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pulled this from elsewhere. pretty good read:
The release of Growth Hormone (GH) is a regulated event. There are positive (+) signals and negative (-) signals. Signals are transmitted through neurons... if we need a simple mental image we can think of wires and attached to one end of a wire is some sort of sensor that can detect a change and at the other end of the wire is something that can do something based on receiving the information that a change has taken place. We can picture a thermometer attached to a wire. If the temperature gets too high it may trigger the sending of that information or signal down the wire. That's how the body works thanks to that wonderful area we refer to as the spinal column. In fact the entire brain and spinal column circuitry is called the Central Nervous System (CNS). Now when that information travels through that wire it ends up somewhere. In humans that somewhere is the brain and in regard to many of the hormones and actions that we are interested in, the region of the brain that receive the signals is the hypothalamus. In our example of the wire sending the temperature signal, it could be attached to a device that electronically dumps a bucket of water based on that signal. If the temperature never gets hot enough for the programmed thermometer setting, no signal is sent and no bucket is dumped. In our brains the end points of those wires are often co-localized next to hormonal secretion points.
This is how the body can tell the brain what's going on. The brain can make a stop or go decision and communicate that by releasing hormones, stopping the release of hormones or even sending further signal elsewhere such as into the pituitary. One reason why GHRP-6 can trigger hunger as well as the release of Growth Hormone Releasing Hormone (GHRH) from the hypothalamus is that the wires trigger serveral responses one of which is triggering the Neuro Peptide Y hunger cascade.
Obviously no one should try to become a doctor or scientist based on the above... but as an armchair scientist it suffices.
Let's take a look at some of what is known about this topic in specific regard to GH and IGF-1 Feedback.
There are several feedback loops (i.e. that thermometer, wire and bucket dumper). Some of the mechanisms operate on a short-term basis; others continue to exert negative feedback on GH release over the long-term.
Short-term (physiological)
The ultrashort feedback loops are those in which the presence of a hormone inhibits its own secretion. It's as if a nightclub room has a maximum occupancy of 100 people. When more than 100 people try to enter a signal is sent that tells some bouncer not to let any more people in. Fairly quickly people do leave the room and more are allowed to enter. GHRH, or the presence of GHRH in the very short-term can inhibit its own further secretion.1,2 GHRH is the the "go" hormone or positive growth hormone releaser. Now Somatostatin the "stop" hormone or the negative growth hormone inhibitor also will suppress its own release from neurons.3 In other words with this mechanism, these hormones actually stop their own further release. This is self inhibition and doesn't last very long at all.
The short feedback loops involve the interplay between the "stop" and "go" hormones. There is more complexity here because this interplay occurs across both the hypothalamus in the brain and into the sack-like pituitary right below it. Remember that the brain/hypothalamus releases precursor hormones to the pituitary which then releases the actual end hormone that will circulate throughout the body often making its way to some specific organ. The brain/hypothalamus releases precursors for the hormones which will eventually interact with the thyroid, adrenal glands, ovaries/testis and the liver. In regard to the GH circuit the brain releases GHRH which goes to the pituitary and binds to the cells their which in turn release GH which makes its way to the liver where it binds to receptors and initiates certain events one of which results in the eventual release of the horomone IGF-1.
In this short feedback loop we do not leave the brain/hypothalamus + pituitary area. The secretion of the "stop" hormone somatostatin is encouraged or stimulated directly by the presense of GHRH. If this were a nightclub room, again we have the limitation on the number of people (ultrashort feedback loop) but now we are adding the rule that there must be a female for every male in the club. So if there are a lot of males in the room (called GHRHs), the bouncer will be instructed to let in more females (called somatostatins). The presence of GHRHs directly stimulates the release of its own inhibitor somatostatin. 4 What happens when females begin to crowd the room. More males are crowded out. That rise in somatostatin directly stimulated by GHRH leads to inhibiting any further release of GHRH.5
Now there is another factor that is able to bring about that balance. That factor is the presence of GH in the pituitary. Of all places GH could end up, when it is in the pituitary at a certain level it sends a signal to the brain/hypothalamus which inhibits hypothalamic GHRH secretion 6,7 and stimulates somatostatin release from hypothalamic neurons 8.
