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.

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"

Gigantism: Tissue Sensitivity to Growth Hormone

Gigantism is more than just elevated levels of Growth Hormone.  There are tons of incidents where people have low or normal levels of Growth Hormone with Gigantism.  Extremely high levels of HGH may increase the number of Growth Hormone Receptors but the pathology of Gigantism is likely to be far more complex.

Evidence that Sensitivity to Growth Hormone (GH) Is Growth Period and Tissue Type Dependent: Studies in GH-Deficient lit/lit Mice

"Overexpression of GH in erythroid cells using ß-globin promoter increases bone size and BMD in transgenic mice"

Transgenic refers to the altering of genes. This B-globin promoter could be useful to us because it did increase bone size.

An explanation of what a lit mice is:
"For our studies, we used lit/lit mice as a model because we predicted that these mice with no detectable endogenous GH levels should respond to exogenous GH much more robustly compared with wild-type mice with normal endogenous GH levels."

Remember these mice are GH deficient so they were already unlikely to reach their height potential and GH may have only given them a boost towards their original height potential.


Groups 1 and 2 were prepubertal, 3 and 4 were pubertal; 5 and 6 were postpubertal; 7 and 8 were fully adult mice.

"Our findings also reveal that GH administration during the prepubertal growth period has little effect on general body growth or on bone accretion. This conclusion is based on the findings that the magnitude of increase in body weight was much smaller when GH was administered between d 7–21 compared with between d 21–34 (< 20% vs. 70%) and that overall changes in many of the parameters studied were similar in mice treated with GH between d 7 and 34 vs. have recently reported that the skeletal deficit is minimal in GH-deficient lit/lit mice compared with control mice at the end of the prepubertal growth period. If these findings can be extrapolated to humans, this would suggest that GH administration during the prepubertal growth period might not be efficacious[efficient] compared with pubertal or postpubertal growth periods in GH-deficient children."

This gives us an important clue perhaps there is something that occurs during puberty that increases sensitivity to Growth Hormone.  You'd expect HGH to still increase height prepuberty by at minimum increasing IGF-1 mediated chondrocyte hypertrophy.  The study did find that HGH mediated IGF-1 increased more post-puberty than pre-puberty.  Maybe pre-puberty the bone relies more on IGF-2. 

The exercise-induced growth hormone response in athletes.

"Human growth hormone (hGH) is secreted in a pulsatile fashion[Altering this pulsatile fashion may be one way to alter height], generally following a circadian rhythm. A number of physiological stimuli can initiate hGH secretion, the most powerful, non-pharmacological of which are sleep[maintaining a regular circadian rhythm is vital for height growth until we know how manipulating the pulses of HGH secretion can manipulate height] and exercise. hGH has many varied roles throughout life, from growth itself, including the turnover of muscle, bone and collagen, to the regulation of selective aspects of metabolic function including increased fat metabolism and the maintenance of a healthier body composition in later life. The exercise-induced growth hormone response (EIGR) is well recognised and although the exact mechanisms remain elusive, a number of candidates have been implicated. These include neural input, direct stimulation by catecholamines, lactate and or nitric oxide, and changes in acid-base balance. Of these, the best candidates appear to be afferent stimulation, nitric oxide and lactate. Resistance training results in a significant EIGR. Evidence suggests that load and frequency are determining factors in the regulation of hGH secretion. Despite the significant EIGR induced by resistance training, much of the stimulus for protein synthesis has been attributed to insulin-like growth factor-1 with modest contributions from the hGH-GH receptor interaction on the cell membrane. The EIGR to endurance exercise is associated with the intensity, duration, frequency and mode of endurance exercise. A number of studies have suggested an intensity 'threshold' exists for EIGR. An exercise intensity above lactate threshold and for a minimum of 10 minutes appears to elicit the greatest stimulus to the secretion of hGH. Exercise training above the lactate threshold may amplify the pulsatile release of hGH at rest, increasing 24-hour hGH secretion. The impact of chronic exercise training on the EIGR remains equivocal. Recent evidence suggests that endurance training results in decreased resting hGH and a blunted EIGR, which may be linked to an increased tissue sensitivity to hGH[increased tissue sensitivity to HGH is way more important increased HGH levels as you can increase HGH easily through other means; thus endurance exercise is good for height growth]. While the potential ergogenic effects of exogenous GH administration are attractive to some athletes, the abuse of GH has been associated with a number of pathologies. Identification of a training programme that will optimise the EIGR may present a viable alternative. Aging is often associated with a progressive decrease in the volume and, especially, the intensity of exercise. A growing body of evidence suggests that higher intensity exercise is effective in eliciting beneficial health, well-being and training outcomes. In a great many cases, the impact of some of the deleterious effects of ageing could be reduced if exercise focused on promoting the EIGR. This review examines the current knowledge and proposed mechanisms for the EIGR, the physiological consequences of endurance, strength and power training on the EIGR and its potential effects in elderly populations, including the aged athlete."


