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
Stature is normally distributed
02
46
810
Percent
50 60 70 80height
02
46
810
Percent
50 60 70 80height
Adult males 5’ 9”
National Health and Nutrition Examination Survey (NHANES) 1999-2002
Adult females 5’ 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”
Definition of short stature < -2 SD (2.5%)
0
24
68
10Percent
50 60 70 80height
<5’ 4”
<5’ 0”
Brook C. J Pediatr 1998; 133:591-2.
But we do see, evaluate, and diagnose Patients with Growth Hormone Deficiency
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
Indications for Recombinant GH
• GH-deficiency (1985)
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
Growth Hormone Approval for Idiopathic Short Stature - July 2003
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
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”
Implications
• Medical
• Policy
• Ethical
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
GH side effects
• Skin/Joint – Injection site
reactions, rash – Arthralgias,
myalgias, edema
• Otitis media • Gynecomastia
• Scoliosis • Endocrine – Hypothyroidism – Mild transient
hyperglycemia
• 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
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.
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
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
Ethical Implications of the ISS indication
“Never ending disorder” 0
24
68
10Percent
50 60 70 80height
Ethical Implications of the ISS indication
• Gender Disparity – 2:1 M:F ratio
• “Slippery slope” – Treatment of children with heights in
the normal range
Ethical Implications of the ISS indication
“Short stature became a disease when unlimited amounts of high-
cost GH became available”
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
IGF-1
IGF-1/IGF-BP
Carl Elliott
“In the great homecoming dance of life how does a short boy get a date
with the head cheerleader?”
“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
“the union of a tall woman with a short man appears offensive to taste”
Beigel, 1954
Societal expectations
http://www.ncbi.nlm.nih.gov/pubmed/17018462
Have you ever heard about this popular treatment for the opposite problem?
Archives of Disease in Childhood,1975
New York Times, 1976
“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
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
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
Estrogen Therapy Side Effects
• Nausea, headaches, weight gain • Breakthrough bleeding • Mild hypertension • Benign breast disease • Ovarian cysts • Post-therapeutic amenorrhea • Thromboembolism
• 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
• 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
Treatment Efficacy: Tall daughters who completed
estrogen tx are shorter than their moms
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”
Indications for estrogen treatment of tall stature in girls
“a defensive kyphotic posture”
“Tall Girl Slump”
• “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
“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
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
Indications for estrogen treatment of tall stature in girls
New Yorker
Physician
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”
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”
Declining use of estrogen therapy
• % pediatric endocrinologists who had ever treated tall girls with estrogen therapy in their lifetime – 1977: 50% – 1999: 23%
NY Times, 1976
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 ?
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
• 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
• 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
• 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
New Yorker
New Yorker
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