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





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 (see table 1a).

Table 1a.

Neurotransmitter system Effect on GH Neurotransmitter or drug
Adrenergic

a2

a1

 

Increase

Decrease

Decrease

 

Clonidine

Methoxamine

Clenbuterol

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).

  1. 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.
  2. 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.
  3. 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 (Adams,1998).

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 2 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.

 

Selected References:

Murray R, Bartoli WP, Eddy DE, Horn MK. Physiological and performance responses to nicotinic-acid ingestion during exercise. Med Sci Sports Exerc 1995 Jul;27(7):1057-62Daughaday WH., Hall K., Raben MS., et al: Somatomedin: A proposed designation for the "sulfation factor" Nature 235:107, 1972Skottner A., Clark RG., Robinson ICAF., et al: Recombinant human insulin-like growth factor: Testing the Somatomedin hypothesis in hypophysectomized rats. J Endocrinol 112:123 1987Rank MB., Savage MO., Chatelain PG., et al: Insulin-like growth factor improves height in growth hormone insensitivity: Two year�s result. Horm Res 44:253, 1995Savage MO., Blum WF., Ranke MB., et al: Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab 77:1465, 1993Green H., Morikawa M., Nixon T. A dual effector theory of growth hormone action. Differentiation 29:195, 1985Spagnoli A, Rosenfeld RG. The mechanisms by which growth hormone brings about growth. The relative contributions of growth hormone and insulin-like growth factors. Endocrinol Metab Clin North Am 1996 Sep;25(3):615-31Phelan JN, Gonyea WJ. Effect of radiation on satellite cell activity and protein expression in overloaded mammalian skeletal muscle. Anat. Rec. 247:179-188, 1997Rosenblatt JD, Parry DJ., Gamma irradiation prevents compensatory hypertrophy of overloaded extensor digitorum longus muscle. J. Appl. Physiol. 73:2538-2543, 1992Rosenblatt JD, Yong D, Parry DJ., Satellite cell activity is required for hypertrophy of overloaded adult rat muscle. Muscle Nerve 17:608-613, 1994Adams GR, McCue SA., Local infusion of IGF-1 results in skeletal muscle hypertrophy in rats. J. Appl. Physiol. 84(5): 1716-1722, 1998Dunn SE., Burns JL., & Michel RN. Calcineurin is required for skeletal muscle hypertrophy. J. Biol. Chem. 274(31):21908-21912, 1999Semsarian C, Wu MJ, Ju YK, Marciniec T, et al. Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signaling pathway. Nature 1999 Aug 5;400 (6744) :576-81Musaro 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


The Role of Androgens in Growth Hormone (GH) Secretion and Insulin-like Growth Factor-1 (IGF-1) Sensitivity

 

Bodybuilding is all about building muscle. In some arenas, this calls for whatever means necessary to grow bigger and leaner then anyone has before. Human progress together with fickle audiences demand that bodybuilders show up bigger and more unnatural looking year after year. As a spectator sport/culture, these two forces are critical to the future of bodybuilding. What would become of bodybuilding if you didn�t have to be bigger and leaner to place higher than you did the year before? I�ll tell you what would happen, audiences would dwindle, the money would dry up, competitors would get small and soft, and the hunger, the drive, the passion, for ever more powerful and massive physiques would extinguish, succumbing to the undertow of the seemingly homoerotic men�s fitness movement.

I left you with a bit of a teaser in the last installment by promising that you would learn just how to incorporate GH and IGF-1 into a bodybuilding regimen to achieve results far beyond what nature intended. Let me make it clear from the onset that GH and/or IGF-1, when used by themselves, are not nearly as effective as esterified androgens. You may ask, "Then why bother with GH or IGF-1 at all?" The answer is simple. There is a limit to how large you can grow with traditional androgen only regimens. This is not to say that a person cannot be successful in bodybuilding without the use of growth factors. That would be blatantly false. On the contrary, some guys can grow to very respectable proportions with androgens alone. My question to you is, "Must we, or more realistically, will we, stop there?" The history of science and man�s need to "go where no man has gone before" tells us that we will indeed continue to push the limits of nature and human evolution.