As of 2011 the scientific thought on this short term feedback loop is that a hypothalamic stimulus (from GHRH, somatostatin or GH) which alters GH secretion automatically extinguishes its own effect. It is this mechanism that plays a primary role in the creation of pulsatile GHRH secretion, somatostatin secretion patterns and ultimately results in the maintenance of pulsatile GH release from the pituitary.
It is this dynamic interaction between the pituitary and the hypothalamus and not just some sort of biological clock function in the hypothalamus itself that is important in creating the pulsatile GH release pattern.
Now these feedback mechanisms operate on a short term basis (3 hours which result in the physiological 3 hour pulse to trough period).9,10
There are longer-term feedback mechanisms which involve IGF-1 and are disruptive to the normal physiological response. (I use the term physiological response as meaning something like "in conformance with nature... [I seem to often imply this to be better no matter what the goal...]".
Long-term (excessively inhibitory)
The long-term negative feedback on GH secretion occurs through a loop involving the end product of GH action (i.e. GH binding to a receptor), the hormone IGF-1. An important point to underscore is that although both liver-derived circulating IGF-1 (endocrine) and local bone-derived IGF-1 (autocrine/paracrine/juxtacrine) can redundantly replace each other in the maintenance of normal longitudinal bone growth, locally derived IGF-1 cannot replace liver-derived IGF-1 as a regulator of GH secretion. 11 In other words it is systemic liver-made endocrine IGF-1 that creates long-term negative feedback on GH secretion and not local IGF-1. I used the term bone-derived because this understanding was derived from studies in bone. However it applies to all locally derived IGF-1. Muscle derived IGF-1 will not create a negative feedback loop hindering GH secretion and neither will local IGF-1 in any tissue, because it is made and it acts in that tissue. It will not circulate. [For other liver IGF-1 differences see the end NOTE]
Before moving on I want to get a graph up for you. I want you to understand that natural levels of somatostatin and indeed IGF-1 play a role in keeping GH pulsatile and natural. There is often talk of suppressing somatostatin. If you do this and also if you were to suppress natural IGF-1 you raise the GH troughs. In other words you create GH bleed. In the instance of somatostatin suppression, you won't even increase the amplitude of pulses. Thus the effects of natural levels of both somatostatin and IGF-I seem be the maintenance of low GH trough levels and thereby the masculinizing effect of pulsatile GH secretion.
The highlighted sections below represent abnormality. If we suppress somatostatin we get elevated GH troughs with a shorter pulse amplitude. If we suppress IGF-1 we get elevated troughs without an effect on pulse amplitude.
The specific mechanism for precisely how IGF-1 exerts feedback is presently unknown. Note: State of knowledge 2011 It is known that regulation of IGF-1 production by GH is mediated via "signaling through the
Janus kinase (JAK)-2 pathways, via the phosphorylation of the transcriptional factor, signal transducer, and activator of transcription (STAT)-5b" 12. But that understanding does not point to an exact site for IGF-1 negative feedback on GH secretory mechanisms. However we can look at the effect. We can see what happens when there is a rise in systemic IGF-1.
Let's look at a continuous infusion of IGF-1 which will be similar to a long lasting analog of IGF-1. A continuous infusion of IGF-1 in young men and women increased plasma IGF-1 concentrations three to four times above the upper limit of the normal range. This reliably suppressed plasma GH concentrations by approximately 5080% in both sexes, at the expense of grossly diminished GH pulse amplitude. 13
What happens if you administer GHRH in that IGF-1 induced GH suppressive environment? Well in the same study, administration of exogenous GHRH to the same individuals, showed a sexually dimorphic effect. In men, IGF-1 infusion grossly suppressed plasma GH response to GHRH, suggesting that the negative feedback of IGF-1 was expressed either directly at the pituitary level or at the hypothalamic level by stimulating somatostatin secretion. On the other hand, administration of exogenous IGF-1 to women was completely ineffective in suppressing their GH responses to GHRH. This suggests that, in women, elevated IGF-1 suppresses GH secretion by selective suppression of the hypothalamic GHRH output.13
What is the lesson?
