The Science of:
H uman Growth Hormone
K U R T H AV E N S
AT O MI C L I FECOACH I NG.COM
1
N OT I C E
This content is for entertainment and educational purposes
only, and I do not make any warranties to its accuracy,
applicability, or completeness.
The content is not intended to be a substitute for professional
medical or legal advice. Always seek the advice of a
qualified health provider. Never disregard professional
medical advice or delay in seeking it because of any
information presented here.
I disclaim all liability to any party for direct, indirect, implied,
punitive, special, incidental, or other consequential damages
arising directly or indirectly its use.
The Science of:
H uman Growth Hor mone
Version 1.0
©2023 Kurt Havens
TABLE O F C ON T EN TS
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Anabolism . . . . . . . . . . . . . . . . . . . . . . . . . 10
Endogenous Growth Hormone . . . . . . . . . . . . . . 17
Insulin Growth Factor-1 . . . . . . . . . . . . . . . . . . 24
Somatopause . . . . . . . . . . . . . . . . . . . . . . . . 33
Growth Hormone And Athletic Performance . . . . . . 36
Direct Effects of GH and IGF-1 on Skeletal Muscle . . . 41
Indirect Effects of GH and IGF-1 on Skeletal Muscle . . . 44
The Addition of Anabolic Androgenic Steroids . . . . . 49
Synergy of AAS with the GH/IGF Axis . . . . . . . . . . . 54
Pharmacokinetics and Pharmacodynamics of
HGH and IGF-1 . . . . . . . . . . . . . . . . . . . . . . . 64
GH/IGF Axis and Other Hormones . . . . . . . . . . . . 78
HGH Mediated Fat Loss . . . . . . . . . . . . . . . . . . 83
Maximum Rate of Lipolysis . . . . . . . . . . . . . . . . . 88
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . 90
References . . . . . . . . . . . . . . . . . . . . . . . . . 99
AT O MI C L I FECOACH I NG.COM
5
HIS
TO
RY
HISTO RY
Human growth hormone is highly anabolic
and will increase lean body mass significantly,
however it doesn’t cause skeletal muscle growth,
at least not directly.
The primary focus of this book will be on males, as
GH is sexually dimorphic [1]. I will not be discussing
insulin, GH secretagogues, anabolic steroids or
peptides. This should be looked at as fundamentals of endogenous and exogenous recombinant
human growth hormone (rHGH).
HGH was first proposed by Harvey Cushing
over 100 years ago. It was first isolated from
human pituitary glands in the 1940’s. The original hypothesis was that this new peptide didn’t
cause growth, rather a group of serum factors,
later referred to as sulfation factors, stimulated
growth in cartilage and tissue. Over the next few
decades, these sulfation factors were demonstrated to have a wide variety of functions on
numerous parts of the body and was referred to
as “the somatomedin hypothesis”. This later was
AT O MI C L I FECOACH I NG.COM
7
clarified to show GH, acting on the liver, stimulated IGF-1 synthesis which acted on target
tissues.
In the 1970’s, human pituitary extracts became
available from human cadavers and scientists
began experimenting with these extracts on
humans and animals. This stopped when cases of
Creutzfeldt-Jakob disease (CJD) were discovered
in subjects that had been administered cadaver
GH. The vast majority of these subjects died shortly
after being diagnosed [26-33].
In 1985, the FDA approved the first synthetic
recombinant growth hormone (rHGH) for use
in humans. This version was Protropin produced
by Genentech [35-37]. Interestingly, this original
version consisted of 192 amino acids (met-hGH)
versus the modern, safer version which consists of
191 amino acids (rHGH) [10-14]. It is speculated
that some of the black market GH might be 192
amino acids, which can cause the inflammatory
response seen at the injection site.
8
TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
AN
A
BOL
ISM
ANA BOLIS M
As for the initial statement, we must define anabolism. This is defined as a state where nitrogen
is positively retained in lean body mass (LBM). It
can be broken down into two main categories:
hypertrophy and hyperplasia. Hypertrophy is the
process in which skeletal muscle mass occurs by
increasing the existing muscle fiber size. Many
factors can contribute to this, including amino
acids, hormones and exercise. The primary driver
of exercise induced hypertrophy is mechanical
tension. Muscle damage and metabolic stress are
not proven mediators of this process at this time.
