Background Short-term administration of growth hormone to childrenwith idiopathic short stature results in increases in growthrate and standard-deviation scores for height. However, theeffect of long-term growth hormone therapy on adult height inthese children is unknown.
Methods We studied 121 children with idiopathic short stature,all of whom had an initial height below the third percentile,low growth rates, and maximal stimulated serum concentrationsof growth hormone of at least 10 µg per liter. The childrenwere treated with growth hormone (0.3 mg per kilogram of bodyweight per week) for 2 to 10 years. Eighty of these childrenhave reached adult height, with a bone age of at least 16 yearsin the boys and at least 14 years in the girls, and pubertalstage 4 or 5. The difference between the predicted adult heightbefore treatment and achieved adult height was compared withthe corresponding difference in three untreated normal or short-staturedcontrol groups.
Results In the 80 children who have reached adult height, growthhormone treatment increased the mean standard-deviation scorefor height (number of standard deviations from the mean heightfor chronologic age) from –2.7 to –1.4. The mean(±SD) difference between predicted adult height beforetreatment and achieved adult height was +5.0±5.1 cm forboys and +5.9±5.2 cm for girls. The difference betweenpredicted and achieved adult height among treated boys was 9.2cm greater than the corresponding difference among untreatedboys with initial standard-deviation scores of less than –2,and the difference among treated girls was 5.7 cm greater thanthe difference among untreated girls.
Conclusions Long-term administration of growth hormone to childrenwith idiopathic short stature can increase adult height to alevel above the predicted adult height and above the adult heightof untreated historical control children.
Before biosynthetic growth hormone became available, sufficientgrowth hormone was available to treat only children with severegrowth hormone deficiency. The presence of severe growth hormonedeficiency was usually identified by a serum growth hormoneresponse to provocative stimuli that was below an arbitraryvalue, frequently 10 µg per liter, or a low mean serumgrowth hormone concentration on frequent sampling over a 12-or 24-hour period. These tests are expensive, have some risk,1depend on the presence or absence of sex steroids,2 do not distinguishwell between normal short children and those with growth hormonedeficiency,3 and may give substantially different results inthe same child at different times.4,5 Many children with shortstature have peak stimulated serum growth hormone concentrationsthat are higher than the usual cutoff value for the diagnosisof growth hormone deficiency but have the same growth-retardationfindings as children in whom growth hormone deficiency is diagnosed.
Several groups6,7,8,9,10 have treated children with short staturewho did not have growth hormone deficiency according to classiccriteria, commonly referred to as idiopathic short stature,and have obtained mixed results. In our previous studies, wefound that such children had increases in growth rate, standard-deviationscore for height, and predicted adult height after one and threeyears of growth hormone treatment.11,12 However, growth hormonetreatment could have a short-term effect on growth but not increaseadult height. In this report, we present the long-term resultsof our study, including data on adult height for 80 childrentreated with growth hormone for 2 to 10 years. The study wasnot placebo-controlled, and therefore we compared our resultswith the final heights of two groups of children from the FelsLongitudinal Study13 and 21 children with idiopathic short staturefollowed in our clinics who were not treated with growth hormone.
Methods
Study Subjects
One hundred twenty-one children with short stature who did notmeet the classic criteria for the diagnosis of growth hormonedeficiency were enrolled in a multicenter study of growth hormonetreatment sponsored by Genentech. Eighty-two percent of thechildren were white, 12 percent were Latino, and 6 percent wereAsian, black, or members of other ethnic groups. The protocolwas reviewed and approved by the human-subject research committeesat all participating centers, and the parents of all childrengave written informed consent for the study. When appropriate,the consent of the children was also obtained. All the childrenhad base-line heights below the 3rd percentile (mean standard-deviationscore [number of standard deviations from the mean height forchronologic age], –2.7), growth rates that were less thanthe 50th percentile for age, and a peak stimulated serum growthhormone concentration of at least 10 µg per liter in responseto at least two of the following stimuli: arginine, levodopa,clonidine, and insulin. All were prepubertal according to physicalexamination and had a bone age of less than 9 years (in girls)or less than 10 years (in boys), and none had any evidence ofmalnutrition or hormonal or systemic disease.
