Gigantism: Non-Pituitary Tumors

In order to find out what's the true cause of Gigantism it would be helpful to know what the common elements are between tumors of the pituitary gland are and tumors in other locations.  We know that Gigantism isn't solely Growth Hormone because Growth Hormone has failed to give height alone in some cases and it isn't about a change in morphology of the pituitary because pituitary morphology was normal in mice with Gigantism(although the fact that the pituitary is enlarged may make a difference) If we know what the real cause of Gigantism is, we can figure out how to keep the bones growing beyond what one would expect genetically.

Acromegaly caused by growth hormone-releasing hormone-producing tumors: long-term observational studies in three patients.

"Acromegaly caused by ectopic extracranial[not in the brain] growth hormone-releasing hormone (GHRH) secretion is a very rare disorder occurring probably in less than 1 % of the acromegalic patients"

1% is very low unless pituitary tumors are more frequent than the other kinds of tumors. Maybe GHRH isn't as effective as causing Gigantism as HGH itself.  Also, there are two requirements versus one:  Not in the brain & involving GHRH versus just being in the brain.

"Most patients with ectopic GHRH syndrome exhibit a paradoxical increase of GH after TRH and glucose (i.e. >50%) and a blunted GH rise (<100%) after exogenous GHRH injection"

The fact that growth hormone does not rise as much as expected after external injections suggests a specific growth hormone mutation otherwise the body wouldn't resist the external growth hormone.  If the Growth Hormone wasn't mutated you'd expect it to respond the same way to external GHRH.

"Independent parameters of residual disease are elevated basal (nonpulsatile) GH secretion and decreased GH secretory regularity."

The GH secretion pulses are less frequent but are stronger.

"Patient 1. The pancreatic tumor had a diameter of 5 cm. Amorphous material was present between the cells, staining as amyloid. On electronmicroscopy, the cells contained neurosecretory granules with a diameter between 100 nm and 200 nm. The tumor stained positively, but sparsely for somatostatin, insulin and glucagon and negatively for cytokeratine, vimentine, neurofilaments, desmine and GH[nothing about this tumor seems anabolic]. In the removed part of the pancreas three additional small adenomas with identical staining characteristics were present.

Patient 2. The diameter of the removed lung tumor was 5 cm, and contained centrally calcified material[sign of heterotopic ossification]. The cells were layered in nests, slightly polymorphic, but without mitotic figures. The tumor cells stained positively for keratine, vimentin, synaptophysin, SCCL (N-CAM), leu 7, and chromogranin and negatively for calcitonin, GH, pancreatic polypeptide, insulin, prolactin, somatostatin, gastrin, ACTH, CEA, and neurofilaments.[again negative for GH and nothing strikingly anabolic]

Patient 3. The dimensions of the tumor were 8 × 7×7 cm³[this is a lung tumor]. The tumor showed clear proliferation of neuroendocrine cells with three mitotic figures per high power field, staining positively for NSE, CD56, and synaptophysin and negatively for keratine, chromogranin, serotonin, somatostatin, prolactin, insulin, glucagons, gastrin, ACTH, GH, and insulin."

 

The only thing anabolic that was elevated was Growth Hormone Releasing Hormone.

 

"GHRH infusion in healthy subjects augments irregular GH secretion"

 

GHRH alters the pulsatile secretory patterns of HGH.  Maybe, a specific manipulation of GH secretion is needed to cause Gigantism.

The Role of Endogenous Growth Hormone-Releasing Hormone in Acromegaly

"We have shown that, in some patients with typical acromegaly due to a pituitary adenoma, GH secretion can be reduced in part by a specific GHRH receptor antagonist in vivo. This suggests that GH secretion in acromegaly is dependent at least in stimulation by endogenous GHRH. Although it has been suggested that pituitary adenomas result from the expansion of a single mutated cell, a role of hypothalamic factors in the genesis or growth of these tumors is possible"

Endogenous means within the body.

"The potential role of GHRH in the pathogenesis of acromegaly is supported by in vitro and in vivo data. In vitro, GHRH stimulates GH synthesis, GH release, and somatotroph cell proliferation[cells in the anterior pituitary that produce growth hormone]. Human GHRH transgenic mice develop marked pituitary hyperplasia and, at age 10–14 months, also develop pituitary adenomas. In humans, ectopic GHRH secretion results in pituitary somatotroph hyperplasia and acromegaly . Secretion of GHRH by neuronal tumors (gangliocytomas, hamartomas, choristomas) in the hypothalamus or the pituitary is associated with pituitary somatotroph adenoma formation and acromegaly. Junctions between the neuronal tumor cells and the pituitary adenoma cells have been described. More recently, a case of a pituitary adenoma cosecreting GHRH and GH and resulting in elevated plasma GHRH concentration was described. These paradigms suggest that exposure to high concentrations of GHRH for a sufficient length of time can result in the formation of a GH-producing pituitary adenoma."

So a single mutation of GHRH could result in a chain reaction that causes an enlargement of the pituitary which could change the way Growth Hormone is perceived throughout the entire body.

It's suggested that a mutation of the gs protein could be the cause of gigantism.

"Furthermore, patients with "cured" acromegaly, as defined by a normal serum IGF-I level and GH suppression by a glucose load, maintain increased GH pulse frequency after successful TSS, suggesting a primary hypothalamic control disturbance"

So Acromegaly(Gigantism) can be cured even if pulse frequency does not return to normal.



So, Gigantism isn't caused by HGH alone nor is it caused by GHRH alone.  The exact cause of Gigantism and how we can use that cause to help us grow taller is unknown.