Nov 2005

Treating Short Stature with Growth Hormone, Commentary 1

Melissa D. Colsman, MA and David E. Sandberg, PhD
Virtual Mentor. 2005;7(11):727-732. doi: 10.1001/virtualmentor.2005.7.11.ccas2-0511.

Case

Mr. and Mrs. Malcolm are worried about the growth of their 5-year-old son, David. David was the shortest child in his preschool classes, and his parents worry that, as he enters kindergarten, he may be teased for his shortness. Looking ahead, they fear all kinds of other consequences; competitive sports could be closed to him, and dating and job finding could be more difficult than for his taller contemporaries. Mrs. Malcolm is 5 ft tall, and Mr. Malcolm is 5 ft 4 in. They have expressed their concerns over the course of David's last few pediatrician visits. The pediatrician, noting in David's chart that he has been approximately 3 standard deviations below the mean for height since 18 months of age, refers the Malcolms to Dr. Tyson, a pediatric endocrinologist.

Dr. Tyson orders several tests to determine whether David's short stature is due to an underlying pathology (eg, Turner's syndrome, renal insufficiency) or growth hormone deficiency. All tests come back negative. After a radiological evaluation, Dr. Tyson concludes that David has idiopathic short stature (ISS), specifically, familial short stature; he is short because his parents are short. The Malcolms are relieved that David does not have a serious illness, but their fears and concerns are not abated by Dr. Tyson's diagnosis. Mr. Malcolm recalls the pain of being a short teen and still feels that people look at him awkwardly when they first meet him. A lawyer, he prefers to do most of his initial client interviews by telephone. Mrs. Malcolm doesn't want her son to be shorter than girls his own age, and she fears that he could be psychologically scarred as he gets closer to puberty.

The Malcolms tell Dr. Tyson that they have read on the Internet that human growth hormone therapy (hGH) is safe and effective for children like their son. They are eager to get David's therapy started as soon as possible and ask Dr. Tyson to prescribe the treatment for him. When Dr. Tyson begins to tell them that most insurance companies do not cover GH therapy for ISS cases, Mr. Malcolm declares that they have decided to look at the therapy as an investment in David's future, as important as private school education, if not more so.

Commentary 1
 

The Malcolms' worries about David's future are understandable in view of the stereotypes about negative experiences of individuals with short stature [1]. The Malcolms believe their son can be spared these problems if he receives growth hormone (GH) therapy. With the possible exceptions of growth hormone deficiency (GHD) and Prader-Willi syndrome, for which metabolic benefits of GH therapy have been documented, the primary rationale for GH treatment has been that extreme short stature constitutes a physical disability and creates a significant psychosocial burden [2-5]. Thus treatment is predicated on the belief that GH-induced increases in height will improve the short individual's quality of life. The abundance of synthetic GH and uncertainty regarding the diagnosis of GHD [6], contribute to the controversy over who should receive treatment. Allen and Fost infer from the growing number of conditions for which GH is prescribed that "the cause of short stature is not morally relevant in deciding who is entitled to treatment" [7]. Instead, they argue that GH therapy is indicated not by virtue of a medical diagnosis but whenever a disability in adaptation can be attributable to short stature. Therapy should be aimed, they say, at correcting this disability through treatment up to the point that an adult height within the "normal range," ie, the 5th percentile, is attained.

Benefits versus Risks

It is assumed that GH-induced increases in stature will improve child and adolescent psychosocial adaptation and adult quality of life. Growth benefits of GH treatment for idiopathic short stature, although reliable, are modest, with an average of 4 to 6 cm gained in adult height [8]. Accordingly, many individuals with ISS remain shorter than average even with treatment. Although clinic-based studies corroborate impressions that short stature is associated with psychosocial stresses like teasing and juvenilization (ie, the tendency to misperceive the individual's age and to treat that person as younger than his or her chronological age) these same studies fail to demonstrate that the experiences are associated with psychological dysfunction [9-11]. Moreover, the relationship between negative social experiences and psychosocial adaptation was weaker than the influence of demographic variables such as parental education and marital status [9].

