Should short children who are not deficient in growth hormone be treated?

There are many causes of short stature during childhood and adolescence.¹ About half of all children referred to pediatric endocrinologists for an evaluation of their growth show normal variants of short stature. This means that their height falls below the conventional cutoff of 2 standard deviations below the mean but they have healthy increments in growth that parallel the growth channels on standard growth charts for the general population.^1,2 A deficiency in growth hormone is the main endocrinologic cause of pathologically short stature.

A major objective of treatment with growth hormone in children (who typically are prepubertal at the start of treatment) is to accelerate the speed of growth to reduce discrepancies in height with peers during childhood and adolescence and to enable them to reach an adult height that is commensurate with their genetic potential.³ Because the sole source of growth hormone before 1985 was pituitary glands taken from cadavers, there was never enough growth hormone available to meet the needs of children who had a deficiency. The treatment was, therefore, restricted to those with the most severe deficiencies. The hormone became more widely available after biosynthetic growth hormone was manufactured in 1985.

The availability of biosynthetic growth hormone ensures that children who are deficient can have replacement therapy, but it also has created the opportunity to treat children who are short but do not have a deficiency. As time passes, some of these newer, nontraditional applications are becoming accepted as the standard of care in the United States.⁴

The treatment of short children who are not deficient in growth hormone is predicated on the widespread belief that being taller improves children's psychological well being.⁵ Moreover, it is thought that increased height will reduce or eliminate their risk status for the development of problems as adults. The broader use of this comparatively intensive, chronic, and costly hormonal intervention is supported by complaints made by short youths of psychosocial stresses related to their height and society's beliefs about the disadvantages of being short.⁶ In the United States, growth hormone is more frequently prescribed to youths who are not deficient in growth hormone than to those who are.⁴ This aspect of clinical practice remains controversial.^{4, 7} Practice guidelines on the use of growth hormone in children who are short clearly state that decisions regarding “instituting or continuing therapy should be individualized... and be guided by the goal of improving the quality of life of the child and future adult.”⁸ Unfortunately, these recommendations, designed for pediatric endocrinologists, provide no guidance in how to conduct an evaluation of the quality of the child's life. Reviewing the assumptions that are frequently made about the quality of life of short children who are not deficient in growth hormone may help clinicians in making decisions on managing these children.

Summary points

• Growth hormone therapy is increasingly being used to treat youths who are not deficient in growth hormone

• The psychosocial difficulties associated with being short seem to be less severe than assumed, and it is unclear whether treatment offers psychological benefit

• Cost-utility analyses of growth hormone therapy should consider the specific circumstances and the value that children or their parents place on the prediction of increased height

METHODS

Because of space limitations, this review is selective. The investigations cited should only be considered as examples. Studies were identified on MEDLINE and PsychINFO using the terms “short stature” or “growth hormone” combined with “behavior (childhood or adolescence).” Priority was given to studies with strong research designs. The Cochrane Database of Systematic Reviews does not include a review of growth hormone therapy in the treatment of short children who are not deficient in the hormone.

ASSUMPTIONS ABOUT QUALITY OF LIFE

Short children and chronic psychosocial stress

Early behavioral research on the psychosocial aspects of short stature showed that it was associated with psychosocial stressors such as stigmatization (teasing) and juvenilization (that is, children being treated as if they were younger than they are because of the misperception of their chronological age).⁹ These studies were generally restricted to patients with complex medical conditions (for example, hypopituitarism, Turner syndrome, or chondrodystrophy). It is not clear if these findings are generalizable to the larger population of children with short stature who are being seen by endocrinologists.

Studies of consecutively referred patients, ages 4 to 18 years (some with normal variants of growth patterns and others with pathologic patterns, including those with growth hormone deficiency), have shown that slightly over half of these patients were regularly teased about being short.^10,11 The same proportion experienced being treated as if they were younger than their chronologic age. These clinical studies corroborate long standing anecdotal reports that being short is associated with psychosocial stress in childhood and adolescence. But not all short children in these studies shared these experiences and in neither study were the stressors related to the child's relative height.

