IGF-1 LR3 and GHRP-6 Run

Pharma
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On this question of whether it is high insulin or high glucose itself that causes GH suppression, and the question of whether studies are in agreement with a report that insulin increases GH production, I’ll post abstracts that seem relevant as I go, and also links to the full free text where that exists.

First up,

Impact of obesity on the growth hormone axis: evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function.

Luque RM, Kineman RD.
Section of Endocrinology and Metabolism, Department of Medicine, University of Illinois at Chicago, Illinois, USA.

There is a negative relationship between obesity and GH. However, it is not known how metabolic changes, associated with obesity, lead to a reduction in GH output.

This study examined the GH axis of two mouse models of obesity, the leptin-deficient (ob/ob) mouse and the diet-induced obese (DIO; high-fat fed) mouse. Both models displayed hyperglycemia and hyperinsulinemia with reduced expression of GH as well as reduced expression of pituitary receptors important for GH synthesis and release [GHRH receptor (DIO only) and the ghrelin receptor (ob/ob and DIO)]. These pituitary changes were not accompanied by changes in hypothalamic expression of GHRH or somatostatin; suggesting that alterations in pituitary function may be precipitated in part by direct effects of systemic signals.

Of the metabolic and hormonal parameters examined (insulin, glucose, corticosterone, free fatty acids, ghrelin, and IGF-I), only insulin/glucose showed a significant, and negative, correlation with pituitary expression.

Pituitaries of DIO mice remained responsive to the acute in vivo actions of insulin, as assessed by phosphorylation of Akt, despite systemic (skeletal muscle and fat) insulin resistance. In addition, treating primary pituitary cell cultures from lean mice with insulin reduced GH release as well as GH, GHRH receptor, and ghrelin receptor mRNA levels compared with vehicle-treated controls, where the magnitude of suppression of pituitary mRNA levels was similar to that observed in the DIO mouse.

These results coupled with the fact that the pituitary expresses the insulin receptor at levels comparable to tissues classically considered insulin sensitive, indicates high circulating insulin levels can directly contribute to the suppression of GH synthesis and release in the obese state.

Full text: Endocrine Press | Endocrine Society

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(edited to be shorter and omitting what I thought irrelevant to the questions at hand)

Pituitary. 2004;7(4):243-8.

Ghrelin, hypothalamus-pituitary-adrenal (HPA) axis and Cushing’s syndrome.

Giordano R, Picu A, Broglio F, Bonelli L, Baldi M, Berardelli R, Ghigo E, Arvat E.
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy.

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the GH Secretagogue receptor type 1a (GHS-R1a), known as specific for synthetic GHS.

Besides strong stimulation of GH secretion, the neuroendocrine ghrelin actions also include significant stimulation of both lactotroph and corticotroph secretion; all these actions depend on acylation of ghrelin in serine-3 that allows binding and activation of the GHS-R1a.

Ghrelin secretion is mainly regulated by metabolic signals, namely inhibited by feeding, glucose and insulin while stimulated by energy restriction.

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Not relevant to these questions but supports another point that is interesting – namely it might be useful to time T3 use with GH-secretagogue use:

J Endocrinol Invest. 2003;26(10 Suppl):27-35.

Hormonal diagnosis of GH hypersecretory states.

Grottoli S, Gasco V, Ragazzoni F, Ghigo E.
Department of Internal Medicine, University of Turin, Turin, Italy.

… Hyperthyroidism is another condition connoted by elevated GH levels that reflects a true GH hypersecretory state and is, in fact, associated with high-normal IGF-I levels; this peculiar condition is likely to be reflecting the stimulatory effect of thyroid hormones on both GH and IGF-I secretion and is promptly reversed by treatment-induced euthyroidism.

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Am J Physiol Endocrinol Metab. 2003 Feb;284(2):E313-6.

The influence of insulin on circulating ghrelin.

Flanagan DE, Evans ML, Monsod TP, Rife F, Heptulla RA, Tamborlane WV, Sherwin RS.
Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Ghrelin is a novel peptide that acts on the growth hormone (GH) secretagogue receptor in the pituitary and hypothalamus. It may function as a third physiological regulator of GH secretion, along with GH-releasing hormone and somatostatin. In addition to the action of ghrelin on the GH axis, it appears to have a role in the determination of energy homeostasis.

