Growing Beyond What Nature Intended


Mechanisms of Action for Growth Hormone (GH) and
Insulin-like Growth Factor-1 (IGF-1)

Warning: The following information is intended only as a
hypothetical consideration of ways in which human physiology may be altered,
through pharmacological means, to achieve striking muscularity. The drugs
discussed in this series of articles are, by and large, prescription drugs and
should not be used without the supervision of a qualified physician. No attempt
should be made to circumvent the laws in your area to obtain these drugs
without a prescription. As always, Meso-Rx does not condone in any way the
illegal acquisition and/or use of prescription drugs for purposes other than
those approved by the FDA or other legally recognized regulatory bodies.

Bodybuilding is a gaudy demonstration of human
accomplishment. The attitude that comes with it reminds me of the Baroque
cathedrals of Europe where every inch of artistry shouts, “More is
better”! At the same time, bodybuilding is a subculture, as well as a
science. It is a multi-disciplinarian science including physiology, biology,
endocrinology, metabolism, cellular physiology, genetics, molecular biology,
and we mustn’t forget, pharmacology. The list of scientific fields pertaining
to bodybuilding is extensive.

I view bodybuilding contests as a county fair of sorts. When
I ponder the present status of professional bodybuilding I often imagine seeing
prize winning cattle being brought before hoards of voyeuristic onlookers,
marveling at the spectacle of seeing something beyond what nature intended.

As a bodybuilder I can’t help but think of all the time,
energy, food, genetic tinkering and drugs that went into creating such an
impressive muscle bound specimen. Here, at the fair, growing prize winning
cattle is not a question of morality or ethics, but rather a manifestation of
dedication, the proper application of knowledge, and perhaps a display of financial
resources. The things done to the animal to make it grow bigger, leaner and
faster are, for the most part, seen as beneficial. I hold bodybuilding in the
same arena as this. Using drugs, and one day soon genetic tinkering, to grow
the human body bigger, leaner, in half the time is not, in and of itself, a
question of morality, but rather an exercise in scientific accomplishment. It
is an expression of human understanding in the scientific fields heretofore
mentioned in order to gain control of the natural world around us, or in this
case, within us.

So why is it that bodybuilding fails to be recognized as a
legitimate area of scientific inquiry among most peer review scientific
journals? The answer is complicated, certainly too philosophical to get into
here. For our purposes lets just say that bodybuilding fails to present
sufficient value to our society to be officially recognized as something worth
devoting time and federal moneys to. In the mean time, scientists will continue
to borrow from the tools and practices of bodybuilding to explore their own
respective, and respected, areas of research. We as bodybuilders will have to
be satisfied, for the time being, gathering up table scraps from laboratory
bench tops to accomplish our goals.

This article will present a holistic picture of some of
the most recent scraps to fall our way from the halls of academia. The focus
will be on the proper application of human growth hormone (GH) and insulin-like
growth factor 1 (IGF-1) for the purpose of building muscle. This information
will be presented in such a way as to describe how these growth factors might
be incorporated into traditional protocols consisting mainly of androgens. It
is important while reading this to remember that my perspective on bodybuilding
will undoubtedly effect the way I present this information. I do not in any way
condone cheating to win a contest, or breaking state or federal laws to
accomplish your goals. Instead, I am simply sharing knowledge with current, or
potential, users with appropriate access to anabolic substances.

The GH/IGF-1 Axis

Your body’s GH levels are tightly regulated by numerous
chemical messengers including macronutrients, neurotransmitters, and hormones.
The signal to increase your body’s GH levels starts in the hypothalamus. There,
two peptide hormones act in concert to increase or decrease GH output from the
pituitary gland. These hormones are somatostatin (SS) and growth
hormone-releasing hormone (GHRH). Somatostatin acts at the pituitary to
decrease GH output. GHRH acts at the pituitary to increase GH output. Together
these hormones regulate, in pulsatile fashion, the level of GH you have
floating around in your body.

Several factors can effect this delicate balance. First,
GH is subject to negative feedback in response to its own release. GH, as well
as IGF-1, circulate back to the hypothalamus and pituitary to increase SS
release, thereby decreasing GH release. GH may also act in an autocrine and
paracrine (i.e. Effecting the source cells and neighboring cells without having
to enter the circulation) fashion within both the hypothalamus and pituitary.

Neurotransmitters also effect GH levels at the
hypothalamus. This neuroendocrine control is still being elucidated but some
factors are already clearly involved.

