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Very interesting Dat...question though, when you say "With GHRP-6 you can dose all the way up to 400mcg & not worry these issues..."
Is that 400mcg a day or per injection?
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Very interesting Dat...question though, when you say "With GHRP-6 you can dose all the way up to 400mcg & not worry these issues..."
Is that 400mcg a day or per injection?
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I love how this thing is evolving, all the information on these GHS, peptides and now, the studies with their cardio and neuro-protective qualities...Dat, I thoroughly appreciate the fact that you keep us updated with newer, relevant studies in this area, I can't get enough......
Love this thread. Haven’t read it all however, so forgive me if this question has been asked already. Did a search and only found one instance of the word "opiate".
Regarding opiates: how were they administered in the tests? Does it matter?
Does just any 'ol opiate stimulate GH release?
In other words, does codeine, oxy/hydro-codone or morphine stimulate GH release when administered orally?
Regarding opiates: how were they administered in the tests? Does it matter?
Does just any 'ol opiate stimulate GH release?
In other words, does codeine, oxy/hydro-codone or morphine stimulate GH release when administered orally?
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Lorken said:
Probably IV. It doesn't matter as long as the opioid receptor is stimulated.
Lorken said:
Not necessarily. Take morphine sulfate for example.
It increases GH. It is an opoid receptor agonist See: The effects of opiate agonists on growth hormone and prolactin release in rats, CJ Shaar and JA Clemens, Fed Proc, June 1, 1980; 39(8): 2539-43.
How much? Well 3 -fold in this study Central opiate modulation of growth hormone and insulin-like growth factor-I, Yojiro Hashiguchi, Patricia E. Molina, Brain Research Bulletin Volume 40, Issue 2, 1996, Pages 99-104
But wait, it inhibits GH release in this study, Opiate inhibition of growth hormone secretion in young chickens, S Harvey and CG Scanes, Gen Comp Endocrinol, January 1, 1987; 65(1): 34-9.
Why? I don't know but a luteinizing hormone surge blunts morhphine sulfate GH releasing activity. See: Opiate modulation of growth hormone secretion is compromised during the steroid-induced luteinizing hormone surge, M Singh, JW Simpkins, MP Layden, TM Romano, and WJ Millard, Neuroendocrinology, February 1, 1992; 55(2): 214-20.
One of the opiates that was used in the study I charted in my original article on page one of this thread was an opiate-like peptide.
Two new related heptapeptides (dermorphins) with potent central and peripheral opiate-like activity have been isolated from the skin of South American frogs, and have been chemically characterized as H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (dermorphin) and H-Tyr-D-Ala-Phe-Gly-Tyr-Hyp-Ser-NH2 (Hyp6-dermorphin). The response of GH to infusion of a synthetic dermorphin (5.5 micrograms/kg/min for 30 min) was studied in 9 healthy men. Dermorphin (D) significantly increased plasma growth hormone (GH) concentrations. The GH response to D was blunted by prior administration of naloxone, suggesting that D interacts with mu-type opiate receptors. However, the evaluation of the physiological significance of D-induced GH release in humans requires further study. - Stimulatory effect of dermorphin, a new synthetic potent opiate-like peptide, on human growth hormone secretion, EC degli Uberti, G Trasforini, S Salvadori, A Margutti, R Tomatis, C Rotola, M Bianconi, and R Pansini, Neuroendocrinology, October 1, 1983; 37(4): 280-3.
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Dat, regarding the fat loss content around P.20, I was curious as to how you control your carbohydrate intake, thus you BG levels. You mentioned low GI carbs (you posted a chart of appropriate low GI foods), glycemic load, watching BG levels (using a glc meter), and fiber.
I am going to limit my carb sources to those found in that chart you posted. But you also mentioned that moderate GI foods are appropriate for pre & post W/O. How many grams pre & post W/O would you recommend? What are a couple of great pre/post W/O carb sources you'd recommend? (I do have WMS, FYI).
Do you have a set daily number of carbs (or a range) which you limit yourself to? Or do you rely on your glc meter to let you know when you're had enough?
I use psyllium husk daily. I add a couple scoops to my protein shake. Besides the fiber's BG modulating effect, it's excellent for the GI tract and BMs. I use NOW brand.
Thanks for any insight!
BTW, I started drinking my coffee w/Splenda only (when I don't have fiber with me). That was a very cool mini study you did on coffee, sweetners, creamer, and fiber! I would NOT have thought Splenda would have affected your BG levels.
I am going to limit my carb sources to those found in that chart you posted. But you also mentioned that moderate GI foods are appropriate for pre & post W/O. How many grams pre & post W/O would you recommend? What are a couple of great pre/post W/O carb sources you'd recommend? (I do have WMS, FYI).
Do you have a set daily number of carbs (or a range) which you limit yourself to? Or do you rely on your glc meter to let you know when you're had enough?
I use psyllium husk daily. I add a couple scoops to my protein shake. Besides the fiber's BG modulating effect, it's excellent for the GI tract and BMs. I use NOW brand.
Thanks for any insight!
BTW, I started drinking my coffee w/Splenda only (when I don't have fiber with me). That was a very cool mini study you did on coffee, sweetners, creamer, and fiber!
I would NOT have thought Splenda would have affected your BG levels.novedex
Question for Dat.I Been following youre protocol with the peptides for a couple months now, low dose, higher on heavy workout days with good results tighter core better body comp. for a 47yr old. I was thinking of adding Noveldex to raise test since it can increase test levels by 150% but it lowers IGF1 levels, would the peptides prevent that? Trying to stay away from test or AAS due to the sides. I was also thinking turinabol might be good choice too?
Question for Dat.I Been following youre protocol with the peptides for a couple months now, low dose, higher on heavy workout days with good results tighter core better body comp. for a 47yr old. I was thinking of adding Noveldex to raise test since it can increase test levels by 150% but it lowers IGF1 levels, would the peptides prevent that? Trying to stay away from test or AAS due to the sides. I was also thinking turinabol might be good choice too?
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Not Dat but my 2 cent
I thought that Nolva didn't lower IGF-1 levels to any significant extent. Could be wrong. There is a ton of stuff in this thread it is possible I overlooked that.
Either way, Nolva, IMO, isn't something you want to rely on, long-term, for testosterone support. Its quite toxic to the liver, among other tissues.
You mentioned your trying to stay away from test because of the sides. So just thought I would throw out that - Nolva has a much, much greater chance to induce sides, especially long term.
You could try something like hcG or hcG + hmG, to help bolster your testicular production.
We are getting a little off topic here, feel free to move this to a new post if so mods.
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Right on.
It would curious to see some quantitative data, such as urinary 24 hour analysis, or perhaps a IGF-1/IGF-1 bp3/somatomedin-c scores, to see just what exactly is going on in little mousers body.
But yea, if our mice are showing increased endurance on the ol' spinning wheel, that will just have to suffice
Keep us updated.
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The way you construct things is very particular to the individual. For instance when my blood glucose rises to 145 and takes a while to come down post-meal I will end up storing some of my nutrient intake in adipose tissue. However for other people, this ill defined "spill threshold" may be 185. So you need to know your body.
Timing is important. After you exercise (weights, cardio, etc.) your body is more likely to store nutrients in the liver, muscle and non-adipose tissue. Thats why doing a couple sessions of activity a day (run, hike, swim, lift, cardio, yoga...) immediately followed by a meal is more beneficial....because you have a couple of windows where nutrient uptake is skewed favorably.