In part 1 we described the mechanisms by which growth hormone (GH) and insulin-like growth factor-I (IGF-1) exert their effects on the body. The overwhelming majority of GH�s anabolic effects are realized through IGF-1 who�s production it stimulates in the liver and other peripheral tissues. GH levels are control by the hypothalamus which can either increase or decrease GH release from the pituitary by way of growth hormone releasing hormone (GHRH) or somatostatin (SS) respectively. The interrelationship between GH levels and IGF-1 levels is called the GH/IGF-1 axis. This axis is effected not only by GHRH and SS but also through negative feedback. GH and IGF-1, once released into circulation, travel back to the hypothalamus and pituitary to stop further GH release. GH and IGF-1 may also cause autocrine and paracrine negative feedback within the very cells of the pituitary and other tissues and organs that produce the hormones.

A holistic approach to optimally stimulate skeletal muscle growth

Androgens are only one of several mechanisms by which the body regulates muscle size and strength. If the goal is to grow as much muscle as humanly possible, one would be foolish not to ignore the other hormones, growth factors, and genes responsible for human muscle development. It would be like relying solely on the carburetor to make a dragster go faster. Sure, a bigger carburetor will significantly increase potential horsepower, but it will go even faster if you can increase the compression, alter the gear ratio, use more combustible fuels, use light weight materials, improve the aerodynamics, even adding computers has shown to be invaluable to achieve maximum performance from these machines. The human body is no different with respect to the need for a multi-system approach in order to achieve maximum performance.

Despite what we now know about GH and IGF-1, androgens are, for now, going to be the primary component of any hormone regimen. Androgens rely on the androgen receptor (AR) to activate genes associated with muscle growth and remodeling. Although there is only one known androgen receptor, different androgens are able to bring about different physiological effects by virtue of their ability to stabilize the receptor.1 For example, most of you are familiar with testosterone and its 5-a -reduced sibling dihydrotestosterone (DHT) (For a more detailed discussion of enzymatic conversion of steroid hormones see, Enzymatic Conversions and Anabolic-Androgenic Steroids by Bill Roberts). It is believed that DHT is primarily responsible for male pattern balding. If their is only one AR, how come DHT is able to accelerate hair loss while plain testosterone has only minimal effects? The answer lies in the fact that DHT is able to stabilize, or remain attached to the AR much longer than testosterone. This difference in association/dissociation properties of the two androgens gives rise to their diverse effects in your body.

It is important to remember that androgens not only have physiological effects by virtue of the intracellular androgen receptor but also through steroid hormone binding proteins (SHBP). Most people will tell you that only free testosterone is biologically active. This is false. Steroid hormones have what are referred to as nongenomic actions. These effects are believed to be the result of SHBP actually embedded in the cell membrane of target tissues, thus acting as a second messenger system, similar to the way in which catecholamines work.2,3 (For a more detailed discussion of second messenger systems, see Pharmacological approaches to fat loss: Targeting the beta adrenergic receptor). It is well known among steroid specialists, and many users, that not all synthetic derivations of testosterone produce the same results, unit per unit. In fact, when not using standard testosterone products, you can achieve synergy between different drugs. One example might be to combine >methandrostenolone (Dianabol) with nandrolone decanoate (Deca). Using the two together produces more gains in size and strength than dose using either alone. This is not the result of simply increasing the quantity of steroids in the system. If total units of steroid remain constant, a combination of the two drugs is more effective than either alone. The ability of steroid hormones to interact at the cell surface gives rise to the secondary effects of some drugs such as >stanozolol (Winstrol) and oxymetholone (Anadrol) among others.

Another important property of androgens is their propensity to aromatize. This process involves the removal of a methyl group resulting in the conversion of testosterone into estrogens. This process is accomplished through the aromatase or P450 enzyme system (once again I would refer you to Enzymatic Conversions and Anabolic-Androgenic Steroids by Bill Roberts for more information). This may sound like something very undesirable but in reality it is critical to getting maximum growth from androgen administration.