Although feeding suppresses ghrelin production and fasting stimulates ghrelin release, the underlying mechanisms controlling this process remain unclear. The purpose of this study was to test the hypotheses, by use of a stepped hyperinsulinemic eu- hypo- hyperglycemic glucose clamp, that either hyperinsulinemia or hypoglycemia may influence ghrelin production.

Having been stable in the period before the clamp, ghrelin levels rapidly fell in response to insulin infusion during euglycemia (baseline ghrelin 207 +/- 12 vs. 169 +/- 10 fmol/ml at t = 30 min, P < 0.001).

Ghrelin remained suppressed during subsequent periods of hypoglycemia (mean glucose 53 +/- 2 mg/dl) and hyperglycemia (mean glucose 163 +/- 6 mg/dl).

Despite suppression of ghrelin, GH showed a significant rise during hypoglycemia (baseline 4.1 +/- 1.3 vs. 28.2 +/- 3.9 microg/l at t = 120 min, P < 0.001). Our data suggest that insulin may suppress circulating ghrelin independently of glucose, although glucose may have an additional effect.

We conclude that the GH response seen during hypoglycemia is not regulated by circulating ghrelin.

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(edited slightly to shorten. Emphasis added at one point.)

Domest Anim Endocrinol. 1999 Nov;17(4):439-47.

Feeding-induced increases in insulin do not suppress secretion of growth hormone.

McMahon CD, Chapin LT, Lookingland KJ, Radcliff RP, Tucker HA.
Department of Animal Science, Michigan State University, East Lansing 48824-1225, USA.

Secretion of growth hormone (GH) is reduced for several hours after feeding when access to feed is restricted to a 2-hr period each day. We hypothesized that increased secretion of insulin after feeding inhibits release of GH from the anterior pituitary gland.

Our objectives were to determine whether: 1) alloxan prevents concentrations of insulin from increasing after feeding steers; 2) concentrations of GH remain high after feeding alloxan-treated steers; and 3) GH-releasing hormone (GHRH) stimulates greater release of GH in alloxan-treated, than in control, steers after feeding.

…Alloxan prevented insulin from increasing (P < 0.001) after feeding (131.8 pmol/1) compared with control steers (442.0 pmol/l) (pooled SEM = 47.5).

IV injection of GHRH stimulated release of GH 1 hr before, but not when injected 1 hr after feeding (P < 0.001).

In addition, net areas under the GH curve were not significantly different between control and alloxan-treated groups. We conclude that increased concentrations of insulin after feeding do not mediate feeding-induced suppression of GH secretion in steers.

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(Emphasis added at two points, on account of how remarkable the effect can be. Note, because of the lag time, this doesn’t seem to address the matter of the acute effect but seems to be an additional chronic effect.)

Endocrinology. 1985 Aug;117(2):532-7.

Insulin suppresses triiodothyronine-induced growth hormone secretion by GH3 rat pituitary cells.

Melmed S, Slanina SM.

Physiological doses of insulin were shown by us to suppress basal and hydrocortisone (HCT)-induced GH secretion and GH mRNA levels in GH3 rat pituitary cells. Because T3 stimulates GH gene expression, the effects of semisynthetic human insulin were tested on T3-induced GH secretion. Cells were first incubated for 48 h in medium containing insulin and fetal calf serum (10%) depleted of T3 and T4 by ion exchange resin. Insulin suppression of basal GH secretion was independent of T3, as insulin (0.7 nM) suppressed basal secretion of GH by 40% in T3-depleted cells. Medium glucose concentrations and cell proliferation did not differ in control or insulin-treated wells. The 4-fold increase in GH secretion induced by added T3 (0.5 nM) during 72 h was suppressed up to 40% by insulin (P less than 0.001). This suppression was maximal with 3.5 nM insulin and occurred after a lag period of 48 h.

The previously described 20-fold synergistic stimulation of GH by T3 (0.5 nM) together with HCT (1 microM) was also suppressed by insulin (3.5 nM) by 80% during 72 h of incubation. The selectivity of the inhibitory effects of insulin on GH were also shown when the T3-induced suppression of PRL secretion was reversed by insulin treatment.