Hyperplasia is the process by which skeletal muscle
mass is achieved by an increase in the actual
number of muscle fibers. This generally occurs (in
humans) in the perinatal period and is predetermined by genetics. This includes myostatin levels
and other polymorphisms in growth related factors
[38-40].
Human growth hormone is anabolic. It stimulates
whole body protein synthesis and has either no
1 0 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
effect or a suppressive effect on protein breakdown, depending on study. The net results of the
studies over the years are inconsistent at best
and further show how complex GH is. GH elicits its
effects by first binding to the GH receptor (GHR),
which increases muscle gene transcription through
downstream signaling pathways, eventually activating mTOR. The effects are fast and acute,
similar to insulin- happening within minutes. The
rapid action suggests that they are directly caused
by GH and not by IGF-1. Its impact, or lack thereof,
on protein breakdown is most likely a result of its
inhibitory effects on insulin. Insulin has been shown
to have a direct effect on protein breakdown, or
proteolysis [2-3].
There are numerous studies where GH was administered to healthy adult subjects and was found
to have no impact on MPS rates. A couple of the
trials even included a resistance training element,
yet still found no increase in local MPS rates. There
are also a handful of studies which did result in
increased rates without any significant changes to
whole body protein synthesis rates [4-5].
AT O MI C L I FECOACH I NG.COM 11
There are many reasons why these results may
not be entirely consistent across studies [45,4752]. One of the primary reasons would be how the
trials were designed with regard to administration. Dosing concentration, locally or systemically
administered, pulsed or constantly injected, 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.
There are differences between GH’s effects on
protein metabolism in the fasted and fed states.
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 by preventing protein breakdown.
This same protein-sparing behavior can be seen
in subjects provided GH and undergoing severe
calorie restriction, obese subjects undergoing
various types of hypocaloric dieting and subjects
being deprived of dietary protein [57-61].
It is well-established that GH regulates postnatal growth and that these growth promoting
effects are primarily mediated through IGF-1.
1 2 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
These growth promoting effects are not exclusive to hypertrophy. Linear growth of an organism
includes changes to skeletal, organ, as well as
muscle tissues [6-8].
The vast majority of GH’s growth promoting effects
are mediated via IGF-1, however there are a
handful of things that are GH or IGF mediated
independently. Animal models where double GH/
IGF “knockout” mutants are more severely growth
retarded than with either GH or IGF “knockout”
alone. But let’s instead look at some of the more
specific effects that have been identified in human
models [9].
The first is hepatic steatosis, also known as “fatty
liver disease”. 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. 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, preventing GH from
stimulating IGF-1 production.
AT O MI C L I FECOACH I NG.COM 13
Another GH-specific action is its ability to enhance
ovarian preantral follicle development. GH has
even been under investigation for its potential
enhancements on female fertility. GHR deficient
animal models have also consistently shown lower
numbers of primary preantral and antral follicles
over control.
Fully intact endocrine IGF-1 levels aren’t necessary
when it comes to postnatal bone growth. As long
as there is 10% of the normal circulating endocrine
IGF-1 present, the combination of autocrine IGF-1
and GH can still ensure normal postnatal bone
growth is achieved. This is likely due to the overlapping roles autocrine and endocrine IGF-1 have as
it relates to this longitudinal bone growth.
The most relevant GH-mediated effect is its
promotion of 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. 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
1 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
mRNA expression. Nascent myotubes are present
in the later stages of muscle cell fusion and GH
was shown to increase the number of nuclei per
myotube.
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.
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). 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. This supports the idea that GH
has autocrine roles in addition to its already well
established endocrine roles.
AT O MI C L I FECOACH I NG.COM 15
END
OG
EN
OUS
ENDO GENOUS GR OW T H
HORMONE
GH is natively pulsatile in all species 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”. 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. 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. It is not entirely clear
why this sexually dimorphic secretory pattern exists.
AT O MI C L I FECOACH I NG.COM 17
The secretion of GH is regulated in a very complex
manner involving the participation of several
neurotransmitters, as well as both hormonal and
metabolic feedback. It is principally positively
regulated by GHRH, aptly named growth hormone
releasing hormone, 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.
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. Humans who had
GHRH suppressed by an antagonist demonstrated
severely impaired pulsatile GH release as well as
suppressed GH response to GHRH, so it is clearly a
vital component within the GH/IGF axis.
