SPECIAL ARTICLE
Lippe and Frasier (J PEDIATRt989;115:585-7) recently reviewed the current status of tests for growth hormone deficiency, and indications for treatment. Allen and Fost now approach the issue from an ethical and philosophical Standpoint. We hope tha t their arguments will contribute to the debate regarding the appropriate use of recombinant growth hormone. Interested readers may benefit from comparing another recent look at this issue (Underwood LE, Rieser PA: Is it ethical to treat healthy short children with growth hormone? Acta Paediatr Scand Suppl 1989;362:I8-23).--J.M.G., Editor
Growth hormone therapy for short stature: P a n a c e a or Pandora's box? David B. Allen, MD, a n d N o r m a n C. Fost, MD, MPH From the Department of Pediatrics, University of Wisconsin Medical School, Madison Increased availability of growth h o r m o n e ( G H ) b e c a u s e of increased production using r e c o m b i n a n t DNA t e c h n o l o g y has led to increased d e m a n d . Many children who do not have classic GH d e f i c i e n c y may respond to GH therapy. These observations require rethinking of the m e d i c a l indications for GH therapy, and raise two central ethical questions: (1) Is it justified to discriminate on the basis of GH deficiency? (2) Whatever the indication for GH treatment, at what height should GH therapy be considered an entitlement? We argue, first, that GH responsiveness not GH deficiency, should be the criterion for GH treatment, and thal prior arguments emphasizing GH d e f i c i e n c y are based on v a g u e or faulty notions of disease, handicap, or potential. Second, we argue that children who are h a n d i c a p p e d (arbitrarily d e f i n e d as including those whose height is b e l o w the Ist percentile) and GH responsive are entitled t o treatment. Children a b o v e that height, whether GH deficient or not, may permissibly be treated, but there is no societal o b l i g a t i o n to do so. Such an a p p r o a c h would reduce, though not eliminate, some of the more severe burdens of short stature without a g g r a v a t ing the pernicious effects of "heightism" in American society. (J PED|ATR 1990;147:16-24)
Limited availability of growth hormone once provided a barrier to its expanded use in non-GH-deficient children. An increased supply of recombinant DNA-derived G H has now created an increased demand, but the more G H we have, the less we agree about who should receive it. While costs are high, benefits unclear; and toxic effects uncertain, prescribing G H for non-GH deficient children outside of research protocols should be resisted.1 However, it now apSubmitted for publication Sept. 29, 1989; accepted Dec. 21, 1989. Reprint requests: David B. Allen, MD, Department of Pediatrics, University of Wisconsin Hospital, 600 Highland Ave., Madison, WI 53792. 9/19/20403
16
pears plausible that many non-GH-deficient children may respond to G H therapy and that the future market for G H will expand dramatically beyond the boundaries of classic G H deficiency. We acknowledge that reports of G H efficacy in these I
GH
Growth hormone
]
children are preliminary and in need of further study. An equally important task, however, is to examine why the many potential uses of G H are being studied so intensively. What is our goal in "treating" short stature? Who is entitled to costly growth-promoting therapy and for how long?
GH therapy for short stature
Volume 117 Number 1, Part 1
Consideration of these questions should be guiding our research and not following on the heels of it. In anticipation of more widespread use of GH, we argue that (1) GH responsiveness, not GH deficiency, should be a criterion for 6t4 therapy; (2) the primary goal of GH therapy should be to alleviate the handicap of short stature, rather than the treatment of GH deficiency; and (3) responsible distribution of and reimbursement for GH therapy should be guided by criteria of GH responsiveness and handicap, and not by a child's diagnosis. GROWTH HORMONE DEFICIENCY, INSUFFICIENCY, AND RESPONSIVENESS Two clinical observations are central to an analysis of the ethical issues regarding use of GH. First, there is no clear boundary between GH deficiency and sufficiency.2 Responses to stimulation tests do not mirror endogenous G H secretion. 3 A continuum of "inadequate" GH secretion spans classically and partially GH-defieient children, children with constitutional growth and pubertal delay,4 and other poorly growing short children s who pass provocative tests but nevertheless secrete less GH than their peers. 6 Thus a poorly growing child who achieves a normal growth rate with GH therapy would meet a functional definition of GH "insufficiency" regardless of diagnostic test results. Second, many children with idiopathic short stature have an initial clinical response to GH therapy similar to that of GH-deficient children, v-l~ Although physiologic explanations for this response have been proposed, v, 11-15 in most children with severe familial or idiopathic short stature, the only known "defect" is inheritance of a growth velocity persistently below the 50th percentile for age, resulting in adult short stature. Since genetically determined patterns of GH secretion and response may influence growth velocity as much as the amount of GH secreted, predicting GH responsiveness on the basis of GH concentrations (as opposed to a therapeutic trial) is arbitrary and impractical. Similarly, response to GH therapy does not necessarily imply GH deficiency. Augmentation of normal GH secretion (e.g., pituitary gigantism) can increase growth velocity and eventual height. GH-treated girls with Turner syndrome grow faster than control subjects] 6 and several have already exceeded their previously predicted adult height. 17 Growth rates of children with idiopathic short stature also increase with G H therapy, 18 although a beneficial effect on final adult height is less certain. 19, 2o Thus there is evidence that GH supplementation in many non-GH-deficient short children will increase short-term growth velocity and may increase eventual adult height.
