Could you elaborate further on how MK-677 would be partially inhibited by rhGH administration. My understanding is that MK-677 is not inhibited by somatostatin and is a somatostatin antagonist.
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Factors that Diminish GH Response (↓Δ IGF-I); The Purpose of the Serum IGF-I Test: A Revision (2.0) [Author: Type-IIx]
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Jin23
Well-known Member
Source?
There was some speculation/talk about mk677 being a "functional" somatostatin antagonist in older studies, where the mechanisms of action of GHRP weren't so well characterized and the GHS-R wasn't even discovered yet. These are studies from around the time frame of 96 - 99. Maybe even later. Are you referring to those?
"Ibutamoren mesylate binds to the ghrelin receptor and was found to not only enhance the pulsatile release of GH but also act as an antagonist to somatostatin allowing for GH levels to remain elevated for up to 360 minutes after a single oral dose."
They cite two studies, from 1998 and 2011. I could not find the full text for the 1998 study, and the other has no mention of somatostatin.
Link to the report:
This is from an article published in 1997. "Since ligands for the GHS-R behave as functional antagonists of somatostatin and amplifiers of GHRH activity, it is predictable that the GHS-R ligands would amplify GH secretion in vivo."
Peptidomimetic Regulation of Growth Hormone Secretion
I. IntroductionII. Identification of Peptidomimetic GH SecretagoguesA. Mechanism of action of GHRH, GHRP-6, and somatostatinB. In vitro assaysIII. Molecular Des
academic.oup.com
Jin23
Well-known Member
This is from an article published in 1997. "Since ligands for the GHS-R behave as functional antagonists of somatostatin and amplifiers of GHRH activity, it is predictable that the GHS-R ligands would amplify GH secretion in vivo."
Peptidomimetic Regulation of Growth Hormone Secretion
I. IntroductionII. Identification of Peptidomimetic GH SecretagoguesA. Mechanism of action of GHRH, GHRP-6, and somatostatinB. In vitro assaysIII. Molecular Des
Yes, this is what I was talking about. Looking at those studies, briefly I must say, the whole idea of mk677 being a functional antagonist of somatostatin, was coming from the still not completely elucidated mechanism of action of GHRP's. The GHS-R was discovered and then cloned somewhere around the studies you are referencing to, and it's ligands actions (the GHRP's) were confirmed a few years later. Thus in these studies they were still being careful and used theory of it being a functional somatostatin antagonist, which was the prevalent thought at the time. Although you can clearly see, from a study which was done in 96, they hinted at the thought of ibutamoren being a ligand for some other receptor, but they still said it's a somatostatin antagonist in order to be "correct".
"Although the mechanism of action of GHRP andrelated compounds is not completely elucidated, several lines of evidence suggest that specific receptors are involved at both the pituitary and the hypothalamic level (3). Current data support the concept that GHRP acts as a somatostatin antagonist via postreceptor mechanisms and stimulates GH release synergistically with GHRH (5) ..."
So as you can see, they clearly "knew" it wasn't a somatostatin antagonist but still due to lack of evidence, reverted to old theory.
In other words, if you don't have published data of another receptor through which GH release can be stimulated, and the GHRH-R is being actively blocked by somatostatin, then the logical conclusion is that ibutamoren must somehow block the action of somatostatin, ie. a functional somatostatin antagonist, and the "functional" part is because it clearly didn't act as an antagonist at the receptor.
That's my reasoning, from as I said, a very brief look at the topic/papers.
Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men
Abstract. To assess the effects of prolonged administration of a novel analog of GH-releasing peptide (MK-677), nine healthy young men participated in a ra
academic.oup.com
Type-IIx
Well-known Member
From my notes,
Mechanism in interference effect of rhGH on secretagogues
The mechanisms suggested for the negative feedback effect of GH on its own secretion include:
* inhibition of (hypothalamic) GHRH synthesis and release
* somatostatin synthesis and release (questionable; investigate)
* stimulation of local IGF-I production from the somatotroph itself
From Massoud, A. F., Hindmarsh, P. C., & Brook, C. G. D. (1995). Hexarelin induced growth hormone release is influenced by exogenous growth hormone. Clinical Endocrinology, 43(5), 617–621. doi:10.1111/j.1365-2265.1995.tb02927.x:
What you have presented is merely some evidence against that mechanism, it doesn't change the fact that partial interference occurs.
Unless you can point to some reason why Ibutamoren (MK-677) does not stand in the place of hexarelin as a Ghrelin mimetic (GHS-R agonist); GHRP, then I see no reason why it confers any particular advantage for this partial interference. Do you have evidence of its not being affected by GH in this regard from a representative study?
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Type-IIx
Well-known Member
I basically agree especially about the dearth of confidence in these early mechanistic studies of secretagogue action, that are replete with speculation.Yes, this is what I was talking about. Looking at those studies, briefly I must say, the whole idea of mk677 being a functional antagonist of somatostatin, was coming from the still not completely elucidated mechanism of action of GHRP's. The GHS-R was discovered and then cloned somewhere around the studies you are referencing to, and it's ligands actions (the GHRP's) were confirmed a few years later. Thus in these studies they were still being careful and used theory of it being a functional somatostatin antagonist, which was the prevalent thought at the time. Although you can clearly see, from a study which was done in 96, they hinted at the thought of ibutamoren being a ligand for some other receptor, but they still said it's a somatostatin antagonist in order to be "correct".
"Although the mechanism of action of GHRP andrelated compounds is not completely elucidated, several lines of evidence suggest that specific receptors are involved at both the pituitary and the hypothalamic level (3). Current data support the concept that GHRP acts as a somatostatin antagonist via postreceptor mechanisms and stimulates GH release synergistically with GHRH (5) ..."
