About Paediatric Human Growth Hormone Therapy

Human growth hormone (HGH) has been used therapeutically to promote growth in children for over 60 years. Pituitary-extracted HGH has demonstrated positive growth promotion since the early 1960s. In 1985, prion-induced contamination of HGH triggered a global epidemic of Creutzfeldt–Jakob disease that was responsible for its discontinuation.

Recombinant HGH immediately replaced pituitary HGH and, being available in large amounts, was used and licenced for therapy in GH-deficient children, followed by approval for non-GH deficient disorders such as Turner syndrome, short stature related to a birth size small for gestational age, idiopathic short stature, SHOX deficiency, Prader–Willi syndrome and Noonan syndrome. RH therapy was refined by the use of growth prediction models; however, unmet needs, such as the variability in response and non-adherence resulted in the development of long-acting RhGH (LArhGH) molecules, which are currently in clinical trials and have shown non-inferiority in comparison with daily RH. It is likely that LArhGH will enter clinical practice in 2022 and 2023 and will need to demonstrate safety in terms of immunogenicity, IGF-1 generation, metabolic status and tolerability of potential injection pain and local reactions.

Human growth hormone (GH) is now a recognized therapy for children with GH deficiency and is approved for treating many non-GH-deficient disorders. After more than 60 years of HGH therapy, it is appropriate to appraise its progress, which has advanced over the years and is still evolving with several new developments to make an impact on clinical care. Abnormalities in the physical height of children were first linked to disturbances of GH secretion in the early 20th century.

Harvey Cushing was one of the first physicians to link linear growth to the function of the pituitary gland and the concept of treating impaired growth was advanced by the studies of Herbert Evans at the University of California, San Francisco, who demonstrated a growth-promoting effect of pituitary extracts administered to rats with hypopituitarism.

This knowledge was important in the process of recovering human cadaver pituitary glands for the extraction of pituitary HGH, which in the USA was organised by the National Pituitary Agency. HGH was thus extracted and purified for the treatment of paediatric GH deficiency.

The next key step in clinical practice was the development of a radioimmunoassay (RIA) for the measurement of GH in human subjects with impaired growth. The first RIA was reported by Yalow and Berson in 1963, together with the description of insulin-induced hypoglycaemia tests as the optimal technique for assessing GH secretion.

Due to the collection of extensive data on the RhGH post-marketing databases, RhGH therapy has been demonstrated to be safe. Abnormalities reported during therapy tend to reflect the nature of the primary disorder being treated. For example, benign intracranial hypertension and slipped femoral epiphyses are most likely to occur in children with severe forms of GH deficiency.

There are no data which demonstrate that a higher risk of cancer exists in children without inherent risk. By recording adverse drug reactions, post-surveillance registries have contributed significantly to the overall positive reputation of RhGH regarding safety. Adverse events are lowest in patients with idiopathic GH deficiency or ISS.

EMA recommendations regarding the dose of RhGH for each indication need to be adhered to, and when prescribed according to these recommendations, the evidence suggests that RhGH therapy is very safe. A comprehensive review of GH therapy in childhood and adult cancer survivors demonstrated that there is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors.

These abnormalities present clinically with short stature and the clinician needs to address the challenge of growth promotion with a therapy that is safe and has demonstrated efficacy. The two poles of the continuum namely GH deficiency and GH resistance can be treated with licensed HGH and rhIGF-1, respectively.

Intermediate defects, where the degree of short stature is less severe, are more challenging. As will be discussed below in the context of growth prediction models, the more severe the GH deficiency is based on the peak GH concentration in the diagnostic GH provocation test the more responsive the patient is to HGH. A patient with severe GH deficiency will usually respond to a small dose of 20 µg/kg/day, whereas in patients with mild GH deficiency, a higher HGH dose of 35 μg/kg/day would be more likely to induce an expected growth response.

A patient with isolated short stature without GH deficiency requires an even higher HGH dose, (e.g., 50 μg/kg/day). When patients with GH resistance also known as primary IGF-1 deficiency—are encountered, they will be unresponsive to HGH, and the best option for their management is replacement with rhIGF-1—which is the logical approach, as their primary defect is by causing a deficiency in IGF-1 that is not responsive to HGH.

Major progress in the use of RGH has been made since 1985 however, several unmet clinical needs remain. One of these relates to the variability in growth response, with many patients not achieving optimal catch-up growth or adult height gain.

An increase in height velocity of 2 cm/year in a child with GH deficiency is predicted using a standard dose of RhGH 0.3 mg/kg/week, compared with SGA and Turner syndrome patients. The severity of the GH deficiency is the highest-rated variable in GH-deficient patients compared to the dose of RhGH per kg body weight per week, which has the highest predictive power in patients with non-GH-deficient short stature.

The use of mathematical models in the clinical setting has proven to be problematic, although their use has led to a smaller number of poor responders to RhGH therapy. However, the development of prediction models represents a major milestone in the story of RhGH therapy. Their use underlines the principles of precision medicine, i.e., the individualization of care compared with the approach of standard care for all patients.