In fact post-exercise your body secretes a different blend of growth hormone.
It releases more of the 20kDa variety then it normally does probably in an attempt to avoid hyperglycemia.
If you are using various compounds and attempting to build muscle you can eat higher GI carbs as well as protein. But if you are attempting to stay lean, if you are recomping or dieting, if you are completely natural and don't want to gain fat then even though the post-exercise window is permissive you still need to watch the amount & Glycemic load of the carbs you ingest.
I gave up whey protein shakes years ago and when I am staying lean my post workout carb source is usually oatmeal and a piece of fruit. The protein source is easy to digest whole foods such as fish followed by a red meat meal.
Razor Ripped preached several great carb sources that have minimal impact on blood sugar. He preached Ezekiel Bread (not the one with raisins), barley, lentils, berries. In the U.S. Ezekiel makes a pasta & a cereal that are identical to the low GI bread. If you are not in the U.S. then look for breads made up of sprouted grains. You can make low G.I. foods yourself with grainy items such as barley, flax-seed, wheat bran, oat bran, wholemeal flour, etc.
Here is a low GI muffin recipe I found on the web last year which I make frequently. Two of them raise my blood glucose level only 8-9 points.
In my opinion people waste money on whey protein & WMS, etc.
Instead they should just use whole food.
I don't have a set amount of carbs. If I am seriously dieting then I switch off of carbs as I approach bed. I want the blood glucose to come down. At bed time I take a little bit of Vanadyl Sulfate so that my blood sugar is gone while I sleep. While I sleep I burn a little fat... when I wake up I drink a little black coffee and do some empty stomach cardio. That cardio session will burn fat immediately and so the entire session is a fat burning session. Then I eat breakfast.
I do something like an intense one hour hike on a mountain trail as a separate session to really get the metabolism going for the day. Afterwards I eat.
There's not a lot of tricks to it. You just reorganize the way you eat. Space out the meals so there is 3 hours between them. Construct meals with a low Glycemic Load. Increase the activity to burn off the mobilized fat.
Don't drastically drop calories!!!
Timing is important. After you exercise (weights, cardio, etc.) your body is more likely to store nutrients in the liver, muscle and non-adipose tissue. Thats why doing a couple sessions of activity a day (run, hike, swim, lift, cardio, yoga...) immediately followed by a meal is more beneficial....because you have a couple of windows where nutrient uptake is skewed favorably.
In fact post-exercise your body secretes a different blend of growth hormone.
It releases more of the 20kDa variety then it normally does probably in an attempt to avoid hyperglycemia.
If you are using various compounds and attempting to build muscle you can eat higher GI carbs as well as protein. But if you are attempting to stay lean, if you are recomping or dieting, if you are completely natural and don't want to gain fat then even though the post-exercise window is permissive you still need to watch the amount & Glycemic load of the carbs you ingest.
I gave up whey protein shakes years ago and when I am staying lean my post workout carb source is usually oatmeal and a piece of fruit. The protein source is easy to digest whole foods such as fish followed by a red meat meal.
Razor Ripped preached several great carb sources that have minimal impact on blood sugar. He preached Ezekiel Bread (not the one with raisins), barley, lentils, berries. In the U.S. Ezekiel makes a pasta & a cereal that are identical to the low GI bread. If you are not in the U.S. then look for breads made up of sprouted grains. You can make low G.I. foods yourself with grainy items such as barley, flax-seed, wheat bran, oat bran, wholemeal flour, etc.
Here is a low GI muffin recipe I found on the web last year which I make frequently. Two of them raise my blood glucose level only 8-9 points.
1 cup wheat bran
1/2 cup oat bran
1 cup whole wheat flour
1/2 cup skim milk
2 each large eggs
1 tablespoon vanilla extract
1/2 teaspoon ground cinnamon
1/8 teaspoon ground nutmeg
1 tablespoon baking powder
1/2 cup Splenda
14 ounces canned pumpkin
Preheat oven to 350f. Spray a muffin tin with cooking spray to prevent sticking. Do not use papers.
Beat eggs and add the milk, vanilla, cinnamon, nutmeg and sweetener. Mix the oat and wheat bran and add the wet ingredients. Set aside for 5 minutes to soften.
Once softened, add the remaining ingredients and stir just to blend.
Spoon into the muffin tin and bake approx 25-30 minutes or until the muffins pull away from the sides of the pan. They are very moist and may not 'test' done.
Let cool for 10 minutes before removing from pan.
Let cool completely and refrigerate any leftovers.
Serving Size : 12 muffins
Per Serving: 101 Calories; 2g Fat (12.7% calories from fat); 5g Protein; 21g Carbohydrate; 5g Dietary Fiber; 36mg Cholesterol; 156mg Sodium.
1/2 cup oat bran
1 cup whole wheat flour
1/2 cup skim milk
2 each large eggs
1 tablespoon vanilla extract
1/2 teaspoon ground cinnamon
1/8 teaspoon ground nutmeg
1 tablespoon baking powder
1/2 cup Splenda
14 ounces canned pumpkin
Preheat oven to 350f. Spray a muffin tin with cooking spray to prevent sticking. Do not use papers.
Beat eggs and add the milk, vanilla, cinnamon, nutmeg and sweetener. Mix the oat and wheat bran and add the wet ingredients. Set aside for 5 minutes to soften.
Once softened, add the remaining ingredients and stir just to blend.
Spoon into the muffin tin and bake approx 25-30 minutes or until the muffins pull away from the sides of the pan. They are very moist and may not 'test' done.
Let cool for 10 minutes before removing from pan.
Let cool completely and refrigerate any leftovers.
Serving Size : 12 muffins
Per Serving: 101 Calories; 2g Fat (12.7% calories from fat); 5g Protein; 21g Carbohydrate; 5g Dietary Fiber; 36mg Cholesterol; 156mg Sodium.
In my opinion people waste money on whey protein & WMS, etc.
Instead they should just use whole food.
I don't have a set amount of carbs. If I am seriously dieting then I switch off of carbs as I approach bed. I want the blood glucose to come down. At bed time I take a little bit of Vanadyl Sulfate so that my blood sugar is gone while I sleep. While I sleep I burn a little fat... when I wake up I drink a little black coffee and do some empty stomach cardio. That cardio session will burn fat immediately and so the entire session is a fat burning session. Then I eat breakfast.
I do something like an intense one hour hike on a mountain trail as a separate session to really get the metabolism going for the day. Afterwards I eat.
There's not a lot of tricks to it. You just reorganize the way you eat. Space out the meals so there is 3 hours between them. Construct meals with a low Glycemic Load. Increase the activity to burn off the mobilized fat.
Don't drastically drop calories!!!
Dat, regarding the fat loss content around P.20, I was curious as to how you control your carbohydrate intake, thus you BG levels. You mentioned low GI carbs (you posted a chart of appropriate low GI foods), glycemic load, watching BG levels (using a glc meter), and fiber.
I am going to limit my carb sources to those found in that chart you posted. But you also mentioned that moderate GI foods are appropriate for pre & post W/O. How many grams pre & post W/O would you recommend? What are a couple of great pre/post W/O carb sources you'd recommend? (I do have WMS, FYI).