HEIGHTISM THERAPY
AND ENTITLEMENT
17
T O GH
Parental concern about disadvantages of their child's short stature is legitimated by a "heightist" premise in modern America: to be tall is good and to be short is to be stigmatized. 2~ Discrimination based on height--"heightism"--pervades American life. 22,23 Mate selection for short males and tall females is difficult. Job recruiters prefer the taller of equally qualified candidates, and business school graduates more than 6 feet tall receive a starting salary 12.4% higher than that shorter graduates receive. 24 The taller candidate for president has won 80% of elections in this century, and of all the presidents, only two have been shorter than average for an American man at the time of election. Stigmatization based on height begins in childhood. Although conclusive causative evidence is lackingY school problems occur more often in growth-retarded children. 26 Parents and teachers interact differently with short and tall children of the same age, accounting, in part, for a positive association between height and either IQ scores or academic achievement.2v,28 Feelings of incompetence and low selfesteem often arise from the short child's struggle with stature, 29 although these problems may depend as much on the projection of parental perceptions of their child's vulnerability and immaturity as on short stature per se. 3~ It is not surprising that parents striving for an athletic or social competitive edge for their short child seek growthpromoting therapy. However, it is questionable whether children made taller enjoy the social advantages of being tall. Adults treated with GH during childhood, although presumably better off than they would have been without GH, continue to have lower self-esteem, lower rates of employment, 31 and less marital success than the general population. 32 Disappointment often occurs when final results of GH therapy fall short of unrealistic expectations. Paradoxically, parents who are most desirous of obtaining GH for their child may confirm by their actions what his classmates' teasing suggests--that he would be a better person if he were taller. 33 Awareness of a continuum of GH secretory capabilities, a large population of short, healthy, but potentially GH-responsive children, and the disadvantages of short stature in our society will bring pressure on physicians to expand the use of GH beyond the unequivocally GH-deficient population. However the remaining medical questions about efficacy and toxicity are resolved, there will be substantial numbers of GH-responsive but non-GH-deficient children whose parents will request treatment. This demand will require a rational response to a series of ethical and policy questions: Who is entitled to such treatment? What
18
Allen and Fost
The Journal of Pediatrics July 1990
ultimate height should be the goal of treatment, regardless of the underlying diagnosis? Who should decide? Should public financing of such treatment be supported? Developing a consensus about the proper use of GH begins with a consensus about the goals of our therapy. If the goal is to alleviate the disability of extreme short stature, we should treat GH-responsive, short, healthy children only until they reach a height within the normal range. On the other hand, if the goal is to achieve each child's maximum height potential, GH therapy should be offered to any potentially responsive short child. As a starting point for the debate and analysis that are needed, and recognizing the limitations of predicting eventual adult height, we propose the following conceptual guidelines: 1. Children (desiring treatment) who have a predicted adult height that is likely to be handicapping (e.g., below the 1st percentile) are entitled to a trial of GH. 2. Treated children who increase their height velocity by at least 2 cm/yr (i.e., who are GH responsive) may continue to receive GH. 3. Like all children with handicapping conditions, these markedly short children are entitled to such treatment, through private insurance or public expense if necessary, until a height no longer considered a handicap (e.g., at the 5th percentile) is attained. 4. Parents of children who do not meet these criteria may seek such treatment. They are not entitled to public funds, and private insurance companies should be discouraged from supporting such treatment. Physicians may choose to treat such children but have no duty to do so. The following discussion defends these guidelines through three arguments: (1) Traditional concepts of disease, handicap, and potential do not distinguish GH-deficient from potentially GH-responsive children with regard to entitlement to GH therapy. (2) Psychologic and financial burdens and potential medical risks make GH responsiveness a necessary, but not sufficient, criterion for treatment. (3) Responsible, ethical use of GH begins with defining the goals of growth-promoting therapy (e.g., attainment of "nonhandicapping" height) and preferentially allocating financial and medical resources toward the alleviation of severe, handicapping short stature regardless of cause. DISEASE,
HANDICAP,
AND POTENTIAL
The American Academy of Pediatrics recommends GH therapy only for GH-deficient children, with carefully controlled clinical trials in non-GH-defieient children. The Academy statement concluded with the old adage "If it ain't broke, don't fix it. ''34 But what exactly is "broke" when it comes to short stature and G H therapy? As described above, "broke" cannot be defined simply by GH deficiency,
because given enough GH, most children's growth rate and, perhaps, ultimate height can be increased. "Broke" in the context of short stature should encompass the psychologic stress and societal prejudice shared by GH-deficient and GH-sufficient short children, and the possibility that both can benefit from GH therapy. From this perspective, consider the following cases: Johnny is a short 11-year-old boy with documented GH deficiency resulting from a brain tumor. His parents are of average height. His predicted adult height without GH treatment is approximately 160 cm (5 feet 3 inches). Billy is a short ll-year-old boy with normal GH secretion according to current testing methods. However, his parents are extremely short, and he has a predicted adult height of t 60 cm (5 feet 3 inches). Who is entitled to treatment with GH? A common response to this question hinges on whether either child has a disease, "an abnormal condition of an organism that impairs normal physiological functioning. ''35 Johnny, who lacks GH and is growing slowly, appears to meet this criterion, whereas Billy does not. To some, treating disease and restoring health, the "well-working of the organism as a whole," is the proper aim of medicine. 36 Supplementing deficient or suppressing excessive levels of hormones, and thus restoring what is perceived as normal hormonal equilibrium, is said to be justified. This narrow view, however, assumes that no physiologic "defect" leads to genetic short stature and excludes psychosocial well-being in considering the "well-working" of the individual. According to the definition quoted, both children have the disease of short stature. If we ask, instead, whether either of these children has a handicap, "a disadvantage or deficiency, especially a physical or mental disability that prevents or restricts normal achievement, ''35 the legitimate function of medicine is expanded. Now a child's well-being is viewed in the context of the environment with which he or she interacts. Administration of GH to very short, GH-responsive patients (e.g., Turner syndrome patients) is justified by the recognition that their extreme short stature can interfere with "normal" activities such as reaching shelves and driving a car. Both boys described above, however, have a height prognosis that exceeds this threshold. Have they then exceeded the point at which short stature is a handicap? Not if we recall that subnormal height imposes a disadvantage in the competition for schools, jobs, income, and mates. Whether these burdens qualify for the designation of handicap is not the central question. However that question is resolved, Johnny and Billy would have the same handicap regardless of the cause of their short stature. A third basis for distinguishing the cases might be potential, based on the Aristotelian notion that each person is in-
Volume 117 Number 1, Part I
GH therapy f o r short stature
tended to be a certain heigtit, which is part of the definition of that person. Johnny, one might argue, is entitled to G H therapy because, in contrast to Billy, he is meant, by virtue of genetic endowment from taller parents, to be taller. Billy is not entitled to GH therapy because to make him taller than his genetically predicted height would be taking him "beyond his potential" (i.e., "tampering with nature"). This analysis fails, however, because although Johnny's ultimate height may be potentially greater than Billy's, to help either child reach his maximum height requires "tampering with nature" in the same way--treating with GH. In summary, the concepts of disease, handicap, and potential do not distinguish between GH-responsive children, one of whom is G H deficient and one who is not. The analysis suggests that children who are GH responsive are equally entitled to GH treatment. It does not follow, however, that all GH-responsive children are entitled to treatment. Resolving that question requires consideration of balancing benefits and risks and asking further questions about allocation of health care resources. BALANCING
BENEFITS
AND BURDENS