The data show that physiological doses of insulin antagonize T3-induced stimulation of GH secretion and also partially block the synergistic stimulation of GH by T3 and HCT. As T3 and HCT probably stimulate GH gene transcription at different sites, insulin may suppress GH gene expression at a more distal site. Alternatively, the inhibitory effects of insulin on T3-induced GH secretion in these cells may be posttranscriptional.

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(Again, because of lag time this isn’t an explanation of the immediate effect, but is related to chronic effect)

J Clin Invest. 1984 May;73(5):1425-33.

Insulin suppresses growth hormone secretion by rat pituitary cells.

Melmed S.

The effects of insulin on basal and hydrocortisone-induced growth hormone (GH) secretion were studied in rat pituitary tumor cells (GH3). Cells were grown in monolayer culture and exposed to exogenously added insulin for up to 8 d. Basal GH secretion was inhibited by insulin (0.7 nM) after a 48-h lag period by approximately 50% (P less than 0.01, vs. untreated control cells). The suppression of GH secretion was reversible, as removal of added insulin resulted in return of GH secretion to normal levels after 24 h. Maximal suppression of basal GH secretion was achieved by 0.7 nM insulin, and these effects were prevented by simultaneous exposure of the cells to guinea pig anti-insulin serum (1:2,000). No effects of insulin on cell replication were evident, and glucose concentration in the medium did not differ in control or insulin-treated wells. Insulin (7 nM) significantly suppressed the fivefold hydrocortisone-induced GH stimulation during 5 d of incubation with up to 1,000 nM of the steroid (P less than 0.001). These inhibitory effects were similarly observed in glucose- and pyruvate-free medium, and in the presence of 2-deoxyglucose. Insulin also reversed the suppression of prolactin (PRL) secretion induced by hydrocortisone (1 uM), and actually stimulated basal PRL secretion by over 50%. Insulin did not alter the inhibitory effect of hydrocortisone on GH3 cell proliferation. Although higher doses (13 nM) of insulin-like growth factor (IGF-I) also suppressed basal GH secretion, IGF-I did not alter the GH and PRL secretory changes induced by hydrocortisone. The results show that insulin exerts a direct, specific inhibitory effect on basal and hydrocortisone-induced GH secretion by GH3 cells unrelated to glucose utilization by the cells.

Full text: JCI - Insulin suppresses growth hormone secretion by rat pituitary cells.

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J Clin Endocrinol Metab. 1981 Jun;52(6):1230-4.

The impact of euglycemia and hyperglycemia on stimulated pituitary hormone release in insulin-dependent diabetics.

Vierhapper H, Grubeck-Loebenstein B, Bratusch-Marrain P, Panzer S, Waldhäusl W.

To study the influence of different blood glucose (BG) concentrations on the release of pituitary hormones, the effect of the simultaneous iv administration of LRH (200 micrograms), TRH (400 micrograms), and arginine (30 g/30 min) upon the serum concentrations of LH, FSH, TSH, PRL, and GH was determined in six male insulin-dependent diabetics. BG concentration was clamped by feedback control and an automated glucose-controlled insulin infusion system at euglycemic (BG 4-5 mmol/liter) or hyperglycemic (BG, 14-18 mmol/liter) levels. Increments in serum concentrations of LH, FSH, TSH, and PRL were similar in the euglycemic and hyperglycemic steady states, whereas the GH response to arginine was suppressed during the hyperglycemic clamp (P less than 0.01). Omission of exogenous insulin during hyperglycemia did not modify the observed hormonal responses. Thus, the release of LH, FSH, TSH, and PRL in response to adequate acute stimuli at the pituitary level is not modulated by hyperglycemia in insulin-dependent diabetes, while arginine-induced GH release is suppressed. Since the effect of arginine on GH is most likely mediated by an action on the hypothalamus, the data suggest that elevated glucose concentrations may exert their modulatory influence on GH secretion at the hypothalamic rather than at the pituitary level.

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Diabete Metab. 1977 Dec;3(4):257-8.

Inhibition of L-dopa induced growth hormone release in normal and diabetic subjects by glucose administration.