Androgens that boost GH/IGF-1 levels

Although this isn�t exactly an article about androgens per se, they play an integral role in the modulation of GH when trying to put on more size. In order to understand this relationship we must look back to those awkward years of pimples, sore nipples, and rapid growth. No, I�m not talking about your first testosterone cycle, I�m talking about puberty. During puberty there is a disruption in your body�s ability to accurately regulate GH levels leading to increased GH, IGF-1, and insulin levels. This combined with elevated testosterone production characterizes puberty. Research has shown that this disruption is caused by the aromatization of testosterone as well as some direct actions of androgens.4,5,6,7,8 In a recent study by Fryburg9 the effects of testosterone and stanozolol were compared for their effects on stimulating GH release. Testosterone enanthate (only 3 mg per kg per week) increased GH levels by 22% and IGF-1 levels by 21% whereas oral stanozolol (0.1mg per kg per day) had no effect whatsoever on GH or IGF-1 levels. A couple of notes about this study. It was only 2-3 weeks long and although stanozolol did not effect GH or IGF-1 levels, it had a similar effect on urinary nitrogen levels. Urinary nitrogen is fraught with confounding variables when used to determine skeletal muscle anabolism and/or catabolism and thus should not be considered an accurate indicator of skeletal muscle growth. Using labeled tracer amino acids as well as 3-methylhistidine is a far more reliable way of determining actual contractile protein synthesis and breakdown respectively. Nevertheless, this study may well explain the observation that many bodybuilders do not respond as well to testosterones with complete estrogenic blockade.

Too much Cytadren or especially Arimidex will prevent gyno and probably a little water bloat, but it will also cut into your muscle gains by virtue of a less robust GH burst activity and lower subsequent IGF-1 levels. In vitro have also shown that some androgens increase muscle satellite cells sensitivity to fibroblast growth factor and IGF-1.10 Remember that satellite cells are required for a muscle cell to grow. Bovine muscle satellite cells were able to fuse 20% more readily when treated with trenbolone and estradiol.11,12 One may surmise that it was not only the trenbolone but also the estradiol that was causing the significantly increased feed efficiency and muscle growth by way of increased GH and IGF-1 production both in the liver as well as in muscle cells. From these studies it is clear that IGF-1 is critical to get maximum anabolic activity from androgens. This means that androgens that increase GH production (i.e. those that aromatize to some degree) will most likely give you the greatest and most rapid gains in muscle mass.

Which androgens are tops for BIG gains?

So the question now stands, which androgens are best with consideration to GH for maximum muscle tissue growth? Well, the answer is probably the testosterones, specifically esterified versions such as enanthate, cypionate, etc.. Esterification of the testosterone molecule increases it�s lipid solubility and leads to a more prolonged release of the drug into the blood stream after deposition in fat tissue. However, the down side to these products is there high incidence of side effects. As explained above, their ability to aromatize and thus increase GH and IGF-1 levels is, in my opinion, part of what makes them superior mass and strength drugs compared to nonaromatizable drugs such as >methenolone (Primobolan), stanozolol (Winstrol), and oxandrolone (Anavar) among others. The conversion of testosterone to DHT may also be of some benefit in performance as DHT is known to alter intracellular Ca+ levels through nongenomic mechanisms (i.e. without the androgen receptor). The effect is neurological stimulation, or a sense of well being and mental endurance during intense training.

Obviously the beneficial properties of testosterone esters are inseparably linked to the negative side effects such as male pattern baldness and gyno. The very best remedy for this is to shave your head and to surgically remove the offending gyno once and for all. Surgery can even turn out to be financially cost effective when comparing the cost of real antiestrogens/aromatase inhibitors over the course of several years.