Do you have a set daily number of carbs (or a range) which you limit yourself to? Or do you rely on your glc meter to let you know when you're had enough?
I use psyllium husk daily. I add a couple scoops to my protein shake. Besides the fiber's BG modulating effect, it's excellent for the GI tract and BMs. I use NOW brand.
Thanks for any insight!
BTW, I started drinking my coffee w/Splenda only (when I don't have fiber with me). That was a very cool mini study you did on coffee, sweetners, creamer, and fiber!
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He who doesn't know what Arginine is can go google it and read wikipedia. There is no need to cut and paste the entire wikepedia fact sheet in this thread.
In response to your question on Arginine I posted a chart and I expected you to look at it and realize "...oh Arginine inhibits Somatostatin".
If you would have posted that then I could have posted relevant information form studies on L-Arginine, its effect on somatostatin, subsequent GH release, how much Arginine is needed, etc.
Part of the difficulty in learning is pulling out what is important from all of the noise. The Internet is full of noise... and when you cut and pasted you brought some of that noise to this thread.
Thats all bro...nothing more than that.
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WC114 said:
Dr. Crisler is the expert in this area 1000-fold over me. I mean he eats, sleeps and craps HRT 24 hours a day.
We covered Tamoxifen and its minimal impact on IGF-1 levels a page or so back. I personally always liked low dose Clomid and the studies that used it to positive effect to increase testosterone.
You might want to consider increasing your free testosterone with Nettle Root extract. All ligands of Nettle Root except one have an affinity for SHBG (except one) so Nettle Root will help free up testosterone. Divanil is the Nettle Root ligand with the highest affinity for SHBG so extracts standardized for this are better.
WC114 said:
I understand but Turinabol is a steroid also.
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HA! Love the recipe...beeeeauuu-ti-ful! I will try those muffins bud!
I just got a new supply of glc strips. Just took PWO BG: 84 mg/dL. Before CJC/GHRP I believe my fasting BG was ~68-78 mg/dL (I have historic data in my meter). I'd sometimes feel hypo...light-headed, sort of slow (prior to CJC/GHRP). And this would be when I'd just be low carbing it for a few days. Nothing real special.
I just had a 44g whey protein shake (at 7:55pm): BG = 89mg/dL. 5pt raise. The All The Whey Chocolate protein has 1g fiber/22g serving, so there were 2 g fiber in my shake.
Next time I'm going to make the 44g shake w/a scoop of psyllium husk.
Love this tinkering. Thanks Dat for sharing all your experiences.
I will try those muffins bud! I just got a new supply of glc strips. Just took PWO BG: 84 mg/dL. Before CJC/GHRP I believe my fasting BG was ~68-78 mg/dL (I have historic data in my meter). I'd sometimes feel hypo...light-headed, sort of slow (prior to CJC/GHRP). And this would be when I'd just be low carbing it for a few days. Nothing real special.
I just had a 44g whey protein shake (at 7:55pm): BG = 89mg/dL. 5pt raise. The All The Whey Chocolate protein has 1g fiber/22g serving, so there were 2 g fiber in my shake.
Next time I'm going to make the 44g shake w/a scoop of psyllium husk.
Love this tinkering. Thanks Dat for sharing all your experiences.
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- 648
I wrote an article on post exercise carbs a few years back:
Post exercise
Immediately after exercise in the post-exercise phase, a restorative rebound in the naturally occurring anabolic hormones occurs. These hormones include insulin, growth hormone (GH), IGF, pineal and thymic factors, as well as the steroid hormones testosterone, DHEA, and estrogens. This post-exercise response is also known as biochemical or metabolic supercompensation. During this supercompensation period HIGH LEVELS of these anabolic hormones, particularly INSULIN, GH, and IGF, are NECESSARY during close post-exercise restorative phase to provide MAXIMAL PROTEIN SYNTHESIS. High levels of these same hormones are also necessary to restore the negative metabolic effect created by catecholamines and glucocorticoids produced during exercise. It should be noted that testosterone is highest during mid-exercise but falls off slightly immediately post-exercise. It does not seem to be involved in the earlier stages of post-exercise as the hormones insulin, GH, and IGF. Testosterone usually appears again during later phases of post-workout recovery. So this tells us that immediately following a bout of exercise, there will be an increase in the production of both GH and INSULIN. Both INSULIN and GH ARE very necessary for optimal protein synthesis.
It should also be noted that literature does support the theory that INSULIN and GH both INCREASE protein synthesis in combination with several other natural occurring hormones. In fact, insulin rebound is required for the release of GH, which in turn releases IGF. It should also be noted once again that synthesis will not be able to occur if there is not a sufficient supply of energy (as in calories) or insufficient free amino acid pools. Thus, many of these sources revealed as I had previously recommended, that amino acid or protein supplements with some added carbs, taken within 2 hours post-exercise, while insulin, growth hormone (GH), IGF, pineal and thymic factors are high, further aids in creating a beneficial environment during recovery by further increasing these hormone levels.
Post-exercise carbs
The addition of dietary carbohydrate causes increases insulin production, which further increases GH release, which in turn further increases the release of IGF. These increases in turn, have been shown to further increase protein synthesis and muscle growth after a bout of exercise as well as increasing the uptake of amino acids. By adding amino acids after exercise we have further increased the available free amino acid pool as well. Amino acids are necessary for protein synthesis to take place. So without the insulin rebound after exercise, the body would remain in a catabolic state.
Let's examine more closely why it is suggested that carbohydrate be taken with protein immediately following a bout if exercise. We know that with the onset of exercise, ATP is the immediate source of energy. As the exercise progresses, the ATP stores are reduced and glycogen and glucose are also utilized by the muscle for fuel. With more muscle glycogen and glucose being used for energy, blood glucose levels soon begin to drop. Insulin levels soon begin to fall as well. This is the point at which FFA is released from the adipose tissue and becomes a reserve source of fuel.
As we near the end of our training, the body is now in a hypoglycemic stage. The blood sugar is low and the insulin level has dropped. Immediately after exercise as explained earlier, GH production is increased as insulin levels start to rebound. A carbohydrate supplement following exercise will elevate blood glucose levels and cause a state of hyperglycemia forcing further production of insulin. The high levels of insulin in the blood now force much needed glucose and amino acids through the receptor sites in the muscle cell at a quicker rate. This high level of blood glucose will eventually cause further GH secretions. Soon the high levels of insulin utilize the extra carbohydrate and the blood glucose levels once again drop. Of course the insulin level now drops as it did during exercise. GH secreats once again starts as the rebound effect begins all over.
Recommendations
How much of each would I recommend? About 0.7 g of protein/kg of body weight with 2 g of carbohydrate/kg of body weight in the first 15-30 minutes after training. The protein source should be high in branched amino acids. I also recommend using a liquid full spectrum amino acid mixture with di- and tri-peptide bonds. Full spectrum amino acids are absorbed quicker due to their small chain structure. Therefore they get into the bloodstream very quickly where they are shuttled quickly into the muscle cell by the increased insulin production.
Oops missed the post on noveldex,Didnt realize it was that hepa toxic either. I know turinabol is a steroid I was just thinking it would be the lesser evil. I'll have to research nettle again, I remember there was a neg. to its use. Thanks.
