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Concerns about Growth Hormone Experiments in Short Children

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Beginning in 1958, human growth hormone (hGH) was extracted from cadavers for use in children who do not produce normal amounts. The hormone increases the height of hormone-deficient short children, although they typically remain much shorter than average. Since the early 1980s, genetic engineering has permitted the mass-production of hGH without resorting to cadavers. However, prior to 2003, the U.S. Food and Drug Administration (FDA) approved hGH for use only in hormone-deficient children and other limited indications: chronic renal insufficiency, Prader-Willi syndrome, children born small for gestational age, and Turner syndrome.

In 1989, researchers at the National Institutes of Health began experiments to test hGH in children who were not deficient in growth hormone, but were simply short. Other research teams had found that the hormone does not cause any change in growth rate for 20 to 50 percent of non-hormone-deficient children. The remaining 50 to 80 percent show short-term increases in growth, although final adult height is affected only modestly.1-9 An FDA report10 found that non-hormone-deficient children, by an average age of 18.8 years, gained an average of 2.8 to 5 cm (1 to 2 inches) beyond predicted height after an average of 4.4 years of treatment. This means, for example, that a child predicted to reach a height of 5’0” without treatment will be only 5’1” to 5’2” with treatment. A higher does used in another study, with injections 6 times per week for an average duration of 5.3 years, resulted in a mean gain in adult height of 7 cm, or about 2.7 inches10.

In 2003, the FDA approved the use of hGH in non-hormone-deficient short children. The long-term risks of hGH injections in children who already produce adequate growth hormone are not known. Possible risks of such treatment relate both to the multiple injections the children receive and to the drug itself:

Injections: The psychological effects of repeated injections on children or on family relationships are not fully known, but investigators have found that, among hospitalized children, hypodermic needles are the most stress-provoking stimulus encountered.11 Diabetic children describe injections as one of the top stressors in their medical treatment.12

Studies of families with diabetic children have also found that the parental attention required for chronic medical treatment can lead to resentment on the part of siblings and can even affect the parental relationship.13 It is not known whether similarly disruptive effects occur with the introduction of chronic hGH treatment.

Increased Stigmatization: Growth hormone injections and the repeated examinations required may build or reinforce a negative self-image and stigmatization. In some cases of hormone-deficient children, unrealistic expectations for growth following hGH therapy have led to disappointment and depression.14,15 Available evidence does not show that hGH improves social adjustment, even when such treatment increases the final height of hormone-deficient children who have emotional problems.16

Cancer Risk: Growth hormone causes the liver to increase its production of insulin-like growth factor (IGF-1), which is thought to play a role in breast cell growth and lactation. Elevations of blood levels of IGF-1 are associated with a greater risk for prostate and breast cancer.17,18 In laboratory tests, IGF-1 encourages breast cancer cells to multiply and is more potent in this regard even than estrogens.19,20 Slight elevations of growth hormone, with corresponding increases in IGF-1, may be one reason why tall women have a higher risk of breast cancer, compared to shorter women.21,23 One study showed that women over 5’6” have double the risk of women below 5’3”, particularly for premenopausal breast cancer.21

Several cases of leukemia have been reported in hormone-deficient children receiving hGH, but there is little evidence implicating hGH as a cause. Hormone deficiencies can be caused by brain tumors, which are sometimes treated with radiation. The leukemia may be linked to the radiation or to underlying genetic abnormalities, rather than to the hGH.

In approving hGH for use in non-hormone-deficient children, the Food and Drug Administration cited a “16-year safety history.”10 However, increased risk of hormone-related cancers may not be detected until after a longer latency period.

Renal Effects: For children who have kidney problems, growth hormone may aggravate their already poor kidney function, possibly by increasing the rate of blood flow through the kidney and the rate at which the kidneys filter the blood. One case report describes a child with preexisting kidney disease went into end-stage kidney failure after treatment with hGH.24

Metabolic Changes: Growth hormone increases the metabolism, that is, the rate at which the cells of the body consume fuel and nutrients. Some children may become unusually lean, losing body fat and becoming inappropriately muscular.25

Antibody Production: In some children, hGH stimulates the production of antibodies to growth hormone. It is presumed that these antibodies will not interfere with their own growth hormone,26 but researchers are monitoring this possibility.

