This is not the case in cirrhotic patients where GH levels in serum were reported to be elevated as the GH secretion rate was found to be increased This fact supported related studies that led to the belief that recombinant human GH was a potent antiaging agent. However, it was later found that while the effects on body composition from rhGH treatment were minor, adverse effects were significant and include the development of diabetes mellitus In a study of people with GHR deficiency, individuals showed IGF-1 deficiency and appeared to be protected against age-related diseases In contrast to the animal models of the absence of GHR signaling, humans with GHR deficiency do not live longer; however, the interpretation of this is complicated by a high rate of deaths caused by alcohol toxicity, liver cirrhosis, convulsive disorders, and other non-age-related deaths such as accidents A recent study investigating a common polymorphism resulting in exon 3-deleted GHR and resulting in increased GH sensitivity found that this polymorphism also correlated with a striking increase in life span in males of around 10 years Moreover, being the process of aging characterized by a low-grade inflammation that is linked to several age-related diseases , the inhibition of the mechanisms that lead to it may consequently affect the development of these pathologies.
According to these data, using GH antagonists or somatostatin analogs should slow aging Currently, these drugs are being used for the treatment of acromegaly. Moreover, they have shown to produce other major adverse effects on the gastrointestinal tract Therefore, it becomes necessary to understand the process of aging as a whole to detect the best target for treating age-related diseases.
GH and its specific receptor, GHR, are involved in multiple biological and physiological actions contributing to cell proliferation and differentiation.
Dysregulation of GH—IGF-1 axis can amplify the synergistic effect of GH and IGF-1 to promote uncontrolled cell proliferation, cell movement, angiogenesis, and suppress apoptosis to increase risk of neoplasia The excessive production of GH and associated complications has been studied long before its broader role in human health was discovered.
Acromegaly is an endocrine condition, which is manifested with excess secretion of pituitary GH accompanied by an elevated level of circulatory IGF-1 Also, another study of year-old females found that girls in the top fifth of height have an adjusted relative risk of over 1.
In addition, meta-analysis of published research investigating the association of IGF-1—IGF-2 and their binding proteins IGFBP-1—6 with prostate cancer confirmed that elevated circulating level of IGF-1 positively correlates with higher prostate cancer risk In stark contrast, GHR-deficient individuals show a lack of deaths from cancer A recent meta-analysis showed that increased height associated with an increased risk of lung cancer The link between GHR signaling and lung cancer has been shown in two independent genetic studies that identified an SNP in GHR that correlated with an increased risk of lung cancer , The link between acromegaly and increased risk of certain diseases especially colorectal cancers is well established, and there is a consensus on this issue even though there are some studies reporting contradictory results However, the extent of this association is unclear since some studies have reported a 7.
GH has been prescribed for children with GH deficiency since late s using hormone extracted from the pituitary gland , and it was successfully produced in using recombinant DNA technology and approved to be administered for treatment of various disorders However, in the past couple of decades, there has been a growing debate on GH treatment and its diabetogenic effects, impaired skeletal growth, and increased risk of de novo or recurrent cancers Long-term survival of childhood cancer patients who have gone under total body or cranial irradiation in preparation for bone marrow transplantation or as a part of treatment for brain tumors or acute lymphoblastic leukemia are at higher risk of developing GH deficiency , Although some initial studies reported recurrent brain tumors as a frequent cause of death in children treated with GH , a study that followed children treated with GH who had brain tumors concluded that there was not a substantial trend in relative risk of recurrence with cumulative time for which GH treatment had been administrated and GH does not result in elevated risk of recurrent brain tumors However, the study also suggested continued surveillance based on the rising trend in mortality relative risks with longer follow-ups.
Initial studies had reported leukemia incidences in children treated with GH replacement in Japan , ; however, later follow-up studies were unsuccessful in establishing a link between GH therapy and leukemia when patients with existing risk factors were excluded Growth hormone receptor has in some settings been observed to have a high degree of localization to the nucleus , and this nuclear localization has been shown to be induced by GH , This nuclear localization has particularly been observed in proliferating cells including a range of different cancers such as colorectal carcinoma, melanoma, uterine cervical neoplasms, breast cancer, and hepatocellular carcinoma.
Nuclear localized GHR has been observed in a number of species such as pig , rat , and fish By targeting the GHR to the nucleus by fusing a nuclear localization signal to the receptor, it was found in the absence of GH that several genes known to be involved in oncogenesis were upregulated, and further studies provided evidence that the GHR can bind to a transcriptional regulator , Studies also suggest that autocrine GH production may play an important role in cancer Hepatocytes generate the majority of circulating IGF-1 that is found in the blood.