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Age-Related Changes in Slow Wave Sleep and Relationship With Growth Hormone Levels
I've tried to emphasize that Slow Wave Sleep (SW) and Growth Hormone (GH) are not merely positively correlated but are intricately bound together such that a change in one leads to a change in the other. That is why from the start I have attempted to underscore that a pre-bed dose of Growth Hormone Releasing Hormone (GHRH) & Growth Hormone Releasing Peptide 6 (GHRP-6) will increase that vital period of sleep known as Slow Wave Sleep which has restorative benefits beyond amplified GH release.
The following study is fascinating for all of us because it reveals that somatopause begins dramatically between age 25 and 35. The following study published in the prestigious Journal of the American Medical Association is well worth examining.
The objective of the study was, to determine the chronology of age-related changes in sleep duration and quality (sleep stages) in healthy men and whether concomitant alterations occur in GH and cortisol levels.
They combined data from a series of studies conducted between 1985 and 1999 at 4 laboratories which examined 149 healthy men, aged 16 to 83 years, with a mean (SD) body mass index of 24.1 (2.3) kg/m2, without sleep complaints or histories of endocrine, psychiatric, or sleep disorders.
They created twenty-four–hour profiles of plasma GH and cortisol levels and polygraphic sleep recordings and found the following results:
For a deeper read I include the following Introduction & Comments which elaborate on the significance of the results. I strongly encourage any one interested in anti-aging to read it so that they can adopt the appropriate compensatory strategies.
ANTI-AGING
I've tried to emphasize that Slow Wave Sleep (SW) and Growth Hormone (GH) are not merely positively correlated but are intricately bound together such that a change in one leads to a change in the other. That is why from the start I have attempted to underscore that a pre-bed dose of Growth Hormone Releasing Hormone (GHRH) & Growth Hormone Releasing Peptide 6 (GHRP-6) will increase that vital period of sleep known as Slow Wave Sleep which has restorative benefits beyond amplified GH release.
The following study is fascinating for all of us because it reveals that somatopause begins dramatically between age 25 and 35. The following study published in the prestigious Journal of the American Medical Association is well worth examining.
The chronology of aging of GH secretion follows a pattern remarkably similar to that of SW sleep. Thus, in men, the so-called "somatopause" occurs early in adulthood, between age 25 and 35 years, an age range that corresponds to the human life expectancy before the development of modern civilization and is essentially completed by the end of the fourth decade.
Our analyses further indicate that reduced amounts of SW sleep, independent of age, are partly responsible for reduced GH secretion in midlife and late life. That this correlative evidence reflects a common mechanism underlying SW sleep generation and GH release rather than an indirect association is supported by 2 studies that have shown that pharmacological enhancement of SW sleep results in increased GH release. - Age-Related Changes in Slow Wave Sleep and REM Sleep and Relationship With Growth Hormone and Cortisol Levels in Healthy Men, Eve Van Cauter, PhD; Rachel Leproult, MS; Laurence Plat, MD,JAMA. 2000;284:861-868
Our analyses further indicate that reduced amounts of SW sleep, independent of age, are partly responsible for reduced GH secretion in midlife and late life. That this correlative evidence reflects a common mechanism underlying SW sleep generation and GH release rather than an indirect association is supported by 2 studies that have shown that pharmacological enhancement of SW sleep results in increased GH release. - Age-Related Changes in Slow Wave Sleep and REM Sleep and Relationship With Growth Hormone and Cortisol Levels in Healthy Men, Eve Van Cauter, PhD; Rachel Leproult, MS; Laurence Plat, MD,JAMA. 2000;284:861-868
The objective of the study was, to determine the chronology of age-related changes in sleep duration and quality (sleep stages) in healthy men and whether concomitant alterations occur in GH and cortisol levels.
They combined data from a series of studies conducted between 1985 and 1999 at 4 laboratories which examined 149 healthy men, aged 16 to 83 years, with a mean (SD) body mass index of 24.1 (2.3) kg/m2, without sleep complaints or histories of endocrine, psychiatric, or sleep disorders.
They created twenty-four–hour profiles of plasma GH and cortisol levels and polygraphic sleep recordings and found the following results:
The mean (SEM) percentage of deep slow wave sleep decreased from 18.9% (1.3%) during early adulthood (age 16-25 years) to 3.4% (1.0%) during midlife (age 36-50 years) and was replaced by lighter sleep (stages 1 and 2) without significant increases in sleep fragmentation or decreases in rapid eye movement (REM) sleep.
The transition from midlife to late life (age 71-83 years) involved no further significant decrease in slow wave sleep but an increase in time awake of 28 minutes per decade at the expense of decreases in both light non-REM sleep (-24 minutes per decade; P<.001) and REM sleep (-10 minutes per decade; P<.001).
The decline in slow wave sleep from early adulthood to midlife was paralleled by a major decline in GH secretion (-372 µg per decade; P<.001). From midlife to late life, GH secretion further declined at a slower rate (-43 µg per decade; P<.02).
Independently of age, the amount of GH secretion was significantly associated with slow wave sleep (P<.001).
Increasing age was associated with an elevation of evening cortisol levels (+19.3 nmol/L per decade; P<.001) that became significant only after age 50 years, when sleep became more fragmented and REM sleep declined. A trend for an association between lower amounts of REM sleep and higher evening cortisol concentrations independent of age was detected (P<.10).
For a deeper read I include the following Introduction & Comments which elaborate on the significance of the results. I strongly encourage any one interested in anti-aging to read it so that they can adopt the appropriate compensatory strategies.
INTRODUCTION
Decreased subjective sleep quality is one of the most common health complaints of older adults.1 The most consistent alterations associated with normal aging include increased number and duration of awakenings and decreased amounts of deep slow wave (SW) sleep (ie, stages 3 and 4 of non–rapid eye movement (non-REM) sleep).2-4 REM sleep appears to be relatively better preserved during aging.3-7 The age at which changes in amount and distribution of sleep stages appear is unclear because the majority of studies have been based on comparisons of young vs older adults. Several investigators have noticed that there are marked decreases in SW sleep in early adulthood in men but not in women.8-11
Sleep is a major modulator of endocrine function, particularly of pituitary-dependent hormonal release. Growth hormone (GH) secretion is stimulated during sleep and, in men, 60% to 70% of daily GH secretion occurs during early sleep, in association with SW sleep.12 Whether decrements in SW sleep contribute to the well-known decrease in GH secretion in normal aging is not known.13-15
In contrast to the enhanced activity of the GH axis during sleep, the hypothalamic-pituitary-adrenal (HPA) axis is acutely inhibited during early SW sleep.16-20 Furthermore, even partial sleep deprivation results in an elevation of cortisol levels the following evening.21 Thus, both decreased SW sleep and sleep loss resulting from increased sleep fragmentation could contribute to elevating cortisol levels. An elevation of evening cortisol levels is a hallmark of aging14-15,22 that is thought to reflect an impairment of the negative feedback control of the HPA axis and could underlie a constellation of metabolic and cognitive alterations.23-25
The present study defines the chronology of age-related changes in sleep duration and quality (ie, amounts of sleep stages), GH secretion, and cortisol levels in healthy men and examines whether decrements in sleep quality are associated with alterations of GH and cortisol levels.
...
COMMENT
The present analysis demonstrates that, in healthy men, aging affects SW sleep and GH release with a similar chronology characterized by major decrements from early adulthood to midlife. In contrast, the impact of age on REM sleep, sleep fragmentation, and HPA function does not become apparent until later in life. The analysis further suggests that age-related alterations in the somatotropic and corticotropic axes may partially reflect decreased sleep quality.
