commonly exists in a 150-kDa ternary complex while in circulation. This ternary complex consists of one molecule each of IGF-1, IGFBP-3, and the acid labile subunit (ALS) – although it can exist in a binary complex with other IGFBPs [139-140]. These complexes serve valuable purposes by increasing the bioavailability of circulating IGFs, extending their serum half-life, transporting the IGFs to target cells, and modulating the interaction of the IGFs with their respective surface cellular membrane receptors [141-144]. For example, in plasma, the ternary complex stabilizes IGF-1, significantly increasing its half-life from less than 5 minutes to over 16 hours in some cases [137].
The IGFBPs normally appear to inhibit the action of IGFs, and this is because they compete with the IGF receptors for IGF binding affinity [145]. This is not always the case though, as IGFBPs are also capable of enhancing IGF actions, potentially by facilitating IGF delivery into the receptors [146]. Although there is a somewhat complex interplay, just remember that the primary role of IGFBPs are to transport IGFs from circulation and into peripheral tissues. Once this has been accomplished, the IGFBPs are released from the binary and ternary complexes either by proteolysis or via binding to the extracellular matrix of the IGF-1 receptor [147]. Once released, the IGF-1 molecules become unbound, active, and believed at this point to become available for action [137,143].
Once in the tissues the IGFBPs modulate IGF’s actions as they have a higher affinity for IGFs than the receptors [148], however they may also exert IGF-independent effects [149]. Some of the direct effects of IGFBPs that have already been elucidated include growth inhibition, direct induction of apoptosis, and modulating the effects of non-IGF growth factors [121].
Alternative splicing of the IGF-1 gene is also known to produce three distinct isoforms in humans which have both direct and indirect actions contributing to the growth promoting effects of IGF-1 [150-151]. Although they are not required for IGF-1 secretion, these isoforms may enhance the actual bioavailability of serum IGF-1 to its receptor [437]. The three isoforms are referred to as IGF-1Ea, IGF-1Eb, and IGF-1Ec. It is worth mentioning here that rodents and fish only possess two isoforms but the article will only be referring to human isoforms, unless otherwise clearly stated, to hopefully keep a confusing topic a little less confusing.
IGF-1Ea is similar to the main IGF isoform expressed by the hepatocytes of the liver and has exon 4 of the mature IGF-1 gene spliced directly to exon 6 [152]. IGF-1Eb is thought to be predominantly expressed in the liver but its role in muscle is still not completely understood [153]. It extends further downstream on exon 5 but only the first 17 aminos of this isoform are identical to those in the final isoform variant which I’ll cover momentarily [154]. This isoform is also thought to be unique to primates as it has not been found in rodents or fish [155].
IGF-1Ec is also referred to as mechano growth factor (MGF) and is named as such due to the fact it is expressed in a manner which responds to mechanical tension and stress [156-157]. Earlier we learned these are two of the primary mechanisms behind the hypertrophy process within skeletal muscle, and we’ll be talking a lot more about MGF as this article goes on. This isoform contains part of exon 5 spliced to exon 6 which results in a frame-shift and this mRNA is translated into an isoform with an alternative 25 aminos at the C-terminus [152]. Rodent IGF-1Eb shares a high homology with human MGF and both are often used interchangeably in the literature [158]. I only mention this because it can become a bit confusing when reviewing the literature on this isoform, especially when hopping back and forth between animal and human models.
MGF has been shown in cell culture models to increase the proliferation and migration of myoblasts, as well as being involved in satellite cell activation. Whether or not this is something that translates into real-world applicability is still a source of contention however. This behavior has been seen even in the presence of IGF-1 inactivation, which suggests MGF has the ability to operate independently of mature IGF-1 [438]. With that said, all IGF-1 isoforms do require a functional IGF-1 receptor to actually produce muscle hypertrophy as they do not affect the receptor in the absence of mature IGF-1 [439-440]. Actual response to MGF relies upon having an environment with active pools of satellite cells, as aged muscle tissues are normally in a state of dormancy. Finally, although finding legitimate injectable MGF is almost unicorn-like in bodybuilding circles, understand that full-length MGF appears to produce less activity in muscle than mature IGF-1, so its inherent value to bodybuilders may actually be overestimated [442].
VII. Somatopause
Studying elderly subjects brings a somewhat unique perspective to the table as it is well-known that sarcopenia, another term for degenerative muscle loss, occurs as we age. It is also well-established that levels of secreted GH and circulating IGF-1 gradually decline over one’s lifetime after peaking during puberty [159-162]. The decline in hormone levels is quite severe, with GH secretion declining by as much as 10-15% every decade after the age of 20 [163]. It was suggested many years ago that these senescent changes in body composition and metabolic functions are directly related to the decrease in hormone levels within the GH/IGF axis. The research community has actually coined the term “somatopause” to describe this phenomenon [159,164]
More succinctly stated, the somatopause hypothesis proposal [128] states:
- Changes in lifestyle and genetic predispositions promote accumulation of body fat with advancing age
- This increased fat mass increases FFA availability and thus induces insulin resistance
- High insulin levels suppress IGFBP-1 resulting in a relative increase in free IGF-1 levels
- Systemic elevations in FFA, insulin, and free IGF-1 suppress pituitary GH release, which further increases fat mass
- Endogenous GH is cleared more rapidly in subjects with increased fat mass
As you can see, this is a bit of a chicken and egg scenario. We gain body fat as we age, which causes insulin resistance, which suppresses GH secretion, which makes us more fat. It is kind of interesting to see that GH pulse frequency remains essentially intact though. The age-related attenuation is actually just a marked reduction in pulse amplitude alongside increased SRIF secretion [165].
The changes associated with somatopause very much resemble those seen in younger adults with clinical growth hormone deficiency (GHD). Although similar, elderly folks are normally not as severely impacted as GHD individuals and somatopause is not considered a disease state [160,166-167]. Examples of some of the changes associated with somatopause include reduced muscle and bone mass, reduced strength, diminished exercise and cardiac capacity, increased body fat (particularly in the visceral region), and cognitive deterioration.
Because of the desire to reverse the many detrimental effects related to aging, there is widespread speculation that GH administration may help as part of a complete hormone replacement therapy (HRT) program. A complete review of HRT and the elderly is beyond the scope of this article, but those who are interested can find a recent discussion on the topic here [168].
VIII. Does Growth Hormone Enhance Athletic Performance?
The emergence of GH as a performance enhancing drug (PED), outside of underground bodybuilding circles, is largely attributed to the release of the now infamous “Underground Steroid Handbook” in the early 1980s [169]. Subsequently, GH hit more of a mainstream audience when 1988 Olympic gold medal winner Ben Johnson admitted to using it alongside AAS after being stripped of his title following a failed blood test [170]. During this era, it was popularly believed that GH would increase muscle mass while simultaneously improving aspects of athletic performance [171]. And, as a response to this belief, in 1989 the IOC banned GH while labeling it as a PED as part of a new doping class of “peptide hormones and analogs”. It banned GH despite there being a lack of a legitimate test for rHGH at the time [172]. Despite all this, the question still remains – even with evidence suggesting that GH has been used in competitive athletics for decades, does it truly provide any measurable performance enhancing effects?
There have actually been multiple systematic reviews that have attempted to answer this question, but unfortunately they have all been far from conclusive as it relates to the ergogenic effects of GH [173-175]. And despite various scandals over the years, as well as the prevalence of GH usage by pro athletes, there is still very little clinical evidence to suggest that GH in isolation has any significant impact on performance enhancement in either healthy adults or younger subjects [173,176-179].
There have been a handful of tightly controlled trials which more directly attempted to look for its impacts on physical performance in healthy and trained subjects. Arguably the most interesting of the bunch demonstrated that supraphysiological doses of GH alongside AAS provided no significant improvements on VO2 consumption, strength, or explosive power as measured by jump height [180]. It did note a slight improvement in anaerobic sprint capacity, which was more noticeable on men and especially in those using the combined treatment. Considering this is an event where fractions of a second could mean the difference between winning and losing, it is certainly something worth noting.
By and large though, no increased aerobic performance is observed with GH administration when looking at the body of literature as a whole. This is the case when GH is administered at physiological doses to healthy subjects [181-182] as well as when it is administered in supraphysiological doses [180,183-184]. Aerobic capacity is also not affected by acute GH administration prior to training [185]. Any and all aerobic performance enhancements by GH actually appear to be mediated via androgens, and this is further supported by the results of a trial demonstrating former AAS users showing increased VO2 max, maximum inspiratory, and maximum expiratory pressure. Although it had been a few months since their last exposure to AAS, this was likely not enough time to entirely rule out any sort of AAS bleed over effect [186].
Healthy elderly subjects who were provided combined doses of testosterone and GH, designed to put them back into youthful hormone ranges, did experience improvements in certain measures of balance and physical performance [187]. These performance improvements seem to be more pronounced in men though, and are marginal at best, even with the combined treatments [188]. As has been discussed earlier, supraphysiological doses of GH may increase anaerobic capacity [180]. This is something that has also been seen on occasion when GHD subjects were treated with GH, putting them back into “normal” hormone ranges [182,189] .
The GH/IGF axis may also play a role in the regulation of vascular tone, or the degree of constriction as compared to a blood vessel’s maximally dilated state, thereby regulating peripheral resistance [190-191]. IGF-1 has been identified as a potent vasodilator, an effect partly mediated by increased nitric oxide release from the endothelium, the tissue that forms a layer of cells lining organs such as the heart and lymphatic vessels [192-194]. This potential for increased blood flow capacity has a myriad of hypothetical benefits on athletic endeavors.
The bottom line here is that, despite the lack of compelling evidence in the literature [434], athletes are often using doses and protocols that are not being replicated in trials. With that said, caution should still be exercised before completely dismissing GH as a performance enhancer simply based upon what the body of literature suggests to us. It is very possible that it is going to be a contributor to elite level athletes, and may be doing so via direct or indirect means.
IX. Direct Effects of GH and IGF-1 – Skeletal Muscle Hypertrophy
Let’s cut right to the chase – in and of itself, GH does not directly cause skeletal muscle hypertrophy. This has been studied extensively for decades and, so far, no credible study has been able to show a clear effect of medium-to-long term rHGH administration on hypertrophy – even in supraphysiological doses provided to high level athletes participating in rigorous resistance training.
The fact that this correlation has not been made is certainly not due to lack of trying. Plenty of research teams through the years have attempted to identify GH-mediated hypertrophy in healthy adult subjects [48,184,195-199] or elderly subjects [188,198,200-203] either unsuccessfully, or inconclusively. Furthermore, the acute exercise-induced increases in GH secretion have also been demonstrated to produce no changes in MPS or hypertrophy [204-205]. Interestingly, although the amount of trials occurring within the literature are significantly less common than those where GH was administered, systemic administration of rhIGF-1 has also been shown to result in no measurable hypertrophic effect in both young [63,206] and elderly [207-208] subjects.
There is recent evidence which suggests that chronic GH exposure increases the expression of the intramuscular pathways responsible for atrophy [209]. It stands to reason that many of the anabolic characteristics demonstrated by GH may be offset by this increased catabolic pathway expression, which could be why chronic exposure to GH does not lead to hypertrophy. It could also be responsible for why chronic GH exposure may produce less efficient and weaker muscles [210]. Quite simply, this may be yet another in long line of negative regulations built into the GH/IGF axis, but further studies are going to need to be conducted to further elucidate this hypothesis.
For those that plan on digging into the literature themselves after reading this article, which I highly encourage by the way, I want to make a very important distinction here which goes all the way back to my opening statement. Most GH trials do report an increase of lean body mass in their subject groups who were administered GH. So, at this juncture, one may be unclear how I can still be making these anti-hypertrophy claims? Well, we must remember that GH is very adept at causing water retention, as well as increasing soft tissue mass which I’ll talk about momentarily. Specifically, GH increases whole-body sodium retention, and consequently extracellular water, in a dose-dependent manner, via its effects on the renin-angiotensin system [211]. These increases in sodium and water retention have also been seen with IGF-1 administration, as IGF-1 itself seems to be a key regulator of renal sodium excretion rate [83,212-213]. So the real takeaway point here is to just be careful when drawing conclusions between reports of increased lean body mass and actual skeletal tissue growth.
X. Indirect Effects of GH and IGF-1 – Skeletal Muscle Hypertrophy
We’ve just spent the entirety of the last section talking about how both GH and IGF-1 have no direct impact on hypertrophy. However, this does not mean they do not contribute at all. My primary goal for this section of the article is to explain a few of the many mechanisms occurring behind the scenes, many of which will still be big factors to someone that is interested in maximizing their hypertrophy potential.
Growth hormone is a potent stimulator of collagen synthesis in both tendons and skeletal muscle. This effect is likely mediated via autocrine IGF-1’s ability to stimulate fibroblasts to synthesize it [214-215]. It actually does this without affecting skeletal muscle protein synthesis, despite both circulating and local IGF-1 being enhanced significantly. This effect is also induced independent of resistance training, and even seen in immobilized subjects provided with GH administration [216]. The connective component of skeletal muscle is vital for the transmission of force, which is produced by muscle fibers, to the tendons and bones for actual movement. Specifically, collagen is an important strength-carrying component of the extracellular matrix, which is continually being loaded during intense movements.
Because of GH’s potent effects on the components of the extracellular matrix, we may now begin to understand why anecdotes over the years suggested that adding GH into a hormone stack produced positive impacts on things like nagging aches and pains. On the other end of the spectrum, this also could be a primary contributing factor to why various side effects are reported by GH users such as soft tissue edema, joint pain, and carpal tunnel syndrome [217-219]. There are also many who believe GH can accelerate injury recovery time, however that is a complex topic that will be discussed another day.
GH’s impacts on collagen synthesis could also be of great interest to strength athletes who are not necessarily motivated by hypertrophy, but whose goals are creating an environment conducive to moving the absolute maximum weight from point A to point B. Stimulating collagen synthesis would potentially help strengthen the entire skeletal muscle support system. Now, it is worth adding a little clarifying side-note here. Despite this sounding great in principle, GH supplementation has never directly resulted in strength gains in any of the trials on otherwise healthy subjects, spanning various groups [48,50,184,196-198,200-201,203,220-221]. Of course, if GH was being used alongside something that did increase strength, it isn’t much of a leap to postulate that it may be a valuable accessory compound.
Decorin is a structural protein, residing primarily in the skeletal muscle extracellular matrix, and whose role is related to muscle growth and repair [222-223]. It was first shown that GH administration could directly increase decorin gene expression in animals a few decades ago [224]. It wasn’t until recently, however, that this effect was also shown to occur in recreationally trained human subjects [225]. In the more recent study, levels of decorin correlated strongly with those of PIIINP, which infers GH-mediated decorin stimulation may be involved in the bone collagen matrix assembly process. This effect is more pronounced in men than women and may be a byproduct of the higher IGF-1 levels seen in men, although this is speculative. The increased expression of decorin was not altered by the addition of testosterone, so this is an androgen-independent effect. After seeing the effects GH has on both collagen and decorin synthesis, it is becoming quite clear that the GH/IGF axis is far more important for strengthening the extracellular supportive matrix as opposed to directly contributing to skeletal muscle tissue growth.
Acute GH administration to healthy subjects has also been shown to cause increased mitochondrial ATP production and increased citrate synthase activity in skeletal muscle, with a higher abundance of muscle mRNAs encoding IGF-1 [226]. Not only could this be a contributing factor for why GH may have the ability to promote increased daily energy expenditure rates (an article for another day) but it may also be involved in the underlying shift to fat substrate fuel preference. Although, as we’ve reviewed earlier, the body of literature does not support this in practice, increased mitochondrial ATP production could play a role in aerobic capacity [227].
