ENDOCRINOLOGY CONSULT
From the 29th Annual Las Vegas Seminars, presented by the American Academy of Pediatrics, California District IX,
Chapters 1,2,3,4
Laura K. Bachrach, MD, Professor of Pediatrics, Department of Pediatric Endocrinology, Stanford University School of
Medicine, Palo Alto, CA
Educational Objectives
| The goal of this program is to improve the medical care of children with endocrine conditions. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Identify the range of normal pubertal timing.
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| 2. Distinguish signs of benign precocious puberty from those of pathologic precocious puberty.
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| 3. Recognize signs and symptoms of delayed puberty.
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| 4. Promote bone health to avoid fractures in childhood.
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| 5. Optimize peak bone mass in childhood to prevent osteoporosis in adulthood.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, Dr. Bachrach disclosed
that she has been a member of the Data Safety Monitoring Boards of Hoffman-La Roche and Novartis Pharmaceuticals
Corporation, and a speaker for Genentech.
Acknowledgments
Dr. Bachrach was recorded at the 29th Annual Las Vegas Seminars, presented November 15-18, 2007, in Las Vegas,
NV, by the American Academy of Pediatrics, California District IX, Chapters 1,2,3,4. The Audio-Digest Foundation
thanks Dr. Bachrach and the Academy for their cooperation in the production of this program.
| Classic teaching: girls—breast buds begin at 10 yr of age (pubic hair ≈6 mo later); menarche at 12.9 yr of age in whites
(12.2 yr of age in blacks); boys—testes enlarge at 11.5 yr of age (followed by pubic hair); maturation at 15 yr of age;
data challenged by newer findings
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| Evidence for earlier puberty: precocious puberty any sign of puberty in girl <8 yr of age or boy <9 yr of age; Herman-
Giddens, 1997—17000 girls; 50% of blacks and 15% of whites had breasts or pubic hair by 8 yr of age
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| Mean age at onset of breast development (Wu, 2002): 9.5 yr of age in blacks, 10.3 yr of age in whites
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Early Bloomers
| Triggers of early puberty: environmental—hormones in cow’s milk less concerning than other factors; estrogen in
hair products; in study, lavender oil and tea tree oil applied to skin associated with gynecomastia in boys; dental plastics;
evidence not definitive; psychosocial factors—recent immigration (transition from undernourished state to well-nourished
state may spark early puberty); mean age at menarche still 12 yr; precocious development of breasts or pubic hair
more common in blacks; obesity significant risk factor, especially in whites
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| Normal variants of early puberty: benign premature thelarche in girls—unilateral or bilateral breast development
(onset 6-24 mo of age); no growth spurt, vaginal bleeding, or pubic hair; regresses or becomes less apparent as child grows;
true puberty occurs at normal time; benign premature adrenarche—activation of adrenal glands produces underarm hair,
pubic hair, body odor, or acne in boys and girls (onset at 3-8 yr of age); no clitoromegaly, breast development, or growth
spurt; more common in black and obese children; remainder of pubertal development happens at normal time; may be
prepubertal manifestation of polycystic ovary syndrome (PCOS)
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Pathologic Early Puberty
| Central precocious puberty: driven by early production of luteinizing hormone (LH) and follicle-stimulating hormone
(FSH) from pituitary gland; may see breasts and pubic hair; case—2.5-yr-old girl with breasts and pubic hair (unlike
benign thelarche); significant growth spurt; condition not benign (if not treated promptly, patient significantly short
in adulthood); evaluation—central precocious puberty more common in girls (but more likely benign), compared to boys
(pathology in <10% of affected girls, 50% of boys); lesion usually in central nervous system (CNS); evaluate any girl <6
yr of age and any boy presenting with signs of precocious puberty
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| Gonadotropin-independent precocious puberty: LH and FSH suppressed; concern autonomously functioning
ovarian, testicular, or adrenal lesion; exogenous causes—most common (screening important); exposure to oral contraceptive
pills (OCPs), estrogen or androgen creams; adrenal, ovarian, or testicular tumors; case 1—boy 6 mo of age presented
with pubic hair, deep cry, and bilateral breast development; penis highly developed for age; source determined by
history (mother using testosterone cream [Androgel] and estrogen cream [Premarin]); with discontinued contact exposure,
condition resolved; case 2—4-yr-old girl presented with few pubic hairs and clitoromegaly; worry about adrenal tumor
or hyperplasia