Human sleep is under the dual control of circadian rhythmicity and of a homeostatic process relating the depth of sleep to the duration of prior wakefulness.44 This homeostatic process involves a putative neural sleep factor that increases during waking and decays exponentially during sleep. Slow wave sleep is primarily controlled by the homeostatic process. Circadian rhythmicity is an oscillation with a near 24-hour period generated by a pacemaker located in the hypothalamic suprachiasmatic nucleus. Circadian rhythmicity plays an important role in sleep timing, sleep consolidation, and the distribution of REM sleep.45 The present data indicate that an alteration in sleep-wake homeostasis is an early biological marker of aging in adult men. In contrast, components of sleep that are under the control of the circadian pacemaker appear to be relatively well preserved until late in life.
The chronology of aging of GH secretion follows a pattern remarkably similar to that of SW sleep. Thus, in men, the so-called "somatopause" occurs early in adulthood, between age 25 and 35 years, an age range that corresponds to the human life expectancy before the development of modern civilization and is essentially completed by the end of the fourth decade. Our analyses further indicate that reduced amounts of SW sleep, independent of age, are partly responsible for reduced GH secretion in midlife and late life. That this correlative evidence reflects a common mechanism underlying SW sleep generation and GH release rather than an indirect association is supported by 2 studies that have shown that pharmacological enhancement of SW sleep results in increased GH release.46-47 Also supporting a causal relationship between decreased sleep quality and reduced nocturnal GH secretion are studies in patients with sleep apnea showing a marked increase in GH release following treatment with positive airway pressure.48-49 The reverse interaction between sleep and GH, ie, a deleterious impact of reduced somatotropic function on sleep, is also possible since studies in both normal and pathological conditions have shown that GH-releasing factor and GH influence sleep quality.12, 50 In the present study of nonobese men, the finding of a negative impact of BMI on both GH secretion during waking and amount of SW sleep is consistent with the hypothesis that inhibition of the GH axis may adversely affect sleep regulation.
While the clinical implications of decreased SW sleep are still unclear, the relative GH deficiency of the elderly is associated with increased fat tissue and abdominal obesity, reduced muscle mass and strength, and reduced exercise capacity.51-53 Multiple trials are currently examining the clinical usefulness and safety of replacement therapy with recombinant GH, the other hormones of the GH axis, and synthetic GH secretagogues in elderly adults without pathological GH deficiency. While the benefits of such interventions are still unproven, the present findings suggest that they should target a younger age range than currently envisioned, ie, individuals in early midlife rather than those older than 65 years, when peripheral tissues have been continuously exposed to very low levels of GH for at least 2 decades. Furthermore, since pharmacological enhancement of SW sleep in young adults has been shown to result in a simultaneous and proportional increase in GH release 46-47 and ongoing studies in our laboratory indicate that similar effects can be obtained in older subjects, drugs that reliably stimulate SW sleep may represent a novel class of GH secretagogues.
The present data demonstrate that the amount of REM sleep is reduced by approximately 50% in late life vs young adulthood. However, reduced amounts of REM sleep and significant sleep fragmentation do not occur until after age 50 years. The impact of aging on cortisol levels followed the same chronology. Aging was associated with an elevation of evening cortisol levels, reflecting an impaired ability to achieve evening quiescence following morning stimulation. Studies in both animals and humans have indicated that deleterious effects of HPA hyperactivity are more pronounced at the time of the trough of the rhythm than at the time of the peak.25, 54 Thus, modest elevations in evening cortisol levels could facilitate the development of central and peripheral disturbances associated with glucocorticoid excess, such as memory deficits and insulin resistance,24-25 and further promote sleep fragmentation. Indeed, elevated cortisol levels may promote awakenings.55-56
Elevated evening cortisol levels in late life probably reflect an impairment of the negative feedback control of the HPA axis in aging. Our analyses suggest that there is a relationship between this alteration of HPA function and decreased amounts of REM sleep that is independent of age. The data generally support the concept that decreased sleep quality contributes to the allostatic load, ie, the wear and tear resulting from overactivity of stress-responsive systems.57
The present study focused on the effects of aging on the relationship between sleep and the somatotopic and corticotropic axes in men because the predominant GH secretion occurs during sleep in men but not in women11 and because there is evidence to suggest that the marked decreases in SW sleep in early adulthood occur in men but not in women.8-11 Whether conclusions similar to those obtained for men hold for women will require a separate evaluation as sex differences in sleep quality as well as 24-hour profiles of GH and cortisol secretion have been well documented in both young and older adults.11-12,22
In conclusion, in healthy men, the distinct changes in sleep quality that characterize the transitions from early adulthood to midlife, on the one hand, and from midlife to old age, on the other hand, are each associated with specific alterations in hormonal systems that are essential for metabolic regulation. Strategies to prevent or limit decrements of sleep quality in midlife and late life may therefore represent an indirect form of hormonal therapy with possible beneficial health consequences.
REFERENCES
1. Prinz PN. Sleep and sleep disorders in older adults. J Clin Neurophysiol. 1995;12:139-146.
2. Feinberg I, Koresko RL, Heller N. EEG sleep patterns as a function of normal and pathological aging in man. Psychiatry Res. 1967;5:107-144.
3. Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Sleep and psychiatric disorders. Arch Gen Psychiatry. 1992;49:651-668.
4. Bliwise DL. Normal aging. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia, Pa: WB Saunders; 1994:26-39.
5. Feinberg I. Functional implications of changes in sleep physiology with age. In: Terry RD, Gershon S, eds. Neurobiology of Aging. New York, NY: Raven Press; 1976:23-41.
6. Ehlers CL, Kupfer DJ. Effects of age on delta and REM sleep parameters. Electroencephalogr Clin Neurophysiol. 1989;72:118-125.
7. Landolt HP, Dijk DJ, Achermann P, Borbely AA. Effects of age on the sleep EEG: slow-wave activity and spindle frequency in young and middle-aged men. Brain Res. 1996;738:205-212.
8. Webb WB. Sleep in older persons: sleep structures of 50- to 60-year-old men and women. J Gerontol. 1982;37:581-586.
9. Dijk DJ, Beersma DG, Bloem GM. Sex differences in the sleep EEG of young adults: visual scoring and spectral analysis. Sleep. 1989;12:500-507.
10. Mourtazaev MS, Kemp B, Zwinderman AH, Kamphuisen HA. Age and gender affect different characteristics of slow waves in the sleep EEG. Sleep. 1995;18:557-564.
11. Ehlers CL, Kupfer DJ. Slow-wave sleep: do young adult men and women age differently? J Sleep Res. 1997;6:211-215.
12. Van Cauter E, Plat L, Copinschi G. Interrelations between sleep and the somatotropic axis. Sleep. 1998;21:553-566.
13. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 1987;64:51-58.
14. van Coevorden A, Mockel J, Laurent E, et al. Neuroendocrine rhythms and sleep in aging men. Am J Physiol. 1991;260:E651-E661.
15. Kern W, Dodt C, Born J, Fehm HL. Changes in cortisol and growth hormone secretion during nocturnal sleep in the course of aging. J Gerontol A Biol Sci Med Sci. 1996;51A:M3-M9.