GH has been shown to promote the fusion of myoblasts with myotubes in cell models [84], an effect that is completely independent of local IGF-1 upregulation. To understand why this may be important, let’s deep-dive a bit further into the cellular factors involved in the hypertrophy of skeletal muscle. Skeletal muscle hypertrophy in humans relies on satellite cells, which are dormant cells located within myofibers, just under the basal lamina layer in the extracellular matrix [148]. Once these satellite cells are activated, often by exercise or muscle damage, they proliferate. After proliferation, these satellite cells migrate to sites of damage where they differentiate and fuse with existing myofibers which provides new nuclei for hypertrophy and repair [228]. It is still not entirely clear whether GH has a direct effect on the proliferation and differentiation of satellite cells [229-230]. It is also worth stating that what is seen in cell cultures may not be entirely indicative of what happens in vivo anyway due to various external factors which cannot be accounted for in lab conditions.
Continuing, there are two distinct stages of this myoblast fusion which take place [85]. The first would be the initial stage of differentiation where a subset of mononucleated cells fuse to form nascent myotubes (myoblast/myoblast fusion). This is followed by the second stage which involves additional available cells fusing with these nascent myotubes and where actual muscle growth occurs (myoblast/myotube fusion). It is within the latter stage where GH exerts its effects.
This is a pretty novel finding, but again, numerous trials on humans have failed to demonstrate a hypertrophic effect of GH in real-world conditions. So, we can probably infer from this that the effects GH has on the fusion of nascent myotubes does not translate directly into hypertrophy. However, what if we added another variable into the equation that could create an environment where enhanced satellite cell numbers existed, creating more raw materials for GH to work with [231]?
XI. Introducing AAS
Unlike GH and IGF, the use of anabolic androgenic steroids (AAS) has a pronounced impact on both hypertrophy and strength. This has been well-known for decades and why they have been used and abused by athletes going as far back as their creation in the 1930s [232]. The AAS family consist of a potent group of synthetic compounds which are similar in chemical structure to testosterone and/or its 5alpha reduced derivative DHT. Various types of individual AAS compounds have been created over the years by first starting with the natural testosterone molecule and then manipulating it via the addition of an ethyl, methyl, hydroxyl, or benzyl group at one or more sites along its structure [233-234]. A few of the more easily recognized AAS variants include 17-alpha alkylated androgens, which are able to be orally administered, and 19-nortestosterone variants which remove the 19-methyl group from the testosterone molecule in an effort to increase its anabolic activity while simultaneously decreasing its aromatization potential. Also referred to as “19nor”, this family includes well-known AAS variants such as nandrolone and trenbolone.
Many of these compound discoveries came about as a result of a low-level desire to increase the anabolic characteristics of testosterone within muscle, while simultaneously lowering the androgenic side-effects natively inherent with the testosterone molecule [235]. Generally speaking, overall side-effect risks from chronic AAS use actually appears to be relatively low when compared to many socially acceptable drugs such as alcohol, tobacco, and various prescription medications [233,236]. Of course, use and abuse are mutually exclusive terms and abusing any substance tends to create a higher risk environment. Unless otherwise clearly noted, from this point forward, I will spend most of my time talking specifically about testosterone as it is the native male endogenous sex hormone as well as the most heavily studied androgen in the literature. For reference, healthy adult males produce between 14-77 mg/week of endogenous testosterone [435].
Testosterone is well-known to regulate muscle mass, and these testosterone-mediated increases in muscle mass are associated with fiber hypertrophy, as well as an increase in satellite cells and myonuclear number [231,237-240]. Skeletal muscle just so happens to be one of the most testosterone-responsive tissues, and circulating testosterone levels have been estimated to account for a large percentage (40-75%) of the gains in muscle mass observed in randomized control trials. If you recall from the last section, it has been demonstrated that GH possesses a very unique ability in that it can increase myoblast fusion during the hypertrophy process. Maximizing this capability relies upon having adequate numbers of available satellite cells. For now, just make a mental note as we’ll be circling back around to this in a bit.
Results consistently show that testosterone treatments result in dose-dependent increases in skeletal muscle mass and strength, independent of whether the subject groups include younger or older males [241-243]. Conversely, in trials with healthy young subjects where endogenous testosterone was artificially suppressed, strength and body composition both suffered significantly [244]. To reiterate our earlier point, testosterone-mediated increases in skeletal muscle mass are hypertrophy-based and not a result of either fiber transition (changing type one fibers to type two fibers or vice versa) or splitting [245]. Because of their unique and non-overlapping anabolic mechanisms, testosterone administration and resistance training have also shown synergistic, additive effects upon one another with regard to stimulating increases in muscle mass [246].
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 [251]. Testosterone treatments have been shown to increase muscle protein synthesis (MPS) rates [252], decrease protein breakdown rates [253], 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 [266]. 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].
XII. 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 [277]. 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 [278].
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 [279]. 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 [286]. I speculate this is due to the fact that nandrolone does not aromatize via the aromatase enzyme like testosterone [287], 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 [292]. 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.
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.
XIII. Pharmacokinetics, Pharmacodynamics and Negative Feedbacks
As I’ve touched on earlier, the liver is the major target for GH, with GH being the chief regulator of hepatic IGF-1 production. To accomplish this, GH binds in the liver with GHRs located within the extracellular domain of hepatocytes and subsequently stimulates the production of endocrine IGF-1 via gene transcription, utilizing the JAK-STAT signaling pathway. Further to this, GH administration has been shown to cause a rapid upregulation of IGF-1 mRNA within the liver [338].
Increased serum levels of IGF-1 also occur very quickly in the presence of a large bolus of rHGH. Significant elevations of IGF-1 are already observable by the 6-12 hour mark post injection [339]. These serum IGF-1 levels continue to increase until they reach their dose-dependent saturation point within 4-7 days, even when using extremely high doses that amount to 20-30 IUs per day of rHGH [340]. This particular saturation point turned out to be somewhere within the 700-800 ng/mL range, and seems to suggest endocrine levels of IGF-1 do have an upper ceiling in healthy adults. The exact mechanisms are yet to be elucidated, but are likely a result of the complex feedback loops which exist in the GH/IGF axis. Even those who feel strongly that elevating endocrine levels of IGF-1 is advantageous to maximizing hypertrophy potential should keep this in mind, as there is a point where more rHGH will simply not result in higher serum IGF-1 levels. I’ve attached the chart from the Tanaka study below.
Now let’s spend a bit of time talking more about what autocrine IGF-1 does, and why it is a crucial mediator of the hypertrophy process, before getting back to further discussions on pharmacodynamics and pharmacokinetics. Signaling from the IGF-1 receptor is actually kind of unique in the sense that it uses two distinct pathways to stimulate either proliferation or differentiation [341-343]. This is quite interesting behavior, as no other growth factor family member has been shown to do this. Since proliferation and differentiation are opposing processes, it was originally difficult for researchers to understand how a single growth factor, via a single receptor, could send a signal which activated both [294]. Since those early discoveries were made, it has been further clarified that IGF-1 does not simultaneously perform these actions. Tests from various cell culture lines have demonstrated that the proliferative effects come first, lasting between 24-36 hours. It is only after this initial proliferative phase that myogenic differentiation occurs [344].
The IGF-1-mediated proliferative effects on myoblasts have been known since the 1970s, when it was first observed in rat liver cells [345]. This proliferative stimulation by IGF-1 results in an increase in cell number, protein levels, DNA synthesis, uptake of aminos, uptake of glucose, and suppression of proteolysis [346]. In human cell lines, IGF-1 has also been shown to increase the size of myotubes independent of whether myoblasts are actively proliferating, or if proliferation has ceased. It regulates myotube size by activating protein synthesis, inhibiting protein degradation, and inducing the fusion of reserve cells [347-348]. IGF’s ability to suppress proteolysis in skeletal muscle, the breakdown of proteins into aminos, has been demonstrated countless times over the years [349-352]. IGF-1 has also been shown to induce proliferation and differentiation of satellite cells into mature myocytes, as determined by an increase in the number of myofibers with centrally versus peripherally located nuclei [148,353-354].
The ability for autocrine IGF-1 to cause myoblast differentiation was actually a hybrid discovery that piggybacked off of studies from the 1960s demonstrating this effect occurred with high levels of insulin [355]. It was later shown that the IGFs are far more potent stimulators of myogenic differentiation than insulin and it was concluded that insulin really acts as an IGF-1 analog in this system [356-357]. The differentiation effects of autocrine IGF-1 are biphasic, with low concentrations progressively stimulating myoblast differentiation but very high concentrations showing all but ceased differentiating activity. The ceiling for differentiation to occur seems to be around 100 ng/mL for IGF-1 or 300 ng/mL for IGF-2 [358]. This is not caused by a switch to proliferation either, as there are no further increases in overall cell numbers observed [294]. It is possible that signaling molecules involved in the negative regulation of the myogenic system are increased, but this is speculative [359-360].
The administration of rHGH elevates local skeletal muscle IGF-1 mRNA expression in numerous cell, human, and animal models [127,150,361-364]. This happens quite quickly, within 60 minutes of a subcutaneous injection of rHGH, and peaks between the 6-12 hour mark [363]. In this particular cited animal model, doubling the dose of GH did not further increase IGF-1 mRNA levels, which suggests there is a ceiling effect with regard to how much GH is required to maximally stimulate local IGF-1 expression in skeletal muscle. We already have seen that IGF-1-mediated myocyte differentiation stops when local concentrations reach approximately 100 ng/mL but just how much GH is required to reach the IGF-1 mRNA expression saturation point?
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.
XIV. 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 [394]. 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 [403]. 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 [407]. Hyperthyroidism has also been hypothesized to accelerate urinary GH clearance [408]. Furthermore, animal studies have shown that thyroid hormones can have major suppressive effects upon GH-stimulated IGF-1 synthesis [409]. 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 [410].
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 [411]. 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 [412]. 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 [416]. 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 [429]. And chronic exposure to GH may actually lead to upregulated expression of myostatin and its receptor [209].
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 [430]. For this very reason, I do not feel it is something folks should necessarily be hyperfocused on.
XV. Practical Applications and Closing Thoughts
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.
I also feel very strongly that if one is going to use GH, it should be an FDA approved brand. These approved brands are required to go through years of tightly controlled trials to demonstrate their safety, purity, and efficacy on human subjects. Advances in technology over the years have made it a lot easier to produce rHGH that elicits GH activity at the receptor. Because of this, manufacturers now come from all over the globe. Often, these manufacturers produce what are referred to as “generic GH” on message boards, but I very much dislike that term. Calling something a “generic” implies it is a perfect replica of approved FDA brands that have lost their patent protection, which is not the case here. In fact, due to the extremely complex nature of the rHGH manufacturing process, the FDA does not even allow the use of the term “generic” when it comes to rHGH and instead uses the term “follow-on protein product” or FOPPs.
Often these off-label brands are a fraction of the cost, and therein lies the dilemma, as this can be very enticing. However, with this reduced cost to the consumer, there is also going to be no manufacturer’s guarantee as to what is in the vial or even how it was even manufactured. The bottom line is that the rHGH manufacturing process is extremely complex, and it is very easy for this process to falter at various stages resulting in protein variations that potentially lead to undesired effects, or even autoimmune responses.
You often see folks relying simply upon serum GH and/or IGF tests to conclude that a brand of GH is “good to go” but we must remember that getting hormone activity is the relatively easy part. Even GH molecules that have been altered or damaged during manufacturing can do this. However, these same damaged or mutated GH molecules can often simultaneously stimulate autoimmune responses. This could cause the body to have a degraded post-receptor response, even to its own endogenous secretions over time [431-432]. This does not even begin to touch on the question of what else is located within the vial, which is also anybody’s guess with these off-label brands.
GH should be used in a pulsatile fashion, to mimic in vivo conditions. In between these injections, a period of refractory must occur or one must consume an insulin-stimulating meal. Exogenous insulin can also be used to bypass many of the refractory period limitations, but this is beyond the scope of this article. Although the cumulation of daily doses should be supraphysiological, individual doses do not need to be highly dosed, as maximal stimulation of autocrine IGF-1 in skeletal muscle tissues happens to occur well within physiological GH concentrations. Anecdotally, there also appears to be a ceiling with which rHGH usage becomes additive in the presence of AAS. It may take some self-experimentation to find out where this individual saturation dose is, but most will find it to be somewhere in the 4-8 IUs/day range. Beyond this dose, most will tend to find that the cost justification as well as the risk/reward ratio tends to fall out of favor quickly.
Do not spend too much time hyper-focusing on when the GH injections must occur, because the elevations in autocrine IGF-1 come quickly and can stay elevated for days. Instead focus on the injection schedule that works best within the context of one’s day, while simultaneously keeping in mind the guidelines for the GH refractory period. Considerations may also be had for how small or large each injection would be, as some may find smaller and more frequent injections ideal while others may find larger and less frequent injections preferable. Of course, the larger the injection is, the higher the likelihood that one exceeds their autocrine IGF-1 ceiling.
Maximizing autocrine IGF-1 expression, while simultaneously keeping endocrine IGF-1 levels suppressed, is going to be a priority. There is evidence supporting the hypothesis that locally injecting GH can help to accomplish this goal, ultimately resulting in a lower chance of negative feedback regulations kicking in. There have been reports that significant increases in muscle size have been observed in as little as two weeks using local injections of IGF-1 [441].
Consider abstaining from compounds which may have detrimental effects on the overall goals at hand. Compounds such as AIs, SERMs, and thyroid have all been shown to demonstrate potential negative effects on the overall hypertrophy process and should be used sparingly, if at all.
This should come as no surprise to anyone – train hard, train smart, and train consistently. Although it was not directly addressed within the article, understand that resistance training has unique and additive impacts on hypertrophy. In fact, some of these mechanisms are not even mediated via the AR and/or GH/IGF axis [433]. Understand that there is no “magic training split”, rather the key will be consistency and ensuring adequate workload is achieved, with progressive overload elements over time. Dialing in your training will only serve to produce an additive effect on top of the hypertrophy potential already present with hormones alone.
I will wrap this up now, and leave you with this. Despite the wealth of evidence presented in this article, we still must always remember that nothing is absolute in the hormone game. Even examining the entire body of evidence will amount to little more than accumulating a set of data which will leave one with an intelligent starting point for further self-experimentation. Along these lines, the best results in practice often come from those who use a combination of applicable scientific principles alongside real-world in the trenches experience. And, even with that said, very rarely will two individuals respond identically to the exogenous supplementation of hormones, so don’t think that it is going to be as simple as finding something that worked for one person and then applying it to someone else.
To this end, I would urge folks to use this article as a starting point for your own self-experimentation, or potentially even motivate others to perform further experiments should they already possess significant hormone experience. Furthermore, I would highly encourage you to dig into the vast number of references provided below to see if you come up with the same conclusions that I do. When something is being cited in the article, ensure the reference listed actually supports the claims being made. Always keep an open mind and try not to ever become married to a singular opinion, especially in the face of new evidence. And finally, never accept someone’s conclusions as gospel, even mine – it is okay to trust but always verify.
Anchor your AAS stack with testosterone and/or nandrolone, use trenbolone sparingly
Avoid compounds which may result in detrimental effects on the hypertrophy process including AIs, SERMs, and thyroid
REFERENCES
1. Dall R, Longobardi S, Ehrnborg C, Keay N, Rosén T, Jørgensen JO, Cuneo RC,Boroujerdi MA, Cittadini A, Napoli R, Christiansen JS, Bengtsson BA, Sacca L,Baxter RC, Basset EE, Sönksen PH. The effect of four weeks of supraphysiological growth hormone administration on the insulin-like growth factor axis in women and men. GH-2000 Study Group. J Clin Endocrinol Metab. 2000 Nov;85(11):4193-200.
2. Kuhn CM. Anabolic steroids. Recent Prog Horm Res. 2002;57:411-34. Review.
3. Ribeiro SML, Kehayias JJ. Sarcopenia and the Analysis of Body Composition. Advances in Nutrition. 2014;5(3):260-267.
4. Schoenfeld BJ. The mechanisms of muscle hypertrophy and their application to resistance training. J Strength Cond Res. 2010 Oct;24 (10):2857-72.
