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Growth Hormone
All of the "GH" supps are crap. Have to go the gear route to get real GH.
All of the "GH" supps are crap. Have to go the gear route to get real GH.
enrage
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Growth hormone (GH) is a 191-amino acid protein or peptide that's naturally released from the pituitary gland. GH, much like Testosterone, is released in a pulsatile or episodic manner. The GH pulse occurs every 2-3 hours so each and every day we get about 8-12 big doses of all-natural growth hormone (Hartman et al 1991). The sum of these GH peaks amounts to about 0.5 mg of GH produced per day. The following is an example of what normal 24 hr GH production might look like, with the highest peaks occurring during the first few hours of sleep:
According to the research review published in a new textbook entitled "Growth Hormone in Adults," the release of GH from the pituitary is governed by a balancing act between 2 hormones; GHRH (growth hormone releasing hormone) and somatostatin. GHRH is responsible for stimulating both the synthesis and the release of GH from the pituitary. Essentially, GHRH initiates the strength of the GH pulse.
GHRH's arch rival, somatostatin, counters these effects, however, by inhibiting GH release. Therefore, somatostatin prevents the GH pulse. In the end, GH release occurs when GHRH is at its peak in stimulating the pituitary, while somatostatin is at its low in inhibiting the pituitary. The result of this high GHRH and low somatostatin period is a big spike in blood levels of GH (Juul, 2000).
The following is a chart adapted from Basic and Clinical Endocrinology, 5th Edition depicting other factors influencing the GH secretion spike:
Factors Increasing GH Secretion
Physiological:
Sleep
Fasting
Fatty Acids
Exercise
High Amino Acid in the Blood
Low Blood Sugar
Pharmacologic:
Any hypoglycemic agent
Estrogens
Estrogens
Beta antagonists
Serotonin
Dopamine
GABA
Factors Decreasing GH Secretion:
Physiological:
Hyperglycemia
Elevated Blood Free Fatty Acids
Obesity
Hyper or Hypothyroidism
Pharmacologic:
GH itself
Somatostatin
Alpha antagonists(yohimbine)
Beta agonists (ephedrine, clenbuterol)
Serotonin antagonists
Dopamine antagonists
Once the GH pulse occurs, blood GH is free to affect target tissues. Some of the well-documented actions of GH are increases in longitudinal bone growth (longer bones), increased bone mineralization (thicker, stronger bones), anabolism (protein building), lipolysis (fat loss), and anti-diuretic actions (Bengtsson, 1999). GH treatment is common in congenital syndromes of GH deficiency and in cases of hypothalamic or pituitary damage.
In addition, it's been recognized that around the age of 30, there's a progressive decline in GH secretion from the pituitary, so much so that by the age of 60, GH production can drop as much as 60%! This means that an aging pituitary that once produced 0.5 mg of GH per day would now produce only 0.2 mg per day, and this is definitely physiologically relevant. In fact, these production levels are often equivalent to those of GH deficient young adults. This age-related GH decline has been termed somatopause by some researchers and treatment requires GH replacement therapy
How GH Works — The GH/IGF-1 AXIS
Due to the rise in recombinant GH availability, the research has been abundant and a clearer picture is emerging of GH action. But make no mistake, the picture isn't all that clear. It may be more like one of those computer-generated 3D pictures that you have to look at in just the right way for just the right amount of time to make any sense of it at all. And no one has yet to look long enough at this particular picture.
With all of this GH floating around, the black market supply of GH has also been on the rise. So after we talk GH action, let's talk bodybuilding. If GH can potentially get bodybuilders big and ripped, then to some, it's a drug worth exploring. So for you die-hard muscle heads, here's a little GH primer with special focus on the pursuit of lean mass.
Circulating GH is thought to act through two distinct but interrelated mechanisms. The first is direct. GH can act directly on many cells in the body via the GH receptor. Once released into the blood from the pituitary, GH either circulates as free GH or circulates bound to GHBP for transport (GH Binding Protein). Free GH is available to interact with cellular receptors to create a response.
Once free GH has interacted with the cellular receptors, it's thought that more GHBPs are formed. With this increased GHBP, some researchers believe that more GH is rendered temporarily unavailable. But at the same time, it stays in the system for a longer amount of time. So although GHBP-bound GH has a much longer half-life, it cannot interact with cellular receptors while bound.
