Monday, September 13, 2010

Human Growth Hormone to Increase Height

Human Growth Hormone has been speculated to play an important role in Gigantism.  Growth Hormone has failed in some instances to treat idiopathic short stature most likely due to the bodies attempts to maintain homeostasis by lowering endogenous growth hormone levels.

Exogenous Growth Hormone increases that do not trigger the bodies negative feedback mechanisms would be very powerful for height increase.  This is why Niacin is so powerful.  Niacin "flushes" the body of free fatty acids and increases the effectiveness of existing growth hormone.

There are numerous potential causes of Gigantism but what they all share in common is more than supranormal levels of growth hormone.  They all have a profound alteration in the bodies homeostatic mechanism like an enlarged pituitary gland.

If there was a way to increase levels of growth hormone without triggering the bodies negative feedback loop then it would be a very powerful height increase method.  What effects does growth hormone have on height increase?

Growth Hormone and Bone

"The finding that GH stimulates longitudinal bone growth directly and increases the local production of IGF-I by stimulating transcription of the IGF-I gene"

Whether this merely increases growth rate or increases adult height is unclear.

"Several studies have shown that systemic administration of recombinant IGF-I stimulates longitudinal bone growth as well as body weight gain in hypophysectomized rats, giving support to the theory that IGF-I has endocrine actions on statural growth"

So IGF-1 does stimulate longitudinal bone growth.

"Furthermore, the differences between GH and IGF-I are quite obvious in transgenic animals overexpressing either GH or IGF-I. Thus, GH-transgenic animals grow to approximately twice the size of their normal littermates[Note transgenic so this alters the bodies homeostatic responses]. In contrast, mice generated from a cross of mice overexpressing IGF-I and mice lacking GH-expressing cells demonstrate an increase in longitudinal bone growth and body weight when compared with their GH-deficient controls. However, IGF-I transgenic mice do not grow more than their nontransgenic siblings, demonstrating that overexpression of GH, but not IGF-I, causes supranormal growth[This is interesting, maybe lack of GH reduces IGF-1 levels?]. Local administration of GH, but not IGF-I, stimulates the local production of IGF-I by stimulating the transcription of the IGF-I gene, giving direct experimental support to the notion that there is an interplay between GH and IGF-I. Administration of antibodies to IGF-I abolishes the stimulatory effect of locally administered GH, supporting the theory that the locally produced IGF-I has an important functional role in the expression of the effect of GH at the site of the local tissue level"

"Taken together, available data suggest that GH stimulates longitudinal bone growth directly by stimulating prechondrocytes in the growth plate followed by a clonal expansion caused both by the GH-induced local production of IGF-I[GH increases stem cell levels], and by a GH-induced increase in circulating levels of IGF-I. GH is the major determinant for the stimulation of progenitor cells, although it is possible that IGF-I might stimulate progenitor cells to some extent"

Effect of GH on osteoblasts which can increase height when they deposit new bone on the longitidunal ends of bones:

"The effective concentrations of GH are in the physiological range (half-maximal stimulation at 10–50 ng/ml), suggesting that GH exerts direct actions on osteoblasts. Not only does GH stimulate the proliferation of osteoblasts, but, in some studies, it also stimulates differentiated functions of these cells. Thus, typical phenotypic functions of osteoblasts such as AP, osteocalcin, and type I collagen are stimulated by GH. For osteoblasts it is difficult to find a good model system for the identification of the actual target cell of GH action. However, bone marrow-derived precursors of human bone cells are responsive to GH, suggesting, in analogy to the actions of GH in early progenitor cells in adipose tissue and cartilage, that GH interacts with progenitor cells."

Since GH interacts with progenitor cells it could help induce chondrogenesis and could increase adult height and not just growth rate.  Also, it could help induce new growth plates in adults.

