Ethical issues in the use of growth hormone (GH) © Copyright 2010

Ethical issues in the use of

growth hormone (GH)

© Copyright 2010

GH - Controversial for decades

• Is short stature - a disease?

- a disability?

- a normal variant?

• Is GH therapy or enhancement?

• Should insurance pay for GH?

Brief history of GH

• 1958: Maurice Raben purified GH from cadaver pituitary glands; treated a 17-year-old patient who had GH deficiency

Maurice S. Raben and the Treatment of Growth Hormone Deficiency. Sawin C. Endocrinologist. March/April 2002.

Brief history of GH

• 1970: Choh Hao Li first synthesizes growth hormone

• 1960: NIH forms National Pituitary Agency to organize the collection and distribution of glands

Brief history of GH

• In the late1970s, a Swedish company, Kabi, purchases pituitary glands from European hospitals for the first commercial GH product, Crescormon. They marketed this to primary care doctors, rather than endocrinologists, with the slogan, “Now you judge the need.”

Brief history of GH

• 1977-9: Scientists at Genentech clone the gene for GH. Produce GH in an E.Coli model

• 1980: Genentech goes public – stock rises from $35 to 88 in an hour

• 1981: Boyer and Swanson use recombinant DNA technology to synthesize GH – the first such use of this technology

Brief history of GH

• 1985: Four cases of Creutzfeldt-Jakob disease in recipients of cadaver-derived GH

• 1985: FDA approves recombinant DNA-derived human GH for children with GH-deficiency

• 1985-2003: FDA gradually expands the list of approved indications for GH

FDA-approved indications

• 1985 -- Growth hormone deficiency• 1993 -- Chronic renal insufficiency• 1996 -- Turner syndrome• 2000 -- Prader-Willi syndrome• 2001 -- Small for gestational age babies• 2003 -- Idiopathic short stature (ISS)

Idiopathic Short Stature (ISS)

• Children who are 2.25 standard deviations below the mean for height, with slow growth velocity and no other diagnosable cause for short stature

Who gets GH?

• A 1996 survey of pediatric endocrinologists found that about half of children getting GH had classic GH deficiency

• Other indications included Turner syndrome, Down syndrome, renal disease, and ISS

Cuttler L, et al. JAMA. 1996.

Who should get GH?

• On a 2007 survey of pediatric endocrinologists, most said that there was no consensus in the field about which children should be treated

Hardin et al, Clin Endocrinol. 2007.

“When deciding whether or not a child could benefit from growth hormone, I consider the following (check all that apply):”

Hardin et al, Clin Endocrinol. 2007.

How bad is it to be short?

• Short stature has been associated with

- low self-esteem

- poor school performance

- stigmatization and teasing (esp. boys)

- other mental health problems

Theoretical hazards of idiopathic short stature

Visser-van Balen et al. Arch Dis Child 2006.

Stature associated self-reported quality of life

Christensen TL et al. Clin Endocrinol. 2007.

Height is presented as “Standard Deviations from the Mean” - above and below

Height associated with success

• Using data from the National Longitudinal Survey of the Bureau of Labor Statistics, researchers showed that height was associated with subjective ratings of work performance, such as supervisors’ evaluations, and objective measures, such as sales volume, even when controlling for sex, age, and weight

• Conclusion: “Height matters for career success”

Judge TA et al. J Appl Psychol. 2002.

Pediatricians believe that short stature impairs emotional well-being in both children and adults

Cuttler et al, JAMA. 1996.

Physicians who think that short stature is detrimental, and that GH helps, are more likely to prescribe it

Cuttler, JAMA. 1996.

On the other hand…

Studies of children

• When children are actually studied, the results suggest that short kids do not have more psychological problems

• For those who do, it is unclear whether treatment with GH helps

Children’s Hospital of Buffalo study

• Subjects:– 180 boys and 78 girls, – 4 to 18 years of age, – height < 5th percentile. – Age-matched controls of normal height.

• All had been referred to endocrinology clinic

Sandberg DE et al. Peds 1994.

