On June 27, 2024, The Lancet published an article titled "Childhood growth hormone treatment: challenges, opportunities, and considerations." The article highlights that while significant growth hormone deficiencies have notable physiological impacts and replacement therapies are valuable, only a few individuals are considered to have a clear deficiency. For those without such deficiencies, growth hormone can increase height, necessitating the monitoring of potential side effects as the therapy extends beyond strict replacement to broader height enhancement.

The Evolution of Growth Hormone Therapy

Growth hormone (GH) is a crucial biochemical signal molecule that activates intracellular signaling pathways, coordinating the metabolic processes of various cell types and regulating the physiological functions of multiple tissues. Introduced into clinical practice in the late 1950s, its initial use was limited. Advances in biotechnology over the following 30 years led to the development of recombinant human growth hormone (rhGH), meeting higher demand and expanding indications.

In 1985, rhGH was first approved to treat childhood growth hormone deficiency. Since then, it has been approved for other pediatric conditions associated with short stature, including chronic kidney disease, Turner syndrome, Prader-Willi syndrome, being small for gestational age, short stature homeobox-containing gene (SHOX) deficiency, and Noonan syndrome. In some countries, it is also approved for idiopathic short stature.

Safety Concerns with Growth Hormone Therapy

In recent years, rhGH has attracted much attention from parents due to its height-increasing effects. The Lancet article emphasizes the importance of ongoing monitoring for safety concerns. It mentions potential risks such as increased cancer, cardiovascular disease, and mortality.

Cancer Risk:The article notes that animal studies and data from specific human conditions with excess GH or impaired GH signaling suggest that increased signaling pathway activity is linked to tumor development. Large-scale population studies have shown that abnormal insulin-like growth factor 1 (IGF-1) expression is associated with higher risks of certain cancers. However, pharmaceutical company databases indicate no increased tumor risk in patients without underlying cancer risk factors.

SAGhE Project:In 2009, eight European countries collaborated to create the Safety and Appropriateness of Growth Hormone treatments in Europe (SAGhE) project, a large meta-analysis cohort involving about 24,000 patients who received childhood GH treatment. The study found no overall increase in cancer incidence or mortality, though specific risks for skeletal and bladder cancers were noted. However, due to limited case numbers and methodological constraints, definitive conclusions could not be drawn.

In 2022, the European Society of Endocrinology (ESE) reviewed the safety of GH replacement in cancer survivors, publishing a consensus statement. It found no increased risk of cancer recurrence in GH-deficient patients treated in childhood, with only a slight increase in secondary tumors. However, the statement does not recommend GH therapy for patients with genetic cancer predispositions.

Swedish Nationwide Study: A recent nationwide study in Sweden covered over 3,400 patients with GH deficiency, idiopathic short stature, or small for gestational age, with follow-up extending 35 years. Compared to controls, the overall tumor risk was slightly higher, but there was no increased risk of malignant tumors following childhood GH treatment. The study noted that patients with longer treatment durations had marginally higher risks, though no significant dose-related trends were observed, challenging the causal link between rhGH treatment and cancer.

Conclusion:Despite being the longest follow-up study of childhood GH treatment patients, the cohort remains relatively young, necessitating further follow-up to assess late adulthood risks. The Lancet article concludes, "Even for approved indications, growth hormone therapy presents many clinical challenges. Physicians must carefully weigh known and unknown risks and benefits for each patient, conducting individualized assessments. Open communication with patients and families is essential, with clear treatment goals and a readiness to reassess diagnoses and treatment plans as needed."

This underscores the importance of vigilance in monitoring and evaluating the long-term safety of growth hormone treatments in children.



2.Boguszewski MCS, Boguszewski CL, Chemaitilly W, et al. Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement. Eur J Endocrinol 2022; 186: 35–P52.