Unfortunately, there's no clear consensus as to whether it's more important to cellular GH action to prolong the half-life of GH (to allow for higher levels to circulate for longer), or to decrease GHBP to allow for higher levels of free GH. And this debate holds true for not only GH, but for other hormones like Testosterone as well. Although the researchers tend to contradict each other and sometimes even themselves on this point, the bottom line is that the effectiveness of GH (and other hormones) is tied up in this balance between bound and unbound GH and the presence of binding proteins.
Binding proteins aside, once free GH does reach the cells, its direct actions include the promotion of lipolytic and hyperglycemic effects. GH can decrease glucose utilization in favor of fat release and oxidation (lipolysis). Unfortunately, because of this shift from carb to fat use, GH also increases insulin resistance. Hyperglycemia is a result of this insulin insensitivity. So although GH itself can make you lean due to lipolysis, this might come at the expense of insulin resistance and might ultimately lead to a diabetic state. As a result, you'll be a lean diabetic rather than a chubby normal guy. I guess it's a trade-off.
The second mechanism by which GH exerts its effects is indirectly through IGF-1. In the liver, circulating GH is converted into IGF-1 and 2 which can travel through the blood to promote their effects. IGF is also bound to one of 6 plasma proteins (IGFBP's 1-6). About 1-5% of IGF-1 is free while 95-99% is bound. Again, this balance is important for hormone action. This systemic IGF is also free to interact with cellular receptors.
In addition to the systemic effects of liver IGF-1, IGF can act locally. Let me explain. GH binding to cells can lead to what is called peripheral conversion of IGF-1. At this specific location (skeletal muscle for example), IGF-1 acts in an autocrine or paracrine fashion to promote its effects. This means that unlike GH, which has endocrine function (it is produced in the pituitary and travels elsewhere to do its work), IGF-1 can both be produced in, and promote changes in, the same tissue or those immediately adjacent to it.
Perhaps the most relevant effect of IGF-1 to this discussion is the ability of IGF-1 to increase protein synthesis by increasing cellular mRNA formation (mRNA makes protein) as well as increasing uptake of amino acids. This effect on protein synthesis can lead to increased lean mass. The research indicates that this effect is dependent on GH presence as well. So IGF-1 alone does not promote such effects. Nor does GH. It appears the combination of the two most consistently lead to increased protein synthesis.
In addition, IGF-1 can also counteract the hyperglycemic effects of GH via insulin-like actions on glucose uptake. Since IGF-1 is typically elevated to a small extent with GH elevations, IGF action is not sufficient to neutralize the hyperglycemic effects of GH, but perhaps it minimizes extreme insulin insensitivity.
The bottom line is that GH and IGF-1 seem to be necessary bedmates. Although each may act most strongly in different tissue types, they are thought to work together to promote anabolism and stimulate lipolysis (Ney 1999, Yarasheski 1994). But all this synergy comes at a price. Both hormones negatively feed back on the pituitary to slow GH production. And this impacts normal GH secretion as well as GH treatment.
When plasma GH levels and IGF-1 levels are elevated with GH treatment, this elevation is non-physiologic. What this means is that after a GH injection, GH levels are elevated for some time and then come crashing down to normal, often being suppressed for hours thereafter. So the pattern seen in the graph above is not the one seen when using exogenous GH. This is probably due to the fact that both GH and IGF-1 are negative regulators of GH release so an increase in either (from a GH injection) reduces the secretion of GH.
So when examining the GH/IGF-1 axis, a few things should be considered. With strong feedback mechanisms in place, it's difficult to maintain consistently high levels of GH without constant exogenous dosing. And that's a hassle. In addition, just like with insulin, there may be something known as GH insensitivity (Grinspoon 1998). It appears that with chronically high levels of GH, liver and peripheral conversions of GH to IGF-1 are decreased. So even with the constant use of exogenous GH, the body may simply try to regulate itself and the actions of GH by preventing the availability of what is thought to be GH's partner, IGF-1.
