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Tall boys and short girls: Pursuit of the American Dream

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This is the story of growth hormone prescribing for idiopathic short stature, and its historical counterpart (estrogen treatment for tall girls). Check out http://archpedi.jamanetwork.com/article.aspx?doi=10.1001/archpedi.160.10.1035

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Tall boys and short girls: Pursuit of the American Dream

  1. 1. Tall Boys and Short Girls: Pursuit of the American Dream Division of Pediatric Endocrinology Child Health Evaluation Research Unit University of Michigan Joyce Lee, MD, MPH Joel Howell, MD, PhD RWJ Clinical Scholars Program
  2. 2. Stature is normally distributed 0246810 Percent 50 60 70 80 height 0246810 Percent 50 60 70 80 height Adult males 5’ 9” National Health and Nutrition Examination Survey (NHANES) 1999-2002 Adult females 5’ 3”
  3. 3. Height is relative Country Males Females Japan 5’ 5” 5’ 0” USA 5’ 9” 5’ 3” Germany 5’ 11” 5’ 6” Netherlands 6’ 0” 5’ 7”
  4. 4. Definition of short stature < -2 SD (2.5%)0246810 Percent 50 60 70 80 height
  5. 5. <5’ 4”
  6. 6. <5’ 0”
  7. 7. Brook C. J Pediatr 1998; 133:591-2.
  8. 8. But we do see, evaluate, and diagnose Patients with Growth Hormone Deficiency
  9. 9. Growth Hormone (GH) •  Pituitary-derived GH (1963 – 1985) – Extracted from pituitary glands of cadavers – National Pituitary Agency (funded by NIH) – Limited supply – Severe GH deficiency – Creutzfeld-Jacob disease •  Recombinant GH (1985 – present) – Recombinant DNA technology – Pharmaceutical companies – Unlimited supply
  10. 10. Indications for Recombinant GH •  GH-deficiency (1985)
  11. 11. Recombinant GH •  GH-deficiency (1985) •  Chronic renal insufficiency (1993) •  Turner syndrome (1996) •  Prader-Willi syndrome (2000) •  Small for gestational age (2001) •  Idiopathic Short Stature (2003) Physiologic dosing Pharmacologic dosing
  12. 12. Growth Hormone Approval for Idiopathic Short Stature - July 2003
  13. 13. 37 GH tx 31 Placebo 16 9 ~1.5 inch increase in adult height for GH treated group Only placebo controlled trial to final height (NICHD) JCEM
  14. 14. Idiopathic short stature indication •  Height threshold for qualification –  “height < -2.25 SD (1.2%)” •  Specific diagnosis is not required for treatment –  “in patients…for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means” •  Predicted adult height a consideration for qualification –  “ [children] with growth rates unlikely to permit attainment of adult height in the normal range”
  15. 15. Implications •  Medical •  Policy •  Ethical
  16. 16. Medical Implications •  Route of Administration –  SQ shot given 6-7 days a week •  Duration of Treatment –  Until epiphyses are fused (5 to 10 years) •  GH efficacy –  1 to 3 inches of final adult height
  17. 17. GH side effects •  Skin/Joint – Injection site reactions, rash – Arthralgias, myalgias, edema •  Otitis media •  Gynecomastia •  Scoliosis •  Endocrine – Hypothyroidism – Mild transient hyperglycemia
  18. 18. •  Rare but severe – Slipped capital femoral epiphysis (SCFE) •  Knee pain, hip pain, limp – Benign intracranial hypertension •  Visual changes, HA, nausea, vomiting •  Unknown long-term effects – Theoretical concern about malignancy – To date no evidence of an increased risk of new tumors or tumor recurrence GH side effects
  19. 19. GH benefits? •  Quality of life – No objective evidence that children with untreated short stature have impaired quality of life (psychosocial adjustment, peer relations) – No objective evidence that GH treatment improves quality of life in children with idiopathic short stature Sandberg et al.
  20. 20. Policy Implications •  Expanded eligibility – 400,000 children ages 4-15 years in the US now qualify •  Resources – Shortage of pediatric endocrinologists – High cost of GH therapy
  21. 21. Policy Implications •  Who should pay? – Insurers •  Reluctance to cover GH therapy due to the high cost and increased numbers of eligible children •  Coverage of a “lifestyle medication”? – Out-of-pocket •  Disparities in access
  22. 22. Ethical Implications of the ISS indication “Never ending disorder”0246810 Percent 50 60 70 80 height
  23. 23. Ethical Implications of the ISS indication •  Gender Disparity – 2:1 M:F ratio •  “Slippery slope” – Treatment of children with heights in the normal range
  24. 24. Ethical Implications of the ISS indication “Short stature became a disease when unlimited amounts of high- cost GH became available”
  25. 25. Brand Name (Manufacturer) Increase in GH sales over 2003 Total pediatric GH sales ($) Genotropin (Pfizer) 53% $736 million Humatrope (Lilly) 16% $430 million Saizen (Serono) 20% $182 million Nutropin (Genentech) 10% $354 million Norditropin (Novo Nordisk) 9% $375 million Hall, S. “The Short of It”, NY Times 2004
  26. 26. IGF-1 IGF-1/IGF-BP
  27. 27. Carl Elliott “In the great homecoming dance of life how does a short boy get a date with the head cheerleader?”
  28. 28. “Most men do not feel attracted to taller women; shorter males, as a rule, do not strike the female as true men.” Beigel, 1954 Societal expectations
  29. 29. “the union of a tall woman with a short man appears offensive to taste” Beigel, 1954 Societal expectations