In men somatostatin rises up when levels of IGF-1 rise. In a rising systemic (but not local) IGF-1 environment this underscores a need to suppress somatostatin and do it correctly. A GHRP (Growth Hormone Reasing Peptides) (Ipamorelin, GHRP-6, GHRP-2) is capable of doing just that and must be used. In women there is no urgency to supress somatostatin, rather GHRH is supressed and thus the need to provide Mod GRF (1-29) (the best analog of GHRH (Growth Hormone Releasing Hormone for humans). As we know both work synergistically and together have the potential to overcome some of the suppression engendered by a rise in systemic IGF-1.
NOTE Liver derived IGF-1 plays a role in the following where as local IGF-1 does not - the regulation of a large number of other parameters including cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors.
References:
1 - Lumpkin MD, McDonald JK. Blockade of growth hormone-releasing factor (GRF) activity in the pituitary and hypothalamus of the conscious rat with a peptidic GRF antagonist. Endocrinology. 1989;124:152231.
2 - Lumpkin MD, Mulroney SE, Haramati A. Inhibition of pulsatile growth hormone (GH) secretion and somatic growth in immature rats with a synthetic GH-releasing factor antagonist. Endocrinology. 1989;124:11549.
3 - Peterfreund RA, Vale WW. Somatostatin analogs inhibit somatostatin secretion from cultured hypothalamus cells. Neuroendocrinology. 1984;39:397402.
4 - Mitsugi N, Arita J, Kimura F. Effects of intracerebroventricular administration of growth hormone-releasing factor and corticotropin-releasing factor on somatostatin secretion into rat hypophysial portal blood. Neuroendocrinology. 1990;51:936.
5 - Yamauchi N, Shibasaki T, Ling N, Demura H. In vitro release of growth hormone-releasing factor (GRF) from the hypothalamus: somatostatin inhibits GRF release. Regul Pept. 1991;33:718.
6 - Frohman MA, Downs TR, Chomczynski P, Frohman LA. Cloning and characterization of mouse growth hormone-releasing hormone (GRH) complementary DNA: increased GRH messenger RNA levels in the growth hormone-deficient lit/lit mouse. Mol Endocrinol. 1989;3:152936.
7 - Chomczynski P, Downs TR, Frohman LA. Feedback regulation of growth hormone (GH)-releasing hormone gene expression by GH in rat hypothalamus. Mol Endocrinol. 1988;2:23641.
8 - Chihara K, Minamitani N, Kaji H, Arimura A, Fujita T. Intraventricularly injected growth hormone stimulates somatostatin release into rat hypophysial portal blood. Endocrinology. 1981;109:227981.
9 - Sato M, Chihara K, Kita T, Kashio Y, Okimura Y, Kitajima N, Fujita T 1989 Physiological role of somatostatin-mediated autofeedback regulation for growth hormone: importance of growth hormone in triggering somatostatin release during a trough period of pulsatile growth hormone release in conscious male rats. Neuroendocrinology 50:139151 Medline
10 - Carlsson L, Jansson JO 1990 Endogenous growth hormone (GH) secretion in male rats is synchronized to pulsatile GH infusions given at 3-hour intervals. Endocrinology 126:610
11 - Ohlsson C, Mohan S, Sjφgren K, Tivesten A, Isgaard J, Isaksson O, et al. The role of liverderived insulin-like growth factor-I. Endocr Rev. 2009;30:494535.
12 - Rosenfeld RG, Hwa V. The growth hormone cascade and its role in mammalian growth. Horm Res. 2009;71 Suppl 2:3640.
13 - Bermann M, Jaffe CA, Tsai W, DeMott-Friberg R, Barkan AL. Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin. J Clin Invest. 1994;94:13845.