Cholinergic Increase Acetylcholine

Opioids Increase Morphine

Dopamine Increase L-Dopa

Gut-brain peptides Increase

Nutrition and metabolic factors also modulate GH levels. A
fall in blood glucose such as during exercise or during sleep causes an
increase in GH secretion. High protein feedings increase acute GH secretion.
Some amino acids such as L-arginine seem to increase GH by decreasing SS
release from the hypothalamus. Even the vitamin Niacin has been shown to
increase exercise induced GH release by 300- 600%(Murray, 1995). In this
particular study there were four separate trials where 10 subjects cycled at
68% VO2 max for 120 min followed by a timed 3.5-mile performance task. Every 15
min during exercise, subjects ingested 3.5 ml./kg lean body weight of one of
four beverages: 1) water placebo (WP), 2) WP + 280 mg nicotinic acid.l-1 (WP +
NA), 3) 6% carbohydrate-electrolyte beverage (CE), and 4) CE + NA. Ingestion of
nicotinic acid (WP + NA and CE + NA) blunted the rise in free fatty acids (FFA)
associated with WP and CE; in fact, nicotinic acid ingestion effectively
prevented FFA from rising above rest values. The low FFA levels with nicotinic
acid feeding were associated with a 3- to 6-fold increase in concentrations of
human growth hormone throughout exercise. The question remains, does this
dramatic, yet temporary, increase in GH lead to a greater training effect? It
may lead to greater glycogen storage capacity but other than that, we really
don’t know.

Caloric restriction dramatically reduces serum levels of
IGF-1 yet at the same time increases GH release. This mechanism effectively
helps the individual adapt metabolically without having anabolic actions which
would potentially hasten death by starvation. It is important to understand that
GH can either be anabolic or catabolic. When nutrient intake is high, GH
secretion is increased leading also to increased levels of IGF-1, IGFBP3 and
insulin. The main role of GH under these conditions is to increase anabolism
through local growth factors like IGF-1 and insulin. Conversely, when nutrient
intake is low, GH is again increased. But this time there is no concomitant
increase in IGF-1, IGFBP3, or insulin. Under these circumstances GH is acting
as a catabolic hormone increasing the utilization of fat for fuel thus sparing
body glucose yet having no muscle building effects. This behavior of the
GH/IGF-1 axis is part of what makes it so difficult to build muscle while
dieting. It should be noted that locally produced IGF-1 in skeletal muscle responds
normally to training while dieting. This makes heavy poundages a must when
trying to get ready for a show without the use of drugs.

Growth Hormone: How does it work?

It is always prudent to have a basic understanding of how
a supplement, hormone or drug works to build and/or preserve muscle before
considering its use. The knowledge of how a hormone acts in the body is
necessary to make your own decisions and manage your own regimens if you plan
on utilizing it. Without this understanding you will no doubt end up wasting a
lot of money and perhaps put your health at risk.

It has been long believed that GH exerts its anabolic
effects on peripheral tissues through IGFs, also known as somatomedins
(“mediator of growth”). Binding proteins play an important role in
moderating the anabolic effects of both GH and IGF-1. IGF-1 is controlled by at
least 6 different binding proteins and there may others waiting to be
elucidated. To date there are a couple theories as to just how GH causes growth
in target tissues. The first theory is called the somatomedin hypothesis
(Daughaday, 1972).

The Somatomedin hypothesis states that GH is released from
the pituitary and then travels to the liver and other peripheral tissues where
it causes the synthesis and release of IGFs. IGFs got there name because of
there structural and functional similarity to proinsulin. This hypothesis
dictates that IGFs work as endocrine growth factors, meaning that they travel
in the blood to the target tissues after being released from cells that
produced it, specifically the liver in this case. Indeed, many studies have
followed showing that in animals that are GH deficient, systemic IGF-1
infusions lead to normal growth. The effects were similar to those observed
after GH administration. Interestingly, additional studies also followed that
showed IGF-1 to be greatly inferior as an endocrine growth factor requiring
almost 50 times the amount to exert that same effects of GH (Skottner, 1987).
Recently rhIGF-1 has become widely more available and is currently approved
form the treatment of HIV associated wasting. This increased availability
allowed testing of this hypothesis in humans. Studies in human subjects with GH
insensitivity (Laron syndrome) has consistently validated the somatomedin hypothesis
(Rank, 1995; Savage, 1993).

The second theory as to how GH produces anabolic effects
is called the Dual Effector theory (Green, 1985). This theory states that GH
itself has anabolic effects on body tissues without the need of IGF-1. This
theory has been supported by studies injecting GH directly into growth plates.
Further evidence supporting this theory lies in genetically altered strains of
mice. When comparing mice who genetically over express GH and mice who over
express IGF-1, GH mice are larger. This evidence has been sited by some to
support the dual effector theory. Interestingly, when IGF-1 antiserum (it
destroys IGF-1) is administered concomitantly with GH, all of the anabolic
effects of GH are abolished.

The Somatomedin theory and the Dual Effector theory are
not all that different. One simply asserts that GH can produce growth without
IGF-1. From the research I am inclined to believe in the Somatomedin theory.
This only becomes an issue when one decides whether or not to use just GH or to
combine it with IGF-1 or insulin.

From the evidence currently available you can count on
three major mechanisms by which GH leads to growth (Spagnoli, 1996).

The effects of GH one bone formation and organ growth are
mediated by the endocrine action of IGF-1. As stated in the Somatomedin
hypothesis, GH, released from the pituitary, causes increased production and
release of IGF-1 into the general circulation. IGF-1 then travels to target
tissues such as bones, organs, and muscle to cause anabolic effects.