5. Stickland NC. Muscle development in the human fetus as exemplified by m.sartorius: a quantitative study. J Anat. 1981 Jun;132(Pt 4):557-79.
6. Antonio J, Gonyea WJ. Skeletal muscle fiber hyperplasia. Med Sci Sports Exerc. 1993 Dec;25(12):1333-45. Review.
7. Fernández AM, Dupont J, Farrar RP, Lee S, Stannard B, Le Roith D.Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle. J Clin Invest. 2002 Feb;109(3):347-55.
8. Kadi F, Thornell LE. Training affects myosin heavy chain phenotype in the trapezius muscle of women. Histochem Cell Biol. 1999 Jul;112(1):73-8.
9. D’Antona G, Lanfranconi F, Pellegrino MA, Brocca L, Adami R, Rossi R, Moro G, Miotti D, Canepari M, Bottinelli R.Skeletal muscle hypertrophy and structure and function of skeletal muscle fibres in male body builders. J Physiol. 2006 Feb 1;570(Pt 3):611-27.
10. Cohen-Gadol AA, Liu JK, Laws ER Jr. Cushing’s first case of transsphenoidal surgery: the launch of the pituitary surgery era. J Neurosurg. 2005 Sep;103(3):570-4.
11. Li CH, Evans HM. THE ISOLATION OF PITUITARY GROWTH HORMONE. Science. 1944 Mar 3;99(2566):183-4.
12. SALMON WD Jr, DAUGHADAY WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med. 1957 Jun;49(6):825-36.
13. Daughaday WH, Reeder C. Synchronous activation of DNA synthesis in hypophysectomized rat cartilage by growth hormone. J Lab Clin Med. 1966 Sep;68(3):357-68.
14. Garland JT, Lottes ME, Kozak S, Daughaday WH. Stimulation of DNA synthesis in isolated chondrocytes by sulfation factor. Endocrinology. 1972 Apr;90(4):1086-90.
15. Daughaday WH, Hall K, Raben MS, Salmon WD Jr, van den Brande JL, van Wyk JJ.Somatomedin: proposed designation for sulphation factor. Nature. 1972 Jan 14;235(5333):107.
16. Le Roith D, Bondy C, Yakar S, Liu JL, Butler A. The somatomedin hypothesis: 2001. Endocr Rev. 2001 Feb;22(1):53-74. Review.
17. D’Ercole AJ, Applewhite GT, Underwood LE. Evidence that somatomedin is synthesized by multiple tissues in the fetus. Dev Biol. 1980 Mar 15;75(2):315-28.
18. Han VK, Lund PK, Lee DC, D’Ercole AJ. Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. J Clin Endocrinol Metab. 1988 Feb;66(2):422-9.
19. Isaksson OG, Jansson JO, Gause IA. Growth hormone stimulates longitudinal bone growth directly. Science. 1982 Jun 11;216 (4551):1237-9.
20. Isaksson OG, Lindahl A, Nilsson A, Isgaard J. Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth. Endocr Rev. 1987 Nov;8(4):426-38. Review.
21. Green H, Morikawa M, Nixon T. A dual effector theory of growth-hormone action. Differentiation. 1985;29(3):195-8. Review.
22. Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem. 1978 Apr 25;253(8):2769-76.
23. Klapper DG, Svoboda ME, Van Wyk JJ. Sequence analysis of somatomedin-C: confirmation of identity with insulin-like growth factor I. Endocrinology. 1983 Jun;112(6):2215-7.
24. Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 1989 Feb;10(1):68-91. Review.
25. Hintz RL, Liu F. Demonstration of specific plasma protein binding sites for somatomedin. J Clin Endocrinol Metab. 1977 Nov;45(5):988-95.
26. BECK JC, McGARRY EE, DYRENFURTH I, VENNING EH. The metabolic effects of human and monkey growth hormone in man. Ann Intern Med. 1958 Nov;49(5):1090-105.
27. IKKOS D, LUFT R, GEMZELL CA. The effect of human growth hormone in man. Lancet. 1958 Apr 5;1(7023):720-1.
28. RABEN MS, HOLLENBERG CH. Effect of growth hormone on plasma fatty acids. J Clin Invest. 1959 Mar;38(3):484-8. PubMed PMID: 13641397
29. RABEN MS. Growth hormone. 1. Physiologic aspects. N Engl J Med. 1962 Jan 4;266:31-5.
30. RABEN MS. Growth hormone. 2. Clinical use of human growth hormone. N Engl J Med. 1962 Jan 11;266:82-6 concl.
31. ZIERLER KL, RABINOWITZ D. ROLES OF INSULIN AND GROWTH HORMONE, BASED ON STUDIES OF FOREARM METABOLISM IN MAN. Medicine (Baltimore). 1963 Nov;42:385-402.
32. RABINOWITZ D, KLASSEN GA, ZIERLER KL. EFFECT OF HUMAN GROWTH HORMONE ON MUSCLE AND ADIPOSE TISSUE METABOLISM IN THE FOREARM OF MAN. J Clin Invest. 1965 Jan;44:51-61.
33. Fineberg SE, Merimee TJ. Acute metabolic effects of human growth hormone. Diabetes. 1974 Jun;23(6):499-504.
34. Appleby BS, Lu M, Bizzi A, et al. Iatrogenic Creutzfeldt-Jakob Disease from Commercial Cadaveric Human Growth Hormone. Emerging Infectious Diseases. 2013;19(4):682-684. doi:10.3201/eid1904.121504.
35.https://www.gene.com/media/press-releases/4235/1985-10-18/fda-approves-genentechs-drug-to-treat-ch
36. Flodh H. Human growth hormone produced with recombinant DNA technology: development and production. Acta Paediatr Scand Suppl. 1986;325:1-9.
37. Crist DM, Peake GT, Egan PA, Waters DL. Body composition response to exogenous GH during training in highly conditioned adults. J Appl Physiol (1985). 1988 Aug;65(2):579-84.
38. Møller N, Copeland KC, Nair KS. Growth hormone effects on protein metabolism. Endocrinol Metab Clin North Am. 2007 Mar;36(1):89-100. Review.
39. Argetsinger LS, Carter-Su C. Mechanism of signaling by growth hormone receptor. Physiol Rev. 1996 Oct;76(4):1089-107. Review.
40. Hayashi AA, Proud CG. The rapid activation of protein synthesis by growth hormone requires signaling through mTOR. Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1647-55.
41. Kostyo JL. Rapid effects of growth hormone on amino acid transport and protein synthesis. Ann N Y Acad Sci. 1968 Feb 5;148(2):389-407.
42. Cameron CM, Kostyo JL, Adamafio NA, Brostedt P, Roos P, Skottner A, Forsman A, Fryklund L, Skoog B. The acute effects of growth hormone on amino acid transport and protein synthesis are due to its insulin-like action. Endocrinology. 1988 Feb;122(2):471-4.
43. Vanderkuur JA, Butch ER, Waters SB, Pessin JE, Guan KL, Carter-Su C. Signaling molecules involved in coupling growth hormone receptor to mitogen-activated protein kinase activation. Endocrinology. 1997 Oct;138(10):4301-7.
44. Costoya JA, Finidori J, Moutoussamy S, Seãris R, Devesa J, Arce VM. Activation of growth hormone receptor delivers an antiapoptotic signal: evidence for a role of Akt in this pathway. Endocrinology. 1999 Dec;140(12):5937-43.
45. Copeland KC, Nair KS. Acute growth hormone effects on amino acid and lipid metabolism. J Clin Endocrinol Metab. 1994 May;78(5):1040-7.
46. Umpleby AM, Boroujerdi MA, Brown PM, Carson ER, Sönksen PH. The effect of metabolic control on leucine metabolism in type 1 (insulin-dependent) diabetic patients. Diabetologia. 1986 Mar;29(3):131-41.
47. Horber FF, Haymond MW. Human growth hormone prevents the protein catabolic side effects of prednisone in humans. J Clin Invest. 1990 Jul;86(1):265-72.
48. Yarasheski KE, Campbell JA, Smith K, Rennie MJ, Holloszy JO, Bier DM. Effect of growth hormone and resistance exercise on muscle growth in young men. Am J Physiol. 1992 Mar;262(3 Pt 1):E261-7.
49. Zachwieja JJ, Bier DM, Yarasheski KE. Growth hormone administration in older adults: effects on albumin synthesis. Am J Physiol. 1994 Jun;266(6 Pt 1):E840-4.
50. Yarasheski KE, Zachwieja JJ, Campbell JA, Bier DM. Effect of growth hormone and resistance exercise on muscle growth and strength in older men. Am J Physiol. 1995 Feb;268(2 Pt 1):E268-76.
51. Healy ML, Gibney J, Russell-Jones DL, Pentecost C, Croos P, Sönksen PH, Umpleby AM. High dose growth hormone exerts an anabolic effect at rest and during exercise in endurance-trained athletes. J Clin Endocrinol Metab. 2003 Nov;88(11):5221-6.
52. Giannoulis MG, Jackson N, Shojaee-Moradie F, Nair KS, Sonksen PH, Martin FC, Umpleby AM. The effects of growth hormone and/or testosterone on whole body protein kinetics and skeletal muscle gene expression in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab. 2008 Aug;93(8):3066-74.
53. Fryburg DA, Gelfand RA, Barrett EJ. Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans. Am J Physiol. 1991 Mar;260(3 Pt 1):E499-504.
54. Fryburg DA, Louard RJ, Gerow KE, Gelfand RA, Barrett EJ. Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin’s antiproteolytic action in humans. Diabetes. 1992 Apr;41(4):424-9.
55. Fryburg DA, Barrett EJ. Growth hormone acutely stimulates skeletal muscle but not whole-body protein synthesis in humans. Metabolism. 1993 Sep;42(9):1223-7.
56. Nørrelund H, Nair KS, Jørgensen JO, Christiansen JS, Møller N. The protein-retaining effects of growth hormone during fasting involve inhibition of muscle-protein breakdown. Diabetes. 2001 Jan;50(1):96-104.
57. Manson JM, Wilmore DW. Positive nitrogen balance with human growth hormone and hypocaloric intravenous feeding. Surgery. 1986 Aug;100(2):188-97.
58. Clemmons DR, Snyder DK, Williams R, Underwood LE. Growth hormone administration conserves lean body mass during dietary restriction in obese subjects. J Clin Endocrinol Metab. 1987 May;64(5):878-83.
59. Snyder DK, Clemmons DR, Underwood LE. Treatment of obese, diet-restricted subjects with growth hormone for 11 weeks: effects on anabolism, lipolysis, and body composition. J Clin Endocrinol Metab. 1988 Jul;67(1):54-61.
60. Tagliaferri M, Scacchi M, Pincelli AI, Berselli ME, Silvestri P, Montesano A, Ortolani S, Dubini A, Cavagnini F. Metabolic effects of biosynthetic growth hormone treatment in severely energy-restricted obese women. Int J Obes Relat Metab Disord. 1998 Sep;22(9):836-41.
61. Nørrelund H, Børglum J, Jørgensen JO, Richelsen B, Møller N, Nair KS, Christiansen JS. Effects of growth hormone administration on protein dynamics andsubstrate metabolism during 4 weeks of dietary restriction in obese women. Clin Endocrinol (Oxf). 2000 Mar;52(3):305-12.
62. Lundeberg S, Belfrage M, Wernerman J, von der Decken A, Thunell S, Vinnars E. Growth hormone improves muscle protein metabolism and whole body nitrogen economy in man during a hyponitrogenous diet. Metabolism. 1991 Mar;40(3):315-22
63. Fryburg DA. Insulin-like growth factor I exerts growth hormone- and insulin-like actions on human muscle protein metabolism. Am J Physiol. 1994 Aug;267(2 Pt 1):E331-6.
64. Russell-Jones DL, Umpleby AM, Hennessy TR, Bowes SB, Shojaee-Moradie F, Hopkins KD, Jackson NC, Kelly JM, Jones RH, Sönksen PH. Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans. Am J Physiol. 1994 Oct;267(4 Pt 1):E591-8.
65. Jacob R, Hu X, Niederstock D, Hasan S, McNulty PH, Sherwin RS, Young LH. IGF-I stimulation of muscle protein synthesis in the awake rat: permissive role of insulin and amino acids. Am J Physiol. 1996 Jan;270(1 Pt 1):E60-6.
66. Buijs MM, Romijn JA, Burggraaf J, De Kam ML, Cohen AF, Frölich M, Stellaard F, Meinders AE, Pijl H. Growth hormone blunts protein oxidation and promotes protein turnover to a similar extent in abdominally obese and normal-weight women. J Clin Endocrinol Metab. 2002 Dec;87(12):5668-74.
67. Gibney J, Wolthers T, Johannsson G, Umpleby AM, Ho KK. Growth hormone and testosterone interact positively to enhance protein and energy metabolism in hypopituitary men. Am J Physiol Endocrinol Metab. 2005 Aug;289(2):E266-71.
68. Le Roith D, Scavo L, Butler A. What is the role of circulating IGF-I? Trends Endocrinol Metab. 2001 Mar;12(2):48-52. Review.
69. Mauras N, Haymond MW. Are the metabolic effects of GH and IGF-I separable? Growth Horm IGF Res. 2005 Feb;15(1):19-27. Review.
70. Laron Z. Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. J Clin Endocrinol Metab. 2004 Mar;89(3):1031-44.
71. Muhammad A, van der Lely AJ, Neggers SJ. Review of current and emerging treatment options in acromegaly. Neth J Med. 2015 Oct;73(8):362-7. Review.
72. Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol. 2001 Jan 1;229(1):141-62.
73. Waters MJ. The growth hormone receptor. Growth Horm IGF Res. 2016 Jun;28:6-10.
74. Laron Z, Ginsberg S, Webb M. Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion – preliminary report. Growth Horm IGF Res. 2008 Oct;18(5):434-8.
75. Sharara FI. Value of growth hormone in ovulation induction? Fertil Steril. 1996 Jun;65(6):1259-61.
76. Kolibianakis EM, Venetis CA, Diedrich K, Tarlatzis BC, Griesinger G. Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in-vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update. 2009 Nov-Dec;15(6):613-22.
77. Russell SM, Spencer EM. Local injections of human or rat growth hormone or of purified human somatomedin-C stimulate unilateral tibial epiphyseal growth in hypophysectomized rats. Endocrinology. 1985 Jun;116(6):2563-7.
78. Schlechter NL, Russell SM, Greenberg S, Spencer EM, Nicoll CS. A direct growth effect of growth hormone in rat hindlimb shown by arterial infusion. Am J Physiol. 1986 Mar;250(3 Pt 1):E231-5.
79. Isaksson OG, Ohlsson C, Nilsson A, Isgaard J, Lindahl A. Regulation of cartilage growth by growth hormone and insulin-like growth factor I. Pediatr Nephrol. 1991 Jul;5(4):451-3. Review.
80. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC. Growth hormone and bone. Endocr Rev. 1998 Feb;19(1):55-79. Review.
81. Wang J, Zhou J, Cheng CM, Kopchick JJ, Bondy CA. Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth. J Endocrinol. 2004 Feb;180(2):247-55.
82. Yakar S, Rosen CJ, Bouxsein ML, Sun H, Mejia W, Kawashima Y, Wu Y, Emerton K, Williams V, Jepsen K, Schaffler MB, Majeska RJ, Gavrilova O, Gutierrez M, Hwang D, Pennisi P, Frystyk J, Boisclair Y, Pintar J, Jasper H, Domene H, Cohen P, Clemmons D, LeRoith D. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. FASEB J. 2009 Mar;23(3):709-19.