The release of Growth Hormone (GH) is a regulated event. There are positive (+) signals and negative (-) signals. Signals are transmitted through neurons... if we need a simple mental image we can think of wires and attached to one end of a wire is some sort of sensor that can detect a change and at the other end of the wire is something that can do something based on receiving the information that a change has taken place. We can picture a thermometer attached to a wire. If the temperature gets too high it may trigger the sending of that information or signal down the wire. That's how the body works thanks to that wonderful area we refer to as the spinal column. In fact the entire brain and spinal column circuitry is called the Central Nervous System (CNS). Now when that information travels through that wire it ends up somewhere. In humans that somewhere is the brain and in regard to many of the hormones and actions that we are interested in, the region of the brain that receive the signals is the hypothalamus. In our example of the wire sending the temperature signal, it could be attached to a device that electronically dumps a bucket of water based on that signal. If the temperature never gets hot enough for the programmed thermometer setting, no signal is sent and no bucket is dumped. In our brains the end points of those wires are often co-localized next to hormonal secretion points.
This is how the body can tell the brain what's going on. The brain can make a stop or go decision and communicate that by releasing hormones, stopping the release of hormones or even sending further signal elsewhere such as into the pituitary. One reason why GHRP-6 can trigger hunger as well as the release of Growth Hormone Releasing Hormone (GHRH) from the hypothalamus is that the wires trigger serveral responses one of which is triggering the Neuro Peptide Y hunger cascade.
Obviously no one should try to become a doctor or scientist based on the above... but as an armchair scientist it suffices.
Let's take a look at some of what is known about this topic in specific regard to GH and IGF-1 Feedback.
There are several feedback loops (i.e. that thermometer, wire and bucket dumper). Some of the mechanisms operate on a short-term basis; others continue to exert negative feedback on GH release over the long-term.
Short-term (physiological)
The ultrashort feedback loops are those in which the presence of a hormone inhibits its own secretion. It's as if a nightclub room has a maximum occupancy of 100 people. When more than 100 people try to enter a signal is sent that tells some bouncer not to let any more people in. Fairly quickly people do leave the room and more are allowed to enter. GHRH, or the presence of GHRH in the very short-term can inhibit its own further secretion.1,2 GHRH is the the "go" hormone or positive growth hormone releaser. Now Somatostatin the "stop" hormone or the negative growth hormone inhibitor also will suppress its own release from neurons.3 In other words with this mechanism, these hormones actually stop their own further release. This is self inhibition and doesn't last very long at all.
The short feedback loops involve the interplay between the "stop" and "go" hormones. There is more complexity here because this interplay occurs across both the hypothalamus in the brain and into the sack-like pituitary right below it. Remember that the brain/hypothalamus releases precursor hormones to the pituitary which then releases the actual end hormone that will circulate throughout the body often making its way to some specific organ. The brain/hypothalamus releases precursors for the hormones which will eventually interact with the thyroid, adrenal glands, ovaries/testis and the liver. In regard to the GH circuit the brain releases GHRH which goes to the pituitary and binds to the cells their which in turn release GH which makes its way to the liver where it binds to receptors and initiates certain events one of which results in the eventual release of the horomone IGF-1.
In this short feedback loop we do not leave the brain/hypothalamus + pituitary area. The secretion of the "stop" hormone somatostatin is encouraged or stimulated directly by the presense of GHRH. If this were a nightclub room, again we have the limitation on the number of people (ultrashort feedback loop) but now we are adding the rule that there must be a female for every male in the club. So if there are a lot of males in the room (called GHRHs), the bouncer will be instructed to let in more females (called somatostatins). The presence of GHRHs directly stimulates the release of its own inhibitor somatostatin. 4 What happens when females begin to crowd the room. More males are crowded out. That rise in somatostatin directly stimulated by GHRH leads to inhibiting any further release of GHRH.5
Now there is another factor that is able to bring about that balance. That factor is the presence of GH in the pituitary. Of all places GH could end up, when it is in the pituitary at a certain level it sends a signal to the brain/hypothalamus which inhibits hypothalamic GHRH secretion 6,7 and stimulates somatostatin release from hypothalamic neurons 8.
