Much has been made of growth hormone(GH) in attempting to make people taller.
The over 7-feet tall Richard Kiel(actor)
According to (http://www.medstudents.com.br/endoc/endoc8.htm) gigantism has an incidence rate of about "[3 per 1 million people]". It defines gigantism as "chronic exposure to GH."
High dose growth hormone treatment limited to the prepubertal period in young children with idiopathic short stature does not increase adult height.
"40 children with no signs of puberty, age at start 4-8 years (girls) or 4-10 (boys) years, height SDS<2.0 SDS and birth length>-2.0 SDS, were randomly allocated to receive GH at a dose of 2 mg/m2/day (equivalent to 75 mug/kg/day at start and 64 mug/kg/day at stop) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment."
It is possible that the dosage of Growth Hormone was too low.
"In 28 cases adult height (AH) was assessed at a mean (SD) age of 20.4 (2.3) years. Results: GH-treated children (mean treatment period on high dose GH 2.3 yr (range 1.2-5.0 yr)) showed an increased mean height SDS at discontinuation of treatment compared with controls (-1.3 (0.8) SDS versus -2.6 (0.8) SDS, respectively). However, bone maturation was significantly accelerated in the GH-group compared with controls (1.6 (0.4) versus 1.0 (0.2) yr, respectively) and pubertal onset tended to advance. After an untreated interval of 3-12 yr, AH was -2.1 (0.7) and -1.9 (0.6) in the GH-treated and control group, respectively. Age was a positive predictor of adult height gain."
Growth Hormone only accelerated growth. It did not increase overall adult height. The key component of proving an hypothesis is that the experiment has to be reproducable. Their are clearly other components involved in gigantism, perhaps a genetic mutation affecting the epiphysis in addition to a large amount of growth hormone produced like DNA hypermethylation. Gigantism already involves one cancerous tumor in the pituitary gland(and occasionally other places) why not others?
Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial.
"Patients were randomly and blindly assigned to treatment with either 3 IU (group A) or 6 IU (group B) GH/m(2).d ( approximately 0.033 or 0.067 mg/kg.d, respectively). The mean (+/-SD) birth length was -3.6 (1.4), the age at the start of the study was 8.1 (1.9) yr, and the height SD score (SDS) at the start of the study -3.0 (0.7). Seventeen of the 54 children were partially GH deficient (stimulated GH peak, 10-20 mU/liter). Fifteen non-GH-treated, non-GH-deficient, short children born SGA, with similar inclusion criteria, served as controls [mean (+/-SD) birth length, -3.3 (1.2); age at start, 7.8 (1.7) yr; height SDS at start, -2.6 (0.5)]."
The dosage of growth hormone was less than the previous study.
"GH treatment resulted in an AH above -2 SDS in 85% of the children after a mean (+/-SD) GH treatment period of 7.8 (1.7) yr. The mean (SD) AH SDS was -1.1 (0.7) for group A and -0.9 (0.8) for group B, resulting from a mean (+/-SD) gain in height SDS of 1.8 (0.7) for group A and 2.1 (0.8) for group B. No significant differences between groups A and B were found for AH SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.2, 0.6; P > 0.2) and gain in height SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.1, 0.7; P > 0.1). When corrected for target height, the mean corrected AH SDS was -0.2 (0.8) for group A and -0.4 (0.9) for group B. The mean (+/-SD) AH SDS of the control group [-2.3 (0.7)] was significantly lower than that of the GH-treated group (P < 0.001). Multiple regression analysis indicated the following predictive variables for AH SDS: target height SDS, height SDS, and chronological age minus bone age (years) at the start of the study. GH dose had no significant effect."
Conclusion: Don't waste your time and money on GH. There's another element of gigantism that's missing.
Other possible causes of gigantism(from www.medstudents.com):
"A rare form [of gigantism is] caused by hypersecretion of GHRH from an ectopic source (pancreatic islet or carcinoid tumors) or from within the central nervous system such as ganglyoneuroma (called eutopic). Even more rare form is a nonpituitary GH secreting tumor documented in a few lung tumors and in those called Ectopic Pituitary Tumor (Esphenoidal)."