16. Weitzman ED, Zimmerman JC, Czeisler CA, Ronda JM. Cortisol secretion is inhibited during sleep in normal man. J Clin Endocrinol Metab. 1983;56:352-358.
17. Spath-Schwalbe E, Uthgenannt D, Voget G, Kern W, Born J, Fehm HL. Corticotropin-releasing hormone-induced adrenocorticotropin and cortisol secretion depends on sleep and wakefulness. J Clin Endocrinol Metab. 1993;77:1170-1173.
18. Spath-Schwalbe E, Uthgenannt D, Korting N, Fehm HL, Born J. Sleep and wakefulness affect the responsiveness of the pituitary-adrenocortical axis to arginine vasopressin in humans. Neuroendocrinology. 1994;60:544-548.
19. Gronfier C, Luthringer R, Follenius M, et al. Temporal relationships between pulsatile cortisol secretion and electroencephalographic activity during sleep in man. Electroencephalogr Clin Neurophysiol. 1997;103:405-408.
20. Bierwolf C, Struve K, Marshall L, Fehm HL. Slow wave sleep drives inhibition of pituitary-adrenal secretion in humans. J Neuroendocrinol. 1997;9:479-484.
21. Leproult R, Copinschi G, Buxton O, Van Cauter E. Sleep loss results in an elevation of cortisol levels the next evening. Sleep. 1997;20:865-870.
22. Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab. 1996;81:2468-2473.
23. Seeman TE, Robbins RJ. Aging and hypothalamo-pituitary-adrenal response to challenge in humans. Endocr Rev. 1994;15:233-260.
24. McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol. 1995;5:205-216.
25. Dallman MF, Strack AL, Akana SF, et al. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol. 1993;14:303-347.
26. Linkowski P, Mendlewicz J, Leclercq R, et al. The 24-hour profile of adrenocorticotropin and cortisol in major depressive illness. J Clin Endocrinol Metab. 1985;61:429-438.
27. Copinschi G, Van Onderbergen A, L'Hermite-Balériaux M, et al. Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men. Sleep. 1990;13:232-244.
28. Van Cauter E, Blackman JD, Roland D, Spire JP, Refetoff S, Polonsky KS. Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. J Clin Invest. 1991;88:934-942.
29. Frank S, Roland DC, Sturis J, et al. Effects of aging on glucose regulation during wakefulness and sleep. Am J Physiol. 1995;269:E1006-E1016.
30. Biston P, Van Cauter E, Ofek G, Linkowski P, Polonsky KS, Degaute JP. Diurnal variations in cardiovascular function and glucose regulation in normotensive humans. Hypertension. 1996;28:863-871.
31. Copinschi G, Leproult R, Van Onderbergen A, et al. Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology. 1997;66:278-286.
32. Linkowski P, Spiegel K, Kerkhofs M, et al. Genetic and environmental influences on prolactin secretion during wake and during sleep. Am J Physiol. 1998;274:E909-E919.
33. Jarrett DJ, Greenhouse JB. Circadian rhythm of cortisol secretion is not disturbed in outpatients with a major depressive disorder. In: Program of the First Meeting of the Society for Research on Biological Rhythms; May 11-14, 1988; Charleston, SC. 97.
34. Jarrett DB, Pollock B, Miewald JM, Kupfer DJ. Acute effects of intravenous clomipramine upon sleep-related hormone secretion in depressed outpatients and healthy control subjects. Biol Psychiatry. 1991;29:3-14.
35. Rubin RT, Poland RE, Lesser IM, Winston RA, Blodgett AL. Neuroendocrine aspects of primary endogenous depression, I: cortisol secretory dynamics in patients and matched controls. Arch Gen Psychiatry. 1987;44:328-336.
36. Rubin RT, Poland RE, Lesser IM. Neuroendocrine aspects of primary endogenous depression, X: serum growth hormone measures in patients and matched control subjects. Biol Psychiatry. 1990;27:1065-1082.
37. Vgontzas AN, Papnicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance and hypercytokinemia. J Clin Endocrinol Metab. 2000;85:1151-1158.
38. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles, Calif: UCLA Brain Information Service/Brain Research Institute; 1968.
39. Virasoro E, Copinschi G, Bruno OD, Leclercq R. Radioimmunoassay of human growth hormone using a charcoal-dextran separation procedure. Clin Chim Acta. 1971;31:294-297.
40. L'Hermite-Balériaux M, Copinschi G, Van Cauter E. Growth hormone assays: early to latest generations compared. Clin Chem. 1996;42:1789-1795.
41. Van Cauter E. Method for characterization of 24-h temporal variation of blood constituents. Am J Physiol. 1979;237:E255-E264.
42. Van Cauter E. Estimating false-positive and false-negative errors in analyses of hormonal pulsatility. Am J Physiol. 1988;254:E786-E794.
43. Van Cauter E, Kerkhofs M, Caufriez A, Van Onderbergen A, Thorner MO, Copinschi G. A quantitative estimation of GH secretion in normal man: reproducibility and relation to sleep and time of day. J Clin Endocrinol Metab. 1992;74:1441-1450.
44. Borbely AA. Processes underlying sleep regulation. Horm Res. 1998;49:114-117.
45. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci. 1995;15:3526-3538.
46. Van Cauter E, Plat L, Scharf M, et al. Simultaneous stimulation of slow-wave sleep and growth hormone secretion by -hydroxybutyrate in normal young men. J Clin Invest. 1997;100:745-753.
47. Gronfier C, Luthringer R, Follenius M, et al. A quantitative evaluation of the relationships between growth hormone secretion and delta wave electroencephalographic activity during normal sleep and after enrichment in delta waves. Sleep. 1996;19:817-824.
48. Saini J, Krieger J, Brandenberger G, Wittersheim G, Simon C, Follenius M. Continuous positive airway pressure treatment: effects on growth hormone, insulin and glucose profiles in obstructive sleep apnea patients. Horm Metab Res. 1993;25:375-381.
49. Cooper BG, White JE, Ashworth LA, Alberti KG, Gibson GJ. Hormonal and metabolic profiles in subjects with obstructive sleep apnea syndrome and the effects of nasal continuous positive airway pressure (CPAP) treatment. Sleep. 1995;18:172-179.
50. Aström C. Interaction between sleep and growth hormone evaluated by manual polysomnography and automatic power spectral analysis. Acta Neurol Scand. 1995;92:281-296.
51. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol. 1992;37:387-397.
52. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 1993;14:20-39.
53. Rosen T, Hansson T, Granhed H, Szucs J, Bengtsson BA. Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol. 1993;129:201-206.
54. Plat L, Féry F, L'Hermite-Balériaux M, Mockel J, Van Cauter E. Metabolic effects of short-term physiological elevations of plasma cortisol are more pronounced in the evening than in the morning. J Clin Endocrinol Metab. 1999;84:3082-3092.
55. Holsboer F, von Bardelein U, Steiger A. Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man. Neuroendocrinology. 1988;48:32-38.
56. Born J, Späth-Schwalbe E, Schwakenhofer H, Kern W, Fehm HL. Influences of corticotropin-releasing hormone, adrenocorticotropin, and cortisol on sleep in normal man. J Clin Endocrinol Metab. 1989;68:904-911.