Cost: Treatment with hGH treatment costs approximately $20,000 per child per year. Of all children born in the U.S. each year, 90,000 will be below the third percentile for height. A single year’s treatment of the 90,000 nine-year-olds, for example, below this height standard would cost $1.8 billion dollars. Given this expense, such treatment would necessarily be restricted to certain groups.

The Psychology of Short Stature

The intellectual capacity of growth hormone-deficient short children is usually normal. Most achieve an educational level comparable to their siblings, although some do not.27 Some hormone-deficient children have shown problems on visual-motor tests,28 and rates of employment and marriage are far below average.16,29 The emotional maturation of growth-hormone-deficient children is often normal30, but varies widely.31,32 Many have poor self-esteem and tend to avoid aggressiveness.14,16

Short children who are not hormone-deficient generally have no resulting intellectual or academic problems.33 Children who are either unusually tall or short often have somewhat lower self esteem, compared to children who are nearer average height.34,35 Short children may favor individual activities to socializing in large groups, and some have less maturity in social judgment.36 Adolescence temporarily increases these characteristics.37 However, children differ from each other in many ways aside from height, all of which can affect their self-confidence in peer relationships during adolescence.

Several steps can improve the adjustment of short children. Parents and teachers can be helpful by reacting to children according to their age, not their height,38 contrary to the natural tendency to treat short children as if they are younger than their chronological age. Teasing and names linked to size can be avoided. Role-playing helps children to anticipate and cope with difficult situations, such as bullying. Involvement in sports for which smaller size is advantageous (e.g., gymnastics) or for which size is not a factor (e.g., skiing, swimming, golf) can be encouraged.

Counteracting prejudice and feelings of shame related to race, gender, disabilities, and other characteristics has long been a goal of both public and private programs, but there has been no major effort to reduce such feelings based on stature.There may be any number of ways of addressing the stigma of short stature.

Psychological approaches38 to improve adjustment in children who are having difficulties merit further investigation before hormonal treatments are used, particularly since hormonal treatments will have, at best, a partial effect.

Summary and Recommendations

The most important concern about hGH use is cancer risk. Because the drug elevates insulin-like growth hormone levels, increased cancer risk is a possibility, and no evidence yet discounts this risk. Other potential risks include the pain or discomfort of the repeated injections, increased stigmatization, renal effects, metabolic changes, and antibody production.

Children are not fully capable of informed consent and cannot adequately weigh the risks or benefits of hGH treatment. Both parents, children, and their physicians may tend to overestimate the potential benefits of hormone treatment and may overlook other ways of handling short stature.

The following recommendations are indicated:

  • The therapeutic use of hGH in children should be limited to those with growth hormone deficiencies and diagnosed medical conditions.
  • Children who have received hGH should be monitered for biological and psychological effects over the long-term.
  • Non-pharmacologic interventions to counteract the stigma of short stature should be investigated.