Marathan runners are not super tall.  Marathan Runners are the kings of endurance training.  If endurance training can increase height by increasing the number of Growth Hormone Receptors then you'd expect marathon runners to be very tall.  Maybe Growth Hormone Receptors don't increase height that much.

Gender Differences in the Effects of Long Term Growth Hormone (GH) Treatment on Bone in Adults with GH Deficiency

"In the present study we observed increases in BMD and BMC at different measurement sites during long term treatment with rhGH in patients with hypopituitarism(a pituatary that does not secrete enough growth hormone). The male patients with GHD gained more from the long term GH treatment with regard to bone mass despite receiving significantly lower doses of rhGH than the women. Furthermore, there were sustained increases in serum markers of bone metabolism and in serum IGF-I; these changes were similar in the men and women despite the difference in rhGH dose."

For possible explanations the study states: "In castrated rabbits the expression of GH receptor messenger ribonucleic acid in both the liver and the growth plate has been reported to be increased by testosterone and decreased by estradiol[The response to Growth Hormone may be based on the presence of sex organs]. This could be a mechanism responsible for the gender difference in the serum IGF-I response to GH treatment and could be of relevance for the present finding of a greater gain in bone mass in the GHD men. On the other hand, in rats estradiol has been found to stimulate GH receptor expression, and testosterone did not influence GH-induced IGF-I expression. Osteoblasts contain receptors for both androgens and estrogens, and in bone cells, estradiol stimulated GH receptor expression. "

Estradiol is an estrogen sex hormone.  Estrogen does have height increasing effects up to a certain point.  Estrogen may increase the number of growth hormone receptors and this can result in increased height until the other effects of estrogen kick in. Also, given the castration effect estrogen may decrease height in females and increase height in males.

Gigantism is likely not caused by an increase in tissue sensitivity to growth hormone.  As then endurance athletes would be incredibly tall unless the sensitivity occurs only in the muscle and not the bone.  But, endurance running also is taxing on the bones as well.  You can get lactic acid in the muscles but not the bones so if the increase in GHR is based on that it would explain the lack of height.  However, Nitric Oxide can build up in the bones as well as the muscle.  So unless the increase in GHR is caused by lactic acid, more Growth Hormone Receptors likely cannot cause Gigantism.

Gigantism is more than just elevated HGH

Hiroki Yokota writes "The working hypothesis is that joint loading can lengthen long bone by activating cellular proliferation and differentiation in the growth plate.   However, joint loading can also affect cells in cortical bone and thicken cortex."  Now, lateral synovial joint loading activates stem cell differentiation into chondrocytes in adult chondrocytes by increasing hydrostatic pressure. I've shown in the past an increase in growth rate(cellular proliferation and differentiation) does not equal an increase in final growth mainly as a result of the factors that regulate chondrocyte senescence like telomere length.  However, Lateral Synovial Joint Loading works by activating new stem cells rather than relying on increasing proliferation of existing chondrocytes.  Joint loading can induce adaptation at only 30 microstrain which would seem to not be a great deal of weight but remember the microstrain is relative to the bone so we'd need a strain gauge to determine the relative strain of the weight given bone resistance.

Gigantism seems to get around these cellular senescence mechanisms.  You'd expect HGH to only affect growth rate(or an effect on chondrocyte hypertrophy) unless HGH had some sort of effect directly on the factors involved in cellular senescence.  If we understood why Gigantism causes such growth given all the limiting factors such as the number of Growth Hormone Receptors, we could better understand height growth. 

