GH IGF-1 Insulin and Thyroid

GH IGF-1 Insulin and Thyroid To Enhance The Anabolic Effect of Androgens


The Feasibility of Using GH, IGF-1, Insulin, and Thryoid to
Enhance the Anabolic Effects of Androgens

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.

In the first installment of this series we discussed the
mechanism by which human growth hormone (GH) exerts its anabolic effects in the
body. We also discussed the important role of insulin-like growth factor-1
(IGF-1) in the anabolic properties of GH. In part two we discussed the role of
androgens in GH secretion and sensitivity in a hypothetical pharmacological
regimen aimed at dramatically increasing skeletal muscle growth. Based on
research looking at the effects of androgens on GH secretion and IGF-1
sensitivity, it was deduced that the testosterone esters should provide the
most potent anabolic stimulus compared to other androgens, especially those
that do not aromatize. Now, in the final installment, we shall look at the
feasibility of using GH, IGF-1, Insulin, and perhaps tri-iodothyronine (T3) to
enhance the anabolic properties of androgens.


So what happened? A lot of people have been trying to figure
that out. Research on GH has exploded over the last 15 years. This has been
possible in that, for the last decade or so, GH has been produced through less
expensive and labor intensive recombinant technology. In fact, there are so
many studies looking at GH that I could not possibly address them all. Instead,
I will try to focus on those few studies involving healthy young subjects and
some sort of exercise when possible.

To put it bluntly, studies involving GH and healthy young
men show that although circulating IGF-1 is elevated with GH therapy there is
little or no change in muscle protein synthesis rates (1,2,3). Deysigg (1)
looked at the effect of recombinant GH on strength, body composition and
endocrine parameters in power athletes. Subjects received in a double-blind manner
either GH treatment (0.09IU/kg/day) or placebo for a period of six weeks. To
avoid confounding factors such as concurrent us of steroids, urine specimens
were tested at regular intervals for these substances. Fat mass and lean body
mass were derived from measurements of skinfolds at ten sites. GH, IGF-I and
IGF-binding protein were in the normal range before therapy and increased
significantly in the GH-treated group. Fasting insulin concentrations increased
insignificantly and thyroxine levels decreased significantly in the GH-treated
group. There was no effect of GH treatment on maximal strength or body
composition.

Other studies have observed similar results. Yarasheski
(2) conducted a 12 week study with sixteen men (21-34 yr) assigned randomly to
a resistance training plus GH group (n = 7) or to a resistance training plus
placebo group (n = 9). Both groups trained all major muscle groups in an
identical fashion while receiving 40 µg GH/kg/day or placebo. Fat-free mass
(FFM) and total body water increased in both groups but more in the GH
recipients. Whole body protein synthesis rate increased more, and whole body
protein balance was greater in the GH-treated group, but quadriceps muscle
protein synthesis rate, torso and limb circumferences, and muscle strength did
not increase more in the GH-treated group. In the young men studied, resistance
exercise with or without GH resulted in similar increments in muscle size,
strength, and muscle protein synthesis. The larger increase in FFM with GH
treatment can simply be attributed to an increase in total body water. In this
study as well as the previous one, resistance training supplemented with GH did
not further enhance muscle growth or strength.

Later, Yarasheski performed a similar study but this time
he used experienced weight lifters (3). Skeletal muscle protein synthesis and
the whole body rate of protein breakdown were determined using labeled amino
acids ([13C]leucine) in 7 young healthy experienced male weight lifters before
and at the end of 14 days of subcutaneous GH administration (40 µg/kg/day). GH
administration doubled fasting insulin-like growth factor-I levels, but did not
increase the rate of muscle protein synthesis or reduce the rate of whole body
protein breakdown. These findings confirm what others have found, namely that
short-term GH treatment does not increase the rate of muscle protein synthesis
or reduce the rate of whole body protein breakdown.

