Recombinant human growth hormone (r-hGH) is used for the treatment of growth hormone deficiency. It has been widely used by children and adolescents with GHD and recently, there has been an increased use of r-hGH in adults for antiaging purposes. Using r-hGH for cosmetic purposes is a controversial topic in the scientific world.
What is r-hGH and what is it used for?
r-hGH is recombinant human GH synthesized in the mammalian or E.coli cell cultures. IT is used for the treatment of isolated GHD, Turner syndrome, chronic renal failure, Prader-Willi syndrome, Noonan syndrome, SHOX deficiency, intrauterine growth retardation, and small for gestational age (SGA) babies, and idiopathic short stature.
Prior to r-hGH development, HGH was extracted from cadaver brains. However, in 1985, this cadaver-derived GH was removed from the market due to cases of Creutzfeldt-Jakob Disease. Prions stay in the brain tissue postmortem and are transferred from cadaver brains to healthy individuals. This lead to widespread controversy and cadaver derived GH was removed permanently. In 1985, Genetech Labs released the biosynthetic form of growth hormone and it is still being used today.
r-hGH has been controversial since its initial release. It may be better than using cadaver-derived GH but it has been postulated that r-hGH can cause cancer. This theory arises from the relation of GH and IGF1, and r-hGH leading to exposure of body tissues to both these hormones. For GH to work efficiently on cells and cause growth, it needs the effects of IGF-1. IGF1 has strong antiapoptotic and mitogenic effects which can lead to cancer formation. This is an alarming effect of GH and many studies have been performed to study this further and find conclusive evidence of causal relation between r-hGH use and cancer development
What is GH and what are its functions?
GH, or somatotropin, is synthesized and released from the anterior pituitary gland in a pulsatile manner. Its release is stimulated by Growth Hormone Releasing Hormone (GHRH), ghrelin, sex hormones like testosterone and estrogen, insulin, glucagon, and deep sleep. Its release is inhibited by somatostatin, concentrations of GH and IGF-1 in the serum, hyperglycemia, and glucocorticoids.
GH has an anabolic effect on the cells and tissues of the body. Apart from helping increase height in childhood, it also helps maintain homeostasis, build muscle mass, synthesize proteins, and promote fat breakdown.
GH is an important hormone for the growth of the human body, and if deficient in childhood, it can cause short stature and delayed sexual maturity. In adults, GH deficiency can result in increase osteoclast function and consequent weak, porous bones, prone to pathological fractures. However, GHD is quite rare in adults and more common in children. It is treated with r-hGH, which is a biosynthetic form of GH.
What is GH/IGF1 axis?
GH is the main regulator of IGF-1 production, and IGF-1, in turn, contributes to the inhibition of GH release through a negative feedback loop. GH performs its function through IGF-1 and since both of these hormones are associated with increased growth, the relation of these hormones with cancer development seems highly likely. Even more so since IGF has been associated with the growth of cancer cells and all human cancer cells express IGF receptors.
Can r-hGH treatment lead to cancer development in the future?
Multiple studies have been conducted to study the causal relationship between r-hGH use and cancer development. The first of which was the National Cooperative Growth published in 1985, stating that r-hGH use is not related to leukemia like it was suggested.
In 2002, another study was performed, this time trying to find the connection between colorectal cancer and r-hGH use. They studied 1848 individuals who were treated for GHD using r-hGH. The results of this study proved there to be a connection between r-hGH use and CRC, however, the number of people who developed cancer was very low. The results for this long-term study led to more in-depth studies being performed to find conclusive answers.
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In 2012, two independent, long-term studies were conducted, one in France and the other in Europe, namely Sweden, Belgium, and the Netherlands. Both these studies were published in the same journal and they reported opposite results. Namely, these studies were European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) and France Safety and Appropriateness of GH treatments in Europe (France SAGhE) Cohort Studies. Both studies focused on individuals who were treated with r-hGH as children for either isolated GHD, isolated short stature, and short stature associated with SGA. The French team studied the effects of r-hGH in about 6500 subjects. They showed increased mortality related to bone cancer, as a result of r-hGH use. The European team studied 2500 subjects with the same criteria and found zero deaths from cancer in their subjects.
However, the French team did note that cancer development and cancer-related deaths occurred in the group of subjects who received the highest dosage of r-hGH.
After the studies were published from France, and all three EU countries; Netherlands, Belgium, and Sweden, more questions arose rather than answered. SAGhE then conducted another study with 24, 232 subjects from 8 different European countries. This study represents the largest and the longest cohort study of GH-treated patients and their follow-up. However, they divided their subjects into three groups; ) low risk: isolated growth failure, including IGHD, ISS, and SGA; (2) high risk: cancer, including patients with the previous history of cancer; (3) intermediate-risk: nonisolated growth failure and non-cancer patients, including all the other patients such as multiple pituitary deficiencies, Turner syndrome, Noonan syndrome and bone dysplasias.
The results of this study showed that there was no increased incidence of cancer in low-risk children. But the French cohort study showed an increase in incidence even in low-risk children.
All these studies came to the same conclusion that r-hGH treatment cannot lead to de novo cancer production. Furthermore, even though GH and IGF1 are related to increased cellular growth of cancers, they do not play a role in the induction of cancer. However, given the antiapoptotic effect of IGF1, long-term surveillance can be really helpful.
Biases and Limitations of SAGhE studies
AGhE EU does not mention the IGF-1 levels, neither did the French researchers consider it in the cases of cancer development they reported. Furthermore, the exact treatment duration for the subjects was not known. Researchers didn’t consider that some subjects may have continued r-hGH treatment after pediatric periods. Hence, there is a possibility that they seriously underestimated the dosage and exposure of the subjects to r-hGH.
Also, obtaining data from 8 countries and approximately 24,000 subjects comes with difficulties of its own. They cannot guarantee they were given all the correct information. On top of that, key information for all the subjects, like family history, genetic predisposition to certain conditions, environmental exposure to toxins, and such, was never obtained from the subjects. All of these are key points that can explain the development of cancer, making lack of these a limitation of the SAGhE cohort.
Should r-hGH use be banned?
Since low-risk children (those with isolated GHD, ISS, and SSD) show no increased risk for cancer development, banning of r-hGH or discontinuing its use goes against the scientific evidence present. Furthermore, as far as r-hGH is being used for the treatment of low-risk children, as in isolated cases, where all other forms of therapy do not show results, rhGH benefits outweigh any risk it may pose. No scientific study has yet shown with concrete evidence that r-hGH is potentially damaging to these children. The same applies to adults with GHD where no other means of treatment have worked. Such adults may be treated with r-hGH.
Further studies need to be conducted, without the biases of SAGhE cohort studies. More information needs to be provided for discontinuation of r-hGH as the benefits of it right now outweigh the risks that we have found.
Cianfarani, Stefano. “Risk of cancer in patients treated with recombinant human growth hormone in childhood.” Annals of pediatric endocrinology & metabolism vol. 24,2 (2019): 92-98. doi:10.6065/apem.2019.24.2.92
Swerdlow, Anthony J et al. “Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study.” The Journal of clinical endocrinology and metabolism vol. 102,5 (2017): 1661-1672. doi:10.1210/jc.2016-2046