I believe that the testosterones are sufficiently anabolic to use by themselves, nevertheless, if one wanted to combine another steroid with a testosterone I would recommend trenbolone acetate because of its high affinity for the androgen receptor and its very successful application in human as well as animal husbandry (love those beefy cows). Of course, for a larger specimen of say a lean 240-250 pounds under 6 feet tall, a combination of a testosterone ester as your base (800 mg per week), and then adding Deca (300-400 mg per week) and Winstrol Depot (just enough to favorably combat the progesterone induced side effects of the Deca i.e. 50mg per day) would undoubtedly give good results but you are looking at quite a hit to the pocket book for legitimate products. All in all, you want to combine a drug that aromatizes, and then add those that don�t if you can afford it. That way you can control the side effects simply by adding complimentary antiestrogens, or if worse comes to worse, decreasing the dose of the aromatizing drug while maintaining the dose of the secondary anabolics. Each individual will be slightly different in their propensity to develop estrogen related side effects so the appropriate course of action may differ from one person to the other. If not using these drugs on a continual basis it is desirable to take a break from the testosterone esters, in which case any non-aromatizable drug would work though I think trenbolone would be a good first choice for most people. There are other sources for planning drug cycles and I would recommend you read them if you are a intermittent user (see Bill Roberts' Anabolic Pharmacology Archives. It may be that you don�t have access to the testosterones I mentioned above. It may also be that you simply disagree with my high opinion of the testosterones. This being the case I suggest you turn to the valuable and extensive contributions of Bill Roberts .

Addressing unwanted side effects

When using testosterones to boost GH and thus IGF-1 it is not necessary to go completely without complimentary antiestrogens and/or estrogen antagonists. A good approach is to use a combination of aminoglutethimide (Cytadren) an aromatase inhibitor, and clomid an estrogen antagonist.

Assuming that you are not exceeding 600-800 milligrams of Testosterone per week I would suggest taking only 1/4 tablet of Cytadren, 2-3 times per day, or every 8-6 hours respectively. This may be less than would be necessary to completely block estrogen related side effects. When using an aromatase inhibitor, the idea is not to completely block aromatization, but to keep it within a reasonable rate. Clomid may also be necessary especially if taking higher doses of testosterone or exogenous IGF-1. IGF-1 is known to have lead to gyno in some cases involving the elderly.13,14 This is presumably because of its ability to co-activate estrogen receptors in breast tissue. The usual practice when taking Clomid is to take a higher dose on the first day and then reduce the dose thereafter. Like Deca, Clomid�s long half life leads to an accumulative effect when taken daily. Once again I would recommend a dosing pattern slightly below the usual. Take one 50 milligram tablet three times per day on the first day, then � tablet per day thereafter. If side effects become unbearable on this dosing pattern, increase the antiestrogen (i.e. Clomid) first, then the aromatase inhibitor (i.e. Cytadren).

Finally, it may be necessary to add a small bit of finistride to the mix in the form of Proscar or Propecia. However, I would prefer that you try Nizoral combined with Minoxidil first. If that is not enough, add the finasteride. Just how much depends on how bad you are losing your hair and how much you value sexual performance. If using Proscar, try taking one half tablet (2.5 mg) per day. It isn�t necessary to take with meals. If using Propecia, just take one tablet per day.

In this the second installment of "Growing Beyond What Nature Intended" we learned that GH and IGF-1 play a complimentary role in the anabolic effects of testosterone. I am not alone in this opinion, in fact, leading researchers in the field attest that GH and thus IGF-1 are absolutely necessary for the full anabolic expression of androgens.9 This explains why some steroids simply out perform others. Those that do not interact with the GH/IGF-1 axis are not able to facilitate the anabolic activity of androgens and thus give you less than stellar gains in mass and strength. Generally, those drugs that do not aromatize will not optimally increase tissue production of IGF-1 and thus are inferior at increasing the activity of muscle satellite cells which are so critical to adaptive muscle growth.

We�re not finished yet...