83. Ohlsson C, Mohan S, Sjögren K, Tivesten A, Isgaard J, Isaksson O, Jansson JO, Svensson J. The role of liver-derived insulin-like growth factor-I. Endocr Rev. 2009 Aug;30(5):494-535.
84. Sotiropoulos A, Ohanna M, Kedzia C, Menon RK, Kopchick JJ, Kelly PA, Pende M. Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation. Proc Natl Acad Sci U S A. 2006 May 9;103(19):7315-20.
85. Wakelam MJ. The fusion of myoblasts. Biochem J. 1985 May 15;228(1):1-12. Review.
86. Pfäffle RW, Blankenstein O, Wüller S, Kentrup H. Combined pituitary hormone deficiency: role of Pit-1 and Prop-1. Acta Paediatr Suppl. 1999 Dec;88(433):33-41. Review.
87. Hemchand K, Anuradha K, Neeti S, Vaman K, Roland P, Werner B, Sharmila B. Entire prophet of Pit-1 (PROP-1) gene deletion in an Indian girl with combined pituitary hormone deficiencies. J Pediatr Endocrinol Metab. 2011;24(7-8):579-80.
88. Waters MJ, Shang CA, Behncken SN, Tam SP, Li H, Shen B, Lobie PE. Growth hormone as a cytokine. Clin Exp Pharmacol Physiol. 1999 Oct;26(10):760-4. Review.
89. Jansson JO, Edén S, Isaksson O. Sexual dimorphism in the control of growth hormone secretion. Endocr Rev. 1985 Spring;6(2):128-50. Review.
90. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev. 1998 Dec;19(6):717-97. Review.
91. Hartman ML, Faria AC, Vance ML, Johnson ML, Thorner MO, Veldhuis JD. Temporal structure of in vivo growth hormone secretory events in humans. Am J Physiol. 1991 Jan;260(1 Pt 1):E101-10.
92. Takahashi Y, Kipnis DM, Daughaday WH. Growth hormone secretion during sleep. J Clin Invest. 1968 Sep;47(9):2079-90.
93. Parker DC, Sassin JF, Mace JW, Gotlin RW, Rossman LG. Human growth hormone release during sleep: electroencephalographic correlation. J Clin Endocrinol Metab. 1969 Jun;29(6):871-4.
94. Ho KY, Veldhuis JD, Johnson ML, Furlanetto R, Evans WS, Alberti KG, Thorner MO. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest. 1988 Apr;81(4):968-75.
95. Jaffe CA, Ocampo-Lim B, Guo W, Krueger K, Sugahara I, DeMott-Friberg R, Bermann M, Barkan AL. Regulatory mechanisms of growth hormone secretion are sexually dimorphic. J Clin Invest. 1998 Jul 1;102(1):153-64.
96. Jessup SK, Dimaraki EV, Symons KV, Barkan AL. Sexual dimorphism of growth hormone (GH) regulation in humans: endogenous GH-releasing hormone maintains basal GH in women but not in men. J Clin Endocrinol Metab. 2003 Oct;88(10):4776-80.
97. Goldenberg N, Barkan A. Factors regulating growth hormone secretion in humans. Endocrinol Metab Clin North Am. 2007 Mar;36(1):37-55. Review.
98. Müller EE, Locatelli V, Cocchi D. Neuroendocrine control of growth hormone secretion. Physiol Rev. 1999 Apr;79(2):511-607. Review.
99. Murray RA, Maheshwari HG, Russell EJ, Baumann G. Pituitary hypoplasia in patients with a mutation in the growth hormone-releasing hormone receptor gene. AJNR Am J Neuroradiol. 2000 Apr;21(4):685-9.
100. Murray PG, Higham CE, Clayton PE. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years. J Endocrinol. 2015 Aug;226(2):T123-40.
101. Russell-Aulet M, Dimaraki EV, Jaffe CA, DeMott-Friberg R, Barkan AL. Aging-related growth hormone (GH) decrease is a selective hypothalamic GH-releasing hormone pulse amplitude mediated phenomenon. J Gerontol A Biol Sci Med Sci. 2001 Feb;56(2):M124-9
102. Dimaraki EV, Jaffe CA, Demott-Friberg R, Russell-Aulet M, Bowers CY, Marbach P, Barkan AL. Generation of growth hormone pulsatility in women: evidence against somatostatin withdrawal as pulse initiator. Am J Physiol Endocrinol Metab. 2001 Mar;280(3):E489-95.
103. Baumann G. Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins. Endocr Rev. 1991 Nov;12(4):424-49. Review.
104. Vijayakumar A, Novosyadlyy R, Wu Y, Yakar S, LeRoith D. Biological effects of growth hormone on carbohydrate and lipid metabolism. Growth Horm IGF Res. 2010 Feb;20(1):1-7. doi: 10.1016/j.ghir.2009.09.002. Epub 2009 Oct 1. Review.
105. Herrington J, Carter-Su C. Signaling pathways activated by the growth hormone receptor. Trends Endocrinol Metab. 2001 Aug;12(6):252-7. Review.
106. Baumann G. Growth hormone binding protein. The soluble growth hormone receptor. Minerva Endocrinol. 2002 Dec;27(4):265-76. Review.
107. Bairoch A, Apweiler R. The SWISS-PROT protein sequence data bank and its new supplement TREMBL. Nucleic Acids Res. 1996 Jan 1;24(1):21-5.
108. Kelly PA, Djiane J, Postel-Vinay MC, Edery M. The prolactin/growth hormone receptor family. Endocr Rev. 1991 Aug;12(3):235-51. Review.
109. Vikman K, Carlsson B, Billig H, Edén S. Expression and regulation of growth hormone (GH) receptor messenger ribonucleic acid (mRNA) in rat adipose tissue, adipocytes, and adipocyte precursor cells: GH regulation of GH receptor mRNA. Endocrinology. 1991 Sep;129(3):1155-61.
110. Zou L, Menon RK, Sperling MA. Induction of mRNAs for the growth hormone receptor gene during mouse 3T3-L1 preadipocyte differentiation. Metabolism. 1997 Jan;46(1):114-8.
111. Leung KC, Waters MJ, Markus I, Baumbach WR, Ho KK. Insulin and insulin-like growth factor-I acutely inhibit surface translocation of growth hormone receptors in osteoblasts: a novel mechanism of growth hormone receptor regulation. Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11381-6.
112. Birzniece V, Sata A, Ho KK. Growth hormone receptor modulators. Rev Endocr Metab Disord. 2009 Jun;10(2):145-56.
113. Sawada T, Arai D, Jing X, Miyajima M, Frank SJ, Sakaguchi K. Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B. PLoS One. 2017 Jul 7;12(7):e0180785.
114. Brooks AJ, Dai W, O’Mara ML, Abankwa D, Chhabra Y, Pelekanos RA, Gardon O, Tunny KA, Blucher KM, Morton CJ, Parker MW, Sierecki E, Gambin Y, Gomez GA, Alexandrov K, Wilson IA, Doxastakis M, Mark AE, Waters MJ. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science. 2014 May 16;344(6185):1249783.
115. Liu Y, Berry PA, Zhang Y, Jiang J, Lobie PE, Paulmurugan R, Langenheim JF, Chen WY, Zinn KR, Frank SJ. Dynamic analysis of GH receptor conformational changes by split luciferase complementation. Mol Endocrinol. 2014 Nov;28(11):1807-19.
116. Waters MJ, Brooks AJ. JAK2 activation by growth hormone and other cytokines. Biochem J. 2015 Feb 15;466(1):1-11.
117. Brown RJ, Adams JJ, Pelekanos RA, Wan Y, McKinstry WJ, Palethorpe K, Seeber RM, Monks TA, Eidne KA, Parker MW, Waters MJ. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat Struct Mol Biol. 2005 Sep;12(9):814-21. Epub 2005 Aug 21.
118. Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord. 2006 Dec;7(4):225-35. Review.
119. Carter-Su C, Schwartz J, Smit LS. Molecular mechanism of growth hormone action. Annu Rev Physiol. 1996;58:187-207. Review.
120. Brooks AJ, Waters MJ. The growth hormone receptor: mechanism of activation and clinical implications. Nat Rev Endocrinol. 2010 Sep;6(9):515-25.
121. Cohen P. Overview of the IGF-I system. Horm Res. 2006;65 Suppl 1:3-8. Epub 2006 Mar 2. Review.
122. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7324-9.
123. Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. Molecular Pathology. 2001;54(5):311-316.
124. Wurzburger MI, Prelevic GM, Sönksen PH, Balint-Peric LA, Wheeler M. The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes. J Clin Endocrinol Metab. 1993 Jul;77(1):267-72.
125. Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002 Sep;110(6):771-81.
126. D’Ercole AJ, Stiles AD, Underwood LE. Tissue concentrations of somatomedin C: further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of action. Proc Natl Acad Sci U S A. 1984 Feb;81(3):935-9.
127. Gosteli-Peter MA, Winterhalter KH, Schmid C, Froesch ER, Zapf J. Expression and regulation of insulin-like growth factor-I (IGF-I) and IGF-binding protein messenger ribonucleic acid levels in tissues of hypophysectomized rats infused with IGF-I and growth hormone. Endocrinology. 1994 Dec;135(6):2558-67.
128. Gunawardane K, Krarup Hansen T, Sandahl Christiansen J, et al. Normal Physiology of Growth Hormone in Adults. [Updated 2015 Nov 12]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
129. Lu C, Lam HN, Menon RK. New members of the insulin family: regulators of metabolism, growth and now … reproduction. Pediatr Res. 2005 May;57(5 Pt 2):70R-73R.
130. Yakar S, Sun H, Zhao H, Pennisi P, Toyoshima Y, Setser J, Stannard B, Scavo L, Leroith D. Metabolic effects of IGF-I deficiency: lessons from mouse models. Pediatr Endocrinol Rev. 2005 Sep;3(1):11-9. Review.
131. Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007 Feb;28(1):20-47. Epub 2006 Aug 24. Review.
132. Clemmons DR. Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinol Metab Clin North Am. 2012 Jun;41(2):425-43, vii-viii.
133. Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res. 2002 Apr;12(2):84-90. Review.
134. Shimizu M, Webster C, Morgan DO, Blau HM, Roth RA. Insulin and insulin-like growth factor receptors and responses in cultured human muscle cells. Am J Physiol. 1986 Nov;251(5 Pt 1):E611-5.
135. Buckway CK, Guevara-Aguirre J, Pratt KL, Burren CP, Rosenfeld RG. The IGF-I generation test revisited: a marker of GH sensitivity. J Clin Endocrinol Metab. 2001 Nov;86(11):5176-83.
136. Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev. 1999 Dec;20(6):761-87. Review.
137. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002 Dec;23(6):824-54. Review.
138. Bach LA, Hsieh S, Sakano K, Fujiwara H, Perdue JF, Rechler MM. Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1-6. J Biol Chem. 1993 May 5;268(13):9246-54.
139. Boisclair YR, Rhoads RP, Ueki I, Wang J, Ooi GT. The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system. J Endocrinol. 2001 Jul;170(1):63-70. Review.
140. Duan C. Specifying the cellular responses to IGF signals: roles of IGF-binding proteins. J Endocrinol. 2002 Oct;175(1):41-54. Review.
141. LeRoith D. Insulin-like growth factor receptors and binding proteins. Baillieres Clin Endocrinol Metab. 1996 Jan;10(1):49-73. Review.
142. Rajaram S, Baylink DJ, Mohan S. Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev. 1997 Dec;18(6):801-31. Review.
143. Monzavi R, Cohen P. IGFs and IGFBPs: role in health and disease. Best Pract Res Clin Endocrinol Metab. 2002 Sep;16(3):433-47. Review.
144. Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev. 2008 Aug;29(5):535-59. Epub 2008 Apr 24. Review.
145. Collett-Solberg PF, Cohen P. Genetics, chemistry, and function of the IGF/IGFBP system. Endocrine. 2000 Apr;12(2):121-36. Review.
146. Wetterau LA, Moore MG, Lee KW, Shim ML, Cohen P. Novel aspects of the insulin-like growth factor binding proteins. Mol Genet Metab. 1999 Oct;68(2):161-81. Review.
147. Parker A, Rees C, Clarke J, Busby WH Jr, Clemmons DR. Binding of insulin-like growth factor (IGF)-binding protein-5 to smooth-muscle cell extracellular matrix is a major determinant of the cellular response to IGF-I. Mol Biol Cell. 1998 Sep;9(9):2383-92.
148. Velloso CP. Regulation of muscle mass by growth hormone and IGF-I. Br J Pharmacol. 2008 Jun;154(3):557-68. Review.
149. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995 Feb;16(1):3-34. Review.
150. Hameed M, Lange KH, Andersen JL, Schjerling P, Kjaer M, Harridge SD, Goldspink G. The effect of recombinant human growth hormone and resistance training on IGF-I mRNA expression in the muscles of elderly men. J Physiol. 2004 Feb 15;555(Pt 1):231-40. Epub 2003 Oct 17.
151. Pfeffer LA, Brisson BK, Lei H, Barton ER. The insulin-like growth factor (IGF)-I E-peptides modulate cell entry of the mature IGF-I protein. Mol Biol Cell. 2009 Sep;20(17):3810-7.
152. Zabłocka B, Goldspink PH, Goldspink G, Górecki DC. Mechano-Growth Factor: an important cog or a loose screw in the repair machinery? Front Endocrinol (Lausanne). 2012 Nov 1;3:131.
153. Rotwein P. Two insulin-like growth factor I messenger RNAs are expressed in human liver. Proc Natl Acad Sci U S A. 1986 Jan;83(1):77-81.
154. Siegfried JM, Kasprzyk PG, Treston AM, Mulshine JL, Quinn KA, Cuttitta F. A mitogenic peptide amide encoded within the E peptide domain of the insulin-like growth factor IB prohormone. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8107-11.
155. Barton ER, DeMeo J, Lei H. The insulin-like growth factor (IGF)-I E-peptides are required for isoform-specific gene expression and muscle hypertrophy after local IGF-I production. J Appl Physiol (1985). 2010 May;108(5):1069-76.
156. Yang S, Alnaqeeb M, Simpson H, Goldspink G. Cloning and characterization of an IGF-1 isoform expressed in skeletal muscle subjected to stretch. J Muscle Res Cell Motil. 1996 Aug;17(4):487-95.
157. McKoy G, Ashley W, Mander J, Yang SY, Williams N, Russell B, Goldspink G. Expression of insulin growth factor-1 splice variants and structural genes in rabbit skeletal muscle induced by stretch and stimulation. J Physiol. 1999 Apr 15;516 (Pt 2):583-92.
158. Yang SY, Goldspink G. Different roles of the IGF-I Ec peptide (MGF) and mature IGF-I in myoblast proliferation and differentiation. FEBS Lett. 2002 Jul 3;522(1-3):156-60. Erratum in: FEBS Lett. 2006 May 1;580(10):2530.
159. Rudman D, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest. 1981 May;67(5):1361-9.
160. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 1993 Feb;14(1):20-39. Review.
161. Veldhuis JD, Liem AY, South S, Weltman A, Weltman J, Clemmons DA, Abbott R, Mulligan T, Johnson ML, Pincus S, et al. Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab. 1995 Nov;80(11):3209-22.
162. Veldhuis JD, Iranmanesh A, Weltman A. Elements in the pathophysiology of diminished growth hormone (GH) secretion in aging humans. Endocrine. 1997 Aug;7(1):41-8. Review.
163. Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab. 1991 Nov;73(5):1081-8
164. Rudman D. Growth hormone, body composition, and aging. J Am Geriatr Soc. 1985 Nov;33(11):800-7. Review.
165. Russell-Aulet M, Jaffe CA, Demott-Friberg R, Barkan AL. In vivo semiquantification of hypothalamic growth hormone-releasing hormone (GHRH) output in humans: evidence for relative GHRH deficiency in aging. J Clin Endocrinol Metab. 1999 Oct;84(10):3490-7.