Clinical Studies and Follow-Up
The children were evaluated at base line to determine height,weight, and Tanner pubertal stage, and they underwent a completephysical examination. A bone-age radiograph of the left handand wrist was obtained; bone ages were determined at the FelsInstitute by a radiologist who was unaware of the group assignments.14Laboratory tests included measurements of serum growth hormone,insulin-like growth factor I, insulin-like growth factor–bindingprotein 3, and growth hormone–binding protein.
During the first year of participation in the study, each ofthe 121 children was randomly assigned to an observational controlgroup or to a group receiving recombinant human growth hormone(total weekly dose, 0.3 mg per kilogram of body weight, withone third of the dose given subcutaneously three times weeklyfor one year). After the first year, all 121 children received0.3 mg of growth hormone per kilogram per week, either dailyor three times a week. During treatment, the children were seenevery 3 months for measurement of height, and bone-age radiographyand laboratory tests were repeated every 6 to 12 months. Growthhormone treatment was discontinued when the growth rate wasless than 2 cm per year or when the parents and the childrenwished to discontinue treatment.
A total of 80 children (57 boys and 23 girls) completed between2 and 10 years of growth hormone treatment and achieved adultheight, as defined by a measured or projected bone age of atleast 16 years for boys or 14 years for girls, and a Tannerpubertal stage of 4 or 5 (according to genitalia in boys andbreasts in girls) at the time of their last height measurement.At these bone ages, more than 98 percent of adult height hasbeen reached.15 Projected bone age was calculated by using thelast measured bone age and assuming one year of advancementof bone age per calendar year.
The difference between the adult height and the predicted adultheight before treatment in the children who received growthhormone was compared with the corresponding difference in twogroups of normal children who were followed in the Fels LongitudinalStudy with serial measurements of height and bone age untilthey reached adult height. These groups included 291 childrenwith initial standard-deviation scores for height that weregreater than –1 and bone ages of 10 years or less and37 children with initial standard-deviation scores of less than–1. In addition, we compared the difference between predictedand achieved adult height in the treated children with thatin a group of children seen at the participating centers whohad idiopathic short stature with initial standard-deviationscores of less than –2 and who were not treated with growthhormone. These children had achieved adult height, as judgedby either bone age or lack of growth during more than one yearof observation. Adult height in the three control groups wasdefined as either the last measured height or the last predictedadult height, whichever was greater. To be conservative, adultheight in the children given growth hormone was defined as thelast measured height.
Heights were standardized for age and sex with use of normalheight curves for children in the United States.16 Predictedadult heights were calculated with the Bayley–Pinneautables15 and a revised Bayley–Pinneau method of predictingadult height (unpublished data) for children with bone agesof three to six years. The midparental target height adjustedfor regression to the mean was calculated from the average ofthe parents' heights, plus 6.55 cm for boys and minus 6.55 cmfor girls.
Statistical Analysis
Ninety-five percent confidence limits were calculated for differencesin means. Multiple linear regression analysis was used to determinewhich explanatory variables were linearly related to the differencebetween predicted adult height and actual adult height. Thevariables considered were base-line chronologic age, bone age,chronologic age minus bone age, standard-deviation score forbone age, height, standard-deviation score for height, predictedadult height, standard-deviation score for predicted adult height,peak stimulated serum growth hormone concentration, mean 12-hournocturnal serum growth hormone concentration, serum growth hormone–bindingprotein, insulin-like growth factor I, and serum insulin-likegrowth factor–binding protein 3 concentration. In addition,sex, midparental target height, standard-deviation score formidparental height, frequency of growth hormone treatment, durationof growth hormone treatment, and percentage of growth hormonedoses reported to have been missed were also considered. Therewere no significant differences in adult height between childrentreated daily and those treated three times a week, or betweenthe children who were given growth hormone in the first yearand those who were not. Therefore, these groups were mergedfor the purposes of analysis.