If youths who are shorter than average, even markedly so, are psychologically as well-adjusted as those of average height, detecting psychological benefits of GH-induced increases in growth becomes a dubious pursuit. In fact, no rigorously designed studies provide evidence demonstrating that GH treatment leads to improved psychosocial adaptation in individuals with ISS [12,13].

With regard to safety of GH, only short-term data are available for individuals receiving the doses approved by the FDA for ISS. The possibility of unforeseen risks in treating children with pharmacologic doses of recombinant human growth hormone (rhGH) [14] is particularly important to parents who report that their main concern about rhGH treatment pertains to its risks [15]. As recently noted in an editorial following the publication of 2 industry-sponsored GH safety studies in ISS [16,17], Cuttler stated that because ISS, by definition, occurs in otherwise healthy children, decision making must consider the morbidity of the untreated state and the anticipated treatment benefits [18]. If the goal of GH therapy is to maintain positive psychosocial adaptation, then evidence must first be provided that short stature is associated with significant problems for the individual and, secondly, that hormone-induced increases in growth ameliorate this situation. As already noted, evidence in support of these assumptions is nonexistent.

Age as a Factor in Clinical Decision Making

At 5 years of age, David lacks the ability to give informed assent to GH therapy; rather, his parents' decisions and their informed consent to medical care are substitutes [19]. To be effective at increasing rate of growth or final adult height, GH administration is typically recommended during childhood before bone epiphyses have fused and growth is no longer possible. Hence treatment would need to begin before David is old enough to give either informed consent or assent.

It has been argued that GH treatment of ISS is largely a cosmetic procedure aimed at augmenting or enhancing health or beauty [20,21]. This claim prompts us to ask whether parents—who have great influence in shaping their child's values, beliefs, and education—should be given the right to extend their decision-making role to physical manipulation of their child's appearance via a lengthy and burdensome medical intervention?

Information to Provide to Parents

Good ethics are predicated on good facts, and, in this instance, it is necessary to provide David's parents with those facts. This can be accomplished by addressing Mr. and Mrs. Malcolm's specific concerns.

Teasing. Some children with short stature do report being teased, but few report difficult psychosocial adaptation as a result of that teasing. Teasing is a normal childhood phenomenon [22] and should not, by itself, be considered a predictor of undesirable outcomes. Also, because growth-promoting benefits of GH treatment are modest and variable, it would be a mistake to assume that height-related teasing will cease with treatment. David's predicted height, based on his parents' average height, is below the mean for adult males, and, even with treatment, David is likely to remain one of the shorter children in his class.

Competitive sports will be closed to him. Indeed, David's size may limit his participation and success in some sports. However, we do not know how important sports are to him now, or if they will be in the future. In the event that he comes to value sports, a variety of sports exist where size is not necessarily a predictor of success (eg, swimming, diving, golf, soccer) and there are some where short stature may even be an advantage (eg, gymnastics, equestrianship).

Job finding will be difficult. Laboratory studies suggest that people hold stereotypic beliefs that shorter people earn less or are afforded less respect; however, when research is brought out of the lab and into the "real world," the effect is diminished and open to other, nonsocial interpretations [1,23]. In this case, Mr. Malcolm appears to have a successful law practice and has found a way to cope with his perceived difficulties.

David will be shorter than girls his age and dating will be difficult.Throughout childhood girls are normally taller than boys because girls enter puberty and achieve their "growth spurt" earlier than boys. The adult sex dimorphism in height (of approximately 5 inches) is related to the later onset of male puberty [24].