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| Estrogen vs androgen: estrogen effects—breast development, vaginal secretions, and menses; androgen effects—pubic
hair, axillary hair, acne and growth of genitalia (in boy) or clitoromegaly (in girl)
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| Signs of adrenarche only: eg, 7-yr-old boy or girl with acne, pubic hair, axillary hair; no enlargement of testes or clitoromegaly;
evaluation—measure LH and FSH to detect sex steroid production by adrenal glands; in boys, consider onset
of true puberty; assess bone age by x-ray; consider ultrasonography (US) of adrenal glands and gonads
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| Signs of estrogen only: key measures estradiol, LH and FSH, and bone age; consider adrenal or ovarian US if estrogen
high, but LH and FSH suppressed (if LH and FSH high, perform magnetic resonance imaging [MRI]); LH and FSH
testing requires highly sensitive assay with pediatric reference data
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| Bone age: patient <2 yr of age—epiphyses too underdeveloped for precise bone age assessment (need “hemiskeleton”
view; radiation not worth it); child >2 yr of age—obtain x-ray of hand for bone age
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| Treating central precocious puberty
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| Why treat? to prevent short stature (particularly in child <7 yr of age), menstrual periods, and sexual abuse; to reduce
psychosocial stress
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| Leuprolide (Lupron Depot): given intramuscularly (IM) every 1 to 3 mo; may not halt adrenarche; prevents menstrual cycles
and progression of breast development; side effects—<5% of children have allergic reaction that causes sterile abscess;
bleeding may continue after first injection (no periods thereafter); quickly reversible (periods resume within 3-6
mo after discontinuation); studies show that women treated during childhood have normal bone density and fertility
(birth defects not increased); leuprolide therapy expensive ($9600/yr)
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| Oral medroxyprogesterone (Provera): alternative to leuprolide; tablet given 1 or 2 times/day; elimination of periods only
effect (does not prevent progression of breast tissue, preserve height, or affect adrenarche)
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| When to stop treatment: usually by 11 yr of age (consider growth rate and psychosocial maturity)
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Late Bloomers
| Boys: no testicular enlargement by 14 yr of age
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| Girls: no breast tissue by 13 yr of age; or, stalled progression—no menarche within 5 yr of breast bud; no menarche by
16 yr of age; no period within 1 yr of maternal menarche
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| Causes of delayed puberty: constitutional delay (normal variant); central failure (lack of increase in LH and FSH);
gonadal failure (primary problem with testes or ovaries)
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| Constitutional delay: most common cause of delayed puberty; history unremarkable—birth weight normal; after first 2
yr of life, growth velocity normal until puberty; often family history of “late bloomers”; on examination, no signs of genital
development—no breast development in girl, no testicular enlargement in boy; no adrenarche
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| Gonadal failure: Turner’s syndrome—1 in 2000 girls lack all or part of X chromosome; most affected girls have ovarian
failure; Klinefelter’s syndrome—boys enter puberty, but testes relatively small for degree of maturation; gonadal damage
due to—radiation or chemotherapy
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| Central hypogonadism (no stimulus to gonads): amenorrhea in athletes or anorexia nervosa; chronic illness or high-dose
glucocorticoid therapy suppresses hypothalamic-pituitary-gonadal axis; CNS tumors and surgery
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| Evaluating delayed puberty: assess bone age; if patient short, reasonable to screen for abnormal growth hormone
levels (measure insulin-like growth factor-1 [IGF-1]); in girl, karyotype for Turner’s syndrome (in boy, Klinefelter’s
syndrome); constitutional delay—as with gonadal failure or central hypogonadism, estrogen/testosterone low; LH and
FSH low; pubic hair delayed; gonadal failure—LH and FSH high; pubic hair may be present; central hypogonadism—
pubic hair development normal (adrenal glands not affected); LH and FSH low
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| Treatment of constitutional delay: reassurance; condition typically occurs in boys; consider—short course of testosterone
(100 mg once/mo for 3 mo); immediate physical changes seen (growth of penis, pubic hair); may “prime pump”
for puberty
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| Long-term sex steroids: indications—pituitary function destroyed by CNS tumor; Turner’s syndrome; damage due to