Vigas M, Klimes I, Jurcovicova J, Kolesar P, Repcekova-Jezova D.

Administration of L-dopa 1 g induced an increase of plasma growth hormone (GH) levels in seven of ten healthy volunteers and in six of ten hyperglycemic insulin-dependent diabetic subjects; the maximal GH response was higher in normal subjects. Addition of 100 g glucose orally to the L-dopa completely abolished the GH response of both groups. The difference between the effect of endogenous hyperglycemia and the effect of a sudden increase of blood sugar after glucose administration on L-dopa induced GH release in diabetic subjects may be explain by the resetting of the hypothalamic control for pituitary GH release to higher levels of blood glucose.

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J Clin Endocrinol Metab. 1975 Mar;40(3):442-9.

Effects of glucocorticoids on pituitary hormonal responses to hypoglycemia. Inhibition of prolactin release.

Copinschi G, L’Hermite M, Leclercq R, Golstein J, Vanhaelst L, Virasoro E, Robyn C.

The characteristics of pituitary hormonal responses to insulin-induced hypoglycemia were investigated in 16 normal men. In all subjects, levels of blood sugar fell below 35 mg/100 ml. A statistically significant increase in mean plasma levels of prolactin, ACTH, cortisol and growth hormone was observed. Prolactin levels increased in all subjects but one; individual peak values were 1.4 minus 8.4 times greater than base levels. The kinetics of prolactin, GH and ACTH responses were similar; in particular, the onset of release (25 min) of prolactin, GH and ACTH was similar. After dexamethasone administration, insulin tolerance tests wererepeated in a number of subjects using adequate amounts of insulin to achieve hypoglycemia equivalent to that obtained in the control experiments. The administration of 1 mg of dexamethasone the evening before the test suppressed basal levels of ACTH and cortisol and the ACTH-but not the cortisol-response to hypoglycemia. Both basal levels of prolactin and prolactin response to hypoglycemia were significantly lowered but growth hormone response was not modified by administration of 1 mg of dexamethasone. The administration of larger doses of dexamethasone (1 mg every 6 h for 2 days) almost completely suppressed basal levels of ACTH, cortisol and prolactin, as well as the hypoglycemia-induced release of these hormones. In contrast, the growth hormone response to hypoglycemia was only partially inhibited. These findings demonstrate that both basal secretion and hypoglycemia-induced release of prolactin, ACTH, cortisol and growth hormone are suppressible by glucocorticoids.

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Brook, would you be able to find the basis (if any was given) for the claim you found that exogenous insulin increases GH release?

That fact, if it is a fact, seems to be fly in the ointment.

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It shuold be a nice peptide cycle :slight_smile: maybe throw in some follistatin for extra kicks :slight_smile:

There are some speculations about the possibility of tumour growth around the hypo, if GHRP is used frequently and for long periods of time. any truth in it guys? brook, bill

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I don’t know, is there evidence given for the speculation?

It does seem to me that this is the sort of thing – stimulating the pituitary – that one ought to not go overboard on.

Given that acromegaly is within the capacity of the pituitary’s production, that doesn’t mean having to go for a low result. But amounts of a given secretagogue that are just way beyond natural could perhaps not be the best thing to do, especially for long periods of time.

That is one of the reasons why the fact that an amount of GHRP-6 plus the same amount of GHRH yielded 4 times the result, thus suggesting one could use half as much of each and get twice the result, impresses me and suggests the best thing may be to use a more moderate amount of each, rather than trying to utterly hammer just one.

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[quote]Bill Roberts wrote:
Brook, would you be able to find the basis (if any was given) for the claim you found that exogenous insulin increases GH release?

That fact, if it is a fact, seems to be fly in the ointment.[/quote]

No probs… i remember reading it - so likely have it saved somewhere in my favourites.

I DO remember it was ‘in passing’ however and not in depth… but i will do a search for more too…

:wink:

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I agree - to an extent. I mean, acromegaly is a real risk BUT look at cutler, while he has facial deformation from excess GH, it is done over YEARS of use, and in massive doses (i assume). GHRP is not as effective as GH… i doubt that any dose of GHRP could emulate the effect from 20iu of GH - and a single shot of 20iu of GH would do very little (except hurt the hands).