  30. 30. http://www.ncbi.nlm.nih.gov/pubmed/ 17018462 Have you ever heard about this popular treatment for the opposite problem?
  31. 31. Archives of Disease in Childhood,1975 New York Times, 1976
  32. 32. “The above title does not mean the use of tall girls in therapy or the therapy of tall girls, but rather the therapy that may be used to help prevent little tall girls from growing into big tall girls.” CMAJ, 1976
  33. 33. Estrogen therapy for constitutional tall stature in girls •  Route of administration –  Oral or injected estrogens •  diethylstilbestrol (DES) (1-10 mg a day) •  conjugated estrogens (0.3-20 mg/day) •  ethinyl estradiol (0.02-0.5 mg/day) •  intramuscular estradiol Pediatrics, 1977
  34. 34. Estrogen therapy for constitutional tall stature in girls •  Duration of Treatment –  Average age of initiation: 12-13 years –  Tx until epiphyses were fused (4-6 years) •  Efficacy –  Reduction of final height by 1 to 3 inches Pediatrics, 1977
  35. 35. Estrogen Therapy Side Effects •  Nausea, headaches, weight gain •  Breakthrough bleeding •  Mild hypertension •  Benign breast disease •  Ovarian cysts •  Post-therapeutic amenorrhea •  Thromboembolism
  36. 36. •  Increased risk of malignancy – Increasing understanding of the role of estrogen in endometrial and breast cancer – Negative publicity about vaginal cancer in daughters of DES-treated mothers Pediatrics,1977 Estrogen Therapy Side Effects
  37. 37. •  Malignancy? –  “imagined hazard” –  “When it comes to cancer, American society is far from rational. We are possessed with fear” –  “American cancerophobia is a disease as serious to society as cancer is to the individual - and morally more devastating” –  “I tell families that the principal untoward side effect is the anxiety [about cancer] that they will experience during treatment.” Pediatrics,1977 Estrogen Therapy Side Effects
  38. 38. Treatment Efficacy: Tall daughters who completed estrogen tx are shorter than their moms
  39. 39. Positive effects of estrogen treatment of tall stature in girls •  Rapid slowing of linear growth •  Improved self-confidence •  Improved self-image •  Improved performance in school and sports •  “More mature” •  “Easier to live with”
  40. 40. Indications for estrogen treatment of tall stature in girls “a defensive kyphotic posture” “Tall Girl Slump”
  41. 41. •  “depression, withdrawal from social contacts” •  “self-consciousness” •  “personality difficulties” •  “the very insecure girl who is overwhelmed by a more attractive shorter and graceful sister” •  Career aspirations for classical ballet Indications for estrogen treatment of tall stature in girls
  42. 42. “Some girls feel so embarrassed with boys shorter than themselves that they believe their choice of male companions, both in the immediate future and as adults, will be seriously jeopardized” Aust Paediatric Journal, 1965 Indications for estrogen treatment of tall stature in girls
  43. 43. Indications for estrogen treatment of tall stature in girls “Frequently the parents are also very tall and are alarmed because they remember their own distress and misery as adolescents and as young adults and they fear that their child may be unable to find a partner” Parental Pediatrics,1977
  44. 44. Indications for estrogen treatment of tall stature in girls New Yorker Physician
  45. 45. Changing societal definition of tall stature in girls Girls being seen in a clinic for possible estrogen therapy were asked by their physicians, “How tall is too tall?” Mid-1960’s 5’ 8” Late-1960’s 5’ 10” 1970’s 6’ 0”
  46. 46. Changing medical definition of tall stature in girls Predicted adult height of girls for which pediatric endocrinologists would recommend estrogen therapy 1956 5’ 9” 1977 5’ 11” 1999 6’ 2”
  47. 47. Declining use of estrogen therapy •  % pediatric endocrinologists who had ever treated tall girls with estrogen therapy in their lifetime – 1977: 50% – 1999: 23%
  48. 48. NY Times, 1976
  49. 49. Parallels in Therapy? Idiopathic Short stature Idiopathic Tall stature Definition Ht < -2 SD Ht > +2 SD Therapy GH Estrogen Population Boys Girls Efficacy 1-3 inches 1-3 inches QOL gains Speculative ? Long-term SE Unknown ?
  50. 50. Long-term studies of women treated with estrogen for tall stature •  Cohort of women who were evaluated as young girls for tall stature in Australia between 1959 and 1993 (n~700) – Half were treated with estrogen therapy – Half were left untreated
  51. 51. •  Treated women had reduced fertility –  Tried for 12 months or more to become pregnant without success • [RR 1.80 (95%CI: 1.40-2.30)] –  Seen a doctor regarding difficulty becoming pregnant • [RR 1.80 (95%CI: 1.39-2.32)] –  Ever taken fertility drugs • [RR 2.05 (95%CI: 1.39-3.04)] Lancet, 2004
  52. 52. •  Both treated and untreated women had EQUALLY poor psychosocial outcomes –  Lifetime major depression –  Eating disorders –  Scores of mental health (SF-36 scores) •  No psychosocial benefit of tx J Affective Disorders, 2006
  53. 53. •  99.1% of the untreated women were glad that they were not treated •  42.1% of the treated women were dissatisfied with the decision that was made Social Science & Medicine, 2005
  54. 54. New Yorker
  55. 55. New Yorker

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