It seems like a no-win situation. And perhaps this is best. The body has feedback mechanisms for a reason… protection. If GH action isn't kept in check, the medical condition known as acromegaly can result. Acromegaly is characterized by abnormal skeletal growth characterized by enlarged jaw and hands. Individuals suffering from this have abnormally high levels of GH, IGF-1, and IGFBPs. It's apparent, then, that the feedback mechanisms of these individuals aren't working all that well.
Often times, GH users smugly tell me that acromegaly is BS because they've been using GH for X amount of time and they didn't get it. Well guys, guess what? Normal individuals probably won't get it because of the feedback mechanisms described above. You know what else? You're probably not getting muscle building results either.
GH and The Athlete
I've never been sure why the use of GH has become popular in athletes and bodybuilders. Perhaps it's the name… Growth Hormone. Sounds like it'll make me big. Or perhaps it's the legend of Pump de Leon. Either way, the research on GH use in bodybuilders and men on resistance training programs has shown it to be all but useless. And this is probably due to the feedback mechanisms like the negative feedback on the pituitary and the GH resistance discussed earlier.
In two landmark GH studies conducted at the Washington University School of Medicine, a world-renowned GH researcher named Kevin Yarasheski studied the effects of GH in combination with weight training (Yarasheski 1992, 1993).
In the first study, 18 untrained men were given either GH and exercise or placebo and exercise for 12 weeks. GH subjects were given 40 micrograms/kg of recombinant GH and all subjects were evaluated before and after treatment for fat mass, fat free mass, total body water, whole body protein synthesis, insulin sensitivity, muscle size and muscle strength. Due to the development of carpal tunnel syndrome, 2 subjects were forced to withdraw from the study.
When comparing the GH+exercise group with the placebo+exercise group, the data showed that there was no fat loss, no change in insulin sensitivity, no increase in muscle size, and no increase in strength! Whole body protein synthesis was increased in the GH group relative to the placebo, but muscle protein synthesis wasn't. In addition, lean body mass was increased, but again, this wasn't muscle mass, but probably a combination of water retention, organ mass, and connective tissue instead. The researchers, who seemed quite objective in their conclusions, decided that non-muscle proteins were being formed instead of muscle contractile protein.
In the follow-up study, Dr. Yarasheski pursued the effects of GH on experienced weight-lifters. Since the GH didn't positively impact strength or body comp in the untrained guys, Dr. Yarasheski wondered if well-trained athletes might be different. So another study was conducted to examine protein synthetic rates in GH-treated athletes. After 2 weeks of GH treatment (40micrograms/kg), the data were clear that short term GH had no effect on whole body protein synthesis or breakdown. The reason they chose 2 weeks was that in a number of previous studies on clinical populations, any increases in protein synthesis had only lasted for about a month and then ceased due to some type of down-regulation (Perhaps GH insensitivity?). In this population, however, GH didn't even promote protein synthesis within this time frame.
With all this negative data, it should be mentioned that one study showed something positive happening, but again, it wasn't all that exciting (Crist 1988). This particular study showed a small 4% gain in lean body mass and a modest 12% loss in body fat with GH doses of 8IU per day (2.6 milligrams). Muscle mass wasn't measured, so there was no way to determine the make-up of the increased LMB (lean body mass).
So it's pretty apparent that in weight trained men, GH alone doesn't increase muscle mass. Resulting lean mass gains from GH treatment are probably a combo of water, connective tissue, or organ mass. I say probably because organ mass and connective tissue mass are hard to measure. The indirect evidence is pretty strong, though.
Since non-muscle protein gains and the development of carpal tunnel syndrome (due to growth in the connective tissue sheath in the wrist) were apparent in these studies, connective tissue gain is a reasonable speculation. In addition, acromegaly patients have increased organ mass as a result of the high responsiveness to GH, so it would stand to reason that this could have occurred in these studies, too.
The next logical question is this: Since a lot of guys are still using GH, what are the implications of increased organ mass and connective tissue? Well, to be honest, we don't know.
Acromegaly patients do not have high rates of organ malfunction or pathophysiology, so although growing large organs isn't ideal, the current literature doesn't indicate that the problem is immediately life-threatening. But, acromegaly patients do die prematurely, so if they were to live longer, perhaps these organ changes could have long-term impact.