Children’s Hospital of Buffalo study

• Outcome measures – Child Behavior Checklist – Children’s self-reports

• Results– Boys showed a few mild signs of dysfunction – Girls indistinguishable from normal-height girls

• Conclusion: “Short stature does not appear to be associated with clinically significant psychosocial morbidity.”

Sandberg DE et al. Peds 1994.

Wessex Growth Study

• Longitudinal non-intervention study

• 106 short normal children recruited from community. 119 controls

• Main outcome measures: Cognitive development, self-concept development, behavior, IQ, school performance, and locus of control

Downie et al. BMJ. 1997.

Wessex conclusions

• “Stature seems to have no direct effect on the measures of attainment, behaviour, self esteem, parent's perception, or self perception. Stature does, however, seem to influence IQ, locus of control, and body satisfaction”

• “These results provide only limited support for the hypothesis that short children are disadvantaged”

How well does GH work for ISS?

Randomized, placebo-controlled trial

• 71 children (55M, 16F)• Inclusion criteria:

– 1) age 10–16 (boys) or 9–15 yr (girls)– 2) bone age of 13y or younger (boys) or 11y or younger (girls)– 3) testicular volume of 10 ml or less (boys) or Tanner stage breast

development at 2 or less (girls) – 4) marked, proportionate short stature– 5) peak stimulated GH more than 7 µg/liter – 6) no chronic illness or genetic syndrome

• Marked short stature was defined by a height SD score (SDS) or predicted adult height SDS –2.5 or less

Leschek et al. J Clin Endocrinol Metab. 2004.

GH RCT (Cont’d)

• Randomly assigned to GH or placebo 3x/week

• Every 6 months, evaluated for– Height (average of 10 stadiometer measurements)– Tanner pubertal stage– Testicular volume– Bone age– Blood count, chemistry panel, insulin, hemoglobin A1C, IGF-I

• Continued until growth rate < 1.5 cm/yr, indicating near adult height

Leschek et al. J Clin Endocrinol Metab. 2004.

Results of RCT• Compared to placebo controls, children on GH grew

faster and reached a final adult height above what had been projected

• Went from >2 SD below the mean to 1-2 SD below the mean

• (Data on next slides)

Leschek EW et al. J Clin Endocrinol Metab. 2004.

Mean ({+/-}SD) adult height (ht) SDS (A), adult height SDS minus baseline height SDS (B), and adult height SDS minus baseline predicted

height SDS (C) in patients receiving GH or placebo

GH group ended up taller – but still short

Copyright ©2004 The Endocrine Society

Leschek EW et al. J Clin Endocrinol Metab. 2004.

Mean ({+/-}SD) height velocity (A-C), height SDS (D-F), and bone age (G-I) in subjects receiving GH (solid circles) or placebo (open circles)

Meta-analysis of uncontrolled studies showed similar results

Copyright restrictions may apply.

Finkelstein BS et al. Arch Pediatr Adolesc Med. 2002.

GH led to increased growth velocity in the first year, and to increased final adult

height

A, Mean ± SE growth velocity at baseline and after 1 year

B, Mean adult height SD scores predicted at baseline and achieved

Taller, but still short

• Adults who, as healthy short children, were treated with growth hormone for between four and seven years are, on average, between 3.5 and 7.5 centimeters taller than they otherwise would have been

• “….treated individuals remain relatively short when compared with peers of normal stature”

P. Cohen et al. J Clin Endocrinol Metab. 2008.

Does GH help with self-esteem?

• “Data demonstrating improved quality of life, better psychological health, etc. have not yet been collected in well-controlled studies”

Cohen P et al. J Clin Endocrinol Metab. 2008.

Risks of GH

• Risks are rare and usually easily managed

• Short-term: joint pain, paresthesias, edema, carbohydrate intolerance, gynecomastia

• Serious and long-term: Slight increase in cancers among children with history of cancer or cancer risk factors

Health Technology Advisory Committee. 2000.