You may argue that in the real world, bodybuilders don’t
use GH alone. It is generally combined with some form of anabolic steroid.
Unfortunately I was unable to find a controlled study looking at the
effectiveness of combining androgens and GH in healthy athletes for the
purposes of building muscle. There is one study however that looked at the
effects of combining both very high doses of androgens (up to 2.4 mg/kg/day)
with or without concomitant GH use (4IU/day) (4). In all cases, using androgens
with GH caused a significant decline in IGFBP3 levels. As you know, this
dramatically decreases the half life of IGF-1 and thus the biological activity
is attenuated. One other very enlightening finding of this study was that on a
low calorie diet, it didn’t matter how much androgens or GH they were using,
both IGF-1 and IGFBP-3 declined significantly. Clearly the effectiveness of any
cycle using androgens with or without GH will be greatly diminished by lowering
calories, and more importantly total protein. Still, the one question you may
have, namely does high dose androgens make GH worth using, was not addresses by
this study. The consensus generally is still no.

In HIV patients work is being done to determine if GH or
androgens will prevent wasting. In these studies Deca Durablolin and other
androgens have proven successful at preserving lean mass while GH has not
proven to be effective (4). Concerning GH treatment in unhealthy populations,
Michael Mooney, a well respected authority on HIV and muscle preservation, has
challenged the claims made by at least one manufacturer of a GH product called
Serostim. He wrote a letter to them challenging their claims that Serostim or
any other brand of GH has true anabolic effects in this population.

“I underline that the only study of Serostim that
included a critical evaluation of changes in muscle tissue to date showed no
change and muscle using MRI (magnetic resonance imaging). All other studies so
far have used Bioelectric Impedance Analysis, which measures lean body mass
(LBM), but can not accurately measure changes in muscle. At the Third International
Conference on Nutrition and HIV Infection at Cannes, France, April, 1999,
Donald Kotler, M.D., of St. Lukes-Roosevelt Medical Center in New York reported
the results of an interim analysis of a 6-month open-label trial of Serostim
growth hormone. Dr. Kotler’s data showed that 6 mg of Serostim per day did not
promote a significant change in muscle tissue during the first 12 weeks in the
8 subjects for whom repeat MRI data were available. Several other studies with
various HIV-negative populations have also shown no apparent improvement in
muscle tissue.”

So even in unhealthy populations, GH treatment does not
increase muscle tissue growth. The final word on current methods of using
subcutaneous GH and muscle growth is that it does not enhance muscle growth
beyond what is accomplished by resistance exercise in healthy individuals.

MK-677?

But…keep your eye out for a new GH secretagogue called
Merck-677 or simply MK-677. A secretagogue is a substance that isn’t GH itself,
but instead causes the body to increase it’s natural GH release. One thing that
is unique about MK-677 is that it works within the body’s natural GH secretion
patterns, as opposed to simply causing bolus and sudden increases in
circulating GH. As mentioned earlier, negative feedback has been one of the
main problems with using GH for muscle growth in adults. MK-677 is orally
active (no more needles), it isn’t a protein based hormone yet it mimics GHRH
and increases GH levels in a pulsatile fashion. Early studies have already
shown it to reverse diet induced muscle loss in healthy adults (5). In fact, a
single oral 25 mg dose per day was all that was needed to reverse muscle
wasting during caloric restriction (18Kcal/kg/day). Merck will be trying to
find as many applications for this drug as possible. Very interesting.
Yes,…very interesting.

IGF-1

IGF-1, or insulin-like growth factor-1, is known to be the
mediator of GH anabolic effects so it is natural that it would also be
investigated as an anabolic. As it turns out, IGF-1 is indeed anabolic. IGF-1′s
anabolic effects are limited only by amino acid supply within muscle cells
(6,7) . In essence, the more you eat, the more you grow with IGF-1.
Unfortunately, simply elevating serum IGF-1 has not proven to be anabolic in
healthy individuals (1,2,3). In addition, the side effects of using significant
dosages make using pure IGF-1 prohibitive. IGF-I does not naturally exist in
quantity free of its binding proteins, and limitations associated with
administering free IGF-I (i.e. Long R3IGF-1) therapeutically have proven
significant: acute insulin effects (e.g. hypoglycemia), suppression of growth
hormone secretion, edema, hypotension, tachycardia, very short circulating half
life, and limited and transient efficacy at safe dosage levels (8,9,10).
LR3IGF-I has very low affinity for the IGF-binding proteins in the rat and
hence is cleared from the circulation more quickly than is IGF-I. Yet because
it stays free from binding proteins it is generally more potent unit per unit.
However, the extremely short half life has made it impractical for muscle
growth.