As far as the issue of increases in connective tissue, the increases themselves may not be too terrible, as long as they don't become pathophysiological. Of course, developing carpel tunnel syndrom is no picnic. On the other hand, if the strength of connective tissue increases with connective tissue growth, athletes could become more injury-resistant. Connective tissue growth will not lead to strength increases in well-trained guys if contractile protein mass doesn't go up, but these connective tissue increases may allow individuals to train with heavier weights with less risk of injury. This, however, merely results from me taking off the "science hat" and speculating a bit.
According to the research review published in a new textbook entitled "Growth Hormone in Adults," the release of GH from the pituitary is governed by a balancing act between 2 hormones; GHRH (growth hormone releasing hormone) and somatostatin. GHRH is responsible for stimulating both the synthesis and the release of GH from the pituitary. Essentially, GHRH initiates the strength of the GH pulse.
GHRH's arch rival, somatostatin, counters these effects, however, by inhibiting GH release. Therefore, somatostatin prevents the GH pulse. In the end, GH release occurs when GHRH is at its peak in stimulating the pituitary, while somatostatin is at its low in inhibiting the pituitary. The result of this high GHRH and low somatostatin period is a big spike in blood levels of GH (Juul, 2000).
The following is a chart adapted from Basic and Clinical Endocrinology, 5th Edition depicting other factors influencing the GH secretion spike:
Factors Increasing GH Secretion
Physiological:
Sleep
Fasting
Fatty Acids
Exercise
High Amino Acid in the Blood
Low Blood Sugar
Pharmacologic:
Any hypoglycemic agent
Estrogens
Estrogens
Beta antagonists
Serotonin
Dopamine
GABA
Factors Decreasing GH Secretion:
Physiological:
Hyperglycemia
Elevated Blood Free Fatty Acids
Obesity
Hyper or Hypothyroidism
Pharmacologic:
GH itself
Somatostatin
Alpha antagonists(yohimbine)
Beta agonists (ephedrine, clenbuterol)
Serotonin antagonists
Dopamine antagonists
Once the GH pulse occurs, blood GH is free to affect target tissues. Some of the well-documented actions of GH are increases in longitudinal bone growth (longer bones), increased bone mineralization (thicker, stronger bones), anabolism (protein building), lipolysis (fat loss), and anti-diuretic actions (Bengtsson, 1999). GH treatment is common in congenital syndromes of GH deficiency and in cases of hypothalamic or pituitary damage.
In addition, it's been recognized that around the age of 30, there's a progressive decline in GH secretion from the pituitary, so much so that by the age of 60, GH production can drop as much as 60%! This means that an aging pituitary that once produced 0.5 mg of GH per day would now produce only 0.2 mg per day, and this is definitely physiologically relevant. In fact, these production levels are often equivalent to those of GH deficient young adults. This age-related GH decline has been termed somatopause by some researchers and treatment requires GH replacement therapy
How GH Works — The GH/IGF-1 AXIS
Due to the rise in recombinant GH availability, the research has been abundant and a clearer picture is emerging of GH action. But make no mistake, the picture isn't all that clear. It may be more like one of those computer-generated 3D pictures that you have to look at in just the right way for just the right amount of time to make any sense of it at all. And no one has yet to look long enough at this particular picture.
With all of this GH floating around, the black market supply of GH has also been on the rise. So after we talk GH action, let's talk bodybuilding. If GH can potentially get bodybuilders big and ripped, then to some, it's a drug worth exploring. So for you die-hard muscle heads, here's a little GH primer with special focus on the pursuit of lean mass.
Circulating GH is thought to act through two distinct but interrelated mechanisms. The first is direct. GH can act directly on many cells in the body via the GH receptor. Once released into the blood from the pituitary, GH either circulates as free GH or circulates bound to GHBP for transport (GH Binding Protein). Free GH is available to interact with cellular receptors to create a response.
Once free GH has interacted with the cellular receptors, it's thought that more GHBPs are formed. With this increased GHBP, some researchers believe that more GH is rendered temporarily unavailable. But at the same time, it stays in the system for a longer amount of time. So although GHBP-bound GH has a much longer half-life, it cannot interact with cellular receptors while bound.
Unfortunately, there's no clear consensus as to whether it's more important to cellular GH action to prolong the half-life of GH (to allow for higher levels to circulate for longer), or to decrease GHBP to allow for higher levels of free GH. And this debate holds true for not only GH, but for other hormones like Testosterone as well. Although the researchers tend to contradict each other and sometimes even themselves on this point, the bottom line is that the effectiveness of GH (and other hormones) is tied up in this balance between bound and unbound GH and the presence of binding proteins.