We have argued that the cause of short stature is less relevant than its responsiveness to treatment in deciding who is entitled to treatment. But there are other considerations. Responsiveness to GH is not an "all or none" phenomenon. In response to the same treatment, one child may add 20 cm to his adult height, and another, 3 to 5 cm. If the purpose of treatment is better psychosocial adaptation, some benefits may be statistically significant but psychologically meaningless because the increment in adult height is so marginal. It is probable that GH-deficient children will in general be more responsive than non-GH-deficient children and therefore will be more appropriate recipients of treatment as a class. As a practical matter, it may be difficult to predict which non-GH-deficient children will achieve a sufficient increase in height to warrant treatment. Decisions about treatment are always based on probability, not certainty, and this pragmatic consideration is one factor in support of preferential treatment for the GH-deficient child. This factor would have little weight if treatment were riskless and free, but that will never be the case. Widespread distribution of GH has been deterred in part by high drug prices and concern about toxicity, impediments that may be resolved soon. Increased competition for an expanding patient population should decrease the price of GH. Theoretic adverse effects of GH therapy (e.g., impaired glucose toelrance, 37 hyperlipidemia, and production of growthattenuating antibodies) 3s have proved to be exceedingly rare among thousands of GH-treated children. The possibly increased risk of leukemia in GH-deficient children
19
treated with G H 39 is small (about 1/20,000) if it exists at all .40 Nevertheless, there should be concern about psychosoeial risks of treatment itself. A short, otherwise normal child who receives thrice-weekly injections to promote growth may be stigmatized because of the implication that his body is unacceptable in his parents' and physicians' eyes. Promoting a supportive and nurturing home environment, 41 rather than GH treatment, may be more effective in achieving a well-adjusted self-concept. Arguably, the GHdeficient child is more likely to view GH therapy as a deserved restoration of normal bodily function. For both children, however, dependence on exogenous hormones for growth sends the same message: shortness (and implicitly each of them) is bad. It is unclear at present whatthe precise benefits and risks of GH treatment will be. Itis likely that the risks will be low. Providing G H therapy only to those with documented GH deficiency and treating them to maximal adult stature is unfair to equally short, non-GH-deficient children who could grow with G H supplementation. If we assume that there is substantial benefit for many non-GH-deficient children, ethical and policy issues remain regarding entitlement to such treatment. TOWARD
RESPONSIBLE
USE OF Gtt
Assuming that clinical trials of G H in non-GH-deficient children show efficacy with acceptable risk, pediatricians and third-party payers must decide who should be candidates for G H treatment and how much treatment is appropriate. Benefit with acceptable risk may not be a suff• basis for providing GH treatment, because some children of above-average height can "benefit" from additional height. The debate over anabolic steroid use to achieve a competitive advantage comes quickly to mind. Some advocate restriction of steroids because of paternalistic concerns about harm, but the major objection appears to be the belief that the use of hormonal augmentation to "redefine" one's potential is unethical, and not the proper province of medicine. These objections have been attacked, 42 but there is broad consensus against such prescribing. One way to avoid moral judgments about who is entitled to treatment would be to consider every child who wants to be taller, whether a 6-foot-tall basketball prospect or a 5foot-tall GH-deficient child, as a candidate for GH. The net effect of "universal" treatment would be to shift the bell-shaped curve of height upward, probably without changing the handicap for those at the lower percentiles in comparing for social, professional, and athletic status. The average height of the excluded would be higher, but the disappointment and lost opportunity would be the same.
20
Allen and Fost
Another approach would be to classify G H treatment as a privilege, not a right, and therefore available to those who can pay but not owed to those who cannot. Many benefits are unevenly distributed in a free society without implying injustice. A society has a duty to provide the basic needs of food, shelter, clothing, education, and perhaps even health care to its citizens, but there is not a duty to provide the very best opportunity for all. Such a goal is unattainable, and an insistence on equality leads only to a reduction in benefits for all. This approach has two problems. First, it would increase the inequality in society, because those already well off would gain even more advantage with greater access to GH. Second, it ignores the fact that, for some children, G H treatment is a necessity, not a luxury. For these extremely short children, whose height is below the 1st percentile, the severity of their handicap creates unreasonable obstacles to success because of inability to drive a car or reach knobs and switches, or because of profound stigmatization. The challenge is to define this group for whom short stature is a severe handicap. The definition of "handicapping height" would be arbitrary, but the difficulty in defining boundaries precisely should not be an obstacle to making distinctions. The guidelines outlined earlier endorse the effort to lessen disadvantages of extreme short stature, regardless of pathogenesis, by bringing such children closer to or within the normal range. The attainment of maximum height potential is not a valid treatment goal, and the use of G H to make normal-statured children taller is opposed. Our proposed policy would alter the normal range of height only slightly, and the medical profession's unintended contribution to heightism would be minimized. CONCLUSIONS Increased availability of a virtually unlimited supply of safe G H has raised new questions about the indications for its use and about entitlement to therapy. If clinical trials show efficacy in non-GH-deficient children, there would be no coherent ethical basis for defining access by G H deficiency. Rather, G H responsiveness should be the central criterion in considering candidates for treatment. Whatever percentile is considered "tall enough" for GH-deficient children should also apply to non-GH-deficient children. Access to potentially efficacious G H cannot be ethically denied to them simply because they lack G H deficiency. However, because of the enormous expense, and because of concerns that universal access would not ameliorate the disadvantages of short stature, it is appropriate to restrict access, even within the group of GH-responsive children. As a starting point, we propose that treatment be limited to those for whom height is not merely a relative disadvan-
The Journal of Pediatrics July 1990
tage but a serious h~ndicap, arbitrarily defined as below the 1st percentile. We do not insist that the 1st percentile is the correct boundary or claim that there is a distinct boundary. The central point is that handicap and G H responsiveness should be the criteria for treatment, not the cause of handicap or the ability to pay. The paradox of G H therapy is that no policy regarding its use will ever eliminate the 1st percentile. The proposed policy can, however, reduce the standard deviation of height so that those in the lowest percentiles differ less strikingly from the rest and are less handicapped in a world where cars and switches are designed for those who have achieved a certain height. Most important, height is not a reliable predictor of happiness and self-esteem. Growth hormone cannot replace parental love and nurturing of a child, regardless of his height. Prudent use of G H will recognize these limitations. The most effective response to heightism is a concerted effort to reveal and rectify it, not unrestricted use of G H . 43 The effective physician should respond to concerns about short stature more often with counseling than with injections. Whatever policy we develop, it will be easier to discuss it rationally before the expanded G H era is on us. The potential of a billion-dollar industry will inevitably distort critical thinking. It will be much more difficult to reverse practices after they have been established. The uses and abuses of G H need not, like the contents of Pandora's box, escape all at once in our haste to open the lid. REFERENCES
1. Lantos J, Siegler M, Cutler L. Ethical issues in growth hormone therapy. JAMA 1989;261:1020-4. 2. Hindmarsh P, Smith PH, Brook CGD, et al. The relationship between height velocity and growth hormone secretion in short prepubertal children. Clin Endocrinol 1987;27:581-91. 3. Rose SR, Ross JL, Uriarte M, et al. The advantage of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency. N Engl J Med 1988;319:201-7. 4. Martin LG, Grossman MS, Connor TB, et al. Effect of androgen on growth hormone secretion and growth in boys with short stature. Acta Endocrinol 1979;91:201-12. 5. Costin G, Kaufman FR. Growth hormone secretory patterns in children with short stature. J PEDIATR 1987;110:362-8. 6. Zadik A, Chalew SA, Raiti S, et al. Do short children secrete insufficient growth hormone? Pediatrics 1985;76:355-60. 7. Van Vliet G, Styne DM, Kaplan SL, et al. Growth hormone treatment for short stature. N Engl J Med 1983;309:1016-22. 8. Gertner JM, Genel M, Gianfredi SP, et al. Prospective clinical trial of human growth hormone in short children without growth hormone deficiency. J PEmATR 1984;104:172-6. 9. Johanson A J, Blizzard R, Cara J, and the National Collaborative Group Genentech Inc. Idiopathic short stature (ISS) characterization and response to growth hormone [Abstract 19]. Symposium III of the Genentech Cooperative Growth Study, Palm Desert, Calif., Oct 1988.