Here�s what you can look forward to   "Growing Beyond What Nature Intended". Learn why previous reports of GH�s effects have been disappointing to say the least. Learn under which conditions that using GH in addition to androgens may be useful. Learn how IGF-1 can be used to sculpt a less than genetically gifted physique. Think you need insulin to look like a pro? Find out the truth. Finally, learn how to use thyroid medications to grow, rather than shrink, your physique. Until then, train smart and train heavy.

References:

1. Evan T. Keller, William B. Ershler, and Chawnshang Chang. The androgen receptor: Mediator of diverse responses. Frontiers in Bioscience 1, d59-d71, March 1, 1996.2. Rosner W., Hryb DJ., Khan MS., et al: Androgens, estrogens, and second messengers. Steroids 63:278-281, 19983. Wehling M. Specific, nongenomic actions of steroid hormones. Annu. Rev. Physiol. 59:365-393, 19974. Veldhuis JD., Metzger DL., Martha, Jr. PM., et al: Estrogen and testosterone, but not nonaromatizable androgen, direct network integration of the hypothalmo-somatotrope (growth hormone)-insulin-like growth factor axis in human: Evidence from pubertal pathophysiology and sex-steroid hormone replacement. J Clin. Endocrinol Metab. 82(10):3414-3420, 19975. Ulloa-Aguirre A., Blizzard RM., Garcia-Rubi E., et al: Testosterone and oxandrolone, a nonaromatizable androgen, specifically amplify the mass and rate of growth hormone (GH) secreted per burst without altering GH secretory burst duration or frequency or the GH half-life. J Clin. Endocrinol Metab. 71(4):846-854, 19906. Illig R., Prader A. Effect of testosterone on growth hormone secretion in patients with anorchia and delayed puberty. J Clin Endocrinol Metab 30:615-618, 19707. Mauras NM., Blizzard RM., Link K., et al: Augmentation of growth hormone secretion during puberty: Evidence for a pulse amplitude-modulated phenomenon. J Clin Endocrinol Metab. 64:596-601, 19878. Kerrigan JR., Rogol AD., The impact of gonadal steroid hormone action on growth hormone secretion during childhood and adolescence. Endocr Rev. 13:281-298, 19929. Fryburg DA., Weltman A., Jahn LA., et al: Short-term modulation of the androgen milieu alters pulsatile, but not exercise- or growth hormone releasing hormone-stimulated GH secretion in healthy men: Impact of gonadal steroid and GH secretory changes on metabolic outcomes. J Clin Endocrinol. Metab. 82(11):3710-37-19, 199710. Thompson SH., Boxhorn LK., Kong W., and Allen RE. Trenbolone alters the responsiveness of skeletal muscle satellite cells to fibroblast growth factor and insulin-like growth factor-I. Endocrinology. 124:2110-2117, 198911. 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 Nov;76(11):2779-86, 199812. Johnson BJ, White ME, Hathaway MR, Christians CJ, Dayton WR. Effect of a combined trenbolone acetate and estradiol implant on steady-state IGF-I mRNA concentrations in the liver of wethers and the longissimus muscle of steers. J Anim Sci Feb;76(2):491-7, 199813. 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 May;53(3):M183-7, 199814. 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) Oct;39(4):417-25, 1993


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

 

Growth hormone

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.8)

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)

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 g 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 g/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 (18), 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.

References:

