tall boys and short girls: pursuit of the american dream

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