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Editorial |
Massachusetts General Hospital Pediatric Endocrine Unit Bartlett 410x Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Lynne L. Levitsky, Massachusetts General Hospital, Pediatric Endocrine Unit Bartlett 410x, Boston, Massachusetts 02114. E-mail: llevitsky{at}partners.org.
Zvi Laron (1) had to wait until the 1980s to demonstrate that biosynthetic IGF-I increased growth rate and altered body composition in children with severe dwarfism and elevated levels of GH (GH insensitivity) he identified first in 1958. By 1990, IGF-I had been synthesized in some quantity, and small numbers of children with "GH insensitivity," later described to have defects in the GH receptor or GH response pathway, were treated with this agent (2). Commercial quantities of IGF-I are now available and approved by the United States Food and Drug Administration for treatment of growth disorders characterized by "IGF-I deficiency" or "GH resistance." However, for many reasons, this is still a drug in search of its rightful place in the pharmacopoeia.
The paper by Chernausek et al. (3) in this issue is the first large, long-term study of the effects of treatment with IGF-I in individuals with GH resistance. Of the 76 children studied at baseline, 23 had a defined molecular defect of the GH receptor and five had absence of GH binding proteins, suggesting a defect in this gene or in its intracellular signaling pathway, whereas nine had neutralizing levels of GH antibody and were GH deficient. The remaining 39 children had clinical GH receptor defects (elevated levels of serum GH) and severe short stature. GH resistance was defined as a failure to increase serum IGF-I concentrations after four daily sc injections of human GH in a dose of 0.1 mg/kg. The children were compiled from several different centers. Some were naive to IGF-I, whereas others had been treated previously. Children were titrated to a fixed dose of IGF-I twice daily, and the dose was different in some of the earlier treated subjects. Of the children initially studied, 67 were treated with IGF-I for at least 1 yr and 39 were treated for 4 yr. Thirteen subjects were followed for 8 yr of treatment. Six subjects have reached adult height. Children grew exceedingly well in the first year, but growth rate thereafter approximated the normal growth rate, and catch-up did not continue at the same rapid rate seen with GH treatment in GH-deficient children. Children treated with the highest doses of IGF-I grew faster. Estimated enhancement of adult height, compared with previous patients studied by Laron, was about 10 cm. Growth of various internal organs, including kidneys, spleen, and thymus, was enhanced and in some individuals exceeded normal. Lymphoid hypertrophy was common, and a coarsening of facial features was noted in many subjects. Children had initial reductions in body fat mass, but after the first 2 yr fat mass returned to baseline. There were minor effects on lipids. Hypoglycemia was common in these subjects at baseline, and severe hypoglycemia was noted with treatment in some but was ameliorated by a meal taken immediately after IGF-I administration.
The results of the study are not entirely unexpected based upon previous short-term data, animal studies, and our understanding of the physiology of GH and IGF-I action (2, 4). This study points to the differential effects of GH and IGF-I on body composition and growth. For children with severe GH resistance, it is an excellent tool to improve height. However, the study does not resolve the questions that remain in regard to expanded criteria for the therapeutic use of IGF-I.
Circulating IGF-I is largely produced in the liver and is responsive to GH. However, paracrine and autocrine actions of IGF-I at the growth plate, and in muscle, are not measured by levels of circulating IGF-I, and these actions cannot be fully mimicked by supplying IGF-I exogenously into the peripheral circulation (2, 4). In tissues such as bone and muscle, IGF-I is released in response to GH but also in response to mechanical stimuli and other local and circulating humoral agents. The now classic studies of Butler and LeRoith (5) demonstrated that mice with hepatic IGF-I gene deletions had very low circulating levels of IGF-I and yet grew entirely normally. Children in this study, as previously demonstrated by others in smaller short-term studies, grew rapidly in the first year of treatment and then maintained growth rates close to normal but did not continue with remarkable catch-up growth (1). In the end, adult height and predicted adult height were improved, but the expectation for catch-up growth as is seen in GH-treated GH deficiency was not met. In addition, body composition remained abnormal, with increased fat mass and decreased lean body mass, throughout the term of treatment. GH-specific effects, such as diminution in adipocyte size because of enhanced basal lipolysis, were not found in these patients. Lack of adipocyte IGF-I receptors make this cell an unlikely target for IGF-I action (6). On the other hand, previously reported GH side effects, felt to be mediated through IGF-I, such as occasional increased intracranial pressure, lymphoid hypertrophy, and coarsening of facial features, were more common.
The study leaves unanswered whether increased dosing or earlier treatment could improve growth rate in this population. Enhanced dosing might increase the risk of side effects. Indeed, a recent revision of the guidelines for the use of the Tercica IGF-I product suggests that one in 75 individuals may develop increased intracranial pressure while under treatment with this drug.
The additional complication of hypoglycemia must also remain of concern. IGF-I shares homology with insulin and binds to the insulin receptor, albeit with a much lower affinity than insulin (2). Nonetheless, severely GH-deficient and IGF-I-deficient individuals are prone to fasting hypoglycemia. This risk seems to be increased during treatment with IGF-I. Feeding after injection of the drug seems to decrease risk but does not entirely eliminate it. It is unclear how severe this risk would be in a less IGF-I-deficient population.
For all or most of the children in this study, IGF-I is the only tool available to help improve adult height. Therefore, lack of improvement in body composition, slower growth rates than in GH-treated children, and potentially uncomfortable side effects are unfortunate but do not detract from the efficacy of this agent in treatment. This population of children is small, however, and there is a question as to whether IGF-I could prove an alternative therapy to GH for height enhancement in the much larger population of children with short stature and relatively low IGF-I. Whether there is pathophysiology or an underlying molecular mechanism to support the diagnosis of "mild or moderate" IGF-I deficiency in the absence of elevated levels of GH, slow growth rate, and the clinical features of IGF-I deficiency or severe GH deficiency seen in the children presented in this study is unclear and hotly debated. Serum IGF-I levels are difficult to measure, and it is open to debate whether determinations of circulating IGF-I in childhood are predictive of adult height or of growth rate. The debate has been presented in this journal as well as others (2, 7, 8, 9). What is clear is that pediatric endocrinologists who now wrestle unsuccessfully with unsatisfactory tools for the diagnosis of isolated GH deficiency must add to this the ambiguity of the diagnosis of IGF-I deficiency. Numerous attempts to codify and define a method to characterize GH responsiveness using various tests of IGF-I generation have led to increased confusion rather than clarity. A relatively recent evaluation of the IGF-I generation test across the age spectrum showed that the test could not clearly differentiate GH-deficient from GH-insensitive children with known GH receptor defects. There even seemed to be a remarkable overlap in the normal population at younger ages (10). Therefore, there are no standards or criteria with which to make this diagnosis and, most important of all, no outcome data. Trials are presently underway to evaluate the effect of IGF-I on growth and, one hopes, adult height prediction in children with low IGF-I levels and short stature but without other signs of genetic "GH insensitivity." Until the data are available from these trials, and until there are comparisons with the effect of GH therapy in similar children, the criteria and rationale for the use of IGF-I as a broader therapy for short stature remain ambiguous.
Footnotes
Disclosure Statement: The author is an investigator in a Tercica-sponsored study of the effects of IGF-I therapy in short children with low IGF-I levels.
Received January 12, 2007.
Accepted January 15, 2007.
References
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