1. Deyssig, R., Frisch H., Blum WF., and Waldhor T. Effect of growth hormone treatment on hormonal parameters, body composition and strength in athletes. Act Endocrinol. 128:313-318, 1998.2. Yarasheski KE., Campbell JA., Smith K., et al: Effect of growth hormone and resistance exercise on muscle growth in young men. Am. J Physiol. 262 (Endocrinol. Metab. 25):E261-E267, 1992.3. Yarasheski KE., Zachwieja JJ., Angelopolous TJ., and Bier DM. Short term growth hormone treatment does not increase muscle protein synthesis in experienced weight lifters. J. Appl. Physiol. 74:3073-3076, 1993.4. Karila T., Koistinen H., Seppala M., Koisten R., & Seppala T. Growth hormone induced increases in serum IGFBP-3 levels is reversed by anabolic steroids in substance abusing power athletes. Clin. Endocrinol. 49:459-463, 19985. Sattler FR, Jaque SV, Schroeder ET, Olson C, Dube MP, Martinez C, Briggs W, Horton R, Azen S. Effects of pharmacological doses of nandrolone decanoate and progressive resistance training in immunodeficient patients infected with human immunodeficiency virus J Clin Endocrinol Metab. 84(4):1268-76, 19996. Murphy MG, Plunkett LM, Gertz BJ, He W, Wittreich J, Polvino WM, Clemmons DR. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 83(2):320-5, 19987. 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. 96(4):1722-9, 19958. Fryburg DA. Insulin-like growth factor I exerts growth hormone- and insulin-like actions on human muscle protein metabolism. Am J Physiol. 267(2 Pt 1):E331-6, 19949. Ebeling PR, Jones JD, O'Fallon WM, Janes CH, Riggs BL. Short-term effects of recombinant human insulin-like growth factor I on bone turnover in normal women. J Clin Endocrinol Metab 77(5):1384-7, 199310. Guler HP, Zapf J, Froesch ER. Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med 317(3):137-40, 198711. Rennert NJ, Boulware SD, Kerr D, Caprio S, Tamborlane WV, Sherwin RS. Metabolic effects of rhIGF-1 in normal human subjects Adv Exp Med Biol. 343:311-8, 199312. Gregory R. Adams & Samuel A. McCue. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats. J Appl Physiol 84(5): 1716-1722, 199813. Elisabeth R. Barton-Davis, Daria I. Shoturma, Antonio Musaro, Nadia Rosenthal, and H. Lee Sweeney. 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 22;95(26):15603-7, 199814. Hillier TA., David A. Fryburg, Linda A. Jahn, and Eugene J. Barrett. Extreme hyperinsulinemia unmasks insulin�s effect to stimulate protein synthesis in human forearm. Am. J. Physiol. 274 (Endocrinol. Metab. 37): E1067-E1074, 199815. Deyssig R., Weissel M. Ingestion of androgenic-anabolic steroids induces mild thyroidal impairment in male body builders. J Clin Endocrin Metab. 76(4): 1069-1071, 199216. Markku A., Rahkila P., Reinila M., & Vihko R. Androgenic-anabolic steroid effects on serum thyroid, pituitary and steroid hormones in athletes. Am J Sports Med. 15(4):357-361, 198717. 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 125(6):2905-14, 198918. Harakawa S, Yamashita S, Tobinaga T, Matsuo K, Hirayu H, Izumi M, Nagataki S, Melmed S. In vivo regulation of hepatic insulin-like growth factor-1 messenger ribonucleic acids with thyroid hormone. Endocrinol Jpn 37(2):205-11, 199019. Hochberg Z, Bick T, Harel Z Alterations of human growth hormone binding by rat liver membranes during hypo- and hyperthyroidism. Endocrinology 126(1):325-9, 199020. Matsuo K, Yamashita S, Niwa M, Kurihara M, Harakawa S, Izumi M, Nagataki S, Melmed S Thyroid hormone regulates rat pituitary insulin-like growth factor-I receptors. Endocrinology 126(1):550-4, 199021. King RA, Smith RM, Meller DJ, Dahlenburg GW, Lineham JD. Effect of growth hormone on growth and myelination in the neonatal hypothyroid rat. J Endocrinol 119(1):117-25, 198822. Nanto-Salonen K, Muller HL, Hoffman AR, Vu TH, Rosenfeld RG. Mechanisms of thyroid hormone action on the insulin-like growth factor system: all thyroid hormone effects are not growth hormone mediated. Endocrinology 132(2):781-8, 199323. Burstein PJ, Draznin B, Johnson CJ, Schalch DS. The effect of hypothyroidism on growth, serum growth hormone, the growth hormone-dependent somatomedin, insulin-like growth factor, and its carrier protein in rats. Endocrinology 104(4):1107-11, 1979


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