GHRH & Pituitary Over-stimulation (I of II)
Written by: M.M. a/k/a DatBtrue
Copyright 2008 by M.M. a/k/a DatBtrue
All rights reserved. No part of this article may be reproduced in any form without the written permission of the copyright owner.
Does GHRH result in Pituitary Over-stimulation?
Has that type of concern ever been raised in regard to long-lasting analogues of Growth Hormone Releasing Hormone?
Yes but not directly in a study itself or by one of its authors.
In a fairly recent editorial in the New England Journal of Medicine in which the results from a clinical trial for Tesamorelin, a long-acting analogue of growth hormone releasing hormone (GHRH) were also reported, several questions were raised by the editor. Among them "
Would such a regimen...overstimulate the pituitary gland...with an increased risk of pituitary neoplasms?" -
Manipulation of the Growth Hormone Axis in Patients with HIV Infection, Marc R. Blackman, M.D., NEJM Volume 357:2397-2399 December 6, 2007
I should point out that the referenced study,
Metabolic Effects of a Growth Hormone–Releasing Factor in Patients with HIV, Julian Falutz, M.D, et al. administered 2 mg per day of tesamorelin by subcutaneous injection for 26 weeks to study participants without any indication whatsoever of pituitary problems or for that matter any other problems.
Yet it is a valid concern and one we should seek to understand.
Before we preceed to see if we can create a better understanding for ourselves...we need to clarify exactly the type of things that most concern us regarding potential pituitary damage since the phrase "overstimulate the pituitary gland" is not used in any other journal article.
Reviewing the actions of GHRH on the pituitary & reviewing the literature leads me to focus on two primary areas of concern: pituitary hyperplasia/somatotroph hyperplasia and tumors/adenomas.
THE NATURAL ORDER OF THINGS
In non-diseased people of all ages there exists very large amounts of growth hormone (in various isoforms) stored in the pituitary. While this store of growth hormone accounts for ten percent (10%) of the pituitary's dry weight only a very small portion (1-2ng/mL) of it is found in the circulation. No other pituitary hormone is stored in such high amounts. In fact the quantity of growth hormone stored in the pituitary is 800 times larger then the stored quantity for any other pituitary hormone. -
Lewis UJ. Growth hormone: what is it and what does it do? Trends Endocrinol Metab 1992;3:117–121
From this simple understanding alone we can fairly accurately surmise that asking the pituitary to release some of that store of growth hormone so that we can achieve youthful levels or double the amount of youthful levels shouldn't "overstimulate it" or tax it in such a way as to force it to unduly expand the somatotroph population.
Only a portion of the population of cells within the pituitary are called upon to secrete growth hormone and this is not static. It is controlled by the three hormones that govern this process - Growth Hormone Releasing Hormone (GHRH), Ghrelin (of which GHRPs are mimetics) and Somatostatin.
GHRH and Ghrelin (i.e. GHRPs) appear to act on different somatotrope subpopulations. GHRP has been shown to increase the number of somatotropes releasing GH, without altering the amount of hormone released by each individual cell. On the other hand, GHRH stimulates both the number of cells secreting GH and the amount of GH secreted per cell.
Somatostatin (the GH inhibiting hormone) has been shown primarily to decrease the number of cells secreting GH without affecting the amount of GH secreted per cell.
In very general terms GHRP increases, while Somatostatin decreases, the number of active GH secreting somatotropes.
On the other hand GHRH does both, but acts primarily by stimulating the amount of secreted GH within the active somatotropes.
So fluctuations in somatotrope populations and secretion activity is a natural occurrence.
SOMATOTROPH HYPERPLASIA
But when we see references in journals and in the medical community to somatotroph hyperplasia and the very rare pituitary hyperplasia they are referring to an abnormal increase in the number of cells with consequent enlargement of tissue.
From an article titled "
Pituitary Hyperplasia" in the May 1999 issue of the journal
Pituitary we see that "Somatotroph hyperplasia is rare; it is limited to cases of GHRH overproduction by extrapituitary endocrine neoplasms and sporadic examples of gigantism."
For the reason that we may be supplying GHRH beyond what is naturally occurring in our body which subsequently binds to receptors on somatotrophs in the pituitary and act on them we need to consider if the amount of GHRH we are supplying is on par with the level of overproduction that can bring about hyperplasia. But first let's examine our other concern.
TUMORS/ADENOMAS
If we were to somehow bring about somatotroph hyperplasia will this result in tumors?
It doesn't appear to be likely. From the 2008 edition of
Diagnosis and Management of Pituitary Disorders,
Edited by Brooke Swearingen, MD, et al.:
"It is a common clinical observation that ectopic overproduction of releasing hormones, such as GHRH or corticotropin-releasing hormone (CRH), results in proliferation of the target cells. However, the vast majority of sporadic pituitary tumors do not show hyperplasia in the surrounding tissue. Although these data suggest that hormonal stimulation is not a primary etiologic mechanism in pituitary tumorigenesis, it is worth noting that aggressive GH-secreting adenomas frequently express high intrapituitary amounts of GHRH (45)."
