Review of the Synthetic Human Growth Hormone Drug Somatropin

Somatropin (GENOTROPIN, HUMATROPE, NORDITROPIN, NUTROPIN, OMNITROPE, SAIZEN, SEROSTIM, ZOMACTON, ZORBTIVE) was first approved in 1987 by the Food and Drug Administration (FDA) for the treatment of short stature in children with growth hormone (GH) deficiency, which is a rare condition.[1],[2]

Somatropin is injected under the skin and is the only synthetic form of naturally occurring human GH currently marketed in the U.S.[3] Natural GH is secreted by the pituitary gland and acts on many tissues throughout the body to promote growth and metabolism. GH secretion begins early in fetal life and continues throughout childhood, with a peak during adolescence, and then declines with age.[4]

Children with GH deficiency secrete low levels of natural GH and typically present with short stature. When these children are treated with somatropin, the vast majority attain a final adult height that is within the lower end of the range expected based on the heights of their parents.[5],[6],[7] In children with GH deficiency, somatropin works by stimulating cartilage growth, particularly in the growth plates, which are the areas of bone growth near the ends of long bones that permanently close during adolescence and are replaced by solid bone. Somatropin should not be initiated in children who already have closed growth plates.[8]

Since 1987, the FDA has approved somatropin for the treatment of several other disorders, including short stature or growth failure in children due to certain genetic diseases or chronic kidney disease; short stature in children who have normal GH levels and no other disease or condition linked to growth failure, a condition known as idiopathic short stature; and GH deficiency in adults that began in childhood or adulthood.[9]

We recommend against using somatropin for some of these conditions because the risk of serious harm outweighs any benefits. We therefore have designated the drug as Limited Use.

Idiopathic Short Stature: Do Not Use

Idiopathic short stature accounts for more than 80 percent of cases of short stature in children and, unlike GH deficiency, is not a rare condition.[10] These children by definition are healthy.

Public Citizen has designated somatropin as Do Not Use for idiopathic short stature in children because the drug results in only modest increases in final adult height (on average, two to three inches following four to seven years of GH use);[11],[12],[13],[14] has not been proven to offer any health benefits, such as improvement in psychological wellbeing;[15],[16],[17] and can cause serious adverse effects.

Because children with idiopathic short stature already have normal levels of natural GH, treatment with somatropin can lead to adverse effects associated with abnormally high GH levels. For example, during a clinical trial that tested Humatrope, one brand-name version of somatropin, children with idiopathic short stature who received Humatrope had higher rates of numerous adverse events than those who received a placebo, including scoliosis (abnormal curvature of the spine), joint and muscle pain, ear infections and cardiovascular disorders.

Although there is limited information on somatropins long-term safety in children with idiopathic short stature,[20] preliminary findings from an ongoing long-term observational study conducted in France showed that adults who had been treated with somatropin during childhood for idiopathic short stature had a 30-percent increased risk of death compared with the general population.[21] This increased mortality appeared to be primarily due to hemorrhagic stroke (stroke associated with bleeding in the brain) and bone cancer. These findings prompted the FDA in 2010 to issue a safety communication for somatropin warning about the increased risk of death.[22] In a 2011 updated safety announcement, the FDA concluded that the evidence for this increased risk of death was "inconclusive" given the limitations in the design of the French study.[23]

Updated findings from the French study published in 2014 and 2018 indicated that somatropin treatment in children with idiopathic short stature was associated with a five-to-sevenfold greater incidence of hemorrhagic stroke and a more than threefold greater incidence of bone tumors — many of them fatal — during adulthood.[24],[25]

Notably, the European Medicines Agency, an agency similar to the FDA, did not approve somatropin for idiopathic short stature primarily because they were concerned that “an increasing number of short but otherwise healthy children” would be treated with somatropin and its very limited benefits are "insufficient to outweigh the potential long-term risks such as tumor promotion and diabetes risk."[26]

Adult-onset GH deficiency: Do Not Use

In children with GH deficiency due to an illness or disorder (for example, a pituitary tumor), GH deficiency typically is permanent and persists into adulthood, which is called childhood-onset GH deficiency in adults. GH deficiency that first develops in adulthood is called adult-onset GH deficiency. Public Citizen has designated somatropin as Do Not Use for adult-onset GH deficiency because it offers limited benefits and can cause numerous serious adverse effects. In addition, information on its long-term effectiveness and safety in adults for this use is limited.