Somatokine?

When IGF-I is bound to binding protein-3 (BP3), as it is
in nature, it does not display these acute limitations. Furthermore, BP3
appears to be critical in the regulation of the release of IGF-I to target
tissue sites, where the hormone is active only when needed. There is some
confusion among athletes that IGF-1 binding proteins actually limit the
effectiveness of IGF-1. In reality, IGFBP3 is necessary to prevent IGF-1 from being
cleared from the system. IGFBP3 extends IGF-1′s half-life from minutes to
hours. BP3 is also a necessary part of the existing system which uses the
binding protein and an acid labile subunit (ALS) which is broken down at target
tissue, releasing the IGF-1 when and where it is needed.

So what is Somatokine? A company called Celtrix
pharmeceuticals produces only one product, namely Somatokine. In fact, the
company hasn’t even received FDA approval yet, though late phase testing is
proving to be very promising (Data privately held by Celtrix). According to
Celtrix feasibility studies looking at muscle function, muscle wasting,
diabetes, osteoporosis, and cardiac function all show promise with minimal to
insignificant side effects. Celtrix is gambling their entire financial future
on this drug. Somatokine is simply an rhIGF-1 peptide complexed with the IGFBP3
protein and the ALS.

Until Somatokine or similar product becomes available,
using isolated rhIGF-1 for muscle growth is simply impractical, ineffective,
and certainly not cost effective. The only exception might be as a locally
applied anabolic. In a study using rats (11), a relatively “unloaded”
muscle, the anterior tibialis, was injection with 0.9 – 1.9 MICROGRAMS/kg/day
of rhIGF-1 which then mimicked the effects of physically loading the muscle,
increasing its mass by ~9% without exercise. There was an increase in protein
content, cross sectional area and DNA content. The increase in muscle DNA is
presumed to be a result of increased proliferation and differentiation of
satellite cells which donate their nuclei upon fusion with damaged or
hypertrophying muscle cells. Take note that the quantities of IGF-1 used in the
injections were extremely small, much smaller than studies that have shown
relatively poor results from administering IGF-1 systemically which range from
1.0 to 6.9 milligrams/kg/day.

Getting IGF-1 inside the muscle as apposed to in the blood
has shown to be extremely anabolic in another exciting animal study using viral
mediated gene therapy (12). In this study, a recombinant adeno-associated
virus, directing overexpression of insulin-like growth factor I (IGF-I) in
mature muscle fibers, was injected into the muscles of mice. The DNA that was
originally in the virus was removed along with markers that stimulate immune
response. DNA coding for IGF-1 was then put into the virus along with a
promoter gene to ensure high rates of transcription. The results were dramatic
causing a 15% increase in muscle mass and a 14% increase in strength in young
adult mice, once again, without additional exercise. Obviously this technology
is not going to be available to bodybuilders any time soon, nevertheless, it’s
exciting to consider the possibilities.

Keeping everything working, . . .or so we thought: Insulin
& T3

Form the very onset let me say that I cannot in good
conscience recommend that a body builder use insulin. This trend started a few
years ago when some prominent people touted insulin as the mother of all
anabolic hormones. Certainly if this were the case, type-II diabetics using
huge amounts of insulin would not be bulging with fat, but instead bulging with
muscles. Insulin is not anabolic in adult humans. Although extreme
hyperinsulinemia has been shown to stimulate protein synthesis in isolated limb
infusion experiments (13), these anabolic properties are ultimately the result
of insulin binding to IGF-1 receptors. It was also used in a last ditch attempt
to get GH to work, the rational being that maybe GH wasn’t working because of
the concomitant insulin resistance. Unfortunately taking more and more insulin
to combat GH induced insulin resistance leads to secondary negative side
effects associated with hyperinsulinemia. Hyperinsulinemia causes the smooth
muscles in your blood vessels to grow until the vessel openings become too
small, predisposing yourself to a heart attack. By the way, the leading cause
of death of type-II diabetics using insulin is from cardiovascular problems. In
general, most bodybuilders are fooled by the tremendous increase in glycogen
and water storage, making them feel “fuller”. The natural
insulinogenic effect of carbohydrates combined with a fast protein like whey
isolate is sufficiently anabolic in high quantities to induce dramatic glucose
and amino acid uptake in muscle tissue. I can’t say as though I blame people
though, when the gains stop coming and you’ve just taken out a second mortgage
to pay for this GH, you find yourself willing to try anything. Nonetheless,
throwing caution to the wind is not the answer.

