Growth hormone administration vs GHRP

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patrick
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2010/07/29 08:35:43 (permalink)

Growth hormone administration vs GHRP

Growth Hormone Administration vs. CJC-1295/GHRP-6 + GHRH


Units of Measurement
Growth Hormone (GH) like other biologically active substances is measured in International Units (abbreviated as IU) which are based on the measured biological activity for that substance the establishment of which is determined by international agreement. International Units are specific to each substance and so one IU of one substance has no equivalence to one IU of another substance.

While it is fairly straightforward to compare the amount of GH among various dosing administrations (a two (2) iu dose is twice the amount of a four (4) iu dose) and it is easy to ask the manufacture the weight of each iu (Nutropin reveals that 1 iu of their GH is equal to 333 mcg while Lilly's Humatrope trials define 1 iu as 370 mcg (2.7iu per 1mg)) it is not so simple to compare Growth Hormone to other "Growth Hormone Releasing" compounds such as CJC-1295 and GHRP-6.

Practically all studies that use Growth Hormone (GH) or Growth Hormone Releasing Hormone (GHRH) or its analog CJC-1295 or Growth Hormone Releasing Peptides all take blood samples to measure the amount of GH present in blood plasma at various points in time. The unit of measurement is a standardized unit which can be used to make comparisons across different compounds.

The studies either report results as "nanograms (ng) per milliliter (ml)" or "micrograms (ug) per liter ". For the reason that ng = 1/1000 ug and ml = 1/1000 L, ng/ml will always equal ug/L. So no matter how the studies report results comparison is straightforward. In making the cross-comparisons contained herein for simplicity I have chosen to report results as ng/ml.

In addition the amount of hormone released into plasma (i.e. concentration) is based on units divided by time. This measurement is called area under the curve (AUC). However some studies will use the hour as the unit of time while others will use the minute. Therefore comparing AUCs between studies using different units of time requires a conversion to a common unit of time.

I will make the conversion herein in written form but be careful when you look at graphs.

Therefore this examination will look to several studies involving administration of the compounds of interest and compare the blood plasma levels of GH and peak concentration as a result of administration of each tested compound. The result of this cross-study examination will reveal the efficaciousness of various doses of GH, CJC-1295 and GHRH + GHRP-6 in increasing GH in blood plasma.


Studies used for comparison

Growth Hormone Administration

The primary study used herein is the Lilly Clinical trial using single dose administration of Humatrope in normal adults to assess pharmacokinetics. The doses used were .05 IU/kg (intravenously) and .27iu/kg (subcutaneously and intramuscular). In an 80kg adult that equates to 4iu and about 22iu. In our comparison we will only look at the 22iu subcutaneous and intramuscular dose.


CJC-1295 Administration

In "Prolonged Stimulation of Growth Hormone (GH) and Insulin-Like Growth Factor I Secretion by CJC-1295, a Long-Acting Analog of GH-Releasing Hormone, in Healthy Adults", Sam L. Teichman, et al. Journal of Clinical Endocrinology & Metabolism 91(3):799-805, sixty-six healthy normal men and women aged 21-61 were administered various doses of CJC-1295 (long-lasting GHRH analog). The CJC-1295 was administered in a single dose and again in some groups 7 days later and other groups 14 days later. For the reason that we are only examining a week's worth of data only the initial dose is of interest. Blood samples were collected before dosing and then at 15, 30, and 60 minutes and 2, 3, 4, 6, 8, 10, 12, and 24 hours afterdosing; and then every 8 hours on days 2–3, then daily on days 4, 5, 6, 7.

The doses administered were: 30mcg/kg; 60mcg/kg; 125mcg/kg; 250mcg/kg

GHRH + GHRP-6 Administration

While we are limited in our choice of GH administration studies and CJC-1295 studies (there are only two, the results of which are available to the public) we have many available studies measuring the effects of co-administration of GHRH and GHRPs.

So we will briefly look at the results from two studies to give us an idea of how much GH release is contributed by the enhanced pulse brought on by this synergistic combination.

They are, "Inhibition of growth hormone release after the combined administration of GHRH and GHRP-6 in patients with Cushing's syndrome", Alfonso Leal-Cerro, et al., Clinical Endocrinology 1994, 41 (5) , 649–654

and

"Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone", Bowers, C.Y., et al. J. Clin. Endocrinol. Metab. 70, 975–982.


What's Normal?

Before we look at the studies lets take a brief look at how much growth hormone (GH) is secreted naturally.

The following very comprehensive study measured growth hormone output over twenty-four hours among healthy normal people of all ages.


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 youngest category, those under 25 years of age secrete about 2iu of GH per 24 hours, while those in older categories sectrete 1 iu or less.

Note that Humatrope indicates that absolute bioavailability of an intramuscular or subcutaneous dose is about 66%. So perhaps 3iu of exogenously administered synthetic GH is a replacement dose equivalent to 2iu of indogenously secreted GH.




For most of the full study see: Post #558 - Age-Related Changes in Slow Wave Sleep and Relationship With Growth Hormone Levels



Comparing GH administration to CJC-1295 administration

Total GH Release:

When CJC-1295 was administered at 30mcg/kg; 60mcg/kg; 125mcg/kg and 250mcg/kg the total GH levels (area under the curve (AUC)) were respectively:

AUC: 758, 969, 977, and 1370 ng/ml per hour



Keep in mind that for a 80kg adult the 30mcg/kg dosing amounts to 2.4mgs of CJC-1295 per week and the 60mcg/kg dosing amounts to 4.8mgs of CJC-1295.