166. Martin FC, Yeo AL, Sonksen PH. Growth hormone secretion in the elderly: aging and the somatopause. Baillieres Clin Endocrinol Metab. 1997 Jul;11(2):223-50. Review.
167. Chertman LS, Merriam GR, Kargi AY. Growth Hormone in Aging. [Updated 2015 May 4]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
168. Sattler FR. Growth hormone in the aging male. Best Pract Res Clin Endocrinol Metab. 2013 Aug;27(4):541-55.
169. Duchaine D. Underground steroid handbook. 1. California: HLR Technical Books; 1983. p. 84
170. Sonksen PH. Insulin, growth hormone and sport. J Endocrinol. 2001 Jul;170(1):13-25. Review.
171. Macintyre JG. Growth hormone and athletes. Sports Med. 1987 Mar-Apr;4(2):129-42. Review.
172. Erotokritou-Mulligan I, Holt RI, Sönksen PH. Growth hormone doping: a review. Open Access Journal of Sports Medicine. 2011;2:99-111.
173. Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B, Bendavid E, Saynina O, Salpeter SR, Garber AM, Hoffman AR. Systematic review: the effects of growth hormone on athletic performance. Ann Intern Med. 2008 May 20;148(10):747-58. Epub 2008 Mar 17. Review.
174. Birzniece V, Nelson AE, Ho KK. Growth hormone and physical performance. Trends Endocrinol Metab. 2011 May;22(5):171-8. Mar 17. Review.
175. Baumann GP. Growth hormone doping in sports: a critical review of use and detection strategies. Endocr Rev. 2012 Apr;33(2):155-86. Epub 2012 Feb 24. Review.
176. Gibney J, Healy ML, Sönksen PH. The growth hormone/insulin-like growth factor-I axis in exercise and sport. Endocr Rev. 2007 Oct;28(6):603-24. Epub 2007 Sep 4. Review.
177. Holt RI, Sönksen PH. Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol. 2008 Jun;154(3):542-56. Epub 2008 Mar 31. Review.
178. Barroso O, Mazzoni I, Rabin O. Hormone abuse in sports: the antidoping perspective. Asian J Androl. 2008 May;10(3):391-402.
179. Frystyk J. Exercise and the growth hormone-insulin-like growth factor axis. Med Sci Sports Exerc. 2010 Jan;42(1):58-66.
180. Meinhardt U, Nelson AE, Hansen JL, Birzniece V, Clifford D, Leung KC, Graham K, Ho KK. The effects of growth hormone on body composition and physical performance in recreational athletes: a randomized trial. Ann Intern Med. 2010 May 4;152(9):568-77.
181. Wallace JD, Cuneo RC, Baxter R, Orskov H, Keay N, Pentecost C, Dall R, Rosén T, Jørgensen JO, Cittadini A, Longobardi S, Sacca L, Christiansen JS, Bengtsson BA, Sönksen PH. Responses of the growth hormone (GH) and insulin-like growth factor axis to exercise, GH administration, and GH withdrawal in trained adult males: a potential test for GH abuse in sport. J Clin Endocrinol Metab. 1999 Oct;84(10):3591-601.
182. Chikani V, Ho KK. Action of GH on skeletal muscle function: molecular and metabolic mechanisms. J Mol Endocrinol. 2013 Dec 19;52(1):R107-23.
183. Lange KH, Larsson B, Flyvbjerg A, Dall R, Bennekou M, Rasmussen MH, Ørskov H, Kjaer M. Acute growth hormone administration causes exaggerated increases in plasma lactate and glycerol during moderate to high intensity bicycling in trained young men. J Clin Endocrinol Metab. 2002 Nov;87(11):4966-75.
184. Berggren A, Ehrnborg C, Rosén T, Ellegård L, Bengtsson BA, Caidahl K. Short-term administration of supraphysiological recombinant human growth hormone (GH) does not increase maximum endurance exercise capacity in healthy, active young men and women with normal GH-insulin-like growth factor I axes. J Clin Endocrinol Metab. 2005 Jun;90(6):3268-73. Epub 2005 Mar 22.
185. Irving BA, Patrie JT, Anderson SM, Watson-Winfield DD, Frick KI, Evans WS, Veldhuis JD, Weltman A. The effects of time following acute growth hormone administration on metabolic and power output measures during acute exercise. J Clin Endocrinol Metab. 2004 Sep;89(9):4298-305. Epub 2004 Aug 24.
186. Graham MR, Baker JS, Evans P, Kicman A, Cowan D, Hullin D, Davies B. Evidence for a decrease in cardiovascular risk factors following recombinant growth hormone administration in abstinent anabolic-androgenic steroid users. Growth Horm IGF Res. 2007 Jun;17(3):201-9. Epub 2007 Feb 26.
187. Brill KT, Weltman AL, Gentili A, Patrie JT, Fryburg DA, Hanks JB, Urban RJ, Veldhuis JD. Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J Clin Endocrinol Metab. 2002 Dec;87(12):5649-57.
188. Blackman MR, Sorkin JD, Münzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O’Connor KG, Christmas C, Tobin JD, Stewart KJ, Cottrell E, St Clair C, Pabst KM, Harman SM. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA. 2002 Nov 13;288(18):2282-92.
189. Chikani V, Cuneo RC, Hickman I, Ho KK. Growth hormone (GH) enhances anaerobic capacity: impact on physical function and quality of life in adults with GH deficiency. Clin Endocrinol (Oxf). 2016 Oct;85(4):660-8.
190. Saccà L, Cittadini A, Fazio S. Growth hormone and the heart. Endocr Rev. 1994 Oct;15(5):555-73. Review.
191. Svensson J, Tivesten A, Isgaard J. Growth hormone and the cardiovascular function. Minerva Endocrinol. 2005 Mar;30(1):1-13. Review.
192. Copeland KC, Nair KS. Recombinant human insulin-like growth factor-I increases forearm blood flow. J Clin Endocrinol Metab. 1994 Jul;79(1):230-2.
193. Pete G, Hu Y, Walsh M, Sowers J, Dunbar JC. Insulin-like growth factor-I decreases mean blood pressure and selectively increases regional blood flow in normal rats. Proc Soc Exp Biol Med. 1996 Nov;213(2):187-92.
194. Walsh MF, Barazi M, Pete G, Muniyappa R, Dunbar JC, Sowers JR. Insulin-like growth factor I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide. Endocrinology. 1996 May;137(5):1798-803.
195. Crist DM, Peake GT, Egan PA, Waters DL. Body composition response to exogenous GH during training in highly conditioned adults. J Appl Physiol (1985). 1988 Aug;65(2):579-84.
196. Deyssig R, Frisch H, Blum WF, Waldhör T. Effect of growth hormone treatment on hormonal parameters, body composition and strength in athletes. Acta Endocrinol (Copenh). 1993 Apr;128(4):313-8.
197. Yarasheski KE, Zachweija JJ, Angelopoulos TJ, Bier DM. Short-term growth hormone treatment does not increase muscle protein synthesis in experienced weight lifters. J Appl Physiol (1985). 1993 Jun;74(6):3073-6.
198. Lange KH, Andersen JL, Beyer N, Isaksson F, Larsson B, Rasmussen MH, Juul A, Bülow J, Kjaer M. GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. J Clin Endocrinol Metab. 2002 Feb;87(2):513-23.
199. Ehrnborg C, Ellegård L, Bosaeus I, Bengtsson BA, Rosén T. Supraphysiological growth hormone: less fat, more extracellular fluid but uncertain effects on muscles in healthy, active young adults. Clin Endocrinol (Oxf). 2005 Apr;62(4):449-57.
200. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE. Effects of human growth hormone in men over 60 years old. N Engl J Med. 1990 Jul 5;323(1):1-6.
201. Taaffe DR, Pruitt L, Reim J, Hintz RL, Butterfield G, Hoffman AR, Marcus R. Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J Clin Endocrinol Metab. 1994 Nov;79(5):1361-6.
202. Taaffe DR, Jin IH, Vu TH, Hoffman AR, Marcus R. Lack of effect of recombinant human growth hormone (GH) on muscle morphology and GH-insulin-like growth factor expression in resistance-trained elderly men. J Clin Endocrinol Metab. 1996 Jan;81(1):421-5.
203. Hennessey JV, Chromiak JA, DellaVentura S, Reinert SE, Puhl J, Kiel DP, Rosen CJ, Vandenburgh H, MacLean DB. Growth hormone administration and exercise effects on muscle fiber type and diameter in moderately frail older people. J Am Geriatr Soc. 2001 Jul;49(7):852-8.
204. West DW, Kujbida GW, Moore DR, Atherton P, Burd NA, Padzik JP, De Lisio M, Tang JE, Parise G, Rennie MJ, Baker SK, Phillips SM. Resistance exercise-induced increases in putative anabolic hormones do not enhance muscle protein synthesis or intracellular signalling in young men. J Physiol. 2009 Nov 1;587(Pt 21):5239-47.
205. West DW, Burd NA, Tang JE, Moore DR, Staples AW, Holwerda AM, Baker SK, Phillips SM. Elevations in ostensibly anabolic hormones with resistance exercise enhance neither training-induced muscle hypertrophy nor strength of the elbow flexors. J Appl Physiol (1985). 2010 Jan;108(1):60-7.
206. Fryburg DA, Jahn LA, Hill SA, Oliveras DM, Barrett EJ. Insulin and insulin-like growth factor-I enhance human skeletal muscle protein anabolism during hyperaminoacidemia by different mechanisms. J Clin Invest. 1995 Oct;96(4):1722-9
207. Butterfield GE, Thompson J, Rennie MJ, Marcus R, Hintz RL, Hoffman AR. Effect of rhGH and rhIGF-I treatment on protein utilization in elderly women. Am J Physiol. 1997 Jan;272(1 Pt 1):E94-9.
208. Friedlander AL, Butterfield GE, Moynihan S, Grillo J, Pollack M, Holloway L, Friedman L, Yesavage J, Matthias D, Lee S, Marcus R, Hoffman AR. One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women. J Clin Endocrinol Metab. 2001 Apr;86(4):1496-503.
209. Consitt LA, Saneda A, Saxena G, List EO, Kopchick JJ. Mice overexpressing growth hormone exhibit increased skeletal muscle myostatin and MuRF1 with attenuation of muscle mass. Skelet Muscle. 2017 Sep 4;7(1):17.
210. Wolf E, Wanke R, Schenck E, Hermanns W, Brem G. Effects of growth hormone overproduction on grip strength of transgenic mice. Eur J Endocrinol. 1995 Dec;133(6):735-40.
211. Ho KY, Weissberger AJ. The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system. Metabolism. 1990 Feb;39(2):133-7.
212. Blazer-Yost BL, Cox M. Insulin-like growth factor 1 stimulates renal epithelial Na+ transport. Am J Physiol. 1988 Sep;255(3 Pt 1):C413-7.
213. Giordano M, DeFronzo RA. Acute effect of human recombinant insulin-like growth factor I on renal function in humans. Nephron. 1995;71(1):10-5.
214. Ehrnborg C, Lange KH, Dall R, Christiansen JS, Lundberg PA, Baxter RC, Boroujerdi MA, Bengtsson BA, Healey ML, Pentecost C, Longobardi S, Napoli R, Rosén T; GH-2000 Study Group. The growth hormone/insulin-like growth factor-I axis hormones and bone markers in elite athletes in response to a maximum exercise test. J Clin Endocrinol Metab. 2003 Jan;88(1):394-401.
215. Doessing S, Heinemeier KM, Holm L, Mackey AL, Schjerling P, Rennie M, Smith K, Reitelseder S, Kappelgaard AM, Rasmussen MH, Flyvbjerg A, Kjaer M. Growth hormone stimulates the collagen synthesis in human tendon and skeletal muscle without affecting myofibrillar protein synthesis. J Physiol. 2010 Jan 15;588(Pt 2):341-51.
216. Boesen AP, Dideriksen K, Couppé C, Magnusson SP, Schjerling P, Boesen M, Kjaer M, Langberg H. Tendon and skeletal muscle matrix gene expression and functional responses to immobilisation and rehabilitation in young males: effect of growth hormone administration. J Physiol. 2013 Dec 1;591(23):6039-52.
217. Cohn L, Feller AG, Draper MW, Rudman IW, Rudman D. Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations. Clin Endocrinol (Oxf). 1993 Oct;39(4):417-25.
218. Sullivan DH, Carter WJ, Warr WR, Williams LH. Side effects resulting from the use of growth hormone and insulin-like growth factor-I as combined therapy to frail elderly patients. J Gerontol A Biol Sci Med Sci. 1998 May;53(3):M183-7.
219. Dickerman RD, Douglas JA, East JW. Bilateral median neuropathy and growth hormone use: a case report. Arch Phys Med Rehabil. 2000 Dec;81(12):1594-5.
220. Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schambelan M, Grunfeld C. Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med. 1996 Apr 15;124(8):708-16.
221. Zachwieja JJ, Yarasheski KE. Does growth hormone therapy in conjunction with resistance exercise increase muscle force production and muscle mass in men and women aged 60 years or older? Phys Ther. 1999 Jan;79(1):76-82. Review.
222. Kishioka Y, Thomas M, Wakamatsu J, Hattori A, Sharma M, Kambadur R, Nishimura T. Decorin enhances the proliferation and differentiation of myogenic cells through suppressing myostatin activity. J Cell Physiol. 2008 Jun;215(3):856-67.
223. Kanzleiter T, Rath M, Görgens SW, Jensen J, Tangen DS, Kolnes AJ, Kolnes KJ, Lee S, Eckel J, Schürmann A, Eckardt K. The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem Biophys Res Commun. 2014 Jul 25;450(2):1089-94.
224. Zhang CZ, Li H, Bartold PM, Young WG, Waters MJ. Effect of growth hormone on the distribution of decorin and biglycan during odontogenesis in the rat incisor. J Dent Res. 1995 Oct;74(10):1636-43.
225. Bahl N, Stone G, McLean M, Ho KKY, Birzniece V. Decorin, a growth hormone regulated protein in humans. Eur J Endocrinol. 2017 Nov 14. pii: EJE-17-0844.
226. Short KR, Moller N, Bigelow ML, Coenen-Schimke J, Nair KS. Enhancement of muscle mitochondrial function by growth hormone. J Clin Endocrinol Metab. 2008 Feb;93(2):597-604. Epub 2007 Nov 13.
227. Lange KH, Isaksson F, Juul A, Rasmussen MH, Bülow J, Kjaer M. Growth hormone enhances effects of endurance training on oxidative muscle metabolism in elderly women. Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E989-96.
228. Chargé SB, Rudnicki MA. Cellular and molecular regulation of muscle regeneration. Physiol Rev. 2004 Jan;84(1):209-38. Review.
229. Halevy O, Hodik V, Mett A. The effects of growth hormone on avian skeletal muscle satellite cell proliferation and differentiation. Gen Comp Endocrinol. 1996 Jan;101(1):43-52.
230. Kim H, Barton E, Muja N, Yakar S, Pennisi P, Leroith D. Intact insulin and insulin-like growth factor-I receptor signaling is required for growth hormone effects on skeletal muscle growth and function in vivo. Endocrinology. 2005 Apr;146(4):1772-9. Epub 2004 Dec 23.
231. Sinha-Hikim I, Roth SM, Lee MI, Bhasin S. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E197-205. Epub 2003 Apr 1.
232. Ruzicka, L., Wettstein, A. and Kägi, H. (1935), Sexualhormone VIII. Darstellung von Testosteron unter Anwendung gemischter Ester. HCA, 18: 1478–1482.
233. Haupt HA, Rovere GD. Anabolic steroids: a review of the literature. Am J Sports Med. 1984 Nov-Dec;12(6):469-84. Review.