Volume l 17 ?Cumber 1, Part 1
10. Lin T, Kirkland RT, Kirkland J. Growth hormone treatment of "normalr" short children [Abstract 18]. Symposium llI of the Genentech National Cooperative Growth Study, Palm Desert, Calif., Oct 1988. 11. Bercu BB, Shulman D, Root AW, et al. Growth hormone provocative testing frequently does not reflect endogenous growth hormone secretion. J Clin Endocrinol Metab 1986;63:709-16. 12. Grunt JA, HowardC, DaughadayWH. Comparison of growth and somatomedin responses following growth hormone treatment in children with small-for-dates short stature, significant idiopathic short stature, and hypopituitarism. Acta Endocrinol 1984;106:168-74. 13. Rudman D, Kutner MH, Goldsmith MA, et al. Further observation on four subgroups of normal variant short stature. J Clin Endcrinol Metab 1980;51:1378-83. 14. Wise PH, Burnet RB, Geary TD, et al. Selective impairment of growth hormone response to pharmacological tests. Arch Dis Child 1975;50:210-4. 15. Lanes P, Plotnick LP, Spencer ME, et al. Dwarfism associated with normal serum growth hormone and increase bioassayable receptor-assayable and immuno-assayable somatomedin. J Clin Endocrinol Metab 1980;50:485-8. 16. Rosenfeld RG, Hintz RL, Johanson A J, et al. Three-year resuits of a randomized prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome. J PED1ATR i988;113:393-400. 17. Lippe B. Growth hormone treatment of girls with Turner syndrome: changing the shape of the "Turner growth curve" [Abstract 8]. Symposium IV of the Genentech National Cooperative Growth Study, palm Desert, Calif., Oct 1989:23-5. 18. Genentech Collaborative Study Group. Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. J PEDIATR 1989;115:713-9. 19. Kaplan SL, Grumbach MM. Long-term treatment with growth hormone of children with non-growth hormone deficient short stature. In: lsaksson O, et al, eds. Growth hormone: basic and clinical aspects. New York: Elsevier Science, 1987. 20. Wit JM, Fokker MH, de Muinck Keizer-Schrama MPF, et al. Effects of two years of methionyl growth hormone therapy in two dosage regimens in prepubertal children with short stature, subnormal growth rate, and normal growth hormone response to secretagogues. J PEDIATR 1989;115:720-5. 21. Feldman SD. The presentation of shortness in everyday life: height and heightism in American society--toward a sociology of stature. In: Feldman SD, ed. Life-styles: diversity in American society. Boston: Little, Brown, 1975:437-42. 22. Schnmacher A. On the significance of stature in human society. J Hum Evol 1982;11:697-701. 23. Gillis JS. Too tall, too small. Champaign, Ill.: Institute for Personality and Ability Testing, 1982:9-25. 24. Deck L. Short workers of the world unite. Psychology Today 1971;5:t02. 25. Richards GE, Marshall RN, Kreuser IL. Effect of stature on school performance. J PEDIATR 1985;107:841-2.
G H therapy f o r short stature
21
26. Holmes CS, Hayford JT;Thompson RG. Parents' and teachers' differing views of short children's behavior. Child Care Health Dev 1982;8:327-36. 27. Wilson DM, Duncan PM, Dornbusch SM, et al. The effects of growth on intellectual function in children and adolescents. In: Stabler B, Underwood L, eds. Slow grows the child. London: Lawrence Erlbaum Associates, 1986. 28. Wilson DM, Duke PM, Dornbusch SM, et al. Height and intellectual development [Abstract]. Pediatr Res 1984; 18:100A. 29. Holmes CS, Hayford JT, Thompson RG. Personality and behavior differences in groups of boys with short stature. Children's Health Care 1982;11:61-4. 30. Rotnem D, Genel M, Hintz R!~, et al, Personality development in children with growth hormone deficiency. J Am Acad Child Psychiatry 1977;16:412-26. 31. Dean H J, McTaggart TL, Fish DG, et al. The educational, vocational, and marital status of growth hormone deficient adults treated with growth hormone during childhood. Am J Dis Child 1985;139:1105-10. 32. Mitchell CM, Joyce S, Johanson AJ, et al. A retrospective evaluation of psych0social impact of long-term growth hormone therapy. Clin Pediatr 1986;25:17-23. 33. Diekema DS: Is taller really better? growth hormone therapy in short children. Perspect Biol Med (in press). 34. Ad Hoc Committee on Growth Hormone Usage, The Lawson Wilkins Pediatric Endocrine Society, and Committee on Drugs, American Academy of Pediatrics. Growth hormone in the treatment of children with short stature. Pediatrics 1983;72:891-4. 35. American Heritage Dictionary. Boston: Houghton Mifflin, 1985. 36. Kass LR. Regarding the end of medicine and the pursuit of health. Public Interest 1975;No. 40:13 f. 37. Davidson MG. Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 1987;8:115-31. 38. Moore WV, Leppert P. Role of aggregated human growth hormone (hGH) in development of antibodies to hGH. J Clin Endocrinol Metab 1981 ;51:691-701. 39. Report of International Workshop on Growth Hormone and Leukemia. Bethesda, Md.: Lawson Wilkins Pediatric Endocrine Society and Human Growth Foundation of the United States, March 5, 1988. 40. Fisher DA, Job J-C, Preece M, et all Leukemia in patients treated with growth hormone. Lancet 1988;1:1159-60. 41. Young-Hyman D. Effects of short stature on social competence. In: Stabler G, Underwood LE, eds. Slow grows the child. Hillsdale, N.J.: Lawrence Erlbaum Associates, 1986. 42. Fost NC. Banning drugs and sports: a skeptical view. Hastings Cent Rep 1986;16(4):5-10. 43. Benjamin M, Muyskens J, Sacnger P. Short children, anxious parents: is growth hormone the answer? Hastings Cent Rep 1984;14(2):5-9.