I do not think that 1.25mg/day of GHRP over 4 weeks can cause a problem - not to mention that if one started to get carpal tunnel (never heard of this with relation to this peptide) then surely one would reduce the dose.

RIGHT - i just found the extract i was referring to:

“Penlava, A, et. al. Effect of growth hormone (GH)-releasing hormone (GHRH), atropine, pyridostigmine, or hypoglycemia on GHRP-6-induced GH secretion in man.J Clin Endocrinol Metab. 1993 Jan;76(1):168-71”

I am looking into the reference to see if i can shed any more light - it was quoted by Mr. Anthony Roberts… so make of it what you will :wink:

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His-DTrp-Ala-Trp-DPhe-Lys-NH2 (GHRP-6) is a synthetic compound that releases GH in a dose-related and specific manner in several species, including man. To further characterize the effects and mechanism of action of GHRP-6 on GH secretion, we assessed in normal man plasma GH responses to that hexapeptide 1) alone and in combination with exogenous GH-releasing hormone (GHRH) administration, 2) in a state of high endogenous somatostatinergic tone after atropine administration, and 3) in a state of low endogenous somatostatinergic tone induced by the cholinergic receptor agonist drug pyridostigmine or after insulin- induced hypoglycemia.

We found a similar increase in plasma GH levels after the administration of either GHRP-6 (1 microgram/kg) or GHRH (1 microgram/kg); the areas under the curve (AUC) were (mean +/- SEM) 973 +/- 181 and 821 +/- 139, respectively. After combined GHRP-6 and GHRH administration, GH responses were considerably greater than those after either compound alone (4412 +/- 842; P < 0.01).

Administration of the cholinergic receptor antagonist atropine (1 mg, im) completely prevented the GH responses to GHRP-6 (area under the curve, 103 +/- 14 vs. 815 +/- 156, respectively). On the other hand, pyridostigmine, a cholinergic agonist, slightly increased GH responses to GHRP-6 (P < 0.01 when comparing the AUC after pyridostigmine administration of 1571 +/- 151 and the AUC after administration of GHRP-6 alone of 815 +/- 156).

Finally, combined GHRP-6 and insulin administration induced a much greater increase in plasma GH levels (AUC, 4047 +/- 327) than insulin alone (1747 +/- 229; P < 0.05) or GHRP-6 alone (1248 +/- 376; P < 0.05). Our results lend support to the view that GHRP-6-induced GH secretion is exerted through a non-GHRH-dependent mechanism.

Furthermore, the fact that enhancement of somatostatinergic tone with atropine completely prevented the GH responses to GHRP-6, while pyridostigmine and insulin-induced hypoglycemia, which increased plasma GH levels by inhibiting hypothalamic somatostatin release, increased the same response suggest that although GHRP-6-induced GH secretion is dependent on the endogenous somatostatinergic tone, the stimulatory effect of GHRP-6 on plasma GH levels is not mediated by a change in hypothalamic somatostatinergic tone.

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So in the above abstract, it seems you were correct in your opinion that Insulin allows a greater GH response curve, due to the low blood glucose level (hypoglycaemia) - rather than the Insulin itself.

This would suggest a low carbohydrate diet would be beneficial in increasing GH levels on a GHRP run, HOWEVER a conflicting interest is apparent.

IF one is using GHRP for the larger GH level, and desires the collagen and fat loss effects, it should be very useful in a dietary state and leading upto a contest instead of the more expensive GH… and use of Insulin would be useful in this state as it is often used among dieting BB’s anyway.

IF one is bulking, and using it primarily for the dietary assistance (caloric intake) then higher doses will be needed, multiple times a day BUT exogenous insulin would be very useful at these times also, injecting the insulin (Humalog) and the GHRP at the same time will give a hypoglycaemic response at the same time as the ghrelin increase - with carbs controlled for the slin AND the GH response.
This should cause less body fat accumulation than slin alone, and allow one to eat more calories in accordance with gaining weight.

I think this is where GHRP should be the most effective in either respect.

Incidentally, in the abstract, they are dosing just 1mcg per KG. That is just 95mcg for myself, a very low dose compared to my regime - and i may yet decide to lower my doses in light of this - likely to 1 500mcg dose and 1x300mcg dose a day… but not yet.