1 8 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
SRIF, the main negative regulator of GH secretion,
suppresses TSH. In addition, to a lesser degree, it
also suppresses prolactin and the adrenocorticotropic hormone. 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. 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.
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.
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.
Circulating GH complexes in humans can consist
of one of two distinct GH molecules (22-kDa and
AT O MI C L I FECOACH I NG.COM 19
20-kDa), with roughly 90% being the 22-kDa molecule despite early estimates putting that number
much lower. Fun fact, modern indirect GH doping
test methodologies can actually leverage the realtime 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.
Ultimately, this circulating GH binds with GHRs,
which are class one cytokine receptors expressed
in numerous cell-type membranes throughout
the body. 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 lowering the responsiveness of these cells
to an external GH stimulus.
As previously mentioned, GHRs exist on cellular
membranes and they exist as preformed and inactive homodimers. This is really just a fancy way of
2 0 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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. 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.
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. Each JAK2 molecule will then perform
AT O MI C L I FECOACH I NG.COM 21
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. 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.
2 2 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
IGF
-1
I NS ULIN GR OW T H
FAC TO R-1
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 [83,122123]. 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
2 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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
AT O MI C L I FECOACH I NG.COM 25
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
2 6 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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
AT O MI C L I FECOACH I NG.COM 27
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 is
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].
2 8 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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
AT O MI C L I FECOACH I NG.COM 29
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]. 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 realworld applicability is still a source of contention.
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
3 0 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
muscle hypertrophy as they do not affect the
receptor in the absence of mature IGF-1 [439440]. 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].
AT O MI C L I FECOACH I NG.COM 31
SO
MAT
OPA
USE
SO MATOPAUS E
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 term “somatopause”
is used to describe this phenomenon [159,164].
THE SOMATOPAUSE HYPOTHESIS PROPOSAL [128]:
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
AT O MI C L I FECOACH I NG.COM 33
As you can see, this is a chicken and egg scenario.
We gain body fat as we age, which causes insulin
resistance, which suppresses GH secretion, which
makes us fatter. 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).
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.
3 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
ATH
LE
TI
CS
G ROWTH HOR M ON E AN D
ATH LETIC PER F OR M A N CE
The emergence of GH as a performance
enhancing drug (PED), 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?
3 6 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
There have actually been multiple systematic
reviews that have attempted to answer this question, but unfortunately they have all been far from
conclusive [173-175]. 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.
AT O MI C L I FECOACH I NG.COM 37
No increased aerobic performance is observed
with GH administration when looking at the literature. 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, and are marginal at
3 8 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
best [188]. Supraphysiological doses of GH may
increase anaerobic capacity [180]. This is something that has also been seen 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 benefits on athletics.
AT O MI C L I FECOACH I NG.COM 39
DI
RE
CT
DIREC T EF F E C TS OF GH A N D
I G F-1 ON S K E L E TA L M U S CL E
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 on hypertrophy, even
in supraphysiological doses.
There is recent evidence which suggests that
chronic GH exposure increases the expression
of the intramuscular pathways responsible for
atrophy [209]. It could also be responsible for why
chronic GH exposure may produce less efficient
and weaker muscles [210]. This may be some of
the negative regulations built into the GH/IGF
axis, but further studies will be needed.
Most GH trials do report an increase of lean body
mass in their subject groups. GH is very adept at
causing water retention, as well as increasing
soft tissue mass. Specifically, GH increases wholebody sodium retention, and consequently extracellular water, in a dose-dependent manner, via
its effects on the renin-angiotensin system [211].
AT O MI C L I FECOACH I NG.COM 41
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]. Increased
lean body mass and actual skeletal tissue growth
are not necessarily the same.
4 2 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
IN
DI
RE
CT
I NDIREC T EF F E C TS OF G H A N D
I G F-1 ON S K E L E TA L M U S CL E
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].
Because of GH’s potent effects on the components of the extracellular matrix, it is suggested
that adding GH into a hormone stack produced
positive impacts on aches and pains. 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, or more accurately peripheral neuropathy [217-219].