testicular radiation; recommendation—start treatment slowly and increase slowly (consult endocrinologist)
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| BONES TODAY, BONES TOMORROW
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| Threats to bone health in childhood: chronic illness; organ transplantation and cancer therapy; fractures in children
increasing; peak bone mass—bone “bank” for adulthood; between birth and early 20s, boys and girls have largest and
strongest bones (after that, progressive loss inevitable); peak achieved by 29 yr of age (98% by 20 yr of age; determinants
genetics and lifestyle
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Modifiable Factors Affecting Peak Bone Mass
| Activity and bone health: activity that loads skeleton by making it work builds stronger bones; gains must be maintained
(use it or lose it); astronauts lose significant bone mass after 1 to 3 mo in space; dose-response curve—in moderately
active adult, walking maintains bone mass (increased stimulus [eg, aerobics, basketball, jump rope] needed to add
mass); sedentary lifestyles—with complete immobility, rapid bone loss occurs; weight-bearing physical activity—
increases bone mass and alters bone geometry (bones become wider, which increases biomechanical strength)
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| Body mass: reflects nutrition and activity (in some patients, abnormal hormone function); obese children may outgrow
maximum load that bones meant to carry
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| Calcium: threshold nutrient (not medication); goal optimal level of consumption; as intake increases, amount of bone increases
until plateau reached; excessive intake increases risks for, eg, renal stones; between 9 and 18 yr of age >50% of
adult bone mass laid down (National Academy of Sciences recommends 1300 mg/day of calcium; girls consume ≈50%
of that amount); in American diet, 75% of calcium comes from dairy products (reasons for avoidance include ethnic preferences,
real or perceived lactose intolerance, and preference for soft drinks); goal 4 servings of dairy products per day
(1300 mg); 1 serving calcium (equivalents)—1.0 cup milk or calcium-fortified orange juice provides 300 mg elemental
calcium; 0.5 cup calcium-fortified tofu; 2.5 cups broccoli; 7 cups of spinach; soft drink consumption—in study, fractures
increased among girls who drank more sodas; biggest problem that child consuming soft drink instead of dairy product;
milk consumption down 40% (soda consumption up 2- to 3-fold); calcium “economics”—availability based on intake,
absorption, and excretion; high-sodium diet removes calcium from body through urine; goal to increase levels of calcium
and activity (either alone less effective in building bone mass)
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| Hormones and medications: estrogen, testosterone, growth hormone, and IGF important in bone acquisition; levels
low in patients with eating disorders; glucocorticoids in pharmacologic doses (especially, systemic steroids) can be deleterious
to bone (in very high doses, inhaled steroids)
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| Threats to bone health: osteogenesis imperfecta—genetic disorder; classic findings blue sclera and dentinogenesis imperfecta;
affected children may be identified by high incidence of fractures beginning early in life; chronic disease as risk
factor—largest group; anorexia nervosa; amenorrhea in athletes; untreated chronic gastrointestinal (GI) disease (eg, celiac
disease) associated with low bone mass and fractures; immobilization due to, eg, cerebral palsy, Duchenne’s muscular
dystrophy; organ transplantation or malignancy; rheumatologic disorders that require long-term use of steroids; other
common risk factors—undernutrition due to lifestyle or illness that inhibits calcium intake or absorption; inactivity; inflammation
(chronic inflammatory cytokines deleterious to bone); endocrine disorders; calcium deficiency caused by sex
steroids, growth hormone, or excessive glucocorticoids; of medications, glucocorticoids “number 1” cause of decreased
bone mass
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| Fractures in otherwise healthy children
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| Incidence of radial fractures in children: peak occurs in peripubertal period (girls 8-12 yr of age; boys 11-14 yr of age);
typically, distal forearm fractures involved; bone growth precedes mineralization by 6 to 9 mo (bone temporarily undermineralized);
over past 40 yr, significant increase in forearm fractures (35% increase in boys; 60% in girls; reason
poor bone health)
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| Studies by Goulding (2000, 2005): children with fractures had significantly lower bone mass, compared to those without
fractures; after first fracture, risk for second doubles (after second, risk for third increased 3-fold); correlate risk
factors—low intake of dairy products; obesity; first fracture at <5 yr of age