Short children and problems with psychosocial adaptation

It is commonly assumed that children who are short have more clinically significant behavioral or emotional problems.⁹ This has not been found in studies of patients between 4 and 18 years of age in which selection biases are minimized. There is little or no evidence from the reports of parents or children that youths of short stature that is either a normal variant or pathologic (including growth hormone deficiency) have either low self-esteem or a higher than average amount of behavioral or emotional problems.^2,10,11

One report found that before starting growth hormone therapy, more problems were reported by the parents of short patients with sufficient growth hormone than by a normative sample.¹² These were the same norms used for comparison in another study that found relatively few differences between the groups.^2,11 Several methodologic problems detailed elsewhere, however, complicate the interpretation of data from the study that identified more psychosocial problems among the short patients.¹³

Contrary to earlier reports, which were largely anecdotal or based on poorly designed studies, the psychosocial adaptation of short children, even those who are referred for medical evaluation, seems to be comparable to youths in the general population.

Short youths in the general population and problems with psychosocial adaptation

Although it is rarely articulated, it is often assumed that short children and adolescents who are not referred for a medical evaluation (in fact the majority of those with short stature) are similarly at risk for problems of psychosocial adjustment. The Wessex Growth Study is a longitudinal, noninterventional study that was conducted in the United Kingdom to assess the psychological development of short youths in the general population.¹⁴ All children with a height below the third centile of the norms for their age and sex were compared with a group of pair-matched classmates of average height (10th to 90th centiles for height). In the most recent report on this cohort (at ages 11-13 years), the short children did not differ from classmates on measures of self-esteem, self-concept, or teacher's report of behavioral problems. The short students were, however, more dissatisfied with their height than the control group.

In a recent epidemiologic study in New York (Sandberg DE, Bukowski WM, Fung C, et al, unpublished data), the popularity, friendships, and reputation of short students among peers in grades 6-12 were investigated using techniques of peer nomination in the classroom. Height was unrelated to popularity, the total number of friends, or whether the friendship was reciprocated. In terms of reputation among peers, short youths were distinguished from classmates on only one item (“looking younger”). No other behavioral characteristic differed between the groups.

The social stress of being short and problems in psychosocial adjustment

More than half of the 522 children and adolescents (4 to 18 years) in one study based in a pediatric endocrinology clinic were teased about their height weekly, on average.¹¹ Experiences of juvenilization were also frequently reported. It is commonly assumed that there is a relationship between these negative social experiences and the level of psychological adaptation. If the influence of the child's demographic background was controlled for, the variable “teased” was a statistically significant predictor of increased emotional problems. Because of the large sample size and the high statistical power to detect even small differences in this study, it is important to look beyond P values and consider effect size. The proportion of unique variance in problem scores attributable to teasing was rather small, about 2%. This proportion increases when the frequency of teasing is taken into account: those participants who were teased more often had more problems, and the effect size was between 4% and 5%. Juvenilization, acting independently, combined with teasing to exert a negative influence on psychosocial adaptation. To interpret the clinical significance of these effects, they must be evaluated in the context of the overall level of adaptive and maladaptive functioning in this sample. The reports of both parents and children of the psychological adaptation by short youths were generally comparable to community norms.^2,11 Thus, stresses relating to height may contribute to variability in adaptation that falls within the normal range.