4 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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 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
a few decades ago [224]. It wasn’t until Recently,
that this effect was also shown to occur in recreationally trained human subjects [225]. This effect
is more pronounced in men than women and
may be a result of the higher IGF-1 levels seen in
men. 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 clear that the GH/IGF axis is far
more important for strengthening the extracellular
AT O MI C L I FECOACH I NG.COM 45
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, but it may also be
involved in the shift to fat as fuel preference.
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. 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
4 6 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
hypertrophy and repair [228]. It is still not entirely
clear whether GH has a direct effect on the proliferation and differentiation of satellite cells [229230]. 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.
The effects GH has on the fusion of nascent
myotubes does not translate directly into hypertrophy, but 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]?
AT O MI C L I FECOACH I NG.COM 47
AAS
THE A D D IT I ON OF A N AB O L IC
AND ROG E N I C S T ER OI D S
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 been used by
athletes going as far back as their creation in the
1930s [232]. The AAS family consists 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
AT O MI C L I FECOACH I NG.COM 49
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
appear to be relatively low when compared to
many socially acceptable drugs such as alcohol,
tobacco, and various prescription medications
[233,236]. Testosterone will be what is discussed,
going forward as it is the most described in scientific 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].
5 0 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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]. Testosterone administration
and resistance training have also shown synergistic
and 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 [247248]. 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].
Testosterone treatments have been shown to
increase muscle protein synthesis (MPS) rates [252],
decrease protein breakdown rates [253], and even
AT O MI C L I FECOACH I NG.COM 51
cause the body to more efficiently utilize readily-available stored amino acids.
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-betacatenin pathway [254-256]. Wingless/Int (Wnt)
are a family of secreted glycoproteins that regulate cellular proliferation and differentiation [257258]. 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 [261262]. This also happens to be the AAS pathway
largely responsible for myogenesis, the formation
of muscular tissues [263-265].
AAS also has non-genomic characteristics which
can rapidly affect numerous hormonal and metabolic processes outside of classical receptor binding
and case studies reinforce this hypothesis [266].
5 2 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
SYN
ER
GY
SY N ERGY OF A A S W I T H
THE GH /IG F A XI S
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
5 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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. 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..
Another potential reason that increased GH
and IGF levels have been seen with testosterone
treatments is due to its direct effects upon GHRs.
AT O MI C L I FECOACH I NG.COM 55
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.
The GHR is expressed in just about all major tissue
types. Although the GHR is expressed in very low
amounts 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]. Whether the GH is being used directly or
5 6 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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].
Testosterone has even been shown to promote
hypertrophy in GH/IGF deficient states [297-298].
This demonstrates that testosterone possesses both
IGF-mediated and IGF-independent anabolic
pathways in muscle tissues and cell models
have shown that testosterone can upregulate
AT O MI C L I FECOACH I NG.COM 57
the expression of various IGF isoforms in skeletal
muscle, even in the absence of GH/IGF-1 [298299]. 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].
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].
5 8 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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 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.
In cell cultures, estrogen has also been shown to
directly alter the MPS and MPB rates of trenbolone
AT O MI C L I FECOACH I NG.COM 59
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 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.
6 0 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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]. These very same collagen markers being
discussed here are the exact indicators that are
examined as part of GH doping tests [320-321].
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].
AT O MI C L I FECOACH I NG.COM 61
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 [333335] 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].
6 2 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
PH
AR
MA
P HA RMAC OK I N E T I C S A N D
P HA RMAC ODY N A M I C S O F
HGH A N D I GF -1
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
6 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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.
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
AT O MI C L I FECOACH I NG.COM 65
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
6 6 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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
AT O MI C L I FECOACH I NG.COM 67
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 [127,150,361364]. 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,
6 8 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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.
AT O MI C L I FECOACH I NG.COM 69
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]. There is 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]. 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
7 0 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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 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. It has also been demonstrated that autocrine
AT O MI C L I FECOACH I NG.COM 71
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].
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
7 2 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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
AT O MI C L I FECOACH I NG.COM 73
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
7 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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.
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
AT O MI C L I FECOACH I NG.COM 75
the somewhat unique ability to resensitize many
of these pathways. 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.
7 6 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
HOR
MO
NES
G H /IG F A XI S A N D OT H E R
HORMONE S
Skeletal muscle is a principal target of thyroid
hormone signaling, with both thyroid hormone
transporters and converting enzymes expressed
locally [394]. It is well-known that GH enhances
the peripheral deiodination of T4 to T3, thus
lowering T4 and reverse T3, while simultaneously
increasing T3 [395-398]. However, 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].