234. Shahidi NT. A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids. Clin Ther. 2001 Sep;23(9):1355-90. Review.
235. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005 Nov;60(11):1451-7
236. Hartgens F, Kuipers H. Effects of androgenic-anabolic steroids in athletes. Sports Med. 2004;34(8):513-54. Review.
237. Kadi F, Eriksson A, Holmner S, Thornell LE. Effects of anabolic steroids on the muscle cells of strength-trained athletes. Med Sci Sports Exerc. 1999 Nov;31(11):1528-34.
238. Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care. 2004 May;7(3):271-7. Review.
239. Eriksson A, Kadi F, Malm C, Thornell LE. Skeletal muscle morphology in power-lifters with and without anabolic steroids. Histochem Cell Biol. 2005 Aug;124(2):167-75.
240. Kadi F. Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle. A basis for illegal performance enhancement. Br J Pharmacol. 2008 Jun;154(3):522-8. Epub 2008 Apr 14. Review.
241. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C, Dzekov J, Bross R, Phillips J, Sinha-Hikim I, Shen R, Storer TW. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001 Dec;281(6):E1172-81.
242. Woodhouse LJ, Reisz-Porszasz S, Javanbakht M, Storer TW, Lee M, Zerounian H, Bhasin S. Development of models to predict anabolic response to testosterone administration in healthy young men. Am J Physiol Endocrinol Metab. 2003 May;284(5):E1009-17.
243. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, Magliano L, Storer TW. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab. 2005 Feb;90(2):678-88. Epub 2004 Nov 23.
244. Kvorning T, Andersen M, Brixen K, Madsen K. Suppression of endogenous testosterone production attenuates the response to strength training: a randomized, placebo-controlled, and blinded intervention study. Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1325-32. Epub 2006 Jul 25.
245. Sinha-Hikim I, Artaza J, Woodhouse L, Gonzalez-Cadavid N, Singh AB, Lee MI, Storer TW, Casaburi R, Shen R, Bhasin S. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol Metab. 2002 Jul;283(1):E154-64.
246. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996 Jul 4;335(1):1-7.
247. Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment. J Clin Endocrinol Metab. 2004 Oct;89(10):5245-55.
248. Klover P, Chen W, Zhu BM, Hennighausen L. Skeletal muscle growth and fiber composition in mice are regulated through the transcription factors STAT5a/b: linking growth hormone to the androgen receptor. FASEB J. 2009 Sep;23(9):3140-8.
249. Sheffield-Moore M, Urban RJ, Wolf SE, Jiang J, Catlin DH, Herndon DN, Wolfe RR, Ferrando AA. Short-term oxandrolone administration stimulates net muscle protein synthesis in young men. J Clin Endocrinol Metab. 1999 Aug;84(8):2705-11.
250. Kadi F, Bonnerud P, Eriksson A, Thornell LE. The expression of androgen receptors in human neck and limb muscles: effects of training and self-administration of androgenic-anabolic steroids. Histochem Cell Biol. 2000 Jan;113(1):25-9.
251. de Rooy C, Grossmann M, Zajac JD, Cheung AS. Targeting muscle signaling pathways to minimize adverse effects of androgen deprivation. Endocr Relat Cancer. 2016 Jan;23(1):R15-26.
252. Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men–a clinical research center study. J Clin Endocrinol Metab. 1996 Oct;81(10):3469-75.
253. Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ. Differential anabolic effects of testosterone and amino acid feeding in older men. J Clin Endocrinol Metab. 2003 Jan;88(1):358-62.
254. Bauer ER, Daxenberger A, Petri T, Sauerwein H, Meyer HH. Characterisation of the affinity of different anabolics and synthetic hormones to the human androgen receptor, human sex hormone binding globulin and to the bovine progestin receptor. APMIS. 2000 Dec;108(12):838-46.
255. Singh R, Artaza JN, Taylor WE, Gonzalez-Cadavid NF, Bhasin S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology. 2003 Nov;144(11):5081-8. Epub 2003 Jul 24.
256. Yarrow JF, McCoy SC, Borst SE. Tissue selectivity and potential clinical applications of trenbolone (17beta-hydroxyestra-4,9,11-trien-3-one): A potent anabolic steroid with reduced androgenic and estrogenic activity. Steroids. 2010 Jun;75(6):377-89.
257. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC. Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? Endocr Rev. 2005 Dec;26(7):898-915. Epub 2005 Aug 26. Review.
258. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006 Nov 3;127(3):469-80. Review.
259. Singh R, Bhasin S, Braga M, Artaza JN, Pervin S, Taylor WE, Krishnan V, Sinha SK, Rajavashisth TB, Jasuja R. Regulation of myogenic differentiation by androgens: cross talk between androgen receptor/ beta-catenin and follistatin/transforming growth factor-beta signaling pathways. Endocrinology. 2009 Mar;150(3):1259-68.
260. Zhao JX, Hu J, Zhu MJ, Du M. Trenbolone enhances myogenic differentiation by enhancing β-catenin signaling in muscle-derived stem cells of cattle. Domest Anim Endocrinol. 2011 May;40(4):222-9.
261. Armstrong DD, Esser KA. Wnt/beta-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy. Am J Physiol Cell Physiol. 2005 Oct;289(4):C853-9. Epub 2005 May 11.
262. Takada I, Kouzmenko AP, Kato S. Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol. 2009 Aug;5(8):442-7.
263. Cossu G, Borello U. Wnt signaling and the activation of myogenesis in mammals. EMBO J. 1999 Dec 15;18(24):6867-72. Review.
264. Buckingham M. Skeletal muscle formation in vertebrates. Curr Opin Genet Dev. 2001 Aug;11(4):440-8. Review.
265. Polesskaya A, Seale P, Rudnicki MA. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell. 2003 Jun 27;113(7):841-52.
266. Tincello DG, Saunders PT, Hodgins MB, Simpson NB, Edwards CR, Hargreaves TB, Wu FC. Correlation of clinical, endocrine and molecular abnormalities with in vivo responses to high-dose testosterone in patients with partial androgen insensitivity syndrome. Clin Endocrinol (Oxf). 1997 Apr;46(4):497-506.
267. Foradori CD, Weiser MJ, Handa RJ. Non-genomic Actions of Androgens. Frontiers in neuroendocrinology. 2008;29(2):169-181.
268. Lucas-Herald AK, Alves-Lopes R, Montezano AC, Ahmed SF, Touyz RM. Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications. Clin Sci (Lond). 2017 Jul 1;131(13):1405-1418.
269. Münzer T, Harman SM, Hees P, Shapiro E, Christmas C, Bellantoni MF, Stevens TE, O’Connor KG, Pabst KM, St Clair C, Sorkin JD, Blackman MR. Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. J Clin Endocrinol Metab. 2001 Aug;86(8):3604-10.
270. Sattler FR, Castaneda-Sceppa C, Binder EF, Schroeder ET, Wang Y, Bhasin S, Kawakubo M, Stewart Y, Yarasheski KE, Ulloor J, Colletti P, Roubenoff R, Azen SP. Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab. 2009 Jun;94(6):1991-2001.
271. Illig R, Prader A. Effect of testosterone on growth hormone secretion in patients with anorchia and delayed puberty. J Clin Endocrinol Metab. 1970 May;30(5):615-8.
272. Pfeilschifter J, Scheidt-Nave C, Leidig-Bruckner G, Woitge HW, Blum WF, Wüster C, Haack D, Ziegler R. Relationship between circulating insulin-like growth factor components and sex hormones in a population-based sample of 50- to 80-year-old men and women. J Clin Endocrinol Metab. 1996 Jul;81(7):2534-40.
273. Erfurth EM, Hagmar LE, Sääf M, Hall K. Serum levels of insulin-like growth factor I and insulin-like growth factor-binding protein 1 correlate with serum free testosterone and sex hormone binding globulin levels in healthy young and middle-aged men. Clin Endocrinol (Oxf). 1996 Jun;44(6):659-64.
274. van Kesteren P, Lips P, Deville W, Popp-Snijders C, Asscheman H, Megens J, Gooren L. The effect of one-year cross-sex hormonal treatment on bone metabolism and serum insulin-like growth factor-1 in transsexuals. J Clin Endocrinol Metab. 1996 Jun;81(6):2227-32.
275. Veldhuis JD, Keenan DM, Mielke K, Miles JM, Bowers CY. Testosterone supplementation in healthy older men drives GH and IGF-I secretion without potentiating peptidyl secretagogue efficacy. Eur J Endocrinol. 2005 Oct;153(4):577-86.
276. Lewis MI, Fournier M, Storer TW, Bhasin S, Porszasz J, Ren SG, Da X, Casaburi R. Skeletal muscle adaptations to testosterone and resistance training in men with COPD. J Appl Physiol (1985). 2007 Oct;103(4):1299-310.
277. Mauras N, Hayes V, Welch S, Rini A, Helgeson K, Dokler M, Veldhuis JD, Urban RJ. Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab. 1998 Jun;83(6):1886-92.
278. Bondanelli M, Ambrosio MR, Margutti A, Franceschetti P, Zatelli MC, degli Uberti EC. Activation of the somatotropic axis by testosterone in adult men: evidence for a role of hypothalamic growth hormone-releasing hormone. Neuroendocrinology. 2003 Jun;77(6):380-7.
279. Veldhuis JD, Metzger DL, Martha PM Jr, Mauras N, Kerrigan JR, Keenan B, Rogol AD, Pincus SM. Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement. J Clin Endocrinol Metab. 1997 Oct;82(10):3414-20.
280. Weissberger AJ, Ho KK. Activation of the somatotropic axis by testosterone in adult males: evidence for the role of aromatization. J Clin Endocrinol Metab. 1993 Jun;76(6):1407-12.
281. Veldhuis JD, Mielke KL, Cosma M, Soares-Welch C, Paulo R, Miles JM, Bowers CY. Aromatase and 5alpha-reductase inhibition during an exogenous testosterone clamp unveils selective sex steroid modulation of somatostatin and growth hormone secretagogue actions in healthy older men. J Clin Endocrinol Metab. 2009 Mar;94(3):973-81.
282. Yamamoto T, Sakai C, Yamaki J, Takamori K, Yoshiji S, Kitawaki J, Fujii M, Yasuda J, Honjo H, Okada H. Estrogen biosynthesis in human liver–a comparison of aromatase activity for C-19 steroids in fetal liver, adult liver and hepatoma tissues of human subjects. Endocrinol Jpn. 1984 Jun;31(3):277-81.
283. Hata S, Miki Y, Saito R, Ishida K, Watanabe M, Sasano H. Aromatase in human liver and its diseases. Cancer Med. 2013 Jun;2(3):305-15.
284. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators — mechanisms of action and application to clinical practice. N Engl J Med. 2003 Feb 13;348(7):618-29. Review. Erratum in: N Engl J Med. 2003 Mar 20;348(12):1192.
285. Löfgren L, Wallberg B, Wilking N, Fornander T, Rutqvist LE, Carlström K, von Schoultz B, von Schoultz E. Tamoxifen and megestrol acetate for postmenopausal breast cancer: diverging effects on liver proteins, androgens, and glucocorticoids. Med Oncol. 2004;21(4):309-18.
286. Hobbs CJ, Plymate SR, Rosen CJ, Adler RA. Testosterone administration increases insulin-like growth factor-I levels in normal men. J Clin Endocrinol Metab. 1993 Sep;77(3):776-9.
287. Centrella M, McCarthy TL, Chang WZ, Labaree DC, Hochberg RB. Estren (4-estren-3alpha,17beta-diol) is a prohormone that regulates both androgenic and estrogenic transcriptional effects through the androgen receptor. Mol Endocrinol. 2004 May;18(5):1120-30.
288. Yu YM, Domené HM, Sztein J, Counts DR, Cassorla F. Developmental changes and differential regulation by testosterone and estradiol of growth hormone receptor expression in the rabbit. Eur J Endocrinol. 1996 Nov;135(5):583-90.
289. Zung A, Phillip M, Chalew SA, Palese T, Kowarski AA, Zadik Z. Testosterone effect on growth and growth mediators of the GH-IGF-I axis in the liver and epiphyseal growth plate of juvenile rats. J Mol Endocrinol. 1999 Oct;23(2):209-21.
290. Hayes VY, Urban RJ, Jiang J, Marcell TJ, Helgeson K, Mauras N. Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects. J Clin Endocrinol Metab. 2001 May;86(5):2211-9.
291. Sculthorpe N, Solomon AM, Sinanan AC, Bouloux PM, Grace F, Lewis MP. Androgens affect myogenesis in vitro and increase local IGF-1 expression. Med Sci Sports Exerc. 2012 Apr;44(4):610-5.
292. Birzniece V, Meinhardt UJ, Umpleby MA, Handelsman DJ, Ho KK. Interaction between testosterone and growth hormone on whole-body protein anabolism occurs in the liver. J Clin Endocrinol Metab. 2011 Apr;96(4):1060-7.
293. Mertani HC, Delehaye-Zervas MC, Martini JF, Postel-Vinay MC, Morel G. Localization of growth hormone receptor messenger RNA in human tissues. Endocrine. 1995 Feb;3(2):135-42.
294. Florini JR, Ewton DZ, Coolican SA. Growth hormone and the insulin-like growth factor system in myogenesis. Endocr Rev. 1996 Oct;17(5):481-517. Review.
295. Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR, Wolfe RR, Ferrando A. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol. 1995 Nov;269(5 Pt 1):E820-6.
296. Ewton DZ, Coolican SA, Mohan S, Chernausek SD, Florini JR. Modulation of insulin-like growth factor actions in L6A1 myoblasts by insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5: a dual role for IGFBP-5. J Cell Physiol. 1998 Oct;177(1):47-57.
297. Venken K, Movérare-Skrtic S, Kopchick JJ, Coschigano KT, Ohlsson C, Boonen S, Bouillon R, Vanderschueren D. Impact of androgens, growth hormone, and IGF-I on bone and muscle in male mice during puberty. J Bone Miner Res. 2007 Jan;22(1):72-82.
298. Serra C, Bhasin S, Tangherlini F, Barton ER, Ganno M, Zhang A, Shansky J, Vandenburgh HH, Travison TG, Jasuja R, Morris C. The role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle. Endocrinology. 2011 Jan;152(1):193-206.
299. Spangenburg EE, Le Roith D, Ward CW, Bodine SC. A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy. J Physiol. 2008 Jan 1;586(1):283-91.
300. Yoshizawa A, Clemmons DR. Testosterone and insulin-like growth factor (IGF) I interact in controlling IGF-binding protein production in androgen-responsive foreskin fibroblasts. J Clin Endocrinol Metab. 2000 Apr;85(4):1627-33.
301. Gayan-Ramirez G, Rollier H, Vanderhoydonc F, Verhoeven G, Gosselink R, Decramer M. Nandrolone decanoate does not enhance training effects but increases IGF-I mRNA in rat diaphragm. J Appl Physiol (1985). 2000 Jan;88(1):26-34.
302. Lewis MI, Horvitz GD, Clemmons DR, Fournier M. Role of IGF-I and IGF-binding proteins within diaphragm muscle in modulating the effects of nandrolone. Am J Physiol Endocrinol Metab. 2002 Feb;282(2):E483-90
303. Salmons S. Myotrophic effects of an anabolic steroid in rabbit limb muscles. Muscle Nerve. 1992 Jul;15(7):806-12.
304. Bisschop A, Gayan-Ramirez G, Rollier H, Dekhuijzen PN, Dom R, de Bock V, Decramer M. Effects of nandrolone decanoate on respiratory and peripheral muscles in male and female rats. J Appl Physiol (1985). 1997 Apr;82(4):1112-8
305. Lewis MI, Fournier M, Yeh AY, Micevych PE, Sieck GC. Alterations in diaphragm contractility after nandrolone administration: an analysis of potential mechanisms. J Appl Physiol (1985). 1999 Mar;86(3):985-92.