So as you can see, they clearly "knew" it wasn't a somatostatin antagonist but still due to lack of evidence, reverted to old theory.
In other words, if you don't have published data of another receptor through which GH release can be stimulated, and the GHRH-R is being actively blocked by somatostatin, then the logical conclusion is that ibutamoren must somehow block the action of somatostatin, ie. a functional somatostatin antagonist, and the "functional" part is because it clearly didn't act as an antagonist at the receptor.
That's my reasoning, from as I said, a very brief look at the topic/papers.
Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men
Abstract. To assess the effects of prolonged administration of a novel analog of GH-releasing peptide (MK-677), nine healthy young men participated in a ra
At the end of the day, the secretagogues aren't as exciting as they seemed initially, mostly to the nerds among us, because of their novel mechanisms of action. They generally underwhelm (e.g., with respect to functional, strength, even body composition outcomes) and are associated with more unfavorable effects (e.g., MK0677 trials being halted due to congestive heart failure, prolactin increases, hyperglycemic effects, depending on use case appetite/hunger, lethargy), and the intolerability of multiple-day pinning in the case of many of these secretagogues makes adherence abysmal when GH-deficient patients & short stature children can't be bothered to pin rhGH on a daily basis, whether 3 - 7X/w.
The smart money is on long-acting GH formulations, and certainly not secretagogue development.
Agree with you, I was definitely wrong about MK677 being a somatostatin antagonist.
Thanks for the new info, never saw this study. MK-677 and hexarelin are identical in how they stimulate GH, so the interference would apply to both. Even with the interference, would MK with GH provide any advantages, since MK-677 would stimulate endogenous production of all isoforms of GH. I remember Leo Longevity talking about this topic. He said bodybuilders running MK+GH were different in how they looked when compared to running only GH. He theorized that the different isoforms of GH have slightly different functions. I know Leo is not a quality source, but I would like to know what you think about this.
After doing a quick browse I found this study: "High doses (> 10(-10) m) of somatostatin/cortistatin did not alter basal GH secretion but blocked GH-releasing hormone (GHRH)- and ghrelin-induced GH release." PubMedID: 22129035 So could somatostatin interfere with the GHS-R? This is in vitro and in baboons, but it does make me rethink the possibility that MK is partially inhibited by somatostatin.
Type-IIx
Well-known Member
No, stimulating other non-22K-GH (rhGH) endogenous GH isoforms is not a rationale for combined Ibutamoren & rhGH.
From A GH and fat loss protocol (rhGH lipolysis) that is science-based:
It's irrelevant minutiae, no? Since secretagogue action is so unfavorable (reduced efficacy, reduced tolerability, & availability of rhGH) vs. rhGH action, delving into minutiae like the degree of modulation by somatostatin is a Fool's Errand, when we have clear data showing a phenomenon (to wit, partial interference by GH on its own secretion) and rhGH is clearly superior for all use cases (besides, perhaps, promoting appetite/hunger or sleep). Who, besides some absolute and total nerd obsessed with secretagogues, really cares about the mechanistic aspects of this partial negative feedback or inhibition? R&D of GH secretagogues has been all but abandoned, for good reason.
Lumos Pharmas is giving excessively high doses of MK-677 to GH deficient children right now, but I agree with your view that rhGH is better than secretagogues in many areas.
songsofpyramids
Well-known Member
Woah, I thought for sure this couldn’t be real but holy shit they’re on phase 2 trials giving PDHD kids ibutomoren. Is this all in a quest to find a solution that doesn’t involve injections because the rhGH injection protocols are hardly ever fully followed by parents? Or is it cause rhGH treatments are so pricy? I would never give my kid ibutomoren over rhGH in this situation… fucking insane. I thank them for sacrificing their children to science for answers on secretagogues for my own selfish curiosity tho I suppose.
ClinicalTrials.gov
classic.clinicaltrials.gov
GuerillaPete
Well-known Member
3.2 mg/kg/day thats crazy high.Woah, I thought for sure this couldn’t be real but holy shit they’re on phase 2 trials giving PDHD kids ibutomoren. Is this all in a quest to find a solution that doesn’t involve injections because the rhGH injection protocols are hardly ever fully followed by parents? Or is it cause rhGH treatments are so pricy? I would never give my kid ibutomoren over rhGH in this situation… fucking insane. I thank them for sacrificing their children to science for answers on secretagogues for my own selfish curiosity tho I suppose.
ClinicalTrials.gov
Type-IIx
Well-known Member
Yes.
Yes.
This is hyperbole, surely, because Ibutamoren isn't particularly harmful. I never pay attention to its efficacy with respect to growth velocity as it's not something we care about. Its effects on body composition & muscle function are underwhelming, but it might be very cost effective for GHD patients, especially considering societies with warm climates, limited transportation & infastructure, and again, that adherence factor is seriously important – if the patient hates injecting daily then rhGH is just a terrible option, as that expensive rhGH will usually just get thrown away without being used.
ClinicalTrials.gov
Gotta tease out dose dependency and establish maximum safe dose, maximum recommended therapeutic dose, and maximum effective doses in this population somehow. Remember, growth retarded children & GH-deficient, meaning very small body masses & virtually no basal GH secretion; they're not getting an augmented secretory burst, they have to be brought up to endogenous GH levels purely by GHS-R stimulation.
D
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@Type-IIx this is completely off-topic but I can't find any reference to PT-141 in your articles or posts, as to wether it could cause any melanoma when used chronically and wether it has other unwanted harmful effects (nausea being an inconvenience but not a harmful side effect).
Have you addressed this peptide anywhere ?
Have you addressed this peptide anywhere ?
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