Lippe and Frasier (J PEDIATRt989;115:585-7) recently reviewed the current status of tests for growth hormone deficiency, and indications for treatment. Allen and Fost now approach the issue from an ethical and philosophical Standpoint. We hope tha t their arguments will contribute to the debate regarding the appropriate use of recombinant growth hormone. Interested readers may benefit from comparing another recent look at this issue (Underwood LE, Rieser PA: Is it ethical to treat healthy short children with growth hormone? Acta Paediatr Scand Suppl 1989;362:I8-23).--J.M.G., Editor
Growth hormone therapy for short stature: P a n a c e a or Pandora's box? David B. Allen, MD, a n d N o r m a n C. Fost, MD, MPH From the Department of Pediatrics, University of Wisconsin Medical School, Madison Increased availability of growth h o r m o n e ( G H ) b e c a u s e of increased production using r e c o m b i n a n t DNA t e c h n o l o g y has led to increased d e m a n d . Many children who do not have classic GH d e f i c i e n c y may respond to GH therapy. These observations require rethinking of the m e d i c a l indications for GH therapy, and raise two central ethical questions: (1) Is it justified to discriminate on the basis of GH deficiency? (2) Whatever the indication for GH treatment, at what height should GH therapy be considered an entitlement? We argue, first, that GH responsiveness not GH deficiency, should be the criterion for GH treatment, and thal prior arguments emphasizing GH d e f i c i e n c y are based on v a g u e or faulty notions of disease, handicap, or potential. Second, we argue that children who are h a n d i c a p p e d (arbitrarily d e f i n e d as including those whose height is b e l o w the Ist percentile) and GH responsive are entitled t o treatment. Children a b o v e that height, whether GH deficient or not, may permissibly be treated, but there is no societal o b l i g a t i o n to do so. Such an a p p r o a c h would reduce, though not eliminate, some of the more severe burdens of short stature without a g g r a v a t ing the pernicious effects of "heightism" in American society. (J PED|ATR 1990;147:16-24)
Limited availability of growth hormone once provided a barrier to its expanded use in non-GH-deficient children. An increased supply of recombinant DNA-derived G H has now created an increased demand, but the more G H we have, the less we agree about who should receive it. While costs are high, benefits unclear; and toxic effects uncertain, prescribing G H for non-GH deficient children outside of research protocols should be resisted.1 However, it now apSubmitted for publication Sept. 29, 1989; accepted Dec. 21, 1989. Reprint requests: David B. Allen, MD, Department of Pediatrics, University of Wisconsin Hospital, 600 Highland Ave., Madison, WI 53792. 9/19/20403
16
pears plausible that many non-GH-deficient children may respond to G H therapy and that the future market for G H will expand dramatically beyond the boundaries of classic G H deficiency. We acknowledge that reports of G H efficacy in these I
GH
Growth hormone
]
children are preliminary and in need of further study. An equally important task, however, is to examine why the many potential uses of G H are being studied so intensively. What is our goal in "treating" short stature? Who is entitled to costly growth-promoting therapy and for how long?
GH therapy for short stature
Volume 117 Number 1, Part 1
Consideration of these questions should be guiding our research and not following on the heels of it. In anticipation of more widespread use of GH, we argue that (1) GH responsiveness, not GH deficiency, should be a criterion for 6t4 therapy; (2) the primary goal of GH therapy should be to alleviate the handicap of short stature, rather than the treatment of GH deficiency; and (3) responsible distribution of and reimbursement for GH therapy should be guided by criteria of GH responsiveness and handicap, and not by a child's diagnosis. GROWTH HORMONE DEFICIENCY, INSUFFICIENCY, AND RESPONSIVENESS Two clinical observations are central to an analysis of the ethical issues regarding use of GH. First, there is no clear boundary between GH deficiency and sufficiency.2 Responses to stimulation tests do not mirror endogenous G H secretion. 3 A continuum of "inadequate" GH secretion spans classically and partially GH-defieient children, children with constitutional growth and pubertal delay,4 and other poorly growing short children s who pass provocative tests but nevertheless secrete less GH than their peers. 6 Thus a poorly growing child who achieves a normal growth rate with GH therapy would meet a functional definition of GH "insufficiency" regardless of diagnostic test results. Second, many children with idiopathic short stature have an initial clinical response to GH therapy similar to that of GH-deficient children, v-l~ Although physiologic explanations for this response have been proposed, v, 11-15 in most children with severe familial or idiopathic short stature, the only known "defect" is inheritance of a growth velocity persistently below the 50th percentile for age, resulting in adult short stature. Since genetically determined patterns of GH secretion and response may influence growth velocity as much as the amount of GH secreted, predicting GH responsiveness on the basis of GH concentrations (as opposed to a therapeutic trial) is arbitrary and impractical. Similarly, response to GH therapy does not necessarily imply GH deficiency. Augmentation of normal GH secretion (e.g., pituitary gigantism) can increase growth velocity and eventual height. GH-treated girls with Turner syndrome grow faster than control subjects] 6 and several have already exceeded their previously predicted adult height. 17 Growth rates of children with idiopathic short stature also increase with G H therapy, 18 although a beneficial effect on final adult height is less certain. 19, 2o Thus there is evidence that GH supplementation in many non-GH-deficient short children will increase short-term growth velocity and may increase eventual adult height.