As of 2011 the scientific thought on this short term feedback loop is that a hypothalamic stimulus (from GHRH, somatostatin or GH) which alters GH secretion automatically extinguishes its own effect. It is this mechanism that plays a primary role in the creation of pulsatile GHRH secretion, somatostatin secretion patterns and ultimately results in the maintenance of pulsatile GH release from the pituitary.
It is this dynamic interaction between the pituitary and the hypothalamus and not just some sort of biological clock function in the hypothalamus itself that is important in creating the pulsatile GH release pattern.
Now these feedback mechanisms operate on a short term basis (3 hours which result in the physiological 3 hour pulse to trough period).9,10
There are longer-term feedback mechanisms which involve IGF-1 and are disruptive to the normal physiological response. (I use the term physiological response as meaning something like "in conformance with nature... [I seem to often imply this to be better no matter what the goal...]".
Long-term (excessively inhibitory)
The long-term negative feedback on GH secretion occurs through a loop involving the end product of GH action (i.e. GH binding to a receptor), the hormone IGF-1. An important point to underscore is that although both liver-derived circulating IGF-1 (endocrine) and local bone-derived IGF-1 (autocrine/paracrine/juxtacrine) can redundantly replace each other in the maintenance of normal longitudinal bone growth, locally derived IGF-1 cannot replace liver-derived IGF-1 as a regulator of GH secretion. 11 In other words it is systemic liver-made endocrine IGF-1 that creates long-term negative feedback on GH secretion and not local IGF-1. I used the term bone-derived because this understanding was derived from studies in bone. However it applies to all locally derived IGF-1. Muscle derived IGF-1 will not create a negative feedback loop hindering GH secretion and neither will local IGF-1 in any tissue, because it is made and it acts in that tissue. It will not circulate. [For other liver IGF-1 differences see the end NOTE]
Before moving on I want to get a graph up for you. I want you to understand that natural levels of somatostatin and indeed IGF-1 play a role in keeping GH pulsatile and natural. There is often talk of suppressing somatostatin. If you do this and also if you were to suppress natural IGF-1 you raise the GH troughs. In other words you create GH bleed. In the instance of somatostatin suppression, you won't even increase the amplitude of pulses. Thus the effects of natural levels of both somatostatin and IGF-I seem be the maintenance of low GH trough levels and thereby the masculinizing effect of pulsatile GH secretion.
The highlighted sections below represent abnormality. If we suppress somatostatin we get elevated GH troughs with a shorter pulse amplitude. If we suppress IGF-1 we get elevated troughs without an effect on pulse amplitude.
The specific mechanism for precisely how IGF-1 exerts feedback is presently unknown. Note: State of knowledge 2011 It is known that regulation of IGF-1 production by GH is mediated via "signaling through the
Janus kinase (JAK)-2 pathways, via the phosphorylation of the transcriptional factor, signal transducer, and activator of transcription (STAT)-5b" 12. But that understanding does not point to an exact site for IGF-1 negative feedback on GH secretory mechanisms. However we can look at the effect. We can see what happens when there is a rise in systemic IGF-1.
Let's look at a continuous infusion of IGF-1 which will be similar to a long lasting analog of IGF-1. A continuous infusion of IGF-1 in young men and women increased plasma IGF-1 concentrations three to four times above the upper limit of the normal range. This reliably suppressed plasma GH concentrations by approximately 5080% in both sexes, at the expense of grossly diminished GH pulse amplitude. 13
What happens if you administer GHRH in that IGF-1 induced GH suppressive environment? Well in the same study, administration of exogenous GHRH to the same individuals, showed a sexually dimorphic effect. In men, IGF-1 infusion grossly suppressed plasma GH response to GHRH, suggesting that the negative feedback of IGF-1 was expressed either directly at the pituitary level or at the hypothalamic level by stimulating somatostatin secretion. On the other hand, administration of exogenous IGF-1 to women was completely ineffective in suppressing their GH responses to GHRH. This suggests that, in women, elevated IGF-1 suppresses GH secretion by selective suppression of the hypothalamic GHRH output.13
What is the lesson?