Binding proteins aside, once free GH does reach the cells, its direct actions include the promotion of lipolytic and hyperglycemic effects. GH can decrease glucose utilization in favor of fat release and oxidation (lipolysis). Unfortunately, because of this shift from carb to fat use, GH also increases insulin resistance. Hyperglycemia is a result of this insulin insensitivity. So although GH itself can make you lean due to lipolysis, this might come at the expense of insulin resistance and might ultimately lead to a diabetic state. As a result, you'll be a lean diabetic rather than a chubby normal guy. I guess it's a trade-off.
The second mechanism by which GH exerts its effects is indirectly through IGF-1. In the liver, circulating GH is converted into IGF-1 and 2 which can travel through the blood to promote their effects. IGF is also bound to one of 6 plasma proteins (IGFBP's 1-6). About 1-5% of IGF-1 is free while 95-99% is bound. Again, this balance is important for hormone action. This systemic IGF is also free to interact with cellular receptors.
In addition to the systemic effects of liver IGF-1, IGF can act locally. Let me explain. GH binding to cells can lead to what is called peripheral conversion of IGF-1. At this specific location (skeletal muscle for example), IGF-1 acts in an autocrine or paracrine fashion to promote its effects. This means that unlike GH, which has endocrine function (it is produced in the pituitary and travels elsewhere to do its work), IGF-1 can both be produced in, and promote changes in, the same tissue or those immediately adjacent to it.
Perhaps the most relevant effect of IGF-1 to this discussion is the ability of IGF-1 to increase protein synthesis by increasing cellular mRNA formation (mRNA makes protein) as well as increasing uptake of amino acids. This effect on protein synthesis can lead to increased lean mass. The research indicates that this effect is dependent on GH presence as well. So IGF-1 alone does not promote such effects. Nor does GH. It appears the combination of the two most consistently lead to increased protein synthesis.
In addition, IGF-1 can also counteract the hyperglycemic effects of GH via insulin-like actions on glucose uptake. Since IGF-1 is typically elevated to a small extent with GH elevations, IGF action is not sufficient to neutralize the hyperglycemic effects of GH, but perhaps it minimizes extreme insulin insensitivity.
The bottom line is that GH and IGF-1 seem to be necessary bedmates. Although each may act most strongly in different tissue types, they are thought to work together to promote anabolism and stimulate lipolysis (Ney 1999, Yarasheski 1994). But all this synergy comes at a price. Both hormones negatively feed back on the pituitary to slow GH production. And this impacts normal GH secretion as well as GH treatment.
When plasma GH levels and IGF-1 levels are elevated with GH treatment, this elevation is non-physiologic. What this means is that after a GH injection, GH levels are elevated for some time and then come crashing down to normal, often being suppressed for hours thereafter. So the pattern seen in the graph above is not the one seen when using exogenous GH. This is probably due to the fact that both GH and IGF-1 are negative regulators of GH release so an increase in either (from a GH injection) reduces the secretion of GH.
So when examining the GH/IGF-1 axis, a few things should be considered. With strong feedback mechanisms in place, it's difficult to maintain consistently high levels of GH without constant exogenous dosing. And that's a hassle. In addition, just like with insulin, there may be something known as GH insensitivity (Grinspoon 1998). It appears that with chronically high levels of GH, liver and peripheral conversions of GH to IGF-1 are decreased. So even with the constant use of exogenous GH, the body may simply try to regulate itself and the actions of GH by preventing the availability of what is thought to be GH's partner, IGF-1.
It seems like a no-win situation. And perhaps this is best. The body has feedback mechanisms for a reason… protection. If GH action isn't kept in check, the medical condition known as acromegaly can result. Acromegaly is characterized by abnormal skeletal growth characterized by enlarged jaw and hands. Individuals suffering from this have abnormally high levels of GH, IGF-1, and IGFBPs. It's apparent, then, that the feedback mechanisms of these individuals aren't working all that well.