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| Evaluating children with early or recurrent fractures: review—diet (including calcium intake); activity; medications; history
or family history of fractures; laboratory studies—calcium; phosphorus; measure 25-hydroxy vitamin D levels
(indicates vitamin D stores; multivitamin use does not assure adequate stores); calcium excretion (ideally, 24-hr specimen;
at minimum, calcium/creatinine ratio to assess calcium loss); screening for celiac disease reasonable; thyroid and
sex steroid levels
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Improving Bone Health
| Address risk factors: optimize nutrition; prescribe activity as tolerated; manage underlying disease; minimize harmful
medications
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| Calcium supplements: calcium carbonate chewable, cheap, and unleaded (avoid oyster shell preparations); specific
sources of calcium carbonate—Tums (200-500 mg elemental calcium); CalBurst; Viactiv (500 mg)
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| Vitamin D: may not be taken as prescribed or effectively absorbed (monitor serum levels); goal to achieve 25-hydroxy
vitamin D level >20 ng/mL; vitamin D from sun exposure—for infant wearing diaper only, allow exposure 30 min/wk
(for older child wearing clothes without hat, 2 hr/wk); no sunscreen (sunscreen with sun protection factor [SPF] 8 blocks
most vitamin D from sunlight)
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| Prescription for activity: optimize skeletal loading; titrate activity to patient; avoid immobilization; excessive athletic
activity can cause amenorrhea (associated with increased risk for fracture and slower weight gain)
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| Selling healthy lifestyles: begin early in life; after weaning, provide calcium through dairy foods; weight bearing must
be habit; avoid obesity
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| Anabolic agents: enhance bone gains; growth hormone used only to treat growth hormone deficiency; parathyroid hormone
effective in older adults, but has black box warning against use in children (can cause bone tumors)
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| Antiresorptive agents: decrease bone loss; specific medications—estrogen and bisphosphonates (eg, alendronate [Fosamax],
ibandronate [Boniva])
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| Estrogen therapy: often prescribed in young women for anorexia nervosa and amenorrhea (weight gain more effective);
Procter-Gray, 2008—randomized controlled trial; 30 mg estradiol and norgestrel (Lo Ovral) vs no steroids in young female
runners; regimen not effective (no significant effect on bone mineral content, bone density, or stress fractures); anorexia
nervosa—in RCTs, estrogen alone not effective; estrogen and IGF-1 cause modest increase in bone mass (therapy
expensive); in 13-mo study looking at young adults, weight gain effective (oral contraceptives not effective)
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| Bisphosphonate therapy (alendronate, ibendronate): restrict use to children with osteogenesis imperfecta or multiple fractures
(not low bone density alone)
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| Question and answer: what is recommendation for vitamin D supplementation in nursing infants? not enough vitamin D
in breast milk; American Academy of Pediatrics recommends 200 IU daily; speaker thinks 400 IU fine
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Suggested Reading
Antoniazzi F et al: Bone mass at final height in precociou.puberty after gonadotropin-releasing hormone agonist with
and without calcium supplementation. J Clin Endocrinol Metab 88:1096, 2003; Bachrach LK: Osteoporosis and measurement
of bone mass in children and adolescents. Endocrinol Metab Clin North Am 34:521, 2005; Badaru A et al: Sequential
comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. J Clin
Endocrinol Metab 91:1862, 2006; Goulding A et al: First fracture is associated with increase risk of new fractures during
growth. J Pediatr 146:286, 2005; Goulding A et al: More broken bones: a 4-year double cohort study of young girls with
and without distal forearm fractures. J Bone Miner Res 15:2011, 2000; Heaney RP et al: Peak bone mass. Osteoporosis
Int 11:985, 2000; Herman-Giddens et al: Secondary sexual characteristics and menses in young girls seen in office
practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99:505, 1997; Procter-Gray E et al:
Effect of oral contraceptives on weight and body composition in young female runners. Med Sci Sports Exerc 40:1205, 2008;
Specker BL et al: Sunshine exposure and serum 25-hydroxyvitamin D concentrations in exclusively breast-fed infants. J
Pediatr 107:372, 1985; Specker BL, Shoenau E: Quantitative bone analysis in children: current methods and recommendations.
J Pediatr 146:726, 2005; Wu T et al: Ethnic differences in the presence of secondary sex characteristics and
menarche among US girls: the Third national Health and Nutrition Examination Survey, 1988-1994. Pediatrics 110:752,
2002.
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