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 humans, both hyper- and
7 8 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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].
AT O MI C L I FECOACH I NG.COM 79
Myostatin is arguably made most famous as a
result of those muscle bound cattle lines possessing
a genetic 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
8 0 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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]. Hypertrophy induced by either
IGF-1 overexpression or myostatin inhibition uses
the exact same pathway – PI3K/Akt/mTOR [426428]. 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].
AT O MI C L I FECOACH I NG.COM 81
CU
TT
IN
G
HGH MED I ATED FAT L O S S
The elevated rates of GH secretion bring with them
several metabolic shifts. The first priority of the
body during fasting is to maintain glucose homeostasis, to provide sufficient glucose to the brain and
red blood cells that are dependent upon this fuel.
To achieve this goal, the body shifts its fuel intake
preference to fat substrates so that it can simultaneously conserve valuable glucose and amino
stores. In parallel to this shift in fuel preference
to fat substrates by muscle tissues and the liver,
mobilization of glycogen will occur as no dietary
intake of glucose is detected. Large amounts of
glucose are also released from the liver into the
blood to help maintain blood glucose levels in the
absence of dietary glucose. This is achievable, in
large part, to the simultaneous drop in serum insulin
levels which prevents the release of glucose from
entering muscle and adipose tissues.
The elevated GH brings with it a state of insulin
resistance, in order to preserve valuable glucose
reserves. These insulin antagonistic effects that
AT O MI C L I FECOACH I NG.COM 83
GH brings with it reduce glucose oxidation and
conversely the need for gluconeogenic precursors from muscle protein stores, effectively
killing two birds with one stone. There are a few
thoughts on whether GH itself or the elevation
in FFAs is primarily responsible for this increased
insulin resistance however that gets more complicated than necessary for this book. To summarize, during fasting GH increased secretion helps
to mobilize FFAs from adipocytes, down-regulates
GLUT-1 to inhibit glucose uptake in peripheral
tissues, prevents glucose oxidation via increased
insulin resistance, and preserve amino stores both
through direct and indirect means.
It is well known that GH influences fat loss, however
the exact mechanisms by which it does remain
elusive. It has been speculated that this may be
multifaceted with GH demonstrating ability to
reduce adipose tissue lipoprotein lipase (LPL), stimulate hormone-sensitive lipase (HSL), and antagonize the antilipolytic effects of insulin. Increased
HSL expression in adipocytes increases lipolytic potential as HSL is intimately involved in the
8 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
triacylglycerol hydrolyzation process. Once activated, HSL is translocated to the periphery of the
intracellular fat droplet where it hydrolyzes triacylglycerol to FFA and glycerol. It is also recognized by many as the rate-determining enzyme for
lipolysis. Not all studies have shown GH to increase
HSL mRNA levels in adipocytes however.
GH has also been shown to have a direct impact
on suppressing LPL activity in human adipose
tissues, although this has not been demonstrated
in skeletal muscle tissues. This is potentially relevant to someone interested in fat loss in that LPL
is directly involved in clearing fatty acids from
the bloodstream and subsequently storing them
in adipocytes and/or providing them to skeletal
muscle tissues for fuel. So, if LPL can be suppressed
in adipose tissues, one could speculate less fat
substrates will be actively stored and more will be
available for fueling metabolic processes.
Studies done on cultured human adipocytes have
demonstrated that GH actually has no direct lipolytic effects, but it does significantly increase catecholamine sensitivity in these cells suggesting
AT O MI C L I FECOACH I NG.COM 85
GH is activating lipolysis at a stage after the
involvement of the beta-adrenoceptors and the
G-proteins. It is reasonable to speculate that GH
may be increasing the density of beta-adrenoceptors. It has been shown previously that there
are extra or spare beta-adrenoceptors on human
adipocytes and an increase in the number of
receptors would increase sensitivity and ultimately
fat burning potential. In animal models, GH has
been shown to increase the expression of Beta3adrenergic receptors in adipocytes, followed by
the activation of HSL. So, it seems logical that the
use of a beta-adrenergic agonist (clenbuterol)
could very likely create an additive effect upon
the lipolytic process.