HEIGHTISM THERAPY
AND ENTITLEMENT
17
T O GH
Parental concern about disadvantages of their child's short stature is legitimated by a "heightist" premise in modern America: to be tall is good and to be short is to be stigmatized. 2~ Discrimination based on height--"heightism"--pervades American life. 22,23 Mate selection for short males and tall females is difficult. Job recruiters prefer the taller of equally qualified candidates, and business school graduates more than 6 feet tall receive a starting salary 12.4% higher than that shorter graduates receive. 24 The taller candidate for president has won 80% of elections in this century, and of all the presidents, only two have been shorter than average for an American man at the time of election. Stigmatization based on height begins in childhood. Although conclusive causative evidence is lackingY school problems occur more often in growth-retarded children. 26 Parents and teachers interact differently with short and tall children of the same age, accounting, in part, for a positive association between height and either IQ scores or academic achievement.2v,28 Feelings of incompetence and low selfesteem often arise from the short child's struggle with stature, 29 although these problems may depend as much on the projection of parental perceptions of their child's vulnerability and immaturity as on short stature per se. 3~ It is not surprising that parents striving for an athletic or social competitive edge for their short child seek growthpromoting therapy. However, it is questionable whether children made taller enjoy the social advantages of being tall. Adults treated with GH during childhood, although presumably better off than they would have been without GH, continue to have lower self-esteem, lower rates of employment, 31 and less marital success than the general population. 32 Disappointment often occurs when final results of GH therapy fall short of unrealistic expectations. Paradoxically, parents who are most desirous of obtaining GH for their child may confirm by their actions what his classmates' teasing suggests--that he would be a better person if he were taller. 33 Awareness of a continuum of GH secretory capabilities, a large population of short, healthy, but potentially GH-responsive children, and the disadvantages of short stature in our society will bring pressure on physicians to expand the use of GH beyond the unequivocally GH-deficient population. However the remaining medical questions about efficacy and toxicity are resolved, there will be substantial numbers of GH-responsive but non-GH-deficient children whose parents will request treatment. This demand will require a rational response to a series of ethical and policy questions: Who is entitled to such treatment? What
18
Allen and Fost
The Journal of Pediatrics July 1990
ultimate height should be the goal of treatment, regardless of the underlying diagnosis? Who should decide? Should public financing of such treatment be supported? Developing a consensus about the proper use of GH begins with a consensus about the goals of our therapy. If the goal is to alleviate the disability of extreme short stature, we should treat GH-responsive, short, healthy children only until they reach a height within the normal range. On the other hand, if the goal is to achieve each child's maximum height potential, GH therapy should be offered to any potentially responsive short child. As a starting point for the debate and analysis that are needed, and recognizing the limitations of predicting eventual adult height, we propose the following conceptual guidelines: 1. Children (desiring treatment) who have a predicted adult height that is likely to be handicapping (e.g., below the 1st percentile) are entitled to a trial of GH. 2. Treated children who increase their height velocity by at least 2 cm/yr (i.e., who are GH responsive) may continue to receive GH. 3. Like all children with handicapping conditions, these markedly short children are entitled to such treatment, through private insurance or public expense if necessary, until a height no longer considered a handicap (e.g., at the 5th percentile) is attained. 4. Parents of children who do not meet these criteria may seek such treatment. They are not entitled to public funds, and private insurance companies should be discouraged from supporting such treatment. Physicians may choose to treat such children but have no duty to do so. The following discussion defends these guidelines through three arguments: (1) Traditional concepts of disease, handicap, and potential do not distinguish GH-deficient from potentially GH-responsive children with regard to entitlement to GH therapy. (2) Psychologic and financial burdens and potential medical risks make GH responsiveness a necessary, but not sufficient, criterion for treatment. (3) Responsible, ethical use of GH begins with defining the goals of growth-promoting therapy (e.g., attainment of "nonhandicapping" height) and preferentially allocating financial and medical resources toward the alleviation of severe, handicapping short stature regardless of cause. DISEASE,
HANDICAP,
AND POTENTIAL
The American Academy of Pediatrics recommends GH therapy only for GH-deficient children, with carefully controlled clinical trials in non-GH-defieient children. The Academy statement concluded with the old adage "If it ain't broke, don't fix it. ''34 But what exactly is "broke" when it comes to short stature and G H therapy? As described above, "broke" cannot be defined simply by GH deficiency,
because given enough GH, most children's growth rate and, perhaps, ultimate height can be increased. "Broke" in the context of short stature should encompass the psychologic stress and societal prejudice shared by GH-deficient and GH-sufficient short children, and the possibility that both can benefit from GH therapy. From this perspective, consider the following cases: Johnny is a short 11-year-old boy with documented GH deficiency resulting from a brain tumor. His parents are of average height. His predicted adult height without GH treatment is approximately 160 cm (5 feet 3 inches). Billy is a short ll-year-old boy with normal GH secretion according to current testing methods. However, his parents are extremely short, and he has a predicted adult height of t 60 cm (5 feet 3 inches). Who is entitled to treatment with GH? A common response to this question hinges on whether either child has a disease, "an abnormal condition of an organism that impairs normal physiological functioning. ''35 Johnny, who lacks GH and is growing slowly, appears to meet this criterion, whereas Billy does not. To some, treating disease and restoring health, the "well-working of the organism as a whole," is the proper aim of medicine. 36 Supplementing deficient or suppressing excessive levels of hormones, and thus restoring what is perceived as normal hormonal equilibrium, is said to be justified. This narrow view, however, assumes that no physiologic "defect" leads to genetic short stature and excludes psychosocial well-being in considering the "well-working" of the individual. According to the definition quoted, both children have the disease of short stature. If we ask, instead, whether either of these children has a handicap, "a disadvantage or deficiency, especially a physical or mental disability that prevents or restricts normal achievement, ''35 the legitimate function of medicine is expanded. Now a child's well-being is viewed in the context of the environment with which he or she interacts. Administration of GH to very short, GH-responsive patients (e.g., Turner syndrome patients) is justified by the recognition that their extreme short stature can interfere with "normal" activities such as reaching shelves and driving a car. Both boys described above, however, have a height prognosis that exceeds this threshold. Have they then exceeded the point at which short stature is a handicap? Not if we recall that subnormal height imposes a disadvantage in the competition for schools, jobs, income, and mates. Whether these burdens qualify for the designation of handicap is not the central question. However that question is resolved, Johnny and Billy would have the same handicap regardless of the cause of their short stature. A third basis for distinguishing the cases might be potential, based on the Aristotelian notion that each person is in-
Volume 117 Number 1, Part I
GH therapy f o r short stature
tended to be a certain heigtit, which is part of the definition of that person. Johnny, one might argue, is entitled to G H therapy because, in contrast to Billy, he is meant, by virtue of genetic endowment from taller parents, to be taller. Billy is not entitled to GH therapy because to make him taller than his genetically predicted height would be taking him "beyond his potential" (i.e., "tampering with nature"). This analysis fails, however, because although Johnny's ultimate height may be potentially greater than Billy's, to help either child reach his maximum height requires "tampering with nature" in the same way--treating with GH. In summary, the concepts of disease, handicap, and potential do not distinguish between GH-responsive children, one of whom is G H deficient and one who is not. The analysis suggests that children who are GH responsive are equally entitled to GH treatment. It does not follow, however, that all GH-responsive children are entitled to treatment. Resolving that question requires consideration of balancing benefits and risks and asking further questions about allocation of health care resources. BALANCING
BENEFITS
AND BURDENS
