Editorial: Growth hormone treatment of "idiopathic short stature": not so fast.

Our society prizes stature like a jeweler values precious stones. Tall men and women embody “power,” “beauty,” and “authority. ” In contrast, short adults are “cute” and inconsequential; if aroused, they may become “Napoleonic. ” Tall children are “mature” and “strong” and garner admiration and respect, whereas short children are too often infantilized, ignored, teased, or bullied. It is hardly surprising, then, that short children and their parents and physicians would seek ways to increase height to an “acceptable” range to meet societal demands and reap its rewards. Previous studies demonstrated that GH administration can enhance short-term height velocity in otherwise normal short children. That long-term GH therapy can also increase adult height was suggested by a meta-analysis of 11 studies involving a total of 413 young people. However, the mean gain in final height relative to pretreatment predicted height was only 0.4 sd or 2.7 cm, approximately 1 in. (summarized in Ref. 1). In many cases, these studies suffered from a lack of randomization, high dropout rates, and the use of historical, rather than placebo-treated, controls. In this issue of JCEM, Leschek et al. (2) present a randomized, double-blind, placebo-controlled trial examining the effects of GH in children and adolescents with “idiopathic short stature. ” They demonstrate that 4.4 yr of GH treatment administered thrice weekly increased ultimate height in boys and girls by a mean of 0.51 sd, equivalent to 3.7 cm (1.5 in.). There were no serious complications of therapy. However, fasting glucose concentrations were significantly higher (95.3 vs. 88.2 mg%) on mornings that followed the previous day’s GH injection. The findings of this study no doubt contributed to the recent decision of the U.S. Food and Drug Administration to approve GH for treatment of children with idiopathic short stature. Current guidelines require that GH be administered only to boys whose height predictions fall at or below 5 ft. 3 in. or to girls with height predictions at or below 4 ft. 11 in. A registry of patients, maintained by pharmaceutical companies, will monitor the effects and potential complications of therapy. Although the use of GH as a physiological replacement for GH deficiency is unquestioned, the administration of pharmacological doses of GH for treatment of idiopathic short stature is problematic. The term “idiopathic short stature” carries the implication of disease; compare, for example, the term “idiopathic epilepsy. ” But most children with idiopathic short stature have no apparent defects in GH production, secretion, or action, and short stature per se confers no specific dysfunction or disability; indeed, otherwise normal short men may have reduced risks of prostate cancer and, if thin, may live longer than tall, heavy men (3, 4). Moreover, previous reports of serious psychological difficulties and cognitive deficits among short children referred to pediatric endocrine clinics have not always been confirmed in randomly selected populations (5). The major liability of short stature is susceptibility to discrimination. But discrimination is a “disease” of society, not of the short individual. In theory, societal intolerance should be addressed by enacting and enforcing antidiscrimination laws, reeducating the public, and counseling the family rather than by medicating the child. In the absence of disease, there is no rationale for defining a cutoff for treatment. For example, how does one justify treating a boy whose height prediction is 5 ft. 3 in. but not one whose height prediction is 5 ft. 3 and 1/32 in. More important, the use of GH in very short children may create an unending cycle of catch-up; increases in the ultimate heights of very short children would necessitate reclassification of some previously normal children (short but with height predictions exceeding current cutoffs) as “idiopathically short. ” This may be the only circumstance in which treatment of one group of children creates illness in another previously healthy group. The long-term benefits of GH in otherwise normal short children appear quite limited; the mean increase in ultimate height in the study by Leschek et al. (2) (3.7 cm) was comparable to the mean increase in height in previous studies (1) of GH treatment of normal short children (2.7 cm). Moreover, there were no significant differences between the GH-treated and placebo groups in final adult height sd values relative to gender-adjusted midparental (target) height sd values. However, one half of the children had a significant response to GH; the remaining half had little or no increase in ultimate height. Together with the finding that the growth response correlated with pretreatment IGF-I levels and bone age delay, the results suggest that the term “idiopathic short stature” comprises a heterogeneous group containing normal and GH-resistant subjects (less responsive) as well as patients with subtle, poorly defined defects in GH production and/or secretion (more responsive). It will be argued that the dose of GH used by Leschek et al. (2) (0.2 mg/kg wk), the age of onset of treatment (9–16 yr), and the duration of therapy (4.4 yr) do not provide for optimal increases in ultimate height. Quite likely true; some investigators recommend doses of 0.375–0.48 mg/kg wk administered on a daily basis. But higher doses of GH in younger children raise the risk of potential complications. For example, many of those treated with higher doses of GH will have been born small for gestational age and may therefore be at higher risk for insulin resistance, glucose intolerance, and the metabolic syndrome in later life (6). The longJCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. 0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(7):3138–3139 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2004-0671