GH regulates the activity of IGF-1 by increasing the
production of binding proteins (specifically IGFBP-3 and another important
protein called the acid-labile subunit) that increase the half-life of IGF-1
from minutes to hours. Circulating proteases then act to break up the binding
protein/hormone complex thereby releasing the IGF-1 in a controlled fashion
over time. GH may even cause target tissues to produce IGFBP-3 increasing its
effectiveness locally.

IGF-1 not only has endocrine actions, but also
paracrine/autocrine actions in target tissues. This means that as GH travels to
my muscles, the muscle cells increase there production of IGF-1. This IGF-1 may
then travel to adjacent cells (especially satellite cells) leading to growth
and enhanced rejuvenative ability of cells that didn’t see any GH. This is as
suggested by the Dual Effector theory.

IGF-1: How does it work?

To understand how IGF-1 works you have to understand how
muscles grow. The ability of muscle tissue to constantly regenerate in response
to activity makes it unique. It’s ability to respond to physical/mechanical
stimuli depends greatly on what are called satellite cells. Satellite cells are
muscle precursor cells. You might think of them as “pro-muscle”
cells. They are cells that reside on and around muscle cells. These cells sit
dormant until called upon by growth factors such as IGF-1. Once this happens
these cells divide and genetically change into cells that have nuclei identical
to those of muscle cells. These new satellite cells with muscle nuclei are
critical if not mandatory to muscle growth.

Without the ability to increase the number of nuclei, a
muscle cell will not grow larger and its ability to repair itself is limited.
The explanation for this is quite simple. The nucleus of the cell is where all
of the blue prints for new muscle come from. The larger the muscle, the more
nuclei you need to maintain it. In fact there is a “nuclear to
volume” ratio that cannot be overridden. Whenever a muscle grows in response
to functional overload there is a positive correlation between the increase in
the number of myonuclei and the increase in fiber cross sectional area (CSA).
When satellite cells are prohibited from donating new nuclei, overloaded muscle
will not grow (Rosenblatt,1992 & 1994; Phelan,1997). So you see, one
important key to unnatural muscle growth is the activation of satellite cells
by growth factors such as IGF-1.

IGF-1 stimulates both proliferation (an increase in cell
number) and differentiation (a conversion to muscle specific nuclei) in an
autocrine-paracrine manner, although it induces differentiation to a much
greater degree. This is in agreement with the Dual Effector theory. In fact,
you can inject a muscle with IGF-1 and it will grow! Studies have shown that ,
when injected locally, IGF-1 increases satellite cell activity, muscle DNA
content, muscle protein content, muscle weight and muscle cross sectional area

On the very cutting edge of research scientists are now
discovering the signaling pathway by which mechanical stimulation and IGF-1
activity leads to all of the above changes in satellite cells, muscle DNA
content, muscle protein content, muscle weight and muscle cross sectional area
just outlined above. This research is stemming from studies done to explain
cardiac hypertrophy. It involves a muscle enzyme called calcineurin which is a
phosphatase enzyme activated by high intracellular calcium ion concentrations
(Dunn, 1999). Note that overloaded muscle is characterized by chronically elevated
intracellular calcium ion concentrations. Other recent research has
demonstrated that IGF-1 increases intracellular calcium ion concentrations
leading to the activation of the signaling pathway, and subsequent muscle fiber
hypertrophy (Semsarian, 1999; Musaro, 1999). I am by no means a geneticist so I
hesitated even bringing this new research up. In summary the researchers
involved in these studies have explained it this way, IGF-1 as well as
activated calcineurin, induces expression of the transcription factor GATA-2,
which accumulates in a subset of myocyte nuclei, where it associates with
calcineurin and a specific dephosphorylated isoform of the transcription factor
nuclear factor of activated T cells or NF-ATc1. Thus, IGF-1 induces calcineurin-mediated
signaling and activation of GATA-2, a marker of skeletal muscle hypertrophy,
which cooperates with selected NF-ATc isoforms to activate gene expression
programs leading to increased contractile protein synthesis and muscle
hypertrophy. Did you get all that?

In this the first part of “Growing beyond what nature
intended” we have discussed the role, function and interaction of growth
hormone and insulin-like growth factor-1 in tissue growth. This is referred to
collectively as the GH/IGF-1 axis. We learned that this axis is controlled by
negative feedback meaning that GH, after being released, circulates back to the
hypothalamus and pituitary to effectively stop further GH release. We learned
that circulating IGF-1 has the same inhibiting effect on GH release. We
discussed very briefly the role of neurotransmitters in regulating GH release
through growth hormone releasing hormone (GHRH) and somatostatin (SS). We even
touched on the nitty gritty details of just how IGF-1 does its magic on muscle
cells. I’m afraid I may have disappointed a few of you waiting for the
“how to” section of this article. Never fear, in part II you will
learn about the effects of these hormones as well as androgens, insulin and
thyroid hormones when given, individually and combined, to previously healthy
individuals. I will remind you that this article is not intended to encourage
you put your health at risk, or to break the law by acquiring and using these
substances illegally. As always, the goal Meso-Rx is not to condone the use of
performance enhancing substances, but to educate by providing unbiased
information about all aspects of high level sport performance and bodybuilding.

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