"GH administration increases cortical bone mass in normal rats. Tetracycline labeling of the mineralization front demonstrates that GH induces subperiosteal bone formation without influencing the endosteal bone surface. The new bone is organized in a manner similar to that of adjacent bone that was formed before the start of GH injection, i.e., in concentric lamellae and with the same direction of the collagen fibers. After withdrawal of GH administration, the subperiosteal bone formation ceases quickly in areas with minimal bone formation before the start of GH treatment. A remaining effect of GH, however, was found in areas where active bone formation occurred before the start of treatment. The new bone formed during GH administration is preserved after discontinuation of the treatment"

Growth Hormone forms new bone beneath the periosteum.  Only some bones have periosteum on the longitidunal ends.  However, the fibrous capsule may be able to be used somehow in a periosteum like role(LSJL pushes the fibrous capsule against the surface of the bone).  Osteoprogenitor cells can be derived directly from the haversian canal of bone as well.

Single cell enzyme activity and proliferation in the growth plate: Effects of growth hormone

"To study the effect of GH on chondrocyte activity, in situ biochemical techniques were used to measure enzyme activities, which are associated with cell differentiation (alkaline phosphatase [ALP]) and osteoclast activity (tartrate‐resistant acid phosphatase [TRAP]), within single cells of the growth plate. Uptake of bromodeoxyuridine (BrdU) was used as a parameter for proliferative activity. In addition, glucose‐6‐phosphate dehydrogenase (G6PD) was measured since increased proliferation has been associated with increased G6PD activity. The role of GH was studied in a model of isolated GH deficiency (dwarf rat) and complete pituitary deficiency (hypophysectomized rat). Groups of GH‐deficient dwarf rats were infused with recombinant human GH in either a continuous or a pulsatile manner, since the pattern of GH secretion is an important regulator of growth in the rat. After 7 days, G6PD activity in proliferative chondrocytes and TRAP activity in osteoclasts was increased, while ALP activity in hypertrophic chondrocytes was decreased. GH not only increased the number of chondrocytes that incorporated BrdU but also the total number of chondrocytes in the proliferative zone; therefore, its ratio, the labeling index (an indicator of proliferative rate), was not increased. The widths of the proliferative and hypertrophic zones were increased by both patterns of GH administration. The width of the resting zone was unaffected by continuous GH but decreased by pulsatile GH. ALP and TRAP activities were, respectively, higher and lower in hypophysectomized rats compared with the GH‐deficient animals. Hypophysectomized rats had smaller growth plates than dwarf rats with a disproportionally wide resting zone, which, like BrdU uptake, was not affected by GH. GH treatment resulted in increased TRAP and decreased ALP activity. These results indicate that GH stimulates the commitment of chondrocytes within the resting/germinal layer to a proliferative phenotype (as opposed to stimulating the rate of chondrocyte proliferation) but only in the presence of other pituitary hormones."

The study also states GH increases DNA synthesis and ECM production.

"Vitamin D3 is also involved in the differentiation of rat chondrocytes. Vitamin D3 receptors are present on hypertrophic growth plate chondrocytes , and vitamin D3 reduces ALP activity and type X collagen synthesis of chondrocytes, interpreted as an inhibition of terminal differentiation.  Since GH is known to modulate renal vitamin D3 production,(5s) and IGF-I stimulates hydroxylation of 25(OH)D3 [the changes in ALP activity could involve Vitamin D3]"

Whole genome microarray analysis of growth hormone-induced gene expression in bone: T-box3, a novel transcription factor, regulates osteoblast proliferation

"We used microarray analysis to evaluate GH signaling pathways in 4-wk-old GH-deficient mice following a single injection of GH (4 mg/kg body wt) or PBS (n = 6/group) at 6 or 24 h after treatment. Six thousand one hundred sixty genes were differentially expressed at P ≤ 0.05, and 17% of these genes were identified at both time points. Several of the genes differentially expressed were expressed sequence tags, and the remaining genes fell into 49 Gene Ontology categories. For subsequent studies, we focused on T-box (Tbx)3, a novel transcription factor, which increased more than twofold at both time points. Real-time RT-PCR analysis determined that pretreatment with IGF-binding protein-4 did not block GH-induced Tbx3 expression in vitro. Pretreatment with TNF-α blocked GH-induced Tbx3 expression[We don't know the role of Tbx3 to chondrocyte differentiation]. Tbx3 expression increased during osteoblast differentiation and following BMP-7 and Wnt3a treatment (P ≤ 0.05). Blocking Tbx3 expression by small interfering RNA decreased cell number and [3H]Thymidine incorporation (P < 0.01)."