With regard to heterosexual dating and partner selection, although a taller male preference exists, this does not preclude shorter men from dating or marriage. Again, there is a laboratory versus real-world difference. For example, Hensley found evidence that, when asked what about the height of an "ideal partner," women preferred taller men and men preferred shorter women; however, the magnitude of this preference was reduced when men and women were asked to report their own heights and that of their current partners [25]. Hensley concluded that shorter men are not necessarily disadvantaged; David's parents are another case in point. Moreover, given that, in the general population, men are taller than women by an average of 5 inches, David, with a mid-parental target height of 5 ft 5 in, would be taller than about half of adult women.

Enhancement Medicine

It can be argued that short stature, unless proven otherwise in the individual case, is a matter of normal variation. The FDA-approved indication of GH treatment for ISS qualifies individuals more than 2.25 standard deviations below the mean for age and sex, or the shortest 1.2 percent of children. If all children under the first percentile received GH therapy, this would shift the mean height and create a new population of those below the first percentile, who would then be eligible to receive treatment and would create a new population below the first percentile, and so on and so on.

One factor that might prevent this "creeping norm" from occurring is cost. Cost does not appear to be an issue for the Malcolm family, so it will not be addressed here other than to say that, given the expense of this treatment regimen (the annual cost for 1 child weighing 30 kg is approximately $15 000 to $20 000 [7] with higher pubertal doses that can exceed $50 000 per year [26]), it is largely inaccessible to any family for whom it is not covered by health insurance. On the societal level, this would have the effect of selectively distributing short stature to the less wealthy or uninsured [19,27].

Role for the Pediatric Endocrinologist

David's parents came in with a diagnosis, prognosis, and treatment plan in mind: that their son (1) has short stature, (2) will suffer from psychosocial problems similar to those of his father who attributes his problems to his own short stature, and (3) needs GH injections so that he is no longer "short" and will, therefore, not experience the associated psychosocial problems. This declaration places the physician in an uncomfortable situation—the parents are asking the physician to rely entirely on their report and treat a psychosocial problem (that is not currently in evidence) with a lengthy pharmacological treatment for which informed assent from the child cannot be obtained.

Pediatric endocrinologists and other health care professionals can be instrumental in countering negative stereotypes attributed to short stature as well as allaying parental concerns which are unfounded and which may be interpreted by a child as evidence that there is something "wrong" with him or her. The physician might recommend counseling for the Malcolms to discuss their unrealistic expectations about the auxologic benefits of GH treatment in GH-sufficient youth [8]. They would also be reassured that, based on the empirical literature, short stature need not limit David's range of interests, experiences, or accomplishments. Should problems emerge, discussions of ways to cope with those problems, possibly with the assistance of a pediatric psychologist, can be helpful. Recommending that the family seek counseling may make the Malcolms feel as though they have not been heard; that the pediatric endocrinologist is recommending a psychosocial treatment for a problem they define as physical/medical. However, the converse is also true: focusing solely on the physical, medical, and pharmacological aspects limits treatment options for addressing the psychosocial adaptation problems, if, in fact, they occur.

References

  1. Sandberg DE, Colsman M, Voss LD. Short stature and quality of life: a review of assumptions and evidence. In: Pescovitz OH, Eugster E, eds. Pediatric Endocrinology: Mechanisms, Manifestations, and Management. Philadelphia, Pa: Lippincourt, Williams & Wilkins; 2004:191-202.
  2. Vance ML, Mauras N. Growth hormone therapy in adults and children. New Engl J Med. 1999;341(16):1206-1216.
  3. Carrel AL, Moerchen V, Myers SE, Bekx MT, Whitman BY, Allen DB. Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome. J Pediatr. 2004;145(6):744-749.
  4. Cassidy SB. Prader-Willi syndrome in the new millennium. Endocrinologist. 2001;10(suppl 1):1S-73S.

  5. Sandberg DE, Voss LD. The psychosocial consequences of short stature: a review of the evidence. Best Pract Res Clin Endocrinol Metab. 2002;16(3):449-463.
  6. Rosenfeld RG. Is growth hormone deficiency a viable diagnosis? J Clin Endocrinol Metab. 1997;82:349-351.