306. Heitzman RJ. The effectiveness of anabolic agents in increasing rate of growth in farm animals; report on experiments in cattle. Environ Qual Saf Suppl. 1976;(5):89-98. Review.
307. Buttery, P., Vernon, B., & Pearson, J. (1978). Anabolic agents—some thoughts on their mode of action. Proceedings of the Nutrition Society, 37(3), 311-315.
308. Hongerholt DD, Crooker BA, Wheaton JE, Carlson KM, Jorgenson DM. Effects of a growth hormone-releasing factor analogue and an estradiol-trenbolone acetate implant on somatotropin, insulin-like growth factor I, and metabolite profiles in growing Hereford steers. J Anim Sci. 1992 May;70(5):1439-48.
309. Tan RS, Scally MC. Anabolic steroid-induced hypogonadism–towards a unified hypothesis of anabolic steroid action. Med Hypotheses. 2009 Jun;72(6):723-8.
310. Kamanga-Sollo E, White ME, Hathaway MR, Weber WJ, Dayton WR. Effect of Estradiol-17beta on protein synthesis and degradation rates in fused bovine satellite cell cultures. Domest Anim Endocrinol. 2010 Jul;39(1):54-62.
311. Kamanga-Sollo E, Thornton KJ, White ME, Dayton WR. Role of G protein-coupled estrogen receptor-1, matrix metalloproteinases 2 and 9, and heparin binding epidermal growth factor-like growth factor in estradiol-17β-stimulated bovine satellite cell proliferation. Domest Anim Endocrinol. 2014 Oct;49:20-6.
312. Dunn JD, Johnson BJ, Kayser JP, Waylan AT, Sissom EK, Drouillard JS. Effects of flax supplementation and a combined trenbolone acetate and estradiol implant on circulating insulin-like growth factor-I and muscle insulin-like growth factor-I messenger RNA levels in beef cattle. J Anim Sci. 2003 Dec;81(12):3028-34.
313. Pampusch MS, Johnson BJ, White ME, Hathaway MR, Dunn JD, Waylan AT, Dayton WR. Time course of changes in growth factor mRNA levels in muscle of steroid-implanted and nonimplanted steers. J Anim Sci. 2003 Nov;81(11):2733-40.
314. Pampusch MS, White ME, Hathaway MR, Baxa TJ, Chung KY, Parr SL, Johnson BJ, Weber WJ, Dayton WR. Effects of implants of trenbolone acetate, estradiol, or both, on muscle insulin-like growth factor-I, insulin-like growth factor-I receptor, estrogen receptor-{alpha}, and androgen receptor messenger ribonucleic acid levels in feedlot steers. J Anim Sci. 2008 Dec;86(12):3418-23.
315. Thompson SH, Boxhorn LK, Kong WY, Allen RE. Trenbolone alters the responsiveness of skeletal muscle satellite cells to fibroblast growth factor and insulin-like growth factor I. Endocrinology. 1989 May;124(5):2110-7.
316. Johnson BJ, Halstead N, White ME, Hathaway MR, DiCostanzo A, Dayton WR. Activation state of muscle satellite cells isolated from steers implanted with a combined trenbolone acetate and estradiol implant. J Anim Sci. 1998 Nov;76(11):2779-86.
317. Dalbo VJ, Roberts MD, Mobley CB, Ballmann C, Kephart WC, Fox CD, Santucci VA, Conover CF, Beggs LA, Balaez A, Hoerr FJ, Yarrow JF, Borst SE, Beck DT. Testosterone and trenbolone enanthate increase mature myostatin protein expression despite increasing skeletal muscle hypertrophy and satellite cell number in rodent muscle. Andrologia. 2017 Apr;49(3).
318. Bhasin S, He EJ, Kawakubo M, Schroeder ET, Yarasheski K, Opiteck GJ, Reicin A, Chen F, Lam R, Tsou JA, Castaneda-Sceppa C, Binder EF, Azen SP, Sattler FR. N-terminal propeptide of type III procollagen as a biomarker of anabolic response to recombinant human GH and testosterone. J Clin Endocrinol Metab. 2009 Nov;94(11):4224-33.
319. Nelson AE, Meinhardt U, Hansen JL, Walker IH, Stone G, Howe CJ, Leung KC, Seibel MJ, Baxter RC, Handelsman DJ, Kazlauskas R, Ho KK. Pharmacodynamics of growth hormone abuse biomarkers and the influence of gender and testosterone: a randomized double-blind placebo-controlled study in young recreational athletes. J Clin Endocrinol Metab. 2008 Jun;93(6):2213-22.
320. Holt RI. Detecting growth hormone misuse in athletes. Indian J Endocrinol Metab. 2013 Oct;17(Suppl 1):S18-22.
321. Tan SH, Lee A, Pascovici D, Care N, Birzniece V, Ho K, Molloy MP, Khan A. Plasma biomarker proteins for detection of human growth hormone administration in athletes. Sci Rep. 2017 Aug 30;7(1):10039.
322. Jørgensen JO, Jessen N, Pedersen SB, Vestergaard E, Gormsen L, Lund SA, Billestrup N. GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus. Am J Physiol Endocrinol Metab. 2006 Nov;291(5):E899-905.
323. Liu X, Robinson GW, Gouilleux F, Groner B, Hennighausen L. Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8831-5.
324. Hennighausen L, Robinson GW. Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev. 2008 Mar 15;22(6):711-21.
325. Eshet R, Laron Z, Pertzelan A, Arnon R, Dintzman M. Defect of human growth hormone receptors in the liver of two patients with Laron-type dwarfism. Isr J Med Sci. 1984 Jan;20(1):8-11.
326. Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell. 1998 May 29;93(5):841-50.
327. Hwa V, Little B, Adiyaman P, Kofoed EM, Pratt KL, Ocal G, Berberoglu M, Rosenfeld RG. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b. J Clin Endocrinol Metab. 2005 Jul;90(7):4260-6. Epub 2005 Apr 12.
328. Rowland JE, Lichanska AM, Kerr LM, White M, d’Aniello EM, Maher SL, Brown R, Teasdale RD, Noakes PG, Waters MJ. In vivo analysis of growth hormone receptor signaling domains and their associated transcripts. Mol Cell Biol. 2005 Jan;25(1):66-77. Erratum in: Mol Cell Biol. 2005 Mar;25(5):2072.
329. Klover P, Hennighausen L. Postnatal body growth is dependent on the transcription factors signal transducers and activators of transcription 5a/b in muscle: a role for autocrine/paracrine insulin-like growth factor I. Endocrinology. 2007 Apr;148(4):1489-97.
330. Barclay JL, Kerr LM, Arthur L, Rowland JE, Nelson CN, Ishikawa M, d’Aniello EM, White M, Noakes PG, Waters MJ. In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2. Mol Endocrinol. 2010 Jan;24(1):204-17.
331. Hwa V, Nadeau K, Wit JM, Rosenfeld RG. STAT5b deficiency: lessons from STAT5b gene mutations. Best Pract Res Clin Endocrinol Metab. 2011 Feb;25(1):61-75.
332. Varco-Merth B, Feigerlová E, Shinde U, Rosenfeld RG, Hwa V, Rotwein P. Severe growth deficiency is associated with STAT5b mutations that disrupt protein folding and activity. Mol Endocrinol. 2013 Jan;27(1):150-61.
333. Davey HW, Xie T, McLachlan MJ, Wilkins RJ, Waxman DJ, Grattan DR. STAT5b is required for GH-induced liver IGF-I gene expression. Endocrinology. 2001 Sep;142(9):3836-41.
334. Woelfle J, Chia DJ, Rotwein P. Mechanisms of growth hormone (GH) action. Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation. J Biol Chem. 2003 Dec 19;278(51):51261-6. Epub 2003 Oct 7.
335. Woelfle J, Billiard J, Rotwein P. Acute control of insulin-like growth factor-I gene transcription by growth hormone through Stat5b. J Biol Chem. 2003 Jun 20;278(25):22696-702. Epub 2003 Apr 7.
336. MacLean HE, Chiu WS, Notini AJ, Axell AM, Davey RA, McManus JF, Ma C, Plant DR, Lynch GS, Zajac JD. Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice. FASEB J. 2008 Aug;22(8):2676-89.
337. Tan SH, Dagvadorj A, Shen F, Gu L, Liao Z, Abdulghani J, Zhang Y, Gelmann EP, Zellweger T, Culig Z, Visakorpi T, Bubendorf L, Kirken RA, Karras J, Nevalainen MT. Transcription factor Stat5 synergizes with androgen receptor in prostate cancer cells. Cancer Res. 2008 Jan 1;68(1):236-48.
338. Mathews LS, Norstedt G, Palmiter RD. Regulation of insulin-like growth factor I gene expression by growth hormone. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9343-7.
339. Keller A, Wu Z, Kratzsch J, Keller E, Blum WF, Kniess A, Preiss R, Teichert J, Strasburger CJ, Bidlingmaier M. Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration. Eur J Endocrinol. 2007 Jun;156(6):647-53.
340. Tanaka T, Seino Y, Fujieda K, Igarashi Y, Yokoya S, Tachibana K, Ogawa Y. Pharmacokinetics and metabolic effects of high-dose growth hormone administration in healthy adult men. Endocr J. 1999 Aug;46(4):605-12.
341. Quinn LS, Steinmetz B, Maas A, Ong L, Kaleko M. Type-1 insulin-like growth factor receptor overexpression produces dual effects on myoblast proliferation and differentiation. J Cell Physiol. 1994 Jun;159(3):387-98.
342. Coolican SA, Samuel DS, Ewton DZ, McWade FJ, Florini JR. The mitogenic and myogenic actions of insulin-like growth factors utilize distinct signaling pathways. J Biol Chem. 1997 Mar 7;272(10):6653-62.
343. Foulstone EJ, Huser C, Crown AL, Holly JM, Stewart CE. Differential signalling mechanisms predisposing primary human skeletal muscle cells to altered proliferation and differentiation: roles of IGF-I and TNFalpha. Exp Cell Res. 2004 Mar 10;294(1):223-35.
344. Ewton DZ, Roof SL, Magri KA, McWade FJ, Florini JR. IGF-II is more active than IGF-I in stimulating L6A1 myogenesis: greater mitogenic actions of IGF-I delay differentiation. J Cell Physiol. 1994 Nov;161(2):277-84.
345. Florini JR, Nicholson ML, Dulak NC. Effects of peptide anabolic hormones on growth of myoblasts in culture. Endocrinology. 1977 Jul;101(1):32-41.
346. Laviola L, Natalicchio A, Giorgino F. The IGF-I signaling pathway. Curr Pharm Des. 2007;13(7):663-9. Review.
347. Jacquemin V, Furling D, Bigot A, Butler-Browne GS, Mouly V. IGF-1 induces human myotube hypertrophy by increasing cell recruitment. Exp Cell Res. 2004 Sep 10;299(1):148-58.
348. Jacquemin V, Butler-Browne GS, Furling D, Mouly V. IL-13 mediates the recruitment of reserve cells for fusion during IGF-1-induced hypertrophy of human myotubes. J Cell Sci. 2007 Feb 15;120(Pt 4):670-81. Epub 2007 Jan 30.
349. Ballard FJ, Francis GL. Effects of anabolic agents on protein breakdown in L6 myoblasts. Biochem J. 1983 Jan 15;210(1):243-9.
350. Ewton DZ, Falen SL, Florini JR. The type II insulin-like growth factor (IGF) receptor has low affinity for IGF-I analogs: pleiotypic actions of IGFs on myoblasts are apparently mediated by the type I receptor. Endocrinology. 1987 Jan;120(1):115-23.
351. Hembree JR, Hathaway MR, Dayton WR. Isolation and culture of fetal porcine myogenic cells and the effect of insulin, IGF-I, and sera on protein turnover in porcine myotube cultures. J Anim Sci. 1991 Aug;69(8):3241-50.
352. Hong D, Forsberg NE. Effects of serum and insulin-like growth factor I on protein degradation and protease gene expression in rat L8 myotubes. J Anim Sci. 1994 Sep;72(9):2279-88.
353. Florini JR, Ewton DZ, Roof SL. Insulin-like growth factor-I stimulates terminal myogenic differentiation by induction of myogenin gene expression. Mol Endocrinol. 1991 May;5(5):718-24.
354. Musarò A, McCullagh KJ, Naya FJ, Olson EN, Rosenthal N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature. 1999 Aug 5;400(6744):581-5.
355. Haba GDL, Cooper GW, Elting V. HORMONAL REQUIREMENTS FOR MYOGENESIS OF STRIATED MUSCLE IN VITRO: INSULIN AND SOMATOTROPIN. Proceedings of the National Academy of Sciences of the United States of America. 1966;56(6):1719-1723.
356. Florini JR, Ewton DZ. Insulin acts as a somatomedin analog in stimulating myoblast growth in serum-free medium. In Vitro. 1981 Sep;17(9):763-8.
357. Schmid C, Steiner T, Froesch ER. Preferential enhancement of myoblast differentiation by insulin-like growth factors (IGF I and IGF II) in primary cultures of chicken embryonic cells. FEBS Lett. 1983 Sep 5;161(1):117-21.
358. Florini JR, Ewton DZ, Falen SL, Van Wyk JJ. Biphasic concentration dependency of stimulation of myoblast differentiation by somatomedins. Am J Physiol. 1986 May;250(5 Pt 1):C771-8.
359. Quinn LS, Ehsan M, Steinmetz B, Kaleko M. Ligand-dependent inhibition of myoblast differentiation by overexpression of the type-1 insulin-like growth factor receptor. J Cell Physiol. 1993 Sep;156(3):453-61.
360. Olson EN. Signal transduction pathways that regulate skeletal muscle gene expression. Mol Endocrinol. 1993 Nov;7(11):1369-78. Review.
361. Murphy LJ, Bell GI, Friesen HG. Growth hormone stimulates sequential induction of c-myc and insulin-like growth factor I expression in vivo. Endocrinology. 1987 May;120(5):1806-12.
362. Turner JD, Rotwein P, Novakofski J, Bechtel PJ. Induction of mRNA for IGF-I and -II during growth hormone-stimulated muscle hypertrophy. Am J Physiol. 1988 Oct;255(4 Pt 1):E513-7.
363. Isgaard J, Nilsson A, Vikman K, Isaksson OG. Growth hormone regulates the level of insulin-like growth factor-I mRNA in rat skeletal muscle. J Endocrinol. 1989 Jan;120(1):107-12.
364. Bichell DP, Kikuchi K, Rotwein P. Growth hormone rapidly activates insulin-like growth factor I gene transcription in vivo. Mol Endocrinol. 1992 Nov;6(11):1899-908.
365. Sadowski CL, Wheeler TT, Wang LH, Sadowski HB. GH regulation of IGF-I and suppressor of cytokine signaling gene expression in C2C12 skeletal muscle cells. Endocrinology. 2001 Sep;142(9):3890-900.
366. Frost RA, Nystrom GJ, Lang CH. Regulation of IGF-I mRNA and signal transducers and activators of transcription-3 and -5 (Stat-3 and -5) by GH in C2C12 myoblasts. Endocrinology. 2002 Feb;143(2):492-503.
367. MacLeod JN, Pampori NA, Shapiro BH. Sex differences in the ultradian pattern of plasma growth hormone concentrations in mice. J Endocrinol. 1991 Dec;131(3):395-9.
368. Rochiccioli P, Messina A, Tauber MT, Enjaume C. Correlation of the parameters of 24-hour growth hormone secretion with growth velocity in 93 children of varying height. Horm Res. 1989;31(3):115-8.
369. Hansen TK, Gravholt CH, ØRskov H, Rasmussen MH, Christiansen JS, Jørgensen JO. Dose dependency of the pharmacokinetics and acute lipolytic actions of growth hormone. J Clin Endocrinol Metab. 2002 Oct;87(10):4691-8.