"When GH binds to its receptors, JAK is phosphorylated and several pathways, including STAT, MAPK, and phosphatidylinositol 3-kinase, are activated. Through these pathways, GH regulates the transcription of specific genes, such as IGF-I. GH may also act independently of IGF-I in bone. The rate of gain in femur length and periosteal circumference during the postpubertal growth period are impaired to a greater extent in GH-deficient lit/lit mice compared with IGF-I knockout mice. IGF-independent effects of GH [may stimulate] growth"

Genes upregulated by GH at either 6 or 24h that were also upregulated by LSJL:

Genes downregulated by GH:

Longitudinal bone growth in vitro: effects of insulin-like growth factor I and growth hormone.

"Longitudinal growth was studied using an in vitro model system of intact rat long bones. Metatarsal bones from 18- and 19-day-old rat fetuses, entirely (18 days) or mainly (19 days) composed of chondrocytes, showed a steady rate of growth and radiolabelled thymidine incorporation for at least 7 days in serum-free media. Addition of recombinant human insulin-like growth factor-I to the culture media resulted in a direct stimulation of the longitudinal growth. Recombinant human growth hormone was also able to stimulate bone growth, although this was generally accomplished after a time lag of more than 2 days. A monoclonal antibody to IGF-I abolished both the IGF-I and GH-stimulated growth. However, the antibody had no effect on the growth of the bone explants in control, serum-free medium. Unlike the fetal long bones, bones from 2-day-old neonatal rats were arrested in their growth after 1-2 days in vitro. The neonatal bones responded to IGF-I and GH in a similar fashion as the fetal bones. Thus in this study in vitro evidence of a direct effect of GH on long bone growth via stimulating local production of IGF by the growth plate chondrocytes is presented."

Recent updates on recombinant human growth hormone outcomes and adverse events.

"Prader Willi Syndrome is associated with hypogonadism, which does not appear to be affected by treatment with rhGH. For patients with Idiopathic Short Stature, the gain in near adult height with treatment with rhGH appears to be 3-4 cm. Certain patient characteristics may help identify those most likely to have a good response to treatment."

Relationship of the human growth hormone receptor exon 3 genotype with final adult height and bone mineral density.

"two of the most common isoforms of the human GH (hGH) receptor (hGHR), exon 3 full-length (3+) and exon 3 deleted (3-), may have differential effects on the growth response of children receiving hGH therapy, whereas others refute this. However, none of the investigations has explored the relationship between these hGHR isoforms and final adult height (FAH) or measures of bone mineral density (BMD) within a healthy adult population.
The study was designed to correlate the hGHR exon 3 genotype of a cohort of healthy adults with FAH, BMDs [spine (L2-L4) and hip (femoral neck)], and quantitative ultrasound (QUS) of the heel.
Participants were 368 unrelated healthy adult white women, aged 18-35 yr.
We analyzed association of hGHR exon 3 genotypes with FAH, BMD, and QUS. Heights were measured using a stadiometer, BMDs using dual-energy x-ray absorptiometry, and QUS by standard technique. .
The distribution of hGHR genotypes in the 368 samples was 53.3% for 3+/3+, 35.6% for 3+/3-, and 11.1% for 3-/3-. There was no correlation between the hGHR exon 3 genotypes and FAH, BMD, or QUS in this cohort.
The hGHR 3+ and 3- isoforms appear not to have differential effects on two major growth outcomes of hGH action, FAH, and BMD in a population of healthy adult women.

"The lack of exon 3 results in a 22-amino-acid truncation of the extracellular domain, N terminal to the hGH binding domain, and loss of one glycosylation site"

3+/3+ were the tallest, 3+/- were in the middle, and 3-/- were the shortest but the results did not approach significance.  .005m difference between 3+/+ and 3-/-.