References
1. Rudman D, Kutner MH, Blackston RD, et al. Children with normal-variant short stature: treatment with human growth hormone for six months. New Engl J Med. 1981;305:123-131.
2. Vliet GV, Styne DM, Kaplan SL, et al. Growth hormone treatment for short stature. New Engl J Med. 1983;309:1016-1022.
3. Gertner JM, Genel M, Gianfredi SP, et al. Prospective clinical trial of human growth hormone in short children without growth hormone deficiency. J Pediatr. 1984;104:172-176.
4. Albertsson-Wikland K. Growth hormone treatment in short children. Acta Paediatr Scand. (Suppl) 1986;325:64-70.
5. Albertsson-Wikland K. Growth hormone treatment in short children—short-term and long-term effects on growth. Acta Paediatr Scand. (Suppl) 1988;343:77-84.
6. Raiti S, Kaplan SL, Vilet GV, et al. Short-term treatment of short stature and subnormal growth rate with human growth hormone. J Pediatr. 1987;110:357-361.
7. Wit JM, Rietveld DHF, Drop SLS, et al. A controlled trial of methionyl growth hormone therapy in prepubertal children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Acta Paediatr Scand. 1989;78:426-435.
8. Wit JM, Fokker MH, de Muinck Keizer-Schrama SMPF, 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;115:720-725.
9. Genentech Collaborative Study Group. Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. J Pediatr. 1989;115:713-719.
10. FDA Endocrinologic and Metabolic Drugs Advisory Committee. Briefing Document. June 10, 2003.
11. Fassler D. The fear of needles in children. Amer J Orthopsychiat. 1985:55:371-77.
12. Rainwater N, Sweet AA, Elliott L, et al. Systematic desensitization in the treatment of needle phobias for children with diabetes. Child Fam Beh Therapy. 1988;10:19-31.
13. Tattersall RB. Psychiatric aspects of diabetes—a physician’s view. Brit J Psychiat. 1981;139:485-493.
14. Kusalic M, Fortin C. Growth hormone treatment in hypopituitary dwarfs: longitudinal psychological effects. Canad Psychiatric Asso J. 1975;20:325-331.
15. Grew RS, Stabler B, Williams RW, et al. Facilitating patient understanding in the treatment of growth delay. Clin Pediatrics. 1983;22:685-690.
16. Lee PDK, Rosenfeld RG. Psychosocial correlates of short stature and delayed puberty. Pediatric and Adolescent Endocrinology. 1987;34:851-863.
17. Cohen P. Serum insulin-like growth factor-I levels and prostate cancer risk—interpreting the evidence. J Natl Cancer Inst. 1998;90:876-879.
18. Hankinson SE, Willet WC, Colditz GA, et al. Circulating concentrations of insulin-like growth factor I and risk of breast cancer. Lancet. 1998;351:1393-1396.
19. Stoll BA. Growth hormone and breast cancer. Clinical Oncology. 1992;4:4-5.
20. Stoll BA. Does extra height justify a higher risk of breast cancer? Ann Oncology. 1992;3:29-30.
21. Vatten LJ, Kvinnsland S. Body height and risk of breast cancer. A prospective study of 23,831 Norwegian women. Br J Cancer. 1990;61:881-85.
22. Swanson CA, Jones DY, Schatzkin A, et al. Breast cancer risk assessed by anthropometry in the NHANES I epidemiological follow-up study. Cancer Research. 1988;48:5363-5367.
23. Tornberg SA, Holm LE, Carstensen JM. Breast cancer risk in relation to serum cholesterol, serum beta-lipoprotein, height, weight, and blood pressure. Acta Oncologica. 1988;27:31-37.
24. Watson AR. Safety of growth hormone. Lancet. 1991;337:108.
25. Walker JM, Bond SA, Voss LD, et al. Treatment of short normal children with growth hormone—a cautionary tale? Lancet. 1990;336:1331-1334.
26. Andersson B. Immune responses to human growth hormone—cellular and humoral aspects. Acta Paediatr Scand. (Suppl) 1987;331:39-41.
27. Pollitt E, Money J. Studies in the psychology of dwarfism I. Intelligence quotient and school achievement. J Pediatrics. 1964;64:415-421.
28. Abbott D, Rotnem D, Genel M, et al. Cognitive and emotional functioning in hypopituitary short-statured children. Schizophrenia Bul. 1982;8:310-319.
29. Dean HJ, McTaggart TL, Fish DG, et al. The educational, vocational, and marital status of growth hormone-deficient adults treated with growth hormone during childhood. AJDC. 1985;139:1105-1110.
30. Drotar D, Owens R, Gotthold J. Personality adjustment of children and adolescents with hypopituitarism. Child Psychiatry and Human Development. 1980;11:59-66.
31. Law CM. The disability of short stature. Arch Dis Child. 1987;62:855-859.
32. Skuse D. The psychological consequences of being small. J Child Psychol Psychiat. 1987;28:641-650.
33. Gordon M, Post EM, Crouthamel C, et al. Do children with constitutional delay really have more learning problems? J Learning Disabilities. 1984;17:291-293.
34. Gordon M, Crouthamel C, Post EM, et al. Psychological aspects of constitutional short stature: social competence, behavior problems, self-esteem, and family functioning. J Pediatrics. 1982;101:477-480.
35. Booth ND. The relationship between height and self-esteem and the mediating effect of self-consciousness. J Social Psychology. 1990;130:609-17.
36. Stabler B, Whitt JK, Moreault DM, et al. Social judgments by children of short stature. Psychological Reports. 1980;46:743-746.
37. Holmes CS, Karlsson JA, Thompson RG. Social and school competencies in children with short stature: longitudinal patterns. Developmental and Behavioral Pediatrics. 1985;6:263-267.
38. Money J, Pollitt E. Studies in the psychology of dwarfism II. Personality maturation and response to growth hormone treatment. J Pediatrics. 1966;68:381-390.

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