During clinical trials, somatropin was associated with improvements in body composition, specifically increased lean body mass and reduced total body fat in patients with either childhood-onset or adult-onset GH deficiency.[27] Reductions in total body fat, however, were not sustained over time in patients with adult-onset GH deficiency. Importantly, clinical signs of GH deficiency were more pronounced (for example, lower lean body mass, muscle strength and bone mineral density) prior to somatropin treatment, and the response to somatropin treatment was much greater (for example, greater increases in lean body mass, muscle strength and bone mineral density) in patients with childhood-onset GH deficiency than in those with adult-onset GH deficiency.[28]

Alongside its minimal benefits in patients with adult-onset GH deficiency, somatropin can cause potentially serious adverse effects. For example, during a clinical trial that tested Norditropin, another brand-name version of somatropin, patients with adult-onset GH deficiency who received Norditropin, compared with those who received a placebo, had higher rates of swelling in the arms and legs, hypertension, type 2 diabetes, infections, muscle pains, numbness and tingling, and headaches.[29]

The majority of these adverse effects are identical to the signs and symptoms observed in patients with acromegaly, a rare pituitary disorder caused by excess production of natural GH that, if left untreated, leads to premature or early death.[30] Excess GH also raises levels of insulin-like growth factor-1, which is known to increase the risk of diabetes and cancer. In fact, the FDA was concerned about these serious risks in somatropin-treated adults with adult-onset GH deficiency due to significant increases in insulin-like growth factor-1 levels observed during clinical testing.[31]

Other adverse effects and warnings

Controlled clinical trials testing somatropin in adult patients without GH deficiency who have critical illness due to complications from open heart surgery, abdominal surgery or severe trauma or who have acute respiratory failure revealed a significantly higher death rate in somatropin-treated subjects than in those who received a placebo (42 percent versus 19 percent, respectively).[32] Therefore, somatropin should never be used in such patients.

Due to an increased risk of malignancy progression, somatropin also should be avoided in patients who have cancer or other tumors. It also should not be used in patients with active or severe diabetic eye disease involving the retina.

Other serious adverse effects reported in patients taking somatropin include the following:

• Pancreatitis, which can cause severe abdominal pain, nausea and vomiting
• Hypothyroidism (low thyroid hormone levels)
• Intracranial hypertension (increased pressure in the skull) and papilledema (swelling of the optic nerve); symptoms may include vision problems, headache, nausea and vomiting.

Unapproved and illicit uses

Although somatropin is only approved by the FDA for specific indications in the U.S., it is often used illicitly in healthy individuals as an anti-aging agent, to improve athletic performance and for body-building.[33] There is no evidence that somatropin prolongs life in aging adults or improves athletic performance in healthy individuals, and such use has been linked with numerous adverse effects.[34],[35] Somatropin should never be used for any of these unapproved uses.

References

[1] Ayyar VS. History of growth hormone therapy. Indian J Endocrinol Metab. 2011;15(Suppl 3):S162-S165.

[2] Eli Lilly and Company. Label: somatropin (HUMATROPE). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019640s104lbl.pdf. Accessed December 12, 2018.

[3] Growth hormone for normal short children. Med Lett Drugs Ther. 2003;45(1169):89-90. Erratum in: Med Lett Drugs Ther. 2004;46(1184):48.

[4] Melmed S. Physiology of growth hormone. UpToDate. November 2018.

[5] Rogol AD, Richmond EJ. Treatment of growth hormone deficiency in children. UpToDate. November 2018.

[6] Darendeliler F, Lindberg A, Wilton P. Response to growth hormone treatment in isolated growth hormone deficiency versus multiple pituitary hormone deficiency. Horm Res Paediatr. 2011;76(Suppl 1):42-46.

[7] Grimberg A, DiVall SA, Polychronakos C, et al. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: Growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr. 2016;86(6):361-397.

[8] Eli Lilly and Company. Label: somatropin (HUMATROPE). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019640s104lbl.pdf. Accessed December 12, 2018.

[9] Eli Lilly and Company. Label: somatropin (HUMATROPE). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019640s104lbl.pdf. Accessed December 12, 2018.

[10] Pedicelli S, Peschiaroli E, Violi E, Cianfarani S. Controversies in the definition and treatment of idiopathic short stature (ISS). J Clin Res Pediatr Endocrinol. 2009;1(3):105-15.