We have argued that the cause of short stature is less relevant than its responsiveness to treatment in deciding who is entitled to treatment. But there are other considerations. Responsiveness to GH is not an "all or none" phenomenon. In response to the same treatment, one child may add 20 cm to his adult height, and another, 3 to 5 cm. If the purpose of treatment is better psychosocial adaptation, some benefits may be statistically significant but psychologically meaningless because the increment in adult height is so marginal. It is probable that GH-deficient children will in general be more responsive than non-GH-deficient children and therefore will be more appropriate recipients of treatment as a class. As a practical matter, it may be difficult to predict which non-GH-deficient children will achieve a sufficient increase in height to warrant treatment. Decisions about treatment are always based on probability, not certainty, and this pragmatic consideration is one factor in support of preferential treatment for the GH-deficient child. This factor would have little weight if treatment were riskless and free, but that will never be the case. Widespread distribution of GH has been deterred in part by high drug prices and concern about toxicity, impediments that may be resolved soon. Increased competition for an expanding patient population should decrease the price of GH. Theoretic adverse effects of GH therapy (e.g., impaired glucose toelrance, 37 hyperlipidemia, and production of growthattenuating antibodies) 3s have proved to be exceedingly rare among thousands of GH-treated children. The possibly increased risk of leukemia in GH-deficient children
19
treated with G H 39 is small (about 1/20,000) if it exists at all .40 Nevertheless, there should be concern about psychosoeial risks of treatment itself. A short, otherwise normal child who receives thrice-weekly injections to promote growth may be stigmatized because of the implication that his body is unacceptable in his parents' and physicians' eyes. Promoting a supportive and nurturing home environment, 41 rather than GH treatment, may be more effective in achieving a well-adjusted self-concept. Arguably, the GHdeficient child is more likely to view GH therapy as a deserved restoration of normal bodily function. For both children, however, dependence on exogenous hormones for growth sends the same message: shortness (and implicitly each of them) is bad. It is unclear at present whatthe precise benefits and risks of GH treatment will be. Itis likely that the risks will be low. Providing G H therapy only to those with documented GH deficiency and treating them to maximal adult stature is unfair to equally short, non-GH-deficient children who could grow with G H supplementation. If we assume that there is substantial benefit for many non-GH-deficient children, ethical and policy issues remain regarding entitlement to such treatment. TOWARD
RESPONSIBLE
USE OF Gtt
Assuming that clinical trials of G H in non-GH-deficient children show efficacy with acceptable risk, pediatricians and third-party payers must decide who should be candidates for G H treatment and how much treatment is appropriate. Benefit with acceptable risk may not be a suff• basis for providing GH treatment, because some children of above-average height can "benefit" from additional height. The debate over anabolic steroid use to achieve a competitive advantage comes quickly to mind. Some advocate restriction of steroids because of paternalistic concerns about harm, but the major objection appears to be the belief that the use of hormonal augmentation to "redefine" one's potential is unethical, and not the proper province of medicine. These objections have been attacked, 42 but there is broad consensus against such prescribing. One way to avoid moral judgments about who is entitled to treatment would be to consider every child who wants to be taller, whether a 6-foot-tall basketball prospect or a 5foot-tall GH-deficient child, as a candidate for GH. The net effect of "universal" treatment would be to shift the bell-shaped curve of height upward, probably without changing the handicap for those at the lower percentiles in comparing for social, professional, and athletic status. The average height of the excluded would be higher, but the disappointment and lost opportunity would be the same.
20
Allen and Fost
Another approach would be to classify G H treatment as a privilege, not a right, and therefore available to those who can pay but not owed to those who cannot. Many benefits are unevenly distributed in a free society without implying injustice. A society has a duty to provide the basic needs of food, shelter, clothing, education, and perhaps even health care to its citizens, but there is not a duty to provide the very best opportunity for all. Such a goal is unattainable, and an insistence on equality leads only to a reduction in benefits for all. This approach has two problems. First, it would increase the inequality in society, because those already well off would gain even more advantage with greater access to GH. Second, it ignores the fact that, for some children, G H treatment is a necessity, not a luxury. For these extremely short children, whose height is below the 1st percentile, the severity of their handicap creates unreasonable obstacles to success because of inability to drive a car or reach knobs and switches, or because of profound stigmatization. The challenge is to define this group for whom short stature is a severe handicap. The definition of "handicapping height" would be arbitrary, but the difficulty in defining boundaries precisely should not be an obstacle to making distinctions. The guidelines outlined earlier endorse the effort to lessen disadvantages of extreme short stature, regardless of pathogenesis, by bringing such children closer to or within the normal range. The attainment of maximum height potential is not a valid treatment goal, and the use of G H to make normal-statured children taller is opposed. Our proposed policy would alter the normal range of height only slightly, and the medical profession's unintended contribution to heightism would be minimized. CONCLUSIONS Increased availability of a virtually unlimited supply of safe G H has raised new questions about the indications for its use and about entitlement to therapy. If clinical trials show efficacy in non-GH-deficient children, there would be no coherent ethical basis for defining access by G H deficiency. Rather, G H responsiveness should be the central criterion in considering candidates for treatment. Whatever percentile is considered "tall enough" for GH-deficient children should also apply to non-GH-deficient children. Access to potentially efficacious G H cannot be ethically denied to them simply because they lack G H deficiency. However, because of the enormous expense, and because of concerns that universal access would not ameliorate the disadvantages of short stature, it is appropriate to restrict access, even within the group of GH-responsive children. As a starting point, we propose that treatment be limited to those for whom height is not merely a relative disadvan-
The Journal of Pediatrics July 1990
tage but a serious h~ndicap, arbitrarily defined as below the 1st percentile. We do not insist that the 1st percentile is the correct boundary or claim that there is a distinct boundary. The central point is that handicap and G H responsiveness should be the criteria for treatment, not the cause of handicap or the ability to pay. The paradox of G H therapy is that no policy regarding its use will ever eliminate the 1st percentile. The proposed policy can, however, reduce the standard deviation of height so that those in the lowest percentiles differ less strikingly from the rest and are less handicapped in a world where cars and switches are designed for those who have achieved a certain height. Most important, height is not a reliable predictor of happiness and self-esteem. Growth hormone cannot replace parental love and nurturing of a child, regardless of his height. Prudent use of G H will recognize these limitations. The most effective response to heightism is a concerted effort to reveal and rectify it, not unrestricted use of G H . 43 The effective physician should respond to concerns about short stature more often with counseling than with injections. Whatever policy we develop, it will be easier to discuss it rationally before the expanded G H era is on us. The potential of a billion-dollar industry will inevitably distort critical thinking. It will be much more difficult to reverse practices after they have been established. The uses and abuses of G H need not, like the contents of Pandora's box, escape all at once in our haste to open the lid. REFERENCES
1. Lantos J, Siegler M, Cutler L. Ethical issues in growth hormone therapy. JAMA 1989;261:1020-4. 2. Hindmarsh P, Smith PH, Brook CGD, et al. The relationship between height velocity and growth hormone secretion in short prepubertal children. Clin Endocrinol 1987;27:581-91. 3. Rose SR, Ross JL, Uriarte M, et al. The advantage of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency. N Engl J Med 1988;319:201-7. 4. Martin LG, Grossman MS, Connor TB, et al. Effect of androgen on growth hormone secretion and growth in boys with short stature. Acta Endocrinol 1979;91:201-12. 5. Costin G, Kaufman FR. Growth hormone secretory patterns in children with short stature. J PEDIATR 1987;110:362-8. 6. Zadik A, Chalew SA, Raiti S, et al. Do short children secrete insufficient growth hormone? Pediatrics 1985;76:355-60. 7. Van Vliet G, Styne DM, Kaplan SL, et al. Growth hormone treatment for short stature. N Engl J Med 1983;309:1016-22. 8. Gertner JM, Genel M, Gianfredi SP, et al. Prospective clinical trial of human growth hormone in short children without growth hormone deficiency. J PEmATR 1984;104:172-6. 9. Johanson A J, Blizzard R, Cara J, and the National Collaborative Group Genentech Inc. Idiopathic short stature (ISS) characterization and response to growth hormone [Abstract 19]. Symposium III of the Genentech Cooperative Growth Study, Palm Desert, Calif., Oct 1988.