Increases in growth and height induced by therapy and improved psychological adaptation

Only one controlled trial has examined the behavior of short children who were not deficient in growth hormone but had been treated with it.¹⁵ Participants were 12 to 13 years old at the time of follow up. After 5 years of growth hormone treatment, 15 children (of 21 who had started) remained in the clinical trial. This group increased in relative height from 2.4 standard deviations below the mean at the start of the trial to 1.2 standard deviations below the mean at follow up. The average height of the 13 short children who had been randomly assigned to receive no treatment remained virtually the same (changing from 2.5 standard deviations below the mean at the start to 2.4 standard deviations at follow up). Classmates of average height were also included in the analysis. Across all behavioral measures, there were no significant differences between any of the groups at recruitment or after 3 and 5 years of treatment. Although more studies are needed, it can be tentatively assumed that growth hormone therapy is not associated with changes in behavior during childhood or early adolescence. A study of short adults without growth hormone deficiency who had previously been treated with growth hormone also failed to identify a psychological benefit from treatment.¹⁶

CONCLUSIONS

Healthcare professionals are being asked to make judgments about treatments using cost-utility analyses.¹⁷ Growth hormone therapy is expensive (about $25,000 per year for a child weighing 36 kg [80 pounds]).⁷ Although it is generally safe, side effects might occur in children who do not have a deficiency and who are treated at doses that are higher than those used for patients with growth hormone deficiency.¹⁸ Less often considered on the cost side is the possibility of negative psychological effects from treatment. Expectations of increased height may outstrip what is generally possible and cause frustration and disappointment (Hunt MA, Hazen RA, Sandberg DE, unpublished data).¹⁹

Is growth hormone therapy useful? Short stature is not a disease, so objective studies of the effectiveness of treatment with growth hormone in youths with sufficient growth hormone are only partially useful in establishing utility.^7,20 The psychosocial morbidity associated with being short is assumed to be more substantial than the data summarized here would seem to indicate. The preference or value that the patient (and often the parents) ascribes to being taller is what becomes important. The types of behavioral studies summarized here are not directly applicable to children who conclude, or whose parents' believe, that their experiences and lifestyle will be hampered by being short. In such cases, clinical management would be facilitated by providing a through psychosocial evaluation of the specific stressors experienced by the child. Because of the salience of short stature, clinicians must be watchful of a process of misattribution on the part of the child, parents, or other that may distract attention from other stresses and problems in the child's life and from prescribing effective psychosocial interventions for problems of maladaptive coping.

Identifying adaptive coping strategies as an alternative, or adjunct, to growth hormone therapy should be an additional goal of such an evaluation. Gathering such detailed information is important because patients who are not deficient in growth hormone but are treated with it will reach adults heights that are still below average and in many cases are not significantly different from the predicted adult height.^7,16,20 In the pediatric endocrine clinic at our hospital, all families bringing their child for an evaluation of short stature receive a brochure on the medical and psychosocial aspects of short stature as part of the routine psychosocial assessment. The guide includes information on practical strategies for coping with being short and for achieving independence both inside and outside the home.²¹ The efficacy of this particular strategy has not been empirically tested but an intervention using cognitive behavioral techniques has shown promise.²²

The psychosocial evaluation should be provided by a mental health professional knowledgeable about the specific psychosocial problems of short stature as well as the medical issues involved. Ideally, this person would be a member of the clinical management team in the pediatric endocrinology clinic. Parents of young children are often concerned about their child's future psychosocial adjustment even if the child currently seems to have adapted successfully. The team member conducting the assessment can offer anticipatory guidance to patients and families, reassuring them that being short does not have to limit their child's happiness in the near term or the child's potential to be productive and successful as an adult. The clinician can confidently state that most healthy short children and adolescents do as well, psychologically and academically, as people of average height. Pediatricians and pediatric endocrinologists can counter negative stereotypes attributed to short stature in our society. The goal is to allay unfounded parental concerns which may be interpreted by the child as evidence that there is something wrong.

And what of those cases in which an informed decision, based on all medical and psychosocial variables, is made to treat the child with growth hormone? These patients and families would still benefit (and adherence to the medical regimen would be improved) by being prepared for the treatment and warned against having unrealistic expectations. A description of such a preparatory protocol is reported elsewhere.¹⁹