Results
Of the 121 children who entered the study, 80 have reached adultheight, and all but 11 have now completed growth hormone therapyafter up to 10 years. Fourteen children left the study becauseof noncompliance, 13 left the study for other reasons, and 11were lost to follow-up. There were no side effects that requireda change in the growth hormone dosage. The age, bone age, andstandard-deviation score for height at base line and the durationof growth hormone therapy for the 80 children who reached adultheight are shown in Table 1. Treatment with growth hormone resultedin a significant increase in the mean growth rate over the base-linegrowth rate, which was maintained for at least seven years (Figure 1A).There was no significant change in the growth rate amongthe children who were not treated during the first year of thestudy, indicating that there was no effect of simply being enrolledin the study.
Figure 1. Effects of Growth Hormone Treatment in Children with Idiopathic Short Stature.
Panel A shows the mean (±SD) growth rate, and Panel B shows the mean (±SD) standard-deviation score for height. The value at time 0 is the growth rate for the preceding year or longer. The numbers below the graphs are the total numbers of children completing each year. Complete data for the pretreatment year were missing for 4 of the 121 children. Fifty-nine of the children were not treated in the first year, and their data are included both with the data for the untreated group and as part of the total data for the treated group. The shading in Panel B represents the normal range for height.
The mean base-line standard-deviation score for height for the121 children with idiopathic short stature was –2.7 (Figure 1B).The score in the 69 children treated for five years increasedto –1.4. The 29 children treated for seven years had amean score of –1.0.
The mean adult height of the 80 treated children was greaterthan the adult height predicted before treatment. In Figure 2,any point above the line of identity indicates an adult heightgreater than predicted. Although individual responses varied,63 of the 80 children (79 percent) had an adult height thatwas greater than predicted.
Figure 2. Final Height as Compared with Predicted Adult Height before Treatment with Growth Hormone in 80 Children with Idiopathic Short Stature Who Reached Adult Height.
The mean (±SD) difference between the achieved and predictedadult height of the growth hormone–treated children was5.0±5.1 cm for boys and 5.9±5.2 cm for girls (Table 1).Although the adult height of both boys and girls was greaterthan predicted, it was still less than the mean midparentaltarget height. Both the pretreatment height and the predictedadult height were an average of 2.6 SD below the mean. Aftergrowth hormone treatment, the mean final height and final predictedadult height were both 1.6 SD below the mean. The mean targetheight for this group was 0.9 SD below the mean.
We compared the results in three historical control groups withthose in the growth hormone–treated children. The normalboys in the Fels Longitudinal Study who had a base-line standard-deviationscore for height that was greater than –1 achieved a meanadult height slightly (1.6±5.4 cm) above their mean pretreatmentpredicted adult height (Figure 3). The other group of boys inthe Fels Study, with a base-line standard-deviation score ofless than –1, did not reach their mean pretreatment predictedadult height, being 1.7±4.2 cm shorter. The trend towardoverprediction of mean adult height in the boys was even morepronounced in the control group of untreated children with idiopathicshort stature, who had base-line standard-deviation scores forheight of less than –2; in this group, the mean differencebetween achieved and predicted adult height was 4.2±7.7cm. Of the 57 boys with idiopathic short stature who were treatedwith growth hormone, 45 (79 percent) exceeded their pretreatmentpredicted adult height, as compared with only 2 of 11 (18 percent)of the boys with idiopathic short stature who were not treated.In addition, 29 of the 57 boys (51 percent) with idiopathicshort stature who were treated with growth hormone and only1 of 11 untreated boys (9 percent) with idiopathic short staturehad a clinically important (more than 5 cm) difference betweenactual adult height and adult height predicted before treatment.