370. Baum WF, Klöditz E, Hesse V, Jahreis G, Schneyer U, Giebler H. [Increase in spontaneous growth hormone secretion in asthmatic children–a symptom of atopic disposition?]. Kinderarztl Prax. 1993 Nov;61(9):323-8.
371. Adams GR, McCue SA. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats. J Appl Physiol (1985). 1998 May;84(5):1716-22.
372. Alzghoul MB, Gerrard D, Watkins BA, Hannon K. Ectopic expression of IGF-I and Shh by skeletal muscle inhibits disuse-mediated skeletal muscle atrophy and bone osteopenia in vivo. FASEB J. 2004 Jan;18(1):221-3. Epub 2003 Nov 3.
373. Lee S, Barton ER, Sweeney HL, Farrar RP. Viral expression of insulin-like growth factor-I enhances muscle hypertrophy in resistance-trained rats. J Appl Physiol (1985). 2004 Mar;96(3):1097-104. Erratum in: J Appl Physiol. 2004 Jun;96(6):2343.
374. Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery C, Schwartz RJ. Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice. J Biol Chem. 1995 May 19;270(20):12109-16.
375. Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15603-7.
376. Musarò A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001 Feb;27(2):195-200
377. Lewis MI, Bulut Y, Biring MS, Da X, Fournier M. (1999) IGF-I administration prevents corticosteroids-induced diaphragm atrophy in emphysema . Am J Respir Crit Care Med 159:A580
378. Fournier M, Huang ZS, Cercek B, Li H, Bykhovskaya I, Lewis MI. (2000) Administration of insulin-like growth factor-1 (IGF-I) and corticosteroids in emphysematous hamsters: influences on diaphragm IGF-I . Am J Respir Crit Care Med 161:A18
379. Shavlakadze T, Grounds M. Of bears, frogs, meat, mice and men: complexity of factors affecting skeletal muscle mass and fat. Bioessays. 2006 Oct;28(10):994-1009. Review.
380. Maiter D, Underwood LE, Maes M, Davenport ML, Ketelslegers JM. Different effects of intermittent and continuous growth hormone (GH) administration on serum somatomedin-C/insulin-like growth factor I and liver GH receptors in hypophysectomized rats. Endocrinology. 1988 Aug;123(2):1053-9.
381. Isgaard J, Carlsson L, Isaksson OG, Jansson JO. Pulsatile intravenous growth hormone (GH) infusion to hypophysectomized rats increases insulin-like growth factor I messenger ribonucleic acid in skeletal tissues more effectively than continuous GH infusion. Endocrinology. 1988 Dec;123(6):2605-10.
382. Clark RG, Jansson JO, Isaksson O, Robinson IC. Intravenous growth hormone: growth responses to patterned infusions in hypophysectomized rats. J Endocrinol. 1985 Jan;104(1):53-61.
383. Bick T, Hochberg Z, Amit T, Isaksson OG, Jansson JO. Roles of pulsatility and continuity of growth hormone (GH) administration in the regulation of hepatic GH-receptors, and circulating GH-binding protein and insulin-like growth factor-I. Endocrinology. 1992 Jul;131(1):423-9.
384. Weltman A, Weltman JY, Schurrer R, Evans WS, Veldhuis JD, Rogol AD. Endurance training amplifies the pulsatile release of growth hormone: effects of training intensity. J Appl Physiol (1985). 1992 Jun;72(6):2188-96.
385. Flores-Morales A, Greenhalgh CJ, Norstedt G, Rico-Bautista E. Negative regulation of growth hormone receptor signaling. Mol Endocrinol. 2006 Feb;20(2):241-53. Epub 2005 Jul 21. Review.
386. Hartman ML, Veldhuis JD, Thorner MO. Normal control of growth hormone secretion. Horm Res. 1993;40(1-3):37-47. Review.
387. Fernández L, Flores-Morales A, Lahuna O, Sliva D, Norstedt G, Haldosén LA, Mode A, Gustafsson JA. Desensitization of the growth hormone-induced Janus kinase 2 (Jak 2)/signal transducer and activator of transcription 5 (Stat5)-signaling pathway requires protein synthesis and phospholipase C. Endocrinology. 1998 Apr;139(4):1815-24.
388. Gebert CA, Park SH, Waxman DJ. Termination of growth hormone pulse-induced STAT5b signaling. Mol Endocrinol. 1999 Jan;13(1):38-56.
389. Ram PA, Waxman DJ. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J Biol Chem. 1999 Dec 10;274(50):35553-61.
390. Ram PA, Waxman DJ. Role of the cytokine-inducible SH2 protein CIS in desensitization of STAT5b signaling by continuous growth hormone. J Biol Chem.2000 Dec 15;275(50):39487-96.
391. Xu J, Keeton AB, Franklin JL, Li X, Venable DY, Frank SJ, Messina JL. Insulin enhances growth hormone induction of the MEK/ERK signaling pathway. J Biol Chem. 2006 Jan 13;281(2):982-92. Epub 2005 Nov 4.
392. Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998;74:49-139. Review.
393. Cobb MH. MAP kinase pathways. Prog Biophys Mol Biol. 1999;71(3-4):479-500. Review.
394. Mebis L, Paletta D, Debaveye Y, Ellger B, Langouche L, D’Hoore A, Darras VM, Visser TJ, Van den Berghe G. Expression of thyroid hormone transporters during critical illness. Eur J Endocrinol. 2009 Aug;161(2):243-50.
395. Jørgensen JO, Pedersen SA, Laurberg P, Weeke J, Skakkebaek NE, Christiansen JS. Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism. J Clin Endocrinol Metab. 1989 Dec;69(6):1127-32.
396. Jørgensen JO, Pedersen SB, Børglum J, Møller N, Schmitz O, Christiansen JS, Richelsen B. Fuel metabolism, energy expenditure, and thyroid function in growth hormone-treated obese women: a double-blind placebo-controlled study. Metabolism. 1994 Jul;43(7):872-7.
397. Wolthers T, Grøftne T, Møller N, Christiansen JS, Orskov H, Weeke J, Jørgensen JO. Calorigenic effects of growth hormone: the role of thyroid hormones. J Clin Endocrinol Metab. 1996 Apr;81(4):1416-9.
398. Feldt-Rasmussen U. Interactions between growth hormone and the thyroid gland — with special reference to biochemical diagnosis. Curr Med Chem. 2007;14(26):2783-8. Review.
399. Kalina-Faska B, Kalina M, Koehler B. Effects of recombinant growth hormone therapy on thyroid hormone concentrations. Int J Clin Pharmacol Ther. 2004 Jan;42(1):30-4.
400. Hubina E, Mersebach H, Rasmussen AK, Juul A, Sneppen SB, Góth MI, Feldt-Rasmussen U. Effect of growth hormone replacement therapy on pituitary hormone secretion and hormone replacement therapies in GHD adults. Horm Res. 2004;61(5):211-7. Epub 2004 Jan 30.
401. Seminara S, Stagi S, Candura L, Scrivano M, Lenzi L, Nanni L, Pagliai F, Chiarelli F. Changes of thyroid function during long-term hGH therapy in GHD children. A possible relationship with catch-up growth? Horm Metab Res. 2005 Dec;37(12):751-6.
402. Losa M, Scavini M, Gatti E, Rossini A, Madaschi S, Formenti I, Caumo A, Stidley CA, Lanzi R. Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency. Thyroid. 2008 Dec;18(12):1249-54.
403. Müller MJ, Seitz HJ. Thyroid hormone action on intermediary metabolism. Part III. Protein metabolism in hyper- and hypothyroidism. Klin Wochenschr. 1984 Feb 1;62(3):97-102.
404. Tawa NE Jr, Odessey R, Goldberg AL. Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles. J Clin Invest. 1997 Jul 1;100(1):197-203. PubMed PMID: 9202072
405. Dace A, Zhao L, Park KS, et al. Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(16):8985-8990.
406. Clément K, Viguerie N, Diehn M, Alizadeh A, Barbe P, Thalamas C, Storey JD, Brown PO, Barsh GS, Langin D. In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res. 2002 Feb;12(2):281-91.
407. Miell JP, Taylor AM, Zini M, Maheshwari HG, Ross RJ, Valcavi R. Effects of hypothyroidism and hyperthyroidism on insulin-like growth factors (IGFs) and growth hormone- and IGF-binding proteins. J Clin Endocrinol Metab. 1993 Apr;76(4):950-5.
408. Murao K, Takahara J, Sato M, Tamaki M, Niimi M, Ishida T. Relationship between thyroid functions and urinary growth hormone secretion in patients with hyper- and hypothyroidism. Endocr J. 1994 Oct;41(5):517-22.
409. Wolf M, Ingbar SH, Moses AC. Thyroid hormone and growth hormone interact to regulate insulin-like growth factor-I messenger ribonucleic acid and circulating levels in the rat. Endocrinology. 1989 Dec;125(6):2905-14.
410. Laron Z. Interactions between the thyroid hormones and the hormones of the growth hormone axis. Pediatr Endocrinol Rev. 2003 Dec;1 Suppl 2:244-9-discussion 250. Review.
411. Fiems LO. Double Muscling in Cattle: Genes, Husbandry, Carcasses and Meat. Animals : an Open Access Journal from MDPI. 2012;2(3):472-506.
412. Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem. 2002 Dec 20;277(51):49831-40. Epub 2002 Sep 18.
413. McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12457-61.
414. Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W, Braun T, Tobin JF, Lee SJ. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004 Jun 24;350(26):2682-8.
415. Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibé B, Bouix J, Caiment F, Elsen JM, Eychenne F, Larzul C, Laville E, Meish F, Milenkovic D, Tobin J, Charlier C, Georges M. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet. 2006 Jul;38(7):813-8.
416. Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, Sinha-Hikim I, Ma K, Ezzat S, Shen R, Lalani R, Asa S, Mamita M, Nair G, Arver S, Bhasin S. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14938-43.
417. Liu W, Thomas SG, Asa SL, Gonzalez-Cadavid N, Bhasin S, Ezzat S. Myostatin is a skeletal muscle target of growth hormone anabolic action. J Clin Endocrinol Metab. 2003 Nov;88(11):5490-6.
418. Oldham JM, Osepchook CC, Jeanplong F, Falconer SJ, Matthews KG, Conaglen JV, Gerrard DF, Smith HK, Wilkins RJ, Bass JJ, McMahon CD. The decrease in mature myostatin protein in male skeletal muscle is developmentally regulated by growth hormone. J Physiol. 2009 Feb 1;587(3):669-77.
419. Williams NG, Interlichia JP, Jackson MF, Hwang D, Cohen P, Rodgers BD. Endocrine actions of myostatin: systemic regulation of the IGF and IGF binding protein axis. Endocrinology. 2011 Jan;152(1):172-80.
420. Winbanks CE, Weeks KL, Thomson RE, Sepulveda PV, Beyer C, Qian H, Chen JL, Allen JM, Lancaster GI, Febbraio MA, Harrison CA, McMullen JR, Chamberlain JS, Gregorevic P. Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. J Cell Biol. 2012 Jun 25;197(7):997-1008.
421. Lach-Trifilieff E, Minetti GC, Sheppard K, Ibebunjo C, Feige JN, Hartmann S, Brachat S, Rivet H, Koelbing C, Morvan F, Hatakeyama S, Glass DJ. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Mol Cell Biol. 2014 Feb;34(4):606-18.
422. Bark TH, McNurlan MA, Lang CH, Garlick PJ. Increased protein synthesis after acute IGF-I or insulin infusion is localized to muscle in mice. Am J Physiol. 1998 Jul;275(1 Pt 1):E118-23.
423. Barton-Davis ER, Shoturma DI, Sweeney HL. Contribution of satellite cells to IGF-I induced hypertrophy of skeletal muscle. Acta Physiol Scand. 1999 Dec;167(4):301-5.
424. Suryawan A, Frank JW, Nguyen HV, Davis TA. Expression of the TGF-beta family of ligands is developmentally regulated in skeletal muscle of neonatal rats. Pediatr Res. 2006 Feb;59(2):175-9.
425. Gilson H, Schakman O, Kalista S, Lause P, Tsuchida K, Thissen JP. Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin. Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E157-64.
426. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol. 2001 Nov;3(11):1014-9.
427. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, Yancopoulos GD, Glass DJ. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol. 2001 Nov;3(11):1009-13.
428. Kalista S, Schakman O, Gilson H, Lause P, Demeulder B, Bertrand L, Pende M, Thissen JP. The type 1 insulin-like growth factor receptor (IGF-IR) pathway is mandatory for the follistatin-induced skeletal muscle hypertrophy. Endocrinology. 2012 Jan;153(1):241-53.
429. Barbé C, Kalista S, Loumaye A, Ritvos O, Lause P, Ferracin B, Thissen JP. Role of IGF-I in follistatin-induced skeletal muscle hypertrophy. Am J Physiol Endocrinol Metab. 2015 Sep 15;309(6):E557-67. doi: 10.1152/ajpendo.00098.2015. Epub 2015 Jul 28.
430. Coffey VG, Shield A, Canny BJ, Carey KA, Cameron-Smith D, Hawley JA. Interaction of contractile activity and training history on mRNA abundance in skeletal muscle from trained athletes. Am J Physiol Endocrinol Metab. 2006 May;290(5):E849-55.
431. Moore WV, Leppert P. Role of aggregated human growth hormone (hGH) in development of antibodies to hGH. J Clin Endocrinol Metab. 1980 Oct;51(4):691-7
432. Dannies PS. Protein folding and deficiencies caused by dominant-negative mutants of hormones. Vitam Horm. 2000;58:1-26. Review.
433. DeVol DL, Rotwein P, Sadow JL, Novakofski J, Bechtel PJ. Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth. Am J Physiol. 1990 Jul;259(1 Pt 1):E89-95.
434. Hermansen K, Bengtsen M, Kjær M, Vestergaard P, Jørgensen JOL. Impact of GH administration on athletic performance in healthy young adults: A systematic review and meta-analysis of placebo-controlled trials. Growth Horm IGF Res. 2017 Jun;34:38-44.
435. de Souza GL, Hallak J. Anabolic steroids and male infertility: a comprehensive review. BJU Int. 2011 Dec;108(11):1860-5.
436. Kraemer WJ, Marchitelli L, Gordon SE, Harman E, Dziados JE, Mello R, Frykman P, McCurry D, Fleck SJ. Hormonal and growth factor responses to heavy resistance exercise protocols. J Appl Physiol (1985). 1990 Oct;69(4):1442-50.
437. Pfeffer LA, Brisson BK, Lei H, Barton ER. The insulin-like growth factor (IGF)-I E-peptides modulate cell entry of the mature IGF-I protein. Mol Biol Cell. 2009 Sep;20(17):3810-7.
438. Mills P, Dominique JC, Lafrenière JF, Bouchentouf M, Tremblay JP. A synthetic mechano growth factor E Peptide enhances myogenic precursor cell transplantation success. Am J Transplant. 2007 Oct;7(10):2247-59.
439. Brisson BK, Barton ER. Insulin-like growth factor-I E-peptide activity is dependent on the IGF-I receptor. PLoS One. 2012;7(9):e45588.
440. Brisson BK, Spinazzola J, Park S, Barton ER. Viral expression of insulin-like growth factor I E-peptides increases skeletal muscle mass but at the expense of strength. Am J Physiol Endocrinol Metab. 2014 Apr 15;306(8):E965-74.
441. Goldspink G, Harridge S. Mechanism for adaptation in skeletal muscle In: Komi P, editor. Strength and power in sport: Olympic encyclopedia of sports medicine. Oxford: Blackwell; 2002. p. 231–51.
442. Janssen JA, Hofland LJ, Strasburger CJ, van den Dungen ES, Thevis M. Potency of Full-Length MGF to Induce Maximal Activation of the IGF-I R Is Similar to Recombinant Human IGF-I at High Equimolar Concentrations. PLoS One. 2016 Mar 18;11(3):e0150453.
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