The Somatomedin hypothesis states that postnatal growth that is induced by GH is mediated by hepatic IGF-1 previously known as Somatomedin C or sulfation factor in an endocrine manner To elucidate this, mice that were deficient of hepatic igf1 using the Cre—loxP system were generated By contrast, igf1 KO in the whole mouse led to mice with dramatically reduced body mass and length — However, several organs were relatively larger, e.
The increase in liver size liver:body weight ratio could be explained by the increase in circulating GH as a result of the lack of the IGFmediated negative feedback mechanism, where circulating IGF-1 produced by the liver can regulate secretion of GH and consequently the size of the liver , — In summary, this study showed that although most circulating IGF-1 is derived from hepatocytes, it is not the main IGF-1 that is required for postnatal growth and development GH deficiency leads to reduced bone mineral density, but administration of GH is able to subvert this effect , Complete igf1 KO mice also demonstrated a similar phenotype — However, this resulted in perinatal lethality of most mice whereas those that survived were only approximately half the size of the control mice Consistent with this observation, patients with IGF1 gene deficiency are growth retarded In mice that have combined KO of ghr and igf1 , the growth deficiency is significantly more severe than in each individual KO , indicating that GH has growth mediating effects that are independent of IGF Studies have shown that GH is capable to directly induce growth.
When GH is infused locally into one leg of a hypophysectomized GH-deficient rat, that leg grows significantly longer than the other However, they also show that GH-mediated SFK signaling does not play a significant role in regulating growth. Nevertheless, it is possible that the relative levels of JAK2 or SFKs in certain cell types may be a determinant as to which kinase would be dominant for signaling Although we have learnt a vast amount on the molecular mechanism of GHR activation, signaling, physiological aspects, and roles of GH signaling in disease states, there is still much to learn.
In particular, this is due to the wide range of physiological roles that GH has, making it an important player in many biological conditions and diseases. At the molecular and cellular level, the activation and role of SFK signaling is still currently not well understood.
As our knowledge of the molecular signaling nature of GHR increases, our ability to specifically target the receptor and its signaling pathways for a diverse range of therapeutic purposes should also increase. All the authors contributed equally. All the authors contributed to drafting and editing the manuscript. All the authors contributed to figures and tables. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors would like to acknowledge the support from The University of Queensland Diamantina Institute. JAK2 activation by growth hormone and other cytokines. Biochem J 1 :1— Cytokine receptors.
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Production of growth hormone is modulated by many factors, including stress, exercise, nutrition, sleep and growth hormone itself. However, its primary controllers are two hypothalamic hormones and one hormone from the stomach:. Growth hormone secretion is also part of a negative feedback loop involving IGF-I. High blood levels of IGF-I lead to decreased secretion of growth hormone not only by directly suppressing the somatotroph, but by stimulating release of somatostatin from the hypothalamus.
Growth hormone also feeds back to inhibit GHRH secretion and probably has a direct autocrine inhibitory effect on secretion from the somatotroph. Integration of all the factors that affect growth hormone synthesis and secretion lead to a pulsatile pattern of release.
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Syed, R. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature , — In adults, excessive growth hormone for a long period of time produces a condition known as acromegaly , in which patients have swelling of the hands and feet and altered facial features. These patients also have organ enlargement and serious functional disorders such as high blood pressure, diabetes and heart disease.
This condition is more common after middle-age when growth is complete so affected individuals do not get any taller. Very rarely, increased growth hormone levels can occur in children before they reach their final height, which can lead to excessive growth of long bones, resulting in the child being abnormally tall. This is commonly known as gigantism a very large increase in height. Overproduction of growth hormone is diagnosed by giving a sugary drink and measuring the growth hormone level over the next few hours.
The sugar should cause growth hormone production to reduce. However, this does not happen in acromegaly. Too little growth hormone deficiency results in poor growth in children. In adults, it causes a reduced sense of wellbeing, increased fat , increased risk of heart disease and weak heart, muscles and bones. The condition may be present from birth where the cause can be unknown, genetic or due to injury to the pituitary gland during development or at birth.
Growth hormone deficiency may also develop in adults due to brain injury, a pituitary tumour or damage to the pituitary gland for example, after brain surgery or radiotherapy for cancer treatment.
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