Figure 3. Mean (±SD) Final Height minus Predicted Adult Height before Treatment for the Three Control Groups and for Children with Idiopathic Short Stature Treated with Growth Hormone.
SDS denotes standard-deviation score for height, and GH growth hormone.
The results among the girls were considerably different (Figure 3).In the 147 normal girls in the Fels Study who had a base-linestandard-deviation score for height that was greater than –1,the pretreatment predicted adult height was less than the actualadult height, with a difference between actual and predictedadult height of 3.3±5.4 cm; this was also the case inthe 23 normal girls with a base-line standard-deviation scoreof less than –1, in whom the difference was 3.6±4.4cm. In the 10 girls with idiopathic short stature who were nottreated with growth hormone, the difference was 0.1±2.9cm. In the 23 girls with idiopathic short stature treated withgrowth hormone, 18 (78 percent) exceeded the adult height predictedbefore treatment. Only 1 of the 21 girls (5 percent) with idiopathicshort stature who were not treated with growth hormone exceededher initial predicted adult height by more than 5 cm, as comparedwith 14 of the 23 girls (61 percent) with idiopathic short staturewho were treated with growth hormone. The overall mean changesseen with growth hormone treatment are summarized in Table 2.As compared with the results in the children with idiopathicshort stature who were not treated with growth hormone, themean increase in adult height was 9.2 cm for boys and 5.7 cmfor girls with idiopathic short stature who were treated withgrowth hormone.
Table 2. Difference between Achieved and Predicted Adult Height in Children with Idiopathic Short Stature Treated with Growth Hormone as Compared with Two Untreated Control Groups of Children.
Since approximately half the children with idiopathic shortstature who were treated with growth hormone had an adult heightat least 5 cm greater than the height predicted before treatment,an important issue is whether a clinician can predict who isgoing to obtain substantial benefit from growth hormone therapy.We found no relation between the difference in the predictedand achieved adult height in the children treated with growthhormone and their pretreatment age, bone age, height, predictedadult height, peak serum growth hormone responses, 12- or 24-hourserum growth hormone concentrations, insulin-like growth factorI concentrations, serum growth hormone–binding proteinconcentrations, growth in response to the first 12 or 24 monthsof growth hormone treatment, or duration of treatment.
Discussion
The majority of the children with idiopathic short stature enrolledin this study of growth hormone therapy had a significant increasein their growth rate,11 which was previously reported to persistfor three years and was associated with an increase in the standard-deviationscore for height and predicted adult height.12 In this study,we found that the effect of growth hormone therapy on the growthrate was sustained and that it led to an increase in adult height.Of the 80 children in this study who have reached adult heightafter having received growth hormone for 2 to 10 years, 50 percenthave reached a height more than 5 cm above the adult heightpredicted before treatment, but few have achieved their meanmidparental target height.
These changes in adult height are consistent with the findingsof some17,18,19 but not other20,21,22,23 studies of the effectsof growth hormone treatment in children with idiopathic shortstature. The differences in the outcomes of these studies maybe related to differences in the children studied. On average,the children in our study were younger at the beginning of growthhormone treatment and were treated longer than the childrenin many of the studies in which growth hormone treatment wasnot beneficial.
The calculated improvement in adult height in our study is dependenton both the reliability of the determinations of bone age andthe validity of the predictions of adult height. The bone agesin this study were read in a masked fashion at the Fels Instituteaccording to the Fels bone-age method.14 This method was validatedin children of normal height and weight, but its applicabilityto children who are substantially shorter than normal is uncertain.The same is true of the Bayley–Pinneau height-predictiontables used in this study. Thus, we considered it importantfor the interpretation of our data to validate the use of theFels method for bone age with the Bayley–Pinneau height-predictionmethod in children with varying degrees of short stature. Thedata from the Fels Longitudinal Study indicated that these methodsare valid for boys of normal stature but overpredict adult heightfor short boys. This finding suggests that the net increasein adult height in the growth hormone–treated boys isa conservative estimate. The overprediction of adult heightin boys with short stature has also been noted in several otherstudies,24,25,26 emphasizing the importance of comparisons withappropriate control data.