In men somatostatin rises up when levels of IGF-1 rise. In a rising systemic (but not local) IGF-1 environment this underscores a need to suppress somatostatin and do it correctly. A GHRP (Growth Hormone Reasing Peptides) (Ipamorelin, GHRP-6, GHRP-2) is capable of doing just that and must be used. In women there is no urgency to supress somatostatin, rather GHRH is supressed and thus the need to provide Mod GRF (1-29) (the best analog of GHRH (Growth Hormone Releasing Hormone for humans). As we know both work synergistically and together have the potential to overcome some of the suppression engendered by a rise in systemic IGF-1.
NOTE Liver derived IGF-1 plays a role in the following where as local IGF-1 does not - the regulation of a large number of other parameters including cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors.
References:
1 - Lumpkin MD, McDonald JK. Blockade of growth hormone-releasing factor (GRF) activity in the pituitary and hypothalamus of the conscious rat with a peptidic GRF antagonist. Endocrinology. 1989;124:152231.
2 - Lumpkin MD, Mulroney SE, Haramati A. Inhibition of pulsatile growth hormone (GH) secretion and somatic growth in immature rats with a synthetic GH-releasing factor antagonist. Endocrinology. 1989;124:11549.
3 - Peterfreund RA, Vale WW. Somatostatin analogs inhibit somatostatin secretion from cultured hypothalamus cells. Neuroendocrinology. 1984;39:397402.
4 - Mitsugi N, Arita J, Kimura F. Effects of intracerebroventricular administration of growth hormone-releasing factor and corticotropin-releasing factor on somatostatin secretion into rat hypophysial portal blood. Neuroendocrinology. 1990;51:936.
5 - Yamauchi N, Shibasaki T, Ling N, Demura H. In vitro release of growth hormone-releasing factor (GRF) from the hypothalamus: somatostatin inhibits GRF release. Regul Pept. 1991;33:718.
6 - Frohman MA, Downs TR, Chomczynski P, Frohman LA. Cloning and characterization of mouse growth hormone-releasing hormone (GRH) complementary DNA: increased GRH messenger RNA levels in the growth hormone-deficient lit/lit mouse. Mol Endocrinol. 1989;3:152936.
7 - Chomczynski P, Downs TR, Frohman LA. Feedback regulation of growth hormone (GH)-releasing hormone gene expression by GH in rat hypothalamus. Mol Endocrinol. 1988;2:23641.
8 - Chihara K, Minamitani N, Kaji H, Arimura A, Fujita T. Intraventricularly injected growth hormone stimulates somatostatin release into rat hypophysial portal blood. Endocrinology. 1981;109:227981.
9 - Sato M, Chihara K, Kita T, Kashio Y, Okimura Y, Kitajima N, Fujita T 1989 Physiological role of somatostatin-mediated autofeedback regulation for growth hormone: importance of growth hormone in triggering somatostatin release during a trough period of pulsatile growth hormone release in conscious male rats. Neuroendocrinology 50:139151 Medline
10 - Carlsson L, Jansson JO 1990 Endogenous growth hormone (GH) secretion in male rats is synchronized to pulsatile GH infusions given at 3-hour intervals. Endocrinology 126:610
11 - Ohlsson C, Mohan S, Sjφgren K, Tivesten A, Isgaard J, Isaksson O, et al. The role of liverderived insulin-like growth factor-I. Endocr Rev. 2009;30:494535.
12 - Rosenfeld RG, Hwa V. The growth hormone cascade and its role in mammalian growth. Horm Res. 2009;71 Suppl 2:3640.
13 - Bermann M, Jaffe CA, Tsai W, DeMott-Friberg R, Barkan AL. Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin. J Clin Invest. 1994;94:13845.
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