8 6 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
LI
PO
LYS
IS
MA X IMU M R ATE OF L I P O LYS IS
This was found to be a dose of around 3mcgs/kg
(corresponding to an average peak GH concentration of 32.4mcgs/liter). The dose was not age
or sex-dependent and works out to roughly the
equivalent of 1.2-1.5IUs for a 100kg (220 pound)
lean male. Dosing anything higher than this does
not actually elicit a greater impact upon fat
burning. This is also the upper limit of naturally
occurring, endogenous secretory bursts. This could
be a limitation caused by renal clearance rates in
conjunction with circulating GHBP levels.
There is some evidence that this is a GH-specific
bottleneck, and that combined treatments with
catecholamine variants produces an additive
effect on lipolysis, greater than either treatment
alone which further supports the view that GH is a
mediator of this process.
8 8 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
CO
NC
LUS
ION
C ON CLU S I ON
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 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 by themselves. Personally, I’d consider using either testosterone or nandrolone as their growth anchor
compound. Trenbolone 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. 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.
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
9 0 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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.
AT O MI C L I FECOACH I NG.COM 91
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.
Often, people rely 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
9 2 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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.
AT O MI C L I FECOACH I NG.COM 93
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].
9 4 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
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.
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.
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 often come from
those who use a combination of applicable scientific principles alongside real-world experiences.
AT O MI C L I FECOACH I NG.COM 95
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 recommend using this guide as a
starting point for your own research, or potentially
motivate others to perform additional exploration
should they already possess significant hormone
experience. Furthermore, I 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.
9 6 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
SUMMARY:
Combining AAS and GH has been seen as more
effective
FDA grade GH and pharmaceutical grade AAS is
considered a better option
Testosterone and/or nandrolone are typically
preferred over trenbolone
GH is typically best in a pulsatile fashion
Most have found the GH ceiling to occur
somewhere between 4-8 IUs/day sans insulin
Avoid compounds which may result in detrimental
effects on the hypertrophy process
Obtain regular blood work, especially between
periods of supraphysiological hormone usage
Ensure lifestyle variables are in check, including
diet, training, stress, and sleep
AT O MI C L I FECOACH I NG.COM 97
REF
ER
EN
CES
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 fibers in male bodybuilders. 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 sulfation 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
June 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.
AT O MI C L I FECOACH I NG.COM 99
REFERENCES
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. 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.
100 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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 and substrate 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.
AT O MI C L I FECOACH I NG.COM 101
REFERENCES
68. Le Roith D, Scavo L, Butler A. What is the role of circulating IGF-I? Trends Endocrinol Metab. 2001 Mar;12(2):4852. 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 19582003. 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-Idependent, 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 liverderived 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.
102 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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.
AT O MI C L I FECOACH I NG.COM 103
REFERENCES
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.
104 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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):6370. 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.
AT O MI C L I FECOACH I NG.COM 105
REFERENCES
155. Barton ER, DeMeo J, Lei H. The insulin-like growth factor (IGF)-I E-peptides are required for isoformspecific 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.
106 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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 anabolicandrogenic 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.
AT O MI C L I FECOACH I NG.COM 107
REFERENCES
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.
108 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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):46984. Review.
AT O MI C L I FECOACH I NG.COM 109
REFERENCES
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.
110 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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 (17betahydroxyestra-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 factorbinding 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.
AT O MI C L I FECOACH I NG.COM 111
REFERENCES
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 5alphareductase 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.
112 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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-17βstimulated bovine satellite cell proliferation. Domest Anim Endocrinol. 2014 Oct;49:20-6.
AT O MI C L I FECOACH I NG.COM 113
REFERENCES
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 insulinlike 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.
114 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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.
AT O MI C L I FECOACH I NG.COM 115
REFERENCES
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 hormonestimulated 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.
116 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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(13):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.
AT O MI C L I FECOACH I NG.COM 117
REFERENCES
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;74:49139. 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 thyroxinesubstituted 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 placebocontrolled 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 hyperand 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.
118 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
REFERENCES
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-1induced 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.
AT O MI C L I FECOACH I NG.COM 119
REFERENCES
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.
120 TH E SC IE N C E O F HUM A N GR O W T H H O R M O NE
w w w .ato mic life c o ac hing. c o m