Idiopathic short stature (ISS) is the most common type of growth retardation in children. The growth velocity (GV) is slow, but the birth weight and length are in the normal range, and the growth hormone (GH) excitation peak is >10μg/L. The growth retardation caused by endocrine, genetic and metabolic diseases, malnutrition and various chronic diseases were excluded. Xu Jinliang, Department of Pediatrics, Shaoxing Maternal and Child Health Hospital, Guizhou Provincial People’s Hospital, Fu Xiaoling, Department of Pediatrics
Replacement therapy with recombinant human growth hormone (rhGH)
In July 2003, the US Food and Drug Administration (FDA) approved rhGH for the treatment of ISS, which is the fifth indication approved by FDA for non-GHD short stature after Turner syndrome, Prader-Willi syndrome (PWS), chronic renal insufficiency, and small for gestational age (SGA). The efficacy of rhGH is related to the age of treatment, bone age, dose and duration of treatment, as well as individual sensitivity to rhGH.
(1) Effectiveness Most of the clinical studies have shown that although children with ISS do not have GH deficiency, treatment with rhGH can help to increase GV and final adult height (FAH) of children. There is also a clear dose-dependence, i.e., the efficacy of high dose is better than low dose.
(2) Safety It has been nearly 30 years since the introduction of rhGH, and its clinical application has been increasing. The importance of the GH-IGF-I (insulin-like growth factor-I) endocrine axis in regulating cell growth and anti-apoptosis has raised clinical concerns about the safety of rhGH. There have been few reports of adverse reactions to rhGH for ISS treatment, and they rarely lead to discontinuation of the drug, mostly due to the fear of injections in children. Many clinical trials have looked at some of the theoretical risks associated with rhGH (e.g., glucose tolerance, hypertension, cardiovascular changes, triglyceride and cholesterol changes, hypothyroidism, idiopathic benign cranial pressure elevation, leukemia, and other malignancies), and no major adverse effects were observed. Kemp et al. reported on the safety analysis of rhGH treatment in 8018 children with ISS by the North American National Growth Study Collaborative Group (NCGS). It should be noted that although rhGH therapy is generally safe, it should be used with caution in children with family history of cancer, history of tumors, history of radiation and chemotherapy, aplastic anemia, Down syndrome, Langhans histiocytosis, and other cancer risk factors, and IGF-I/IGFBP3 levels should be monitored. The treatment plan should be adjusted promptly for children with significantly increased IGF-I.
(3) Dosage The effective dose of ISS should be 0.15-0.2 IU/(kg・d), similar to that of Turner syndrome. In other previous indications of rhGH, the efficacy of high-dose growth support has been demonstrated to be better than low-dose, especially for children entering puberty, which should be treated with higher doses to mimic the physiological increase of GH secretion during accelerated growth in puberty. Recently, prospective studies of rhGH treatment in children with ISS have been reported, with the aim of observing the degree of improvement of FAH in relation to the treatment dose.
Recently, it has been suggested that the dose of rhGH treatment should be individualized, and a method to assess the dose and efficacy of rhGH treatment has been proposed. rhGH individualization strategy should consider at least two aspects:
(i) the bioavailability of the drug in the body; (ii) the sensitivity of the body to rhGH response
The biological effect of human GH is to contribute to IGF-I synthesis, and the efficacy of exogenous GH is found to be positively correlated with IGF-I levels. The effectiveness of rhGH therapy can be initially determined by monitoring peripheral blood IGF-I levels, and the changes in GV after treatment can be used as a basis for adjusting the drug dose. This kind of individualized medication may be more helpful for the efficacy of the drug and reduce the adverse effects. Many clinical studies have demonstrated that with standardized individualized rhGH treatment, the majority of ISS can achieve effective prolonged efficacy. Clinicians should provide each child with an individualized treatment plan that is both effective and free of significant adverse effects. In addition, individualized treatment should emphasize the child’s compliance, including parental understanding and acceptance of medication doses and treatment costs. For whatever reason, treatment that is unacceptable to the child cannot be called individualized, and treatment that is too costly may discourage some children.
(4) Frequency of injection In the past clinical practice, rhGH treatment for both GHD and non-GHD children is more effective when injected every night before bedtime, so most children are still treated by daily injection.
(5) Duration of treatment The association between the duration of rhGH treatment and the efficacy of rhGH in children with ISS is well established, with the most significant increase in GV and HtSDS in the first year of treatment and a decreasing trend in growth-promoting efficacy thereafter. Nevertheless, the GV of prepubertal children with ISS was still greater than the pre-treatment level after a long course of treatment (up to 7 years). This confirms that rhGH treatment in children with ISS leads to a sustained increase in GV, i.e., a short course of treatment can increase GV and a long course of treatment can help increase FAH.
(6) Factors affecting the efficacy of treatment The factors affecting the efficacy of ISS promotion (especially the positive effect on FAH) are roughly the same as those of GHD, including basal height at the beginning of treatment, GV, bone age (BA), age of onset of pubertal sexual development, GV in the first year of treatment, duration of treatment, genetic height and length at birth. The younger the actual age at the start of treatment, the more pronounced the BA delay, the lower the GV and IGF-I levels, and the better the genetic height, the better the outcome. On the contrary, if there is no significant increase in GV in the first year of treatment, discontinuation of the drug can be considered.
In conclusion, the treatment of children with ISS with recombinant human growth hormone rhGH replacement therapy can effectively improve the annual growth rate and increase the lifetime height of children with ISS, and the long-term use of the drug is safe and effective without serious side effects.