Often times, GH users smugly tell me that acromegaly is BS because they've been using GH for X amount of time and they didn't get it. Well guys, guess what? Normal individuals probably won't get it because of the feedback mechanisms described above. You know what else? You're probably not getting muscle building results either.
GH and The Athlete
I've never been sure why the use of GH has become popular in athletes and bodybuilders. Perhaps it's the name… Growth Hormone. Sounds like it'll make me big. Or perhaps it's the legend of Pump de Leon. Either way, the research on GH use in bodybuilders and men on resistance training programs has shown it to be all but useless. And this is probably due to the feedback mechanisms like the negative feedback on the pituitary and the GH resistance discussed earlier.
In two landmark GH studies conducted at the Washington University School of Medicine, a world-renowned GH researcher named Kevin Yarasheski studied the effects of GH in combination with weight training (Yarasheski 1992, 1993).
In the first study, 18 untrained men were given either GH and exercise or placebo and exercise for 12 weeks. GH subjects were given 40 micrograms/kg of recombinant GH and all subjects were evaluated before and after treatment for fat mass, fat free mass, total body water, whole body protein synthesis, insulin sensitivity, muscle size and muscle strength. Due to the development of carpal tunnel syndrome, 2 subjects were forced to withdraw from the study.
When comparing the GH+exercise group with the placebo+exercise group, the data showed that there was no fat loss, no change in insulin sensitivity, no increase in muscle size, and no increase in strength! Whole body protein synthesis was increased in the GH group relative to the placebo, but muscle protein synthesis wasn't. In addition, lean body mass was increased, but again, this wasn't muscle mass, but probably a combination of water retention, organ mass, and connective tissue instead. The researchers, who seemed quite objective in their conclusions, decided that non-muscle proteins were being formed instead of muscle contractile protein.
In the follow-up study, Dr. Yarasheski pursued the effects of GH on experienced weight-lifters. Since the GH didn't positively impact strength or body comp in the untrained guys, Dr. Yarasheski wondered if well-trained athletes might be different. So another study was conducted to examine protein synthetic rates in GH-treated athletes. After 2 weeks of GH treatment (40micrograms/kg), the data were clear that short term GH had no effect on whole body protein synthesis or breakdown. The reason they chose 2 weeks was that in a number of previous studies on clinical populations, any increases in protein synthesis had only lasted for about a month and then ceased due to some type of down-regulation (Perhaps GH insensitivity?). In this population, however, GH didn't even promote protein synthesis within this time frame.
With all this negative data, it should be mentioned that one study showed something positive happening, but again, it wasn't all that exciting (Crist 1988). This particular study showed a small 4% gain in lean body mass and a modest 12% loss in body fat with GH doses of 8IU per day (2.6 milligrams). Muscle mass wasn't measured, so there was no way to determine the make-up of the increased LMB (lean body mass).
So it's pretty apparent that in weight trained men, GH alone doesn't increase muscle mass. Resulting lean mass gains from GH treatment are probably a combo of water, connective tissue, or organ mass. I say probably because organ mass and connective tissue mass are hard to measure. The indirect evidence is pretty strong, though.
Since non-muscle protein gains and the development of carpal tunnel syndrome (due to growth in the connective tissue sheath in the wrist) were apparent in these studies, connective tissue gain is a reasonable speculation. In addition, acromegaly patients have increased organ mass as a result of the high responsiveness to GH, so it would stand to reason that this could have occurred in these studies, too.
The next logical question is this: Since a lot of guys are still using GH, what are the implications of increased organ mass and connective tissue? Well, to be honest, we don't know.
Acromegaly patients do not have high rates of organ malfunction or pathophysiology, so although growing large organs isn't ideal, the current literature doesn't indicate that the problem is immediately life-threatening. But, acromegaly patients do die prematurely, so if they were to live longer, perhaps these organ changes could have long-term impact.
As far as the issue of increases in connective tissue, the increases themselves may not be too terrible, as long as they don't become pathophysiological. Of course, developing carpel tunnel syndrom is no picnic. On the other hand, if the strength of connective tissue increases with connective tissue growth, athletes could become more injury-resistant. Connective tissue growth will not lead to strength increases in well-trained guys if contractile protein mass doesn't go up, but these connective tissue increases may allow individuals to train with heavier weights with less risk of injury. This, however, merely results from me taking off the "science hat" and speculating a bit.
