Prevention of growth deceleration after withdrawal of growth hormone therapy in idiopathic short stature.
The treatment of children with idiopathic short stature by daily injections of human GH (hGH) is followed after its withdrawal by a growth deceleration with normal serum GH and IGF-I levels. The present study was designed to understand and prevent growth deceleration. We hypothesized that this phenomenon is due to tolerance at the target organ level, that tolerance develops in response to the unphysiological pharmacokinetics of daily-injected hGH, and that alternate day hGH therapy will prevent it. Thirty-eight prepubertal children with idiopathic short stature, aged 3.3-9.0 yr, were studied. Their heights were less than -2 SD score, growth rate was above the 10th percentile for age, bone age was less than 75% of chronological age, and the stimulated serum GH concentration was greater than 10 microg/liter. The children were matched for sex, height, and growth velocity SD score to receive daily or alternate day hGH at the same weekly dose of 6 mg/m(2) for a period of 2 yr. The 1st and 2nd year mean growth velocities were 3.4 and 2.3 SD score for the daily therapy group and 3.0 and 2.0 SD score for the alternate day group, respectively (P = NS). Over the initial 6 months after withdrawal of therapy, and growth velocity decelerated to a nadir of -3.9 SD score in the daily therapy group, whereas it decelerated in the alternate day group to only -0.2 SD score (P < 0.01). Over the entire 2 yr off therapy the latter group maintained mean growth rates of -0.2 to -1.2 SD score, similar to their pretreatment velocities. The daily group recovered slowly to resume their mean pretreatment rate only on the fourth semiannual evaluation off therapy. The cumulative 4-yr growth velocity (2 yr on and 2 yr off therapy) of the alternate day group was greater than that of the daily therapy group (mean, 0.9 vs. 0.3 SD score; P < 0.002). At the end of the 4-yr therapy period, the adult height prediction of the alternate day group was greater than that of the daily group by a mean 6.5 cm (P = 0.06). It is concluded that growth deceleration after withdrawal of hGH therapy in idiopathic short stature is due to tolerance to GH and IGF-I in response to the unphysiological pharmacokinetics of daily-injected hGH and that alternate day therapy allows for an alternate day physiological GH profile, thus preventing tolerance during therapy and growth deceleration thereafter.
Lampit
Meir
M
Department of Pediatrics, Meyer Children's Hospital, Haifa 31096, Israel.
Hochberg
Ze'ev
Z
D001827:Body Height / Q000187:drug effects*; D001846:Bone Development / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004361:Drug Tolerance; D005260:Female; D005317:Fetal Growth Retardation / Q000188:drug therapy; D006130:Growth Disorders / Q000188:drug therapy* / Q000517:prevention & control*; D019382:Human Growth Hormone / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D016896:Treatment Outcome
D019382:Human Growth Hormone