Saturday, March 20, 2010

Gigantism: The Pituitary Gland

What is it about the pituitary gland that enables it to cause gigantism without being subject to the regulation mechanisms that prevent excess height growth from that plague for example Growth Hormone treatment?  Excess HGH has been shown to reduce the number of GHR in some cases.   How does an enlarged pituitary gland cause the body to grow in stature so rapidly?

Evidence for Growth Hormone (GH) Autoregulation in Pituitary Somatotrophs in GH Antagonist-Transgenic Mice and GH Receptor-Deficient Mice

"Growth hormone (GH) modulates the hypothalamic release of somatostatin and GH-releasing hormone; however, there has been no evidence of GH autoregulation on the pituitary somatotroph. To determine the effects of GH on its own regulation, we examined the pituitaries of giant transgenic mice expressing a GH agonist (E117L)."

A somatotroph is the part of the pituitary gland that secretes growth hormone.

"In the E117L transgenic [giant] mice, the number and distribution of pituitary GH-immunoreactive cells were unchanged from nontransgenic littermate controls; an ultrastructural examination revealed typical, densely granulated somatotrophs."

So, it's probably not the somatotrophic part of the pituitary that causes gigantism.  If morphological changes to the pituitary caused Gigantism you'd except the pituitary to be different in GH agonist(an agonist stimulates HGH).

In the study the experiments found evidence of "direct GH feedback inhibition on pituitary somatotrophs."  So people with gigantism could have a mutation on growth hormone itself that does not inhibit the pituitary or the enlarged pituitary gland present in gigantism could be resistant to inhibition.  Also, if growth hormone is produced by a source other than the pituitary gland and growth hormone responses to increased serum levels by reducing somatotrophic growth hormone response then in that case you'd get around the negative feedback response.

"Growth hormone (GH) secretion is under the complex control of the hypothalamus with predominant stimulation by GH-releasing hormone (GHRH) and GH-related peptide (GHRP) and inhibition by somatostatin (SRIH). These effects are modulated by peripheral negative feedback signals, including the target growth factor of GH insulin-like growth factor-I (IGF-I), certain amino acids and nutrient metabolites, and other hormones, including glucocorticoids, that act at the level of the adenohypophysis and the hypothalamus. GH itself can alter its own regulation at the level of the hypothalamus, where it modulates the release of GHRH and SRIH."

"n the E117L transgenic [Giant] mice, all organs were proportionately large but exhibited a relatively normal morphology."

It's probably a mutation in the growth hormone itself that causes gigantism.  However, they used mice with mutated growth hormone so it's not surprising that mutated growth hormone is the cause of gigantism.  Maybe the mutated growth hormone can't negatively regulate itself as efficiently.

"The role of GH in regulating its own expression and secretion is governed by a multilevel system of endocrine, autocrine, and paracrine interactions between GH and its putative regulators. These include central factors such as GHRH, GHRP, and SRIH[somatostatin], as well as peripheral factors, including IGF-I and GH itself. GHRH and GHRP favor GH secretion, whereas SRIH inhibits GH secretion as is evidenced by in vitro and in vivo studies. In vivo GH administration [such as artificially injecting growth hormone] reduces GH responsiveness to GHRH stimulation in humans. This rapid inhibitory effect occurs prior to a corresponding rise in plasma IGF-I. These findings have been cited as evidence that reduces the likelihood that IGF-1 is responsible for the feedback observed. The role of central GHRH, SRIF, and GH is further complicated by the reciprocal interactions between the GHRH and SRIF regulation within the hypothalamus. GHRH and SRIF expression are closely coupled with evidence that SRIF neurons from the periventricular nuclei synapse on GHRH neurons in the arcuate nucleus. These findings are suggestive of hypothalamic control of an inverse relationship between GHRH and SRIF. Moreover, GH appears to also suppress the hypothalamic expression of the GH receptor. The intracerebroventricular administration of an antisense GH receptor oligonucleotide augments GH secretion while reducing the hypothalamic SRIF expression in the rat. These findings suggest a role for the GH receptor, as well as SRIF, in mediating the inhibition of GH-induced negative feedback. Additionally, GH has been suggested to decrease GHRP receptor expression, further adding to the central indirect mechanisms by which GH can modulate itself. Peripheral negative feedback inhibition by IGF-I on the somatotroph has been well characterized. The in vivo as well as in vitro administration of IGF-I has been shown to reduce GH secretion and gene transcription."

Gigantism can also be caused by tumors in the lungs, pancreas, and adrenal glands.  The lungs can possibly affect ph levels which could denature the growth hormone.  Gigantism has to be caused more than just a change in the systematic negative feedback mechanism because Growth Hormone has the ability to regulate itself.  There has to be a change in the growth hormone molecule itself that inhibits it's negative feedback mechanisms.

Altered microRNA expression profile in human pituitary GH adenomas: down-regulation of miRNA targeting HMGA1, HMGA2, and E2F1.

An adenoma is a benign tumor.

"Using a miRNACHIP microarray, we have analyzed the miRNA expression profile of human GH adenomas vs. normal pituitary gland.
We report the identification of a set of miRNA, including miR-34b, miR-326, miR-432, miR-548c-3p, miR-570, and miR-603, drastically and constantly down-regulated in GH adenomas. We demonstrate that these miRNA target genes such as high-mobility group A1 (HMGA1), HMGA2{up in LSJL}, and E2F1{down}, whose overexpression and/or activation plays a critical role in pituitary tumorigenesis. We also show that the enforced expression of the down-regulated miRNA has a negative role on the growth regulation of pituitary adenoma cells. Finally, an inverse correlation is found between the expression of these miRNA and HMGA1 and HMGA2 protein levels in GH adenomas."

miRNA's altered in pituary GH adenomas and their targets: 

"miR-326, miR-432, and miR-570 potentially target the HMGA2 gene, two miRNA (miR-34b and miR-548c-3p) have both the HMGA1 and HMGA2 genes as predicted targets, and two (miR-326 and miR-603) are predicted to regulate E2F1"

"Transfection of miR-34b and miR-548c-3p decreased both HMGA1 and HMGA2 protein levels, whereas miR-326, miR-432, and miR-570 overexpression resulted in the decrease of HMGA2 protein levels only"

"the down-regulation of these miRNA may account for the increased HMGA and E2F1 protein levels observed in pituitary adenomas. This appears extremely interesting because HMGA2 overexpression, after amplification and/or rearrangement of the HMGA2 gene associated with trisomy of chromosome 12, where the HMGA2 gene is located, has been frequently observed in PRL adenomas"

1 comment:

  1. IS Giantism a positive or negitive mutation?