Thyroid hormones, on the other hand, offer significant
benefits when used cautiously and “properly”. They should not be used
haphazardly as a fat loss agent however, instead they are valuable in
correcting thyroid dysfunction brought on by androgen use. When done properly,
T3 is used as “replacement therapy” and serves only to normalize
decreased T3 levels. Research has shown that high dose androgens pushes T3
levels down (14,15). This is significant because the real value of optimal
thyroid levels is not for fat loss, but instead for optimum anabolic activity.
T3 has diverse facilitative anabolic effects including, increasing GH
secretion(16,17), up-regulating GH receptors (1, up-regulating IGF-1 receptors
(19,20), and other less well defined anabolic effects (21,22). Don’t get the
wrong idea however, for T3 to facilitate anabolism, it must stay in the high
normal range. A little too high or a little too low significantly changes the
biological effects of thyroid hormones. Bringing T3 levels too high will
undoubtedly backfire and lead to muscle, strength losses, and rebound fat gain.

You will need regular blood tests to determine the optimal
dose of T3 (e.g. Cytomel) to bring you up to the optimum range. If you are
unwilling, or do not have access to, regular blood work I would not recommend
using T3. The old “take your morning temperature” recommendation is
simply too inaccurate. Most people use way too much T3 and cause more problems
than anything else. However, if you are willing to take care of yourself while
optimizing muscle gains, have your free T3 checked before using any T3, yet
during your full dose androgen regimen. Try to bring your free T3 levels up to
~7.0-7.4 pmol/L. Your doctor may use conventional units on your blood work
which means it will read in “pg/dL”. If that’s the case bring your
levels up to about 450-480 pg/dL. Doing this will allow optimal caloric intake
while minimizing fat gain, as well as optimize the anabolic actions of the
androgens you are using.

In summary, GH acting primarily through IGF-1 is a very
powerful anabolic hormone. So powerful that the body has set in place complex
systems to control the anabolic effects of both GH and IGF-1 in order to
prevent unnatural muscle growth. These systems have thwarted our attempts at
using bolus injections of GH and IGF-1 in their isolated forms to grow beyond
what nature intended. Hope may be on the horizon however, as new ways of
increasing GH levels (e.g. MK-677) that more closely matches naturally
occurring secretion patterns show promise, as well as new forms of IGF-1 that
are identical to naturally occurring forms (e.g. Somatokine) show more
predictable anabolic properties with fewer side effects. Initial results are
indeed promising and could lead to the emergence of a mandatory addition to our
present androgen-based regimens.

What would an article about GH be without some useful
discussion of GH! First let me quote a well known bodybuilding advisor named
Daniel Duchaine;

“Wow, is this great stuff! It is the best for permanent
muscle gains….People who use it can expect to gain 30 to 40 pounds of muscle
in ten weeks.”

(Duchaine D. Steroid Underground handbook for men and
women. Venice, Ca: HLR Technical Books, 1982, p.

As many of you may know, GH has not lived up to Mr.
Duchaine’s expectations or any body else’s. Mr. Duchaine later recanted his
previous enthusiasm.

“I’d guess that almost 90% of all athletes taking STH
[growth hormone] got no anabolic results from it (this includes at least two
Mr. Olympia competitors). ”

(Ultimate muscle mass, edited by Dan Duchaine. Mile High
Publishing, Golden Co., 1993, p.20)


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