If we follow up that footnote (45) we discover that the overexpression of GHRH referred to comes from the tumor itself. In other words like a lot of tumors the hormone in question is locally produced and locally used by the tumor within. -
Thapar K, Kovacs K, Stefaneau L, et al. Overexpression of the growth-hormone-releasing hormone gene in acromegaly associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior, Am J Pathol 1997;151:769–84.
Let's take a look at someone who had a tumor that hyper-secreted GHRH. This type of overproduction is known as ectopic GHRH hypersecretion. From the autopsy:
"In this report we describe the functional and morphological features of the pituitary removed from a patient with a 10-yr history of a disseminated bronchial carcinoid producing GHRH.
...
Although somatotroph proliferation was widely evident, there was no evidence of adenomatous transformation.
...
We conclude that sustained exposure to ectopic GHRH leads to somatotroph hyperplasia, but, at least in this case, was not sufficient for adenomatous transformation." - Somatotroph hyperplasia without pituitary adenoma associated with a long standing growth hormone-releasing hormone-producing bronchial carcinoid , S Ezzat, SL Asa, L Stefaneanu, R Whittom, HS Smyth, E Horvath, K Kovacs, and LA Frohman, J. Clin. Endocrinol. Metab., Mar 1994; 78: 555 - 560
The general conclusion drawn from similar case studies is that GHRH induced hyperplasia does not bring about tumors.
WHAT DOES BRING ABOUT TUMORS?
From another case study:
"...it is still not known whether hypothalamic hormones have a role in tumorigenesis in human pituitary adenomas.
...
Despite extremely high local levels of hypothalamic releasing hormone, adenoma formation did not occur in our patient. This study provides further evidence that although hypothalamic hormone excess may be important in cellular proliferation, the pathogenesis of pituitary adenoma formation may be mediated by other factors including new oncogenes and suppressor genes that are as yet uncharacterized." - A Growth Hormone-Releasing Hormone-Producing Pancreatic Islet Cell Tumor Metastasized to the Pituitary Is Associated with Pituitary Somatotroph Hyperplasia and Acromegaly, N. Sanno, A. Teramoto, R. Y. Osamura, S. Genka, H. Katakami, L. Jin, R. V. Lloyd, and K. Kovacs, J. Clin. Endocrinol. Metab., August 1, 1997; 82(8): 2731 - 2737
Eventually though we get to the one study that was able to bring about tumor formation in mice after a year of bombardment. What they found was that GHRH hyperstimulation was not sufficient without other factors to bring about adenomas. In fact GHRH by itself was not sufficient to bring about hyperplasia. They highlighted a codependence between GHRH and GH/IGF-I on pituitary cell proliferation.
Tumor formation was likely dependent on other factors relevant to GH signaling. What was most interesting was the process:
"Although supraphysiological levels of hGHRH were present in pituitaries and hypothalami of both GHR+,hGHRH and GHR-/-,hGHRH mice, the appearance of pituitary adenomas was not preceded by a progressive increase in pituitary size. In fact, tumor formation was preceded by a static pituitary growth phase in which mean pituitary weight remained constant for a minimum of 4 months, and in 8% of 12-month-old mice expressing the hGHRH transgene, pituitary weights and gross morphology were indistinguishable from those observed at 2 months of age." - The Effect of GHRH on Somatotrope Hyperplasia and Tumor Formation in the Presence and Absence of GH Signaling, R. D. Kineman, L. T. Teixeira, G. V. Amargo, K. T. Coschigano, J. J. Kopchick, and L. A. Frohman, Endocrinology, Sep 2001; 142: 3764.
This leads us into understanding that the pituitary has defense mechanisms that protect it from such dangers. Nothing happens overnight. The speculation on the actual defense mechanism which resisted adenoma formation for 4 months in mice is as follows:
"...adult somatotropes may become desensitized to the proliferative actions of GHRH. Alternatively, the normal somatotrope may be capable of only a finite number of divisions regardless of the time of onset and duration of GHRH hyperstimulation. Finally, GHRH hyperstimulation could result in an increase in somatotrope proliferation independently of age, but the increase in the rate of proliferation is counterbalanced by an increase in the rate of cell death in the adult gland. Although the exact mechanisms involved in the maintenance of pituitary mass in the presence of elevated GHRH remains to be determined, it is clear that sustained supraphysiological levels of GHRH secondary to expression of the hGHRH transgene ultimately led to a loss of these protective mechanisms in select cells (presumably caused by somatic mutations), thereby allowing for clonal expansion and adenoma formation."
Continued Below