Burdens of GH

• For maximum benefit, growth hormone therapy requires a daily shot for about four to seven years

• For many children, the treatment is too burdensome and they stop taking GH

Coste J et al. BMJ. 1997.

Stigmatization?

• “Currently, little to no consideration is given to the potential psychological harm that treatment could inflict on the child we seek to help”

Sandberg D, FDA Decisions and Clinical Practice, Atrium: 2006.

Costs

• The average cost of GH is $52,634 for each inch of height gained

Lee JMM et al. Arch Peds Adolesc Med. 2006.

• In one study, annual income was higher by $789 per inch per year

• Over a 40-year career, each extra inch may be worth $31,560

Is GH cost-effective?

Judge TA et al. J Appl Psychol. 2004.

Does Insurance Pay for GH?

• Survey of insurance companies

• Given four scenarios

• Most have policies not to pay for GH, even in conditions for which GH has FDA approval

Researchers presented four different cases of idiopathic short stature to a group of health insurance companies and asked if they would pay for GH. They also asked primary care doctors and endocrinologists if they would recommend treatment.

Finkelstein BS et al. JAMA 1998.

Referrals, treatment recommendations,

and insurer decisionsPercentage of primary care physicians who would refer each of the cases, the percentage of endocrinologists who would recommend GH therapy, and the proportion of children for whom GH therapy would be approved by insurers.

Finkelstein BS et al. JAMA 1998.

Recommendations from pediatric endocrinologists in US

and Europe

Current recommendations

• ISS may be a risk factor for psychosocial problems

• True psychopathology is rare

• Consider psychological care “instead of or as an adjunct to” GH

• The shorter the child, the more GH should be considered

Cohen P et al. J Clin Endocrinol Metab. 2008.

What is best for the child?

• Need to balance:– benefits of being taller (short and long-term)– cost of GH– burden of therapy– risk of low self-esteem– risk of stigmatization from treatment

What is a pediatrician to do?

• Each case is different

• Discuss the potential benefits, burdens, and costs with patient and family

• May be necessary to advocate for patients to insurance companies in order to get coverage

ResourcesAllen DB, Fost NC. Growth hormone therapy for short stature: panacea of Pandora’s box? J Peds. 1990;117:16-21.

Allen DB, Fost N. hGH for short stature: ethical issues raised by expanded access. J Peds. 2004;144:648-52.

Bolt LL, Mul D. Growth hormone in short children: Beyond Medicine? Acta Paediatr. 2001;90(1):69-73.

Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM; 2007 ISS Consensus Workshop participants. Consensus statement on the diagnosis and treatment of chidlren with idiopathic short stature: summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. 2008 Nov;93(11):4210-7.

Cuttler L, Silvers JB, Singh J, Marrero U, Finkelstein B, Tannin G, Neuhauser D. Short stature and GH therapy: A national study of physician recommendation patterns. JAMA.1996; 276:531-7.

Downie AB, Mulligan J, Stratford RJ, Betts PR, Voss LD. Are short normal children at a disadvantage? The Wessex growth study. BMJ. 1997;314(7074):97-100.

Resources (cont’d)

Health Technology Advisory Committee. The Use of Human Growth Hormone for Children with Idiopathic Short Stature. National Library of Medicine. Feb 2000.

Macklin R. Growth hormone in short children: medically appropriate treatment. Acta Paediatr. 2001;90(1):5-6.

Ross JL, Sandberg DE, Rose SR, Leschek EW, Baron J, Chipman JJ, Cassoria FG, Quigley CA, Crowe BJ, Roberts K, Cutler GB Jr. Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. J Clin Endocrinol Metab. 2004 Oct;89(10):4873-8.

Sandberg DE, Bukowski WM, Fung CM, Noll RB. Height and Social Adjustment: Are Extremes a Cause for Concern and Action? Pediatrics. 2004;114;744-750.. Voss LD. A personal reflection on the problems of treating shortness as a disease: Voss LD. Personal view: Short but Normal. Archives of Disease in Childhood. 1999. 81(4).

Last updated 3/19/10