57. McEwen BS. Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci. 1998;840:33-44.
Decreased subjective sleep quality is one of the most common health complaints of older adults.1 The most consistent alterations associated with normal aging include increased number and duration of awakenings and decreased amounts of deep slow wave (SW) sleep (ie, stages 3 and 4 of non–rapid eye movement (non-REM) sleep).2-4 REM sleep appears to be relatively better preserved during aging.3-7 The age at which changes in amount and distribution of sleep stages appear is unclear because the majority of studies have been based on comparisons of young vs older adults. Several investigators have noticed that there are marked decreases in SW sleep in early adulthood in men but not in women.8-11
Sleep is a major modulator of endocrine function, particularly of pituitary-dependent hormonal release. Growth hormone (GH) secretion is stimulated during sleep and, in men, 60% to 70% of daily GH secretion occurs during early sleep, in association with SW sleep.12 Whether decrements in SW sleep contribute to the well-known decrease in GH secretion in normal aging is not known.13-15
In contrast to the enhanced activity of the GH axis during sleep, the hypothalamic-pituitary-adrenal (HPA) axis is acutely inhibited during early SW sleep.16-20 Furthermore, even partial sleep deprivation results in an elevation of cortisol levels the following evening.21 Thus, both decreased SW sleep and sleep loss resulting from increased sleep fragmentation could contribute to elevating cortisol levels. An elevation of evening cortisol levels is a hallmark of aging14-15,22 that is thought to reflect an impairment of the negative feedback control of the HPA axis and could underlie a constellation of metabolic and cognitive alterations.23-25
The present study defines the chronology of age-related changes in sleep duration and quality (ie, amounts of sleep stages), GH secretion, and cortisol levels in healthy men and examines whether decrements in sleep quality are associated with alterations of GH and cortisol levels.
...
COMMENT
The present analysis demonstrates that, in healthy men, aging affects SW sleep and GH release with a similar chronology characterized by major decrements from early adulthood to midlife. In contrast, the impact of age on REM sleep, sleep fragmentation, and HPA function does not become apparent until later in life. The analysis further suggests that age-related alterations in the somatotropic and corticotropic axes may partially reflect decreased sleep quality.
Human sleep is under the dual control of circadian rhythmicity and of a homeostatic process relating the depth of sleep to the duration of prior wakefulness.44 This homeostatic process involves a putative neural sleep factor that increases during waking and decays exponentially during sleep. Slow wave sleep is primarily controlled by the homeostatic process. Circadian rhythmicity is an oscillation with a near 24-hour period generated by a pacemaker located in the hypothalamic suprachiasmatic nucleus. Circadian rhythmicity plays an important role in sleep timing, sleep consolidation, and the distribution of REM sleep.45 The present data indicate that an alteration in sleep-wake homeostasis is an early biological marker of aging in adult men. In contrast, components of sleep that are under the control of the circadian pacemaker appear to be relatively well preserved until late in life.
The chronology of aging of GH secretion follows a pattern remarkably similar to that of SW sleep. Thus, in men, the so-called "somatopause" occurs early in adulthood, between age 25 and 35 years, an age range that corresponds to the human life expectancy before the development of modern civilization and is essentially completed by the end of the fourth decade. Our analyses further indicate that reduced amounts of SW sleep, independent of age, are partly responsible for reduced GH secretion in midlife and late life. That this correlative evidence reflects a common mechanism underlying SW sleep generation and GH release rather than an indirect association is supported by 2 studies that have shown that pharmacological enhancement of SW sleep results in increased GH release.46-47 Also supporting a causal relationship between decreased sleep quality and reduced nocturnal GH secretion are studies in patients with sleep apnea showing a marked increase in GH release following treatment with positive airway pressure.48-49 The reverse interaction between sleep and GH, ie, a deleterious impact of reduced somatotropic function on sleep, is also possible since studies in both normal and pathological conditions have shown that GH-releasing factor and GH influence sleep quality.12, 50 In the present study of nonobese men, the finding of a negative impact of BMI on both GH secretion during waking and amount of SW sleep is consistent with the hypothesis that inhibition of the GH axis may adversely affect sleep regulation.
While the clinical implications of decreased SW sleep are still unclear, the relative GH deficiency of the elderly is associated with increased fat tissue and abdominal obesity, reduced muscle mass and strength, and reduced exercise capacity.51-53 Multiple trials are currently examining the clinical usefulness and safety of replacement therapy with recombinant GH, the other hormones of the GH axis, and synthetic GH secretagogues in elderly adults without pathological GH deficiency. While the benefits of such interventions are still unproven, the present findings suggest that they should target a younger age range than currently envisioned, ie, individuals in early midlife rather than those older than 65 years, when peripheral tissues have been continuously exposed to very low levels of GH for at least 2 decades. Furthermore, since pharmacological enhancement of SW sleep in young adults has been shown to result in a simultaneous and proportional increase in GH release 46-47 and ongoing studies in our laboratory indicate that similar effects can be obtained in older subjects, drugs that reliably stimulate SW sleep may represent a novel class of GH secretagogues.
The present data demonstrate that the amount of REM sleep is reduced by approximately 50% in late life vs young adulthood. However, reduced amounts of REM sleep and significant sleep fragmentation do not occur until after age 50 years. The impact of aging on cortisol levels followed the same chronology. Aging was associated with an elevation of evening cortisol levels, reflecting an impaired ability to achieve evening quiescence following morning stimulation. Studies in both animals and humans have indicated that deleterious effects of HPA hyperactivity are more pronounced at the time of the trough of the rhythm than at the time of the peak.25, 54 Thus, modest elevations in evening cortisol levels could facilitate the development of central and peripheral disturbances associated with glucocorticoid excess, such as memory deficits and insulin resistance,24-25 and further promote sleep fragmentation. Indeed, elevated cortisol levels may promote awakenings.55-56
Elevated evening cortisol levels in late life probably reflect an impairment of the negative feedback control of the HPA axis in aging. Our analyses suggest that there is a relationship between this alteration of HPA function and decreased amounts of REM sleep that is independent of age. The data generally support the concept that decreased sleep quality contributes to the allostatic load, ie, the wear and tear resulting from overactivity of stress-responsive systems.57
The present study focused on the effects of aging on the relationship between sleep and the somatotopic and corticotropic axes in men because the predominant GH secretion occurs during sleep in men but not in women11 and because there is evidence to suggest that the marked decreases in SW sleep in early adulthood occur in men but not in women.8-11 Whether conclusions similar to those obtained for men hold for women will require a separate evaluation as sex differences in sleep quality as well as 24-hour profiles of GH and cortisol secretion have been well documented in both young and older adults.11-12,22
In conclusion, in healthy men, the distinct changes in sleep quality that characterize the transitions from early adulthood to midlife, on the one hand, and from midlife to old age, on the other hand, are each associated with specific alterations in hormonal systems that are essential for metabolic regulation. Strategies to prevent or limit decrements of sleep quality in midlife and late life may therefore represent an indirect form of hormonal therapy with possible beneficial health consequences.
REFERENCES
1. Prinz PN. Sleep and sleep disorders in older adults. J Clin Neurophysiol. 1995;12:139-146.
2. Feinberg I, Koresko RL, Heller N. EEG sleep patterns as a function of normal and pathological aging in man. Psychiatry Res. 1967;5:107-144.
3. Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Sleep and psychiatric disorders. Arch Gen Psychiatry. 1992;49:651-668.