Unlike the findings in boys, the initial predicted adult heightamong normal girls in the Fels Study significantly underestimatedadult height, whereas the height prediction for girls with idiopathicshort stature who were not treated was accurate.
The children with idiopathic short stature in this study hadmean pretreatment heights and predicted adult heights that weremore than 2 SD below the mean for chronologic age. The gainsresulting from growth hormone therapy represent an average increaseof approximately 1 SD in adult height. However, the mean adultheight still remained substantially below the mean midparentaltarget height. Furthermore, the responses to treatment in individualchildren were highly variable, and some had no apparent benefit.
The gains in adult height with growth hormone treatment in thesechildren with idiopathic short stature are similar to thosereported in another group of children with severe short stature,but without classic growth hormone deficiency — namely,girls with Turner's syndrome.27,28,29 The similarity of thelong-term growth response in these two groups suggests thatother children with severe short stature who do not have growthhormone deficiency may have a similar response to growth hormonetreatment.
Whether the increase in adult height in these children withidiopathic short stature treated with growth hormone is dueto treatment of an abnormality of growth hormone secretion oraction or to the pharmacologic effects of growth hormone isnot known. The difficult questions of the ethical and financialjustification of growth hormone treatment for these childrenwith severe short stature must be faced squarely.30 If therewere no long-term benefit of treatment with growth hormone inchildren with idiopathic short stature, there would be no reasonto treat and therefore no ethical problem. However, our studydemonstrates that treatment may be effective. Thus, the decisionto treat must involve a difficult judgment of the relative benefits,risks, and costs of the treatment.
Supported by Genentech and by grants (RR-06020 to Cornell MedicalCenter and RR-0865-24 to the University of California, Los Angeles)from the Public Health Service.
Dr. Hintz has served as a paid consultant to Genentech.
We are indebted to Mrs. Lily Brelsford, clinical research associate,Genentech, and the study coordinators at each center for theircontributions to this study.
* Other members of the Genentech Collaborative Group are listedin the Appendix.
Source Information
From Stanford University, Stanford, Calif. (R.L.H.); Genentech, South San Francisco, Calif. (K.M.A., J.B.); and Wright State University, Yellow Springs, Ohio (A.R.). Presented in part at the annual meeting of the American Pediatric Society and the Society for Pediatric Research, San Diego, Calif., May 9, 1995.
Address reprint requests to Dr. Hintz at the Department of Pediatrics, Rm. S-302, Stanford University Medical Center, Stanford, CA 94305.
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Appendix
Other members of the Genentech Collaborative Group were as follows:R. Blizzard (University of Virginia), J. Cara (University ofChicago), S. Chernausek (University of Cincinnati), M. Geffner(University of California, Los Angeles), J. Gertner (CornellMedical Center), N. Hopwood (University of Michigan), S. Kaplan(University of California, San Francisco), B. Lippe (Universityof California, Los Angeles), L. Plotnick (Johns Hopkins University),A. Rogol (University of Virginia), P. Saenger (Montefiore MedicalCenter), G. Leboeuf (Hôpital Ste.-Justine), A.J. Johanson(Genentech), and J. Kuntze (Genentech).
Several members of the collaborative group are now or have beenconsultants to Genentech (Drs. Blizzard, Cara, Chernausek, Gertner,Hopwood, Kaplan, and Rogol), Eli Lilly (Drs. Gertner and Hopwood),Pharmacia–Upjohn (Dr. Geffner), and Serono (Drs. Caraand Rogol), makers of growth hormone, or to Biotechnology General(Dr. Rogol), maker of an anabolic steroid.
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