GH dependence and GH withdrawal syndrome in GH treatment of short normal children: evidence from growth and cardiac output

Abstract

The child's age is a significant determinant of the outcome of GH therapy; prepubertal children respond better on both short term and long term growth, whereas adolescents tend to accelerate their bone maturation more than growth. The present study was designed to evaluate the efficacy of an interrupted GH therapy protocol of young, short normal children. GH was given for a period of 3 years, or until they reached the 25th percentile, then discontinued at a young age (not more than 9 years), and then the children's growth followed until final height. Yet, after discontinuation of GH therapy, growth came close to a complete stand-still. The present report focuses on describing the period beyond GH withdrawal and its impact on growth and cardiac performance. Twenty-two children received daily s.c. injections of 0.9 mg/m 2 hGH and 12 children were the control, untreated group. Growth and echocardiography were followed during therapy and 2 years thereafter. During GH treatment growth velocity accelerated markedly over the first year; it slowed down over the second and third years, and decelerated after GH withdrawal to a velocity that was significantly lower than pretreatment values. Growth rate remained low for the next year, and recovered to pretreatment velocity by the fourth semiannual measurement. To evaluate the role of the GH-IGF-I axis during the growth deceleration, serum IGF-I, insulin-like growth factor-binding protein-3 (IGFBP-3), and an arginine stimulation test were performed at 1, 3 or 6 months after GH withdrawal, and compared with pretreatment response. GH response was 70% of pretreatment values by 1 month and recovered completely by 3 months post treatment. Serum IGF-I and IGFBP-3 levels were normal throughout. End-systolic and end-diastolic left ventricular dimensions as well as cardiac output did not change during the 2 year course of GH therapy, but fell significantly during the initial 6 months of GH withdrawal. Thus, daily injections of GH to prepubertal short normal children is associated with development of drug dependence, followed during the abstinence period by deceleration of growth and reduction of cardiac output to levels that are lower than pretreatment values. After GH therapy for 30-36 months the withdrawal syndrome persists for 18 months, and is not induced by alterations of serum levels of GH or IGF-I.

Effects of Growth Hormone Treatment on Left Ventricular Dimensions in Children with Noonan’s Syndrome

“…In addition, we could not confirm the negative effect of discontinuing GH treatment on left ventricular dimensions, as was reported in short normal children [20]. …”

Final height in young women with Turner syndrome after GH therapy: an open controlled study

“…It would seem more straightforward to initiate treatment at the age of 10-11 years and to continue for 3-4 years. Initiation of GH treatment at a younger age, and its termination before final height has been attained, may introduce catch down growth after withdrawal of therapy, as shown for children with idiopathic short stature (23).…”

Rapid cardiovascular effects of growth hormone treatment in short prepubertal children: impact of treatment duration

“…found no difference in LV diameter during 2 years of GH treatment (dose 33 μg/kg/day). However, 6 months after cessation of treatment, both LV diameter and cardiac output were reduced compared with baseline . In another study, Daubeney et al .…”

“…Furthermore, it has been shown that the actual dose given should be individualized to optimize the growth response for all individuals . From the cardiovascular perspective, short‐ and medium‐term GH treatment has been shown to be without negative effects in children with GHD and ISS . Several studies have focussed on the impact of GH therapy on the structure and function of the heart; however, most studies have included only a limited number of children with either GHD or ISS and the given dose of GH has not been individualized.…”

“…5 From the cardiovascular perspective, short-and medium-term GH treatment has been shown to be without negative effects in children with GHD and ISS. [9][10][11][12][13][14][15] Several studies have focussed on the impact of GH therapy on the structure and function of the heart; however, most studies have included only a limited number of children with either GHD or ISS and the given dose of GH has not been individualized. Left ventricular (LV) mass indexed to body surface area (BSA) has been shown to increase during treatment in three studies reporting the effects of approximately 30 lg/kg/day on cardiac dimensions in 12, 24 and 30 children with GHD.…”