[11] Allen DB, Cutler L. Clinical practice. Short stature in childhood—challenges and choices. N Engl J Med. 2013;368(13):1220-1228.

[12] Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. 2008;93(11):4210-7.

[13] Eli Lilly and Company. Label: somatropin (HUMATROPE). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019640s104lbl.pdf. Accessed December 12, 2018.

[14] Albertsson-Wikland K, Aronson AS, Gustafsson J, et al. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. J Clin Endocrinol Metab. 2008;93(11):4342-4350.

[15] Ibid.

[16] Downie AB, Mulligan J, McCaughey ES, et al. Psychological response to growth hormone treatment in short normal children. Arch Dis Child. 1996;75(1):32-35.

[17] Visser-van Balen H, Geenen R, Kamp GA, et al. Long-term psychosocial consequences of hormone treatment for short stature. Acta Paediatr. 2007;96(5):715-719.

[18] Eli Lilly and Company. Label: somatropin (HUMATROPE). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019640s104lbl.pdf. Accessed December 12, 2018

[19] Food and Drug Administration. Medical Review for sNDA#19640 for somatropin (HUMATROPE]. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/019640_S033_HUMATROPE_AP.pdf. Accessed December 14, 2018. PDF pages 98-99

[20] Grimberg A, Allen DB. Growth hormone treatment for growth hormone deficiency and idiopathic short stature: new guidelines shaped by the presence and absence of evidence. Curr Opin Pediatr. 2017;29(4):466-471.

[21] Food and Drug Administration. FDA drug safety communication: Ongoing safety review of Recombinant Human Growth Hormone (somatropin) and possible increased risk of death. December 22, 2010. https://wayback.archive-it.org/7993/20170406044147/https://www.fda.gov/Drugs/DrugSafety/ucm237773.htm. Accessed December 14, 2018.

[22] Ibid.

[23] Food and Drug Administration. FDA drug safety communication: Safety review update of Recombinant Human Growth Hormone (somatropin) and possible increased risk of death. August 4, 2011. https://www.fda.gov/Drugs/DrugSafety/ucm265865.htm. Accessed December 14, 2018.

[24] Poidvin A, Touzé E, Ecosse E, et al. Growth hormone treatment for childhood short stature and risk of stroke in early adulthood. Neurology. 2014;83(9):780-786.

[25] Poidvin A, Carel JC, Ecosse E, et al. Increased risk of bone tumors after growth hormone treatment in childhood: A population-base cohort study in France. Cancer Med. 2018;7(7):3465-3473.

[26] European Medicines Agency. Withdrawal Assessment Report for Nutropin AQ. January 28, 2008. https://www.ema.europa.eu/documents/withdrawal-report/withdrawal-assessment-report-nutropinaq_en.pdf. Accessed December 14, 2018.

[27] Eli Lilly and Company. Label: somatropin (HUMATROPE). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019640s104lbl.pdf. Accessed December 12, 2018.

[28] Koranyi J, Svensson J, Götherström G, et al. Baseline characteristics and the effects of five years of GH replacement therapy in adults with GH deficiency of childhood or adulthood onset: a comparative, prospective study. J Clin Endocrinol Metab. 2001;86(10):4693-4699.

[29] Novo Nordisk. Label: somatropin (NORDITROPIN). February 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021148s037s038lbl.pdf. Accessed December 14, 2018.

[30] Vilar L, Vilar CF, Lyra R, et al. Acromegaly: clinical features at diagnosis. Pituitary. 2017;20(1):22-32.

[31] Food and Drug Administration. Medical Review. Nutropin (somatropin), supplemental NDA#19676-s13. https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/19676S13_nutropin_medr.pdf Accessed December 14, 2018.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019640s104lbl.pdf. Accessed December 12, 2018.

[33] Drug Enforcement Agency. Human growth hormone. October 2018. https://www.deadiversion.usdoj.gov/drug_chem_info/hgh.pdf. Accessed December 14, 2018.

[34] Liu H, Bravata DM, Olkin I, et al. Systematic review: The effects of growth hormone on athletic performance. Ann Intern Med. 2008;148(10):747-758.

[35] Liu H, Bravata DM, Olkin I, et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med. 2007 Jan 16;146(2):104-115.