Volume l 17 ?Cumber 1, Part 1
10. Lin T, Kirkland RT, Kirkland J. Growth hormone treatment of "normalr" short children [Abstract 18]. Symposium llI of the Genentech National Cooperative Growth Study, Palm Desert, Calif., Oct 1988. 11. Bercu BB, Shulman D, Root AW, et al. Growth hormone provocative testing frequently does not reflect endogenous growth hormone secretion. J Clin Endocrinol Metab 1986;63:709-16. 12. Grunt JA, HowardC, DaughadayWH. Comparison of growth and somatomedin responses following growth hormone treatment in children with small-for-dates short stature, significant idiopathic short stature, and hypopituitarism. Acta Endocrinol 1984;106:168-74. 13. Rudman D, Kutner MH, Goldsmith MA, et al. Further observation on four subgroups of normal variant short stature. J Clin Endcrinol Metab 1980;51:1378-83. 14. Wise PH, Burnet RB, Geary TD, et al. Selective impairment of growth hormone response to pharmacological tests. Arch Dis Child 1975;50:210-4. 15. Lanes P, Plotnick LP, Spencer ME, et al. Dwarfism associated with normal serum growth hormone and increase bioassayable receptor-assayable and immuno-assayable somatomedin. J Clin Endocrinol Metab 1980;50:485-8. 16. Rosenfeld RG, Hintz RL, Johanson A J, et al. Three-year resuits of a randomized prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome. J PED1ATR i988;113:393-400. 17. Lippe B. Growth hormone treatment of girls with Turner syndrome: changing the shape of the "Turner growth curve" [Abstract 8]. Symposium IV of the Genentech National Cooperative Growth Study, palm Desert, Calif., Oct 1989:23-5. 18. Genentech Collaborative Study Group. Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. J PEDIATR 1989;115:713-9. 19. Kaplan SL, Grumbach MM. Long-term treatment with growth hormone of children with non-growth hormone deficient short stature. In: lsaksson O, et al, eds. Growth hormone: basic and clinical aspects. New York: Elsevier Science, 1987. 20. Wit JM, Fokker MH, de Muinck Keizer-Schrama MPF, et al. Effects of two years of methionyl growth hormone therapy in two dosage regimens in prepubertal children with short stature, subnormal growth rate, and normal growth hormone response to secretagogues. J PEDIATR 1989;115:720-5. 21. Feldman SD. The presentation of shortness in everyday life: height and heightism in American society--toward a sociology of stature. In: Feldman SD, ed. Life-styles: diversity in American society. Boston: Little, Brown, 1975:437-42. 22. Schnmacher A. On the significance of stature in human society. J Hum Evol 1982;11:697-701. 23. Gillis JS. Too tall, too small. Champaign, Ill.: Institute for Personality and Ability Testing, 1982:9-25. 24. Deck L. Short workers of the world unite. Psychology Today 1971;5:t02. 25. Richards GE, Marshall RN, Kreuser IL. Effect of stature on school performance. J PEDIATR 1985;107:841-2.
G H therapy f o r short stature
21
26. Holmes CS, Hayford JT;Thompson RG. Parents' and teachers' differing views of short children's behavior. Child Care Health Dev 1982;8:327-36. 27. Wilson DM, Duncan PM, Dornbusch SM, et al. The effects of growth on intellectual function in children and adolescents. In: Stabler B, Underwood L, eds. Slow grows the child. London: Lawrence Erlbaum Associates, 1986. 28. Wilson DM, Duke PM, Dornbusch SM, et al. Height and intellectual development [Abstract]. Pediatr Res 1984; 18:100A. 29. Holmes CS, Hayford JT, Thompson RG. Personality and behavior differences in groups of boys with short stature. Children's Health Care 1982;11:61-4. 30. Rotnem D, Genel M, Hintz R!~, et al, Personality development in children with growth hormone deficiency. J Am Acad Child Psychiatry 1977;16:412-26. 31. Dean H J, McTaggart TL, Fish DG, et al. The educational, vocational, and marital status of growth hormone deficient adults treated with growth hormone during childhood. Am J Dis Child 1985;139:1105-10. 32. Mitchell CM, Joyce S, Johanson AJ, et al. A retrospective evaluation of psych0social impact of long-term growth hormone therapy. Clin Pediatr 1986;25:17-23. 33. Diekema DS: Is taller really better? growth hormone therapy in short children. Perspect Biol Med (in press). 34. Ad Hoc Committee on Growth Hormone Usage, The Lawson Wilkins Pediatric Endocrine Society, and Committee on Drugs, American Academy of Pediatrics. Growth hormone in the treatment of children with short stature. Pediatrics 1983;72:891-4. 35. American Heritage Dictionary. Boston: Houghton Mifflin, 1985. 36. Kass LR. Regarding the end of medicine and the pursuit of health. Public Interest 1975;No. 40:13 f. 37. Davidson MG. Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 1987;8:115-31. 38. Moore WV, Leppert P. Role of aggregated human growth hormone (hGH) in development of antibodies to hGH. J Clin Endocrinol Metab 1981 ;51:691-701. 39. Report of International Workshop on Growth Hormone and Leukemia. Bethesda, Md.: Lawson Wilkins Pediatric Endocrine Society and Human Growth Foundation of the United States, March 5, 1988. 40. Fisher DA, Job J-C, Preece M, et all Leukemia in patients treated with growth hormone. Lancet 1988;1:1159-60. 41. Young-Hyman D. Effects of short stature on social competence. In: Stabler G, Underwood LE, eds. Slow grows the child. Hillsdale, N.J.: Lawrence Erlbaum Associates, 1986. 42. Fost NC. Banning drugs and sports: a skeptical view. Hastings Cent Rep 1986;16(4):5-10. 43. Benjamin M, Muyskens J, Sacnger P. Short children, anxious parents: is growth hormone the answer? Hastings Cent Rep 1984;14(2):5-9.
