In most populations, the mean age of onset of puberty is 10.5 years in girls and 11.5 years in boys.
The first sign of puberty in girls is most commonly breast development (thelarche), followed by pubic hair development (pubarche), and then menarche, which generally occurs 2 " “3 years after thelarche; in boys, the first sign is usually testicular enlargement, followed by pubarche and penile growth.
Precocious puberty has traditionally been defined as physical signs of sexual development before age 8 years in girls and age 9 in boys (2.5 " “3 standard deviations below the mean age of onset of puberty).
Recent guidelines propose lowering the age considered to be normal for sexual development in girls to as young as age 6 years in black girls and age 7 years in white girls. These new guidelines have not been universally adopted.
When evaluating precocious puberty, the entire clinical picture, including rate of pubertal progression and the presence of any neurologic symptoms, must be considered.
Epidemiology
Occurs in ¢ ˆ ¼1 in 5,000 children
Precocious puberty is up to 10 times more common in girls than boys.
Racial differences observed in girls: African-American girls may enter puberty 1 year sooner on average than Caucasian girls. Racial difference not present in males.
Increased incidence in internationally adopted children and in children born premature or small for gestational age
In girls: 80 " “90% of central precocious puberty are idiopathic.
In boys: Precocious puberty is more likely to be associated with underlying pathology.
¢