This document summarizes research on the use of growth hormone (GH) therapy for short stature and estrogen therapy for tall stature in children. It describes how GH therapy was approved for conditions like idiopathic short stature and how this expanded eligibility and costs. It also discusses potential medical and ethical implications like side effects and "slippery slope" concerns. Similarly, it outlines how estrogen therapy was used historically for tall girls but was found to reduce fertility and have no psychosocial benefits, and its use has declined. The document draws parallels between the two therapies but ultimately questions the indications and impacts.

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. 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. 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. Definition of short stature
< -2 SD (2.5%)0246810
Percent
50 60 70 80
height

5. <5’ 4”

6. <5’ 0”

7. Brook C. J Pediatr 1998; 133:591-2.

8. But we do see, evaluate, and diagnose
Patients with Growth Hormone Deficiency

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. Indications for Recombinant GH
• GH-deficiency (1985)

12. 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

13. Growth Hormone Approval for
Idiopathic Short Stature - July 2003

14. 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

16. 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”

18. Implications
• Medical
• Policy
• Ethical

19. 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

20. GH side effects
• Skin/Joint
– Injection site
reactions, rash
– Arthralgias,
myalgias, edema
• Otitis media
• Gynecomastia
• Scoliosis
• Endocrine
– Hypothyroidism
– Mild transient
hyperglycemia

21. • 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

24. 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.

25. 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

27. 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

28. Ethical Implications of the ISS indication
“Never ending disorder”0246810
Percent
50 60 70 80
height

29. Ethical Implications of the ISS indication
• Gender Disparity
– 2:1 M:F ratio
• “Slippery slope”
– Treatment of children with heights in
the normal range

30. Ethical Implications of the ISS indication
“Short stature became a disease
when unlimited amounts of high-
cost GH became available”

31. 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

38. IGF-1
IGF-1/IGF-BP

41. Carl Elliott
“In the great homecoming dance of
life how does a short boy get a date
with the head cheerleader?”

42. “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

43. “the union of a tall woman with a short man
appears offensive to taste”
Beigel, 1954
Societal expectations

44. http://www.ncbi.nlm.nih.gov/pubmed/
17018462
Have you ever heard about this popular
treatment for the opposite problem?

45. Archives of Disease in Childhood,1975
New York Times, 1976

46. “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

48. 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

49. 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

50. Estrogen Therapy Side Effects
• Nausea, headaches, weight gain
• Breakthrough bleeding
• Mild hypertension
• Benign breast disease
• Ovarian cysts
• Post-therapeutic amenorrhea
• Thromboembolism

51. • 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

52. • 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

53. Treatment Efficacy:
Tall daughters who completed
estrogen tx are shorter than their moms

54. 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”

55. Indications for estrogen treatment
of tall stature in girls
“a defensive kyphotic
posture”
“Tall Girl Slump”

56. • “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

57. “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

58. 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

59. Indications for estrogen treatment
of tall stature in girls
New Yorker
Physician

60. 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”

61. 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”

62. Declining use of estrogen therapy
• % pediatric endocrinologists who
had ever treated tall girls with
estrogen therapy in their lifetime
– 1977: 50%
– 1999: 23%

63. NY Times, 1976

65. 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 ?

66. 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

67. • 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

68. • 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

69. • 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

70. New Yorker

71. New Yorker