Protein markers predict body composition during growth hormone (GH) treatment in short prepubertal children.

"The study population consisted of 128 prepubertal children receiving GH treatment. Thirty-nine were short as a result of GH deficiency and 89 had idiopathic short stature (ISS). Serum protein expression profiles at study start and after one year of GH treatment were analysed"

"Specific protein expression patterns associated with GH response in different body compartments were identified. Among identified proteins different isoforms of nutrition markers such as apolipoproteins (Apo) were recognized; Apo C-I, Apo A-II, serum amyloid A4 (SAA4) and transthyretin (TTR). In addition, unidentified peaks were associated with GH effects on specific body compartments."  HBA was also associated with GH.

"No differences between the ISS and GHD groups were present at any time point."

"Apo C-1 is involved in many biological process, e.g. lipid and cholesterol transport, negative regulation of fatty acid synthesis, lipoprotein lipase activity and positive regulation of cholesterol esterification"

"Apolipoprotein A-II and SAA 4 belongs to the HDL (high density lipoprotein) fraction and serve as transport molecules of cholesterol from peripheral adipose tissue towards the liver for degradation and re-utilization."

"the ratio of LDL to HDL-cholesterol decreased over the two treatment years only in the GHD group and remained unchanged in the ISS group"

"Dimeric Apo A-II affects HDL metabolism and phosphorylation sites which are present in the extracellular fluid"

Endocrine Control of Growth.

"Growth can be divided into four phases: (1) fetal, where the predominant endocrine factors controlling growth are insulin and the insulin-like growth factors. (2) Infancy, where growth is mainly dependent upon nutrition. (3) Childhood, where the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis and thyroid hormone are most important. (4) Puberty, where along with the GH-IGF-I axis the activation of the hypothalamo-pituitary-gonadal axis to generate sex steroid secretion becomes vital to the completion of growth. GH is released from the pituitary in a pulsatile fashion under the control of GHRH, Ghrelin, and somatostatin and, via a complex signal transduction cascade, initiates the release of IGF-I within many tissues but predominantly the liver and at the growth plate. IGF-I acts in an autocrine and paracrine manner via the IGF-I receptor to stimulate cell proliferation and longitudinal growth. Activation of the pituitary-gonadal axis during puberty occurs via a complex interaction of factors including kisspeptin, leptin, gonadotrophin releasing hormone, and tachykinin ultimately leading to augmentation of GH secretion, the pubertal growth spurt, and fusion of the growth plates. Many other hormones can affect the GH-IGF-I system or directly affect cell proliferation at the growth plate including thyroid hormone, vitamin D, and corticosteroids. "

There is a lot of useful information in this study so if possible you should get your hands on it.

"IGF-I and IGF-II levels correlate to size at birth"

"Androgens appear to have a direct effect on the growth plate with administration of dihydrotestosterone stimulating longitudinal growth without any effect upon the GH-IGF-I axis. In addition local injection of testosterone increases unilateral rat tibial growth plate width"

"While GHRH stimulates membrane depolarization (leading to hormone secretion) by opening sodium channels, activation of somatostatin receptors leads to opening of potassium channels and membrane hyperpolarization"

"Binding of GH to the GHR leads to activation of protein kinase C (PKC) via phospholipase C. Activated PKC stimulates lipogenesis, c-fos expression and increases intracellular calcium levels by activating type 1 calcium channels. The mechanism of activation of phospholipase C is unknown but is independent of Jak2."

"Deletion of Igf2r leads to an increase in size to 130% of wild type. It therefore appears that in mouse the IGF-IIR has a role in negatively regulating the availability of IGF-II. "

"Short stature occurs in non-vitamin D deficiency forms of rickets such as hypophosphatemic rickets and a mineral rich diet can normalize the growth plates of vitamin D receptor ablated mice  suggesting that the growth plate effects are mediated by impaired mineralization rather than a direct effect on the growth plate itself." 

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