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[quote]Bill Roberts wrote:
Just in principle, not from practical experience or knowledge of others’ track records with it, it doesn’t at all seem to me either that GHRP-6 could be counterproductive with IGF-1.

Myself I’m going to try something that I think is interesting, and is inexpensive and which perhaps you might want to try if it appeals to you.

There’s an interesting study showing the combination of GHRP-6 and GHRH to be far more effective than either alone: Acute dexamethasone administration enhances GH responsiveness to GH releasing peptide-6 (GHRP-6) in man - PubMed

The main objective of the study was to study effects of dexamethasone – a glucocorticoid – on GH release, which was triggered by either GHRP-6 alone (1 mcg per kg), GHRH (100 mcg), or both together; either after dexamethasone treatment or not.

Without the dexamethasone, GHRP-6 yielded area-under-the-curve GH of 2300 mU min/l, while GHRH yielded a statistically-not-necessarily-different AUC of 2900. But the two together gave an AUC of 10,000!

(Figures are rounded.)

If anyone cares about the effect of dexamethasone, it increased the effect of GHRP-6, but not of GHRH or the combination.

I’m not aware of a source of GHRH (not that such doesn’t exist) but CJC1295 (modified) works the same.

I would surely think I am not the first to suggest the combination: undoubtedly this is an already-tried thing: it is simple lack of knowledge that I don’t know of cases. [/quote]

From my recent reading and research it seems that this synergistic effect is due to the GHRH acting to primarily increase GH secretion, and the GHRP while doing this ALSO giving somatostatin inhibition.

This would greatly increase the effect of the GHRH when GHRP is used alongside it seems - and should be the precise reason for your findings here.

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Thanks!

I must not have been clear on the part where I mentioned acromegaly as an evidence that the pituitary can produce large amounts of GH, enough so as to in the long term actually be more than desired. I wasn’t meaning that I think there is risk of acromegaly from a GHRP-6 cycle. It was simply in reply to the concern whether the pituitary can withstand being stimulated enough to produce a lot of GH, at least when the stimulation is occurring in a balanced and natural way.

I don’t really see the point though in using a drug at an amount that is perhaps far more than saturating its pathway, if it is. If one is going to get an adverse effect on the pituitary – which I don’t guess is that likely but still it’s the kind of thing one wants to maintain some degree of caution about particularly with new protocols that have not withstood any test of time – it seems to me that giving a totally unbalanced stimulus, extremely heavy on one and nothing added for another that is synergistic with it, doesn’t seem the best way to go compared to using more moderate doses of each.

It seems unlikely to me that a 500 mcg injection of GHRP-6 is going to do as much as 100 each of GHRP-6 and CJC-etc wouldo do, but the latter seems much more conservative.

I wouldn’t be surprised if 500 mcg of GHRP-6 does nothing more than my roughly-200 mcg injections did.

The study on the combination with GHRH suggests that the reason for limited response with the dose of GHRP-6 used is not so much from lack of more GHRP-6 as it is lack of more GHRH.

Using 500 mcg injections of GHRP-6 alone may be kind of like bringing 3 guns to a gunfight but only one bullet. Three bullets – cartridges really of course – and one gun would be better (To make a horrible analogy.)

And if nothing else, almost undoubtedly the same total use spread into more injections would give more result even if not using the CJC. E.g., if a 500 mcg injection gives only 10% more GH than a 250 mcg injection, then two 250 mcg injections may well give nearly twice the total GH. Even if it is the case that 500 mcg gives 50% more GH than 250 mcg does, two 250 mcg injections could still be 33% better. I just can’t imagine 500 mcg injections as being the efficient way to go.

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[quote] Brook wrote:

From my recent reading and research it seems that this synergistic effect is due to the GHRH acting to primarily increase GH secretion, and the GHRP while doing this ALSO giving somatostatin inhibition.

This would greatly increase the effect of the GHRH when GHRP is used alongside it seems - and should be the precise reason for your findings here.[/quote]

Interesting! Perhaps CJC-etc could enable IGF-1LR3 use to not inhibit or less inhibit concurrent attempt at GH release with GHRP-6.