So 2.4 mgs of CJC-1295 produced an AUC of 758 ng/ml per hour.

When synthetic Growth Hormone (Humatrope) was administered at the equivalent of 22iu (in someone weighing 80+ kg) the following GH levels (area under the curve (AUC)) were reached:

AUC Intramuscular: 495 +/- 106

AUC Subcutaneous: 585 +/- 90



Peak Concentration:

However the GH release pattern results in a much higher mean maximum concentration for the GH administration than the CJC-1295 administration.

The GH study resulted in peaks of 53 to 63 ng/ml.

The CJC-1295 study resulted in dose respected peaks of 6.6; 9.6; 9.9; 13.3 ng/ml.




Total GH Release:

The Alfonso Leal-Cerro study demonstrated the following GH release:
GHRH by itself dosed at 100mcg resulted in:
(AUC) 120 minutes = 1420 ± 330 ng/ml when we convert that to AUC measued in hours we get about 25 ng/ml

GHRP-6 by itself dosed at 100mcg resulted in:
(AUC) 120 minutes = 2278 ± 290 ng/ml when we convert that to AUC measued in hours we get about 40 ng/ml

GHRH + GHRP-6 dosed together at 100mcg each resulted in:
(AUC) 120 minutes = 7332 ± 592 ng/ml when we convert that to AUC measued in hours we get about 130 ng/ml
The Bowers study demonstrated that a small dose of GHRP (.1mcg/kg) added to a saturation dose of GHRH (1mcg/kg) resulted in the following GH release:
(AUC) 120 minutes = 10,065 ng/ml when we convert that to AUC measued in hours we get about 170 ng/ml

In comparison to synthetic GH administration we find that:

22iu of synthetic GH results in 495 - 585 ng/ml
Saturation doses of GHRH & GHRP results in 130 - 170 ng/ml


These results indicate that 22iu is between 3.8 and 3.4 more efficacious then a single administration of GHRH & GHRP which means that a single dose of GHRH & GHRP has the potential to produce better then the equivalent of 5iu of GH in plasma.

A dosing protocol of GHRH + GHRP at saturation dose, administered 3 times per day has the potential to exceed the equivalent of 15iu.

Note though that using this methodology GHRP-6 at a saturation dose by itself may add the equivalent of 1.4 to 1.8 iu per administration... or 4.2 to 5.4 iu per day if administered three times.


Peak Concentration:

From the graphs it is easy to see that GHRH+GHRP results in short-term peaks of 80 to 130 ng/ml.

While the synthetic GH study resulted in less pronounced peaks of 53 to 63 ng/ml of longer duration.



Systemic IGF-1 levels

Simply stated the synthetic Growth Hormone when administered intramuscularly or subcutaneously in high enough dose results in a release profile that is not pulsatile. The release profile is an elevation and this elevation results in higher levels of systemic IGF-1 in circulation then either an intravenous administration of GH or administration of the pulsatile peptides.

While multiple daily dosings of GHRH/GHRP result in a significant rise in systemic IGF-1 (not graphed out here) they do not over time result in as substantial an elevation of circulating IGF-1 as synthetic GH administered non-intravenously.

To understand the difference in GH in plasma profile of synthetic GH administered by intravenous I provide a copy of the GH study graph identical to the clinical study graph posted above with the addition of the intravenous dosing of GH. As you can see intravenous dosing of GH results in what could be described as a pulse because GH is elevated very high and then clears quickly.



So what does a high dose of synthetic GH administered subcutaneously or intramuscularly (but not by IV) do to systemic levels of IGF-1?

To find out we must switch to a Japanese study which undertook such study.

In Pharmacokinetics and Metabolic Effects of High-Dose Growth Hormone Administration in Healthy Adult Men, Toshiaki Tanaka, et al., Endocrine Journal 1999, 46 (4), 605-612, fifteen healthy normal Japanese adult males aged from 20 to 27 years were administered various doses of recombinant GH (Norditropin). The GH was administered in a single dose at 9:00 a.m. after overnight fasting. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 9, 12 and 24 hours after the single injection.

The doses administered were: .075iu/kg; .15iu/kg and .30iu/kg
When the average weight of each test subject is accounted for the doses administered approximated: 5iu; 10iu and 20iu

In the higher dose category the study dosed every day for a week and collected blood samples each day.

IGF-1 levels were measured and can be graphed as follows:



From this graph a few quick things can clearly be understood:
  • IGF-1 creation is a slow ongoing process that increases every day that you administer GH until it plateaus after a week. This should tell you that there is no fear that anything will specifically interfere with GH's ability to instigate IGF-1 creation. All of the timing protocols which fear that insulin or "this and that" will interfere with IGF-1 creation are baseless and such "write-ups" that call for timing are flawed.
  • It is constant GH elevations that result in ever higher levels of systemic IGF-1 creation

What none of this tells us

This does not tell us what is happening locally. By locally I mean IGF-1 that is not made in the liver and circulated systemically. Local IGFs are made in small amounts and used exclusively in the tissue of their birth.

Local IGF-1 in muscle has been demonstrated to be responsible for muscle growth and only if muscle-made IGF-1 is lacking does systemic IGF-1 play a significant (although incomplete) role.

Local IGFs in muscle are increased by growth hormone and testosterone. It is conjectured that pulsatile GH (such as IV dosing) or the use of GHRH/GHRPs results in high levels of muscle IGFs w/o creating high levels of systemic circulating IGFs.

If this proves to be true then that would be an advantage because high systemic levels of IGF-1 are positively correlated w/ cancer and mortality.

More detailed discussions about these sorts of things take place deeper in this thread.
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