Growth Hormone Treatment for Short Normal Girls?

ABSTRACT & COMMENTARY

Synopsis: Eight short (> 2SD) but otherwise normal girls treated with growth hormone grew an average 7.5 cm more than control girls.

Source: McCaughey ES, et al. Randomized trial of growth hormone in short normal girls. Lancet 1998;351:9440-9444.

In a randomized, controlled study, eight girls with a mean age of 8 years and heights 2 SD or more below normal for age were treated with 30 IU/m2 of growth hormone per week as daily subcutaneous injection. Their growth and development was compared to a control group of 10 randomized short girls who were not treated and 20 short girls who refused randomization.

By 16.4 years of age in the treated girls, the mean height SD score changed from -2.42 to -1.14 and, on the average, they were 7.5 cm taller than girls in the control groups (height SD scores did not change from -2.25). The timing of each pubertal stage was similar for both groups.

COMMENT BY MYRON GENEL, MD, FAAP

The availability of ample quantities of human growth hormone produced by recombinant DNA techniques has solved the problem of scarcity for children with classical growth hormone deficiency, but its relative abundance has created new indications for use (such as in Turner Syndrome and in children with chronic renal insufficiency) while raising a host of new questions with ethical, economic, and social implications. Equally predictable, there has been a plethora of articles on the use of recombinant growth hormone for treatment of a variety of conditions associated with short stature. Most of these are reports of relatively short-term "trials" and most suggest potential benefit in terms of ultimate adult height. Few studies, however, have been carried out to completion of adult or "near adult" height. Fewer, still, have been adequately controlled, and virtually none of these would measure up to the gold standard of a randomized, clinical trial.

The report by McCaughey and associates from the Southhampton University in the United Kingdom comes close to fulfilling this ideal (but has several limitations) notwithstanding the average increment of 7.5 cm in the girls who completed a long-term course of growth hormone therapy as compared to randomized controls. To begin with, the number of girls who completed the trial was quite small-seven on growth hormone and six without. While the group differences achieve statistical significance, there is some overlap in the final height with respect to mid-parental heights, less so with respect to predicted height based on bone age upon entry. Most significantly, the control group was not a pure control in that these girls did not receive placebo injections; ethical issues aside, a purist would insist on this to ensure that the only difference between the two groups was the use of the active substance in the treatment group. Indeed, such a trial is now ongoing at the National Institutes of Health. Many of us await these results with great interest. My own suspicion is that some youngsters treated with placebo will demonstrate good growth.

For the most part, treatment of patients with so-called "idiopathic short stature" would be regarded as experimental and should be conducted as part of an approved, well-constructed research protocol, of which several are ongoing in the United States and throughout the world. Indeed, a report of a multicenter European trial that compared a three-dose regimen over a four-year period, the highest of which was similar to that used in the McCaughey study. Modest height improvements were made. Advances in skeletal age were also observed so that the final height outcome was uncertain.1

Ultimately, decisions on therapy have to be made on an individual basis. For all of our sophistication in providing therapy, we have not made comparable progress in identifying children who will clearly benefit from growth hormone therapy. Recognizing that there is a continuum from frank growth hormone deficiency through growth hormone sufficiency, it remains difficult to reliably identify children who lie in between-who are not frankly deficient but have relatively insufficient growth hormone production. Increasingly, we are relying on auxologic (measurement) rather than biochemical criteria and considering offering children who are growing poorly a trial of growth hormone therapy.

Whether the gain in ultimate height is worth the cost, in terms of emotional stress, the inconvenience of frequent monitoring and blood-letting as well as economic, is something that has to be determined on a case-by-case basis. This is without regard to potential and as yet unrecognized long-term side effects. McCaughey and associates conclude their paper with a brief discussion of these issues, though they make no definitive judgments or recommendations. The reader can draw his or her own conclusions as to whether the probably modest increased growth is worth a cost of $18,000 per cm of height!

Reference

    1. Rikers-Mombarg LTM. Growth hormone therapy with three dosage regimen in children with idiopathic short stature. J Pediatr 1998;132:455-460.