Endochondral gigantism: a newly recognized skeletal dysplasia with pre- and postnatal overgrowth and endocrine abnormalities 

"We report on a 3-year-old male, born at 34 weeks of gestation, with marked pre- and postnatal overgrowth, birth weight of 6,600 g, length of 61 cm, and head circumference of 38.5 cm. A striking phenotype was recorded at birth, which became more evident during the follow-up period. He had macrobrachycephaly, facial abnormalities, small thoracic cage, long trunk, deformed spine, rhizomelia, large hands and feets, absent subcutaneous fat, small umbilical hernia, inguinal hernias, and large joints with mild contractures. Hypoglycemic episodes and obstructive apnea complicated the neonatal period. During follow-up, overgrowth continued with a height of 146 cm (+11.65 SDS) and a weight of 39 kg (BMI 18.3 kg/m(2)) at 3.5 years. Endocrinological work-up disclosed extremely low levels of growth hormone, insulin-like growth factors, and insulin. What makes our patient unique is the association of marked prenatal overgrowth; unusual phenotype; skeletal dysplasia caused by accelerated endochondral ossification resulting in cartilage hyperplasia of the skull base and spine, and postnatal gigantism; and complete absence of subcutaneous fat. Other well-known overgrowth syndromes were excluded. We hypothesize that autocrine/paracrine growth factors could be the cause of excessive endochondral ossification. Alternately, activating mutations in transcription factors involved in both growth AND endocrine/metabolic homeostasis could be responsible for this unusual phenotype." 

There is always more to Gigantism than elevated HGH.  There is almost always some sort of tumor involved.   Scientists speculate that it is an enlargement of the pituatary gland which causes gigantism not just excess growth hormone.  An enlarged pituatary gland would affect endocrine and metabolic homeostasis.  

[Gigantism with low serum level of growth hormone: a case report] 

"Gigantism with low or normal basal concentrations of growth hormone (GH) is a rare condition, possibly due to abnormal GH secretory patterns, enhanced tissue sensitivity to GH, or the existence of an unidentified growth promoting factor. Here we report an 11 year-old female case of gigantism with a normal pituitary gland. Her height was 181 cm, body weight 77 kg, and bone age 11.1 years. Her basal serum GH levels were lower than 1 ng/ml. The levels of T3, T4, FT3, FT4, TSH, E2, LH, FSH, PRL, PTC and ACTH were normal. Serum GH response to insulin-induced hypoglycemia or arginine stimulation tests was blunted. In this case, non-pulsatile GH secretion and enhanced tissue sensitivity to GH may induce hypersecretion of IGF-1 and the existence of an unidentified growth promoting factor or biologically active anti-GH receptor antibodies may cause clinical gigantism." 

Enhanced tissue sensitivity to GH could indicate an increased number of Growth Hormone Receptors.  There's also a non-pulsatile secretion of HGH.  Maybe the rate of HGH secretion affects growing taller as well.  A change in HGH secretion pattern would affect homeostasis and could alter cellular pathways.  There are way more hormones that affect height growth than what they measured so there are other confounding variables involved.

Osteoarticular Changes in Acromegaly

"Acromegaly is caused by hypersecretion of growth hormone (GH) and consequently of insulin-like growth factor-I (IGF-1) due to pituitary tumor. Other causes, such as increased growth-hormone releasing hormone (GHRH) production, ectopic GHRH production, and ectopic GH secretion, are rare. The issue of osteoarticular manifestations is still very actual, due to development of complications in the majority of patients with acromegaly. Traditionally, acromegaly is considered as a cause of secondary osteoporosis. GH excess leads to increased bone turnover, defined by changes of bone markers."

"The effect rhGH on bone remodeling is biphasic: rhGH causes a maximal effect on bone resorption after 3 months and on bone formation after 6 month. The effect on bone formation is sustained for prolonged periods of time. The effect of rhGH on biochemical markers of bone turnover is dose dependent but not influenced by the modality of administration. RhGH causes an increase in urinary and serum calcium after 3–6 months, an effect caused by calcium mobilization from the skeleton, an increase in intestinal calcium absorption and in the renal reabsorption of calcium due to increased sensitivity to PTH. RhGH is antiphosphaturic and increases the intestinal absorption of phosphate which leads to increased levels of serum phosphate. RhGH may also normalize the circadian rhythm of PTH secretion. Receptors for IGF and GH have been demonstrated in osteoclasts, thus GH and IGF-1 may directly affect their function and activity. In addition, GH/IGF-1 axis indirectly affects bone resorption by stimulating the release of paracrine mediators that regulate the resorption of bone"

"Radiological changes in early phase [of acromegaly] are joint space widening and periarticular soft tissue hypertrophy."  Later stages of acromegaly are characterized by narrowing of joint spaces.