All of these causes are still related to GH however. It is clear that gigantism is correlated with high volumes of growth hormone. Since long bone growth does not occur after the growth plates have closed in gigantism(except for Robert Wadlow and other cases) the signs point to the fact that individuals with gigantism probably have special characteristics in the epiphyseal part of their bones. It may be worthwhile to study this to try to apply to our pursuits.
Growth Hormone may be related to DNA Methylation which controls growth plate senesence.
DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells
"Directed by microarray analyses, we report that autocrine human growth hormone (hGH) increased the mRNA and protein expression of DNA methyltransferase 1 (DNMT1), DNMT3A and DNMT3B in mammary carcinoma cells. Autocrine hGH stimulation of DNMT3A and DNMT3B expression was mediated by JAK2 and Src kinases, and treatment of mammary carcinoma cells with the DNMT inhibitor, 5′-aza-2′-deoxycytidine (AZA), abrogated autocrine hGH-stimulated cellular proliferation, apoptosis and anchorage-independent growth. AZA reversed the epitheliomesenchymal transition of mammary carcinoma cells induced by autocrine hGH, to an epithelioid morphology and abrogated cell migration stimulated by autocrine hGH. Autocrine hGH-stimulated hypermethylation of the first exon of the PLAKOGLOBIN gene and AZA abrogated the ability of autocrine hGH to repress plakoglobin gene transcription. Small interfering RNA (siRNA)-mediated depletion of the individual DNMT molecules did not release autocrine hGH repression of PLAKOGLOBIN promoter activity nor did individual DNMT depletion affect autocrine hGH-stimulated migration. However, concomitant siRNA-mediated depletion of both DNMT3A and DNMT3B abrogated hypermethylation of the PLAKOGLOBIN gene stimulated by autocrine hGH and subsequent repression of plakoglobin gene transcription and increased cell migration. Thus, the autocrine hGH-stimulated increases in DNMT3A and DNMT3B expression mediate repression of plakoglobin gene transcription by direct hypermethylation of its promoter and consequent phenotypic conversion of mammary carcinoma cells. Autocrine hGH, therefore, utilizes DNA methylation as a mechanism to exert its oncogenic effects in mammary carcinoma cells."
"Plakoglobin is a component of the adherens junctions complex, and is a multifunctional protein involved in cell–cell adhesion and transcriptional regulation. Loss of plakoglobin expression results in dissolution of adherens junctions"
"CpG hypermethylation of the plakoglobin promoter has also been demonstrated to be responsible for the loss of plakoglobin expression"
"Small interfering RNA (siRNA)-mediated depletion of DNMT3A and DNMT3B specifically increased PLAKOGLOBIN gene promoter activity and expression, and subsequently abrogated autocrine hGH stimulated mammary carcinoma cell migration"<-DNMT3A/B and therefore GH may reduce migration and encourage mesenchymal condensation.
HGH represses PLAKOGLOBLIN promoter activity.
Different tissue than chondrocytes but I think we can safely assume that HGH increases DNA methylation. However, we don't know if HGH affects telomere length and both DNA methylation and telomere lengthening are needed to avert cellular senescence.
Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production.
"Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two- to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions."
"growth hormone receptor knockout (GHRKO) mice have decreased femoral length,"
"GH stimulates IGF-1 production"
"the reduction in mean femoral length (Le) owing to pegvisomant was not significantly different between LID (approximately 7%) and control mice (approximately 5%). "
"Ghr/Igf1 nullizygotes have more severe growth retardation than mice with single ablations of either the Ghr or the Igf1 gene."
"Femur length (Le) was reduced significantly in pegvisomant-treated LID mice, indicating reduced GH action in the femoral growth plate. Interestingly, these reductions in femur length (Le) were proportionally matched to reductions in transverse bone size such that pegvisomant-treated LID mice (as well as control mice) had identical robustness values when compared with vehicle-treated animals. Thus loss of GH action during puberty appears to hinder both transverse and longitudinal bone growth in a coordinated fashion, whereas loss of hepatic IGF-1, as reported previously in the LID mouse, reduces transverse bone growth but not longitudinal growth, thereby resulting in a less robust, more slender phenotype for LID mice"
it turns out wadlow had so much gh going through his body his system prevented estrogen from ever activating puberty. his pituitary glad was hypertrophic, extremely enlarged. he was 22 when he died and he had not gone through puberty.
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