4. Bliwise DL. Normal aging. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia, Pa: WB Saunders; 1994:26-39.
5. Feinberg I. Functional implications of changes in sleep physiology with age. In: Terry RD, Gershon S, eds. Neurobiology of Aging. New York, NY: Raven Press; 1976:23-41.
6. Ehlers CL, Kupfer DJ. Effects of age on delta and REM sleep parameters. Electroencephalogr Clin Neurophysiol. 1989;72:118-125.
7. Landolt HP, Dijk DJ, Achermann P, Borbely AA. Effects of age on the sleep EEG: slow-wave activity and spindle frequency in young and middle-aged men. Brain Res. 1996;738:205-212.
8. Webb WB. Sleep in older persons: sleep structures of 50- to 60-year-old men and women. J Gerontol. 1982;37:581-586.
9. Dijk DJ, Beersma DG, Bloem GM. Sex differences in the sleep EEG of young adults: visual scoring and spectral analysis. Sleep. 1989;12:500-507.
10. Mourtazaev MS, Kemp B, Zwinderman AH, Kamphuisen HA. Age and gender affect different characteristics of slow waves in the sleep EEG. Sleep. 1995;18:557-564.
11. Ehlers CL, Kupfer DJ. Slow-wave sleep: do young adult men and women age differently? J Sleep Res. 1997;6:211-215.
12. Van Cauter E, Plat L, Copinschi G. Interrelations between sleep and the somatotropic axis. Sleep. 1998;21:553-566.
13. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 1987;64:51-58.
14. van Coevorden A, Mockel J, Laurent E, et al. Neuroendocrine rhythms and sleep in aging men. Am J Physiol. 1991;260:E651-E661.
15. Kern W, Dodt C, Born J, Fehm HL. Changes in cortisol and growth hormone secretion during nocturnal sleep in the course of aging. J Gerontol A Biol Sci Med Sci. 1996;51A:M3-M9.
16. Weitzman ED, Zimmerman JC, Czeisler CA, Ronda JM. Cortisol secretion is inhibited during sleep in normal man. J Clin Endocrinol Metab. 1983;56:352-358.
17. Spath-Schwalbe E, Uthgenannt D, Voget G, Kern W, Born J, Fehm HL. Corticotropin-releasing hormone-induced adrenocorticotropin and cortisol secretion depends on sleep and wakefulness. J Clin Endocrinol Metab. 1993;77:1170-1173.
18. Spath-Schwalbe E, Uthgenannt D, Korting N, Fehm HL, Born J. Sleep and wakefulness affect the responsiveness of the pituitary-adrenocortical axis to arginine vasopressin in humans. Neuroendocrinology. 1994;60:544-548.
19. Gronfier C, Luthringer R, Follenius M, et al. Temporal relationships between pulsatile cortisol secretion and electroencephalographic activity during sleep in man. Electroencephalogr Clin Neurophysiol. 1997;103:405-408.
20. Bierwolf C, Struve K, Marshall L, Fehm HL. Slow wave sleep drives inhibition of pituitary-adrenal secretion in humans. J Neuroendocrinol. 1997;9:479-484.
21. Leproult R, Copinschi G, Buxton O, Van Cauter E. Sleep loss results in an elevation of cortisol levels the next evening. Sleep. 1997;20:865-870.
22. Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab. 1996;81:2468-2473.
23. Seeman TE, Robbins RJ. Aging and hypothalamo-pituitary-adrenal response to challenge in humans. Endocr Rev. 1994;15:233-260.
24. McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol. 1995;5:205-216.
25. Dallman MF, Strack AL, Akana SF, et al. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol. 1993;14:303-347.
26. Linkowski P, Mendlewicz J, Leclercq R, et al. The 24-hour profile of adrenocorticotropin and cortisol in major depressive illness. J Clin Endocrinol Metab. 1985;61:429-438.
27. Copinschi G, Van Onderbergen A, L'Hermite-Balériaux M, et al. Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men. Sleep. 1990;13:232-244.
28. Van Cauter E, Blackman JD, Roland D, Spire JP, Refetoff S, Polonsky KS. Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. J Clin Invest. 1991;88:934-942.
29. Frank S, Roland DC, Sturis J, et al. Effects of aging on glucose regulation during wakefulness and sleep. Am J Physiol. 1995;269:E1006-E1016.
30. Biston P, Van Cauter E, Ofek G, Linkowski P, Polonsky KS, Degaute JP. Diurnal variations in cardiovascular function and glucose regulation in normotensive humans. Hypertension. 1996;28:863-871.
31. Copinschi G, Leproult R, Van Onderbergen A, et al. Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology. 1997;66:278-286.
32. Linkowski P, Spiegel K, Kerkhofs M, et al. Genetic and environmental influences on prolactin secretion during wake and during sleep. Am J Physiol. 1998;274:E909-E919.
33. Jarrett DJ, Greenhouse JB. Circadian rhythm of cortisol secretion is not disturbed in outpatients with a major depressive disorder. In: Program of the First Meeting of the Society for Research on Biological Rhythms; May 11-14, 1988; Charleston, SC. 97.
34. Jarrett DB, Pollock B, Miewald JM, Kupfer DJ. Acute effects of intravenous clomipramine upon sleep-related hormone secretion in depressed outpatients and healthy control subjects. Biol Psychiatry. 1991;29:3-14.
35. Rubin RT, Poland RE, Lesser IM, Winston RA, Blodgett AL. Neuroendocrine aspects of primary endogenous depression, I: cortisol secretory dynamics in patients and matched controls. Arch Gen Psychiatry. 1987;44:328-336.
36. Rubin RT, Poland RE, Lesser IM. Neuroendocrine aspects of primary endogenous depression, X: serum growth hormone measures in patients and matched control subjects. Biol Psychiatry. 1990;27:1065-1082.
37. Vgontzas AN, Papnicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance and hypercytokinemia. J Clin Endocrinol Metab. 2000;85:1151-1158.
38. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles, Calif: UCLA Brain Information Service/Brain Research Institute; 1968.
39. Virasoro E, Copinschi G, Bruno OD, Leclercq R. Radioimmunoassay of human growth hormone using a charcoal-dextran separation procedure. Clin Chim Acta. 1971;31:294-297.
40. L'Hermite-Balériaux M, Copinschi G, Van Cauter E. Growth hormone assays: early to latest generations compared. Clin Chem. 1996;42:1789-1795.
41. Van Cauter E. Method for characterization of 24-h temporal variation of blood constituents. Am J Physiol. 1979;237:E255-E264.
42. Van Cauter E. Estimating false-positive and false-negative errors in analyses of hormonal pulsatility. Am J Physiol. 1988;254:E786-E794.
43. Van Cauter E, Kerkhofs M, Caufriez A, Van Onderbergen A, Thorner MO, Copinschi G. A quantitative estimation of GH secretion in normal man: reproducibility and relation to sleep and time of day. J Clin Endocrinol Metab. 1992;74:1441-1450.
44. Borbely AA. Processes underlying sleep regulation. Horm Res. 1998;49:114-117.
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GoneForever
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Where is this post? I got my ast/alt and bilirubin tested when I was on 40mg nolvadex for like 4months and they were perfect.
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Dat, have you come across any other research examining the relationship between GHS and ACE activity? This is of particular interest to me. Thanks!
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Awesome, awesome post. Thank you Dat
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