  7. Allen DB, Fost N. hGH for short stature: ethical issues raised by expanded access. J Pediatr. 2004;144(5):648-652.
  8. Finkelstein BS, Imperiale TF, Speroff T, Marrero U, Radcliffe DJ, Cuttler L. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med. 2002;156(3):230-240.
  9. Sandberg DE, Michael P. Psychosocial stresses related to short stature: does their presence imply psychiatric dysfunction? In: Drotar D, ed. Assessing Pediatric Health-Related Quality of Life and Functional Status: Implications for Research. Mahwah, NJ: Lawrence Erlbaum Associates; 1998:287-312.

  10. Zimet GD, Cutler M, Litvene M, Dahms W, Owens R, Cuttler L. Psychological adjustment of children evaluated for short stature: a preliminary report. J Dev Behav Pediatr. 1995;16(4):264-270.
  11. Sandberg DE, Brook AE, Campos SP. Short stature: a psychosocial burden requiring growth hormone therapy? Pediatrics. 1994;94:832-840.

  12. Ross JL, Sandberg DE, Rose SR, et al. Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. J Clin Endocrinol Metab. 2004;89(10):4873-4878.
  13. Theunissen NC, Kamp GA, Koopman HM, Zwinderman KA, Vogels T, Wit JM. Quality of life and self-esteem in children treated for idiopathic short stature. J Pediatr. 2002;140(5):507-515.
  14. Slyper A. The safety and effectiveness of human growth hormone using pharmacological dosing. Med Hypotheses. 1995;45(6):523-528.
  15. Finkelstein BS, Singh J, Silvers JB, Marrero U, Neuhauser D, Cuttler L. Patient attitudes and preferences regarding treatment: GH therapy for childhood short stature. Horm Res. 1999;51(Suppl 1):67-72.

  16. Quigley CA, Gill AM, Crowe BJ, et al. Safety of growth hormone treatment in pediatric patients with idiopathic short stature. J Clin Endocrinol Metab. 2005;90(9):5188-5196.
  17. Kemp SF, Kuntze J, Attie KM, et al. Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature. J Clin Endocrinol Metab. 2005;90(9):5247-5253.
  18. Cuttler L. Editorial: safety and efficacy of growth hormone treatment for idiopathic short stature. J Endocrinol Metab. 2005;91(9):5502-5504.
  19. Diekema DS. Is maximizing height good parenting? Endocrinologist. 2001;11(4, Suppl 1):67S-71S.

  20. Lantos J, Siegler M, Cuttler L. Ethical issues in growth hormone therapy. JAMA. 1989;261(7):1020-1024.
  21. Tauer CA. The NIH trials of growth hormone for short stature. IRB. 1994;16(3):1-9.
  22. Keltner D, Capps L, Kring AM, Young RC, Heerey EA. Just teasing: a conceptual analysis and empirical review. Psychol Bull. 2001;127(2):229-248.
  23. Barker DJ, Eriksson JG, Forsen T, Osmond C. Infant growth and income 50 years later. Arch Dis Child. 2005;90(3):272-273.
  24. Reiter EO, Rosenfeld RG. Normal and aberrant growth. In: Larsen RP, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. Philadelphia, Pa: Saunders; 2003:1003-1114.

  25. Hensley WE. Height as a basis for interpersonal attraction. Adolescence. 1994;29(114):469-474.
  26. Mauras N, Attie KM, Reiter EO, Saenger P, Baptista J. High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group. J Clin Endocrinol Metab. 2000;85:3653-3660.

  27. Pauly M. Access to growth hormone therapy: an economist's perspective. Endocrinologist. 2001;11(4, Suppl 1):47S-55S.

Citation

Virtual Mentor. 2005;7(11): 727-732.

DOI

10.1001/virtualmentor.2005.7.11.ccas2-0511.

The people and events in this case are fictional. Resemblance to real events or to names of people, living or dead, is entirely coincidental. The viewpoints expressed on this site are those of the authors and do not necessarily reflect the views and policies of the AMA.