Growth hormone in combination with leuprorelin in pubertal children with idiopathic short stature

Abstract

Objective: There is a scarcity of data from randomised controlled trials on the association of growth hormone (GH) with gonadotrophin-releasing hormone agonists in idiopathic short stature (ISS), although this off-label use is common. We aimed to test whether delaying pubertal progression could increase near-adult height (NAH) in GH-treated patients with ISS.

Methods: Patients with ISS at puberty onset were randomised to GH with leuprorelin (combination, n = 46) or GH alone (n = 45). NAH standard deviation score (SDS) was the primary outcome measure. The French regulatory authority requested premature discontinuation of study treatments after approximately 2.4 years; patients from France were followed for safety.

Results: Mean (s.d.) baseline height SDS was -2.5 (0.5) in both groups, increasing at 2 years to -2.3 (0.6) with combination and -1.8 (0.7) with GH alone. NAH SDS was -1.8 (0.5) with combination (n = 19) and -1.9 (0.8) with GH alone (n = 16). Treatment-emergent adverse events and bone fractures occurred more frequently with combination than GH alone.

Conclusion: Due to premature discontinuation of treatments, statistical comparison of NAH SDS between the two cohorts was not possible. During the first 2-3 years of treatment, patients treated with the combination grew more slowly than those receiving GH alone. However, mean NAH SDS was similar in the two groups. No new GH-related safety concerns were revealed. A potentially deleterious effect of combined treatment on bone fracture incidence was identified.

Keywords: GH treatment; growth; idiopathic short stature; leuprorelin treatment; near-adult height.

Figure 1

Patient disposition during the study. ^aOne patient randomised to growth hormone (GH) alone also received leuprorelin; this patient was evaluated in the GH alone group for auxology and in the GH plus leuprorelin group for safety. ^bAn additional three patients from a previous control group who did not meet entry criteria received GH treatment for ethical reasons and hence were included for safety analyses only. ^cStudy treatment stopped at request of the French Agency for the Safety of Medicines and Health Products. ^dStudy treatment stopped and the relevant study discontinuation report forms were not completed by the investigator. ^eIncluded one patient from each treatment group who reached near-adult height prior to study drug termination.

Figure 2

Height velocity over time for patients with idiopathic short stature treated with growth hormone (GH) with or without leuprorelin. Data shown as mean ± standard deviation (s.d.). The mean (s.d.) duration of leuprorelin treatment in the combination group was 20.9 (6.4) months.

Figure 3

Height standard deviation (s.d.) score (SDS) over time for patients with idiopathic short stature treated with growth hormone (GH) with or without leuprorelin. Data show mean ± s.d. The mean (s.d.) duration of leuprorelin treatment in the combination group was 20.9 (6.4) months.

Figure 4

Scatter plots of insulin-like growth factor (IGF)-I standard deviation score (SDS) vs IGF-binding protein (IGFBP)-3 SDS at baseline (open circles) and after 24 months (filled circles) in patients with idiopathic short stature treated with either growth hormone (GH) plus leuprorelin (A) or GH alone (B). Horizontal lines show IGF-I SDS ± 0.5 and vertical lines show IGFBP-3 ± 0.5.

Figure 5

Total body bone mineral density Z-score, bone mineral content, fat mass and lean body mass at baseline and during treatment and at near-adult height (NAH) with either growth hormone (GH) plus leuprorelin (shaded bars) or GH alone (white bars). Data are shown as mean ± standard deviation (s.d.). Mean (s.d.) duration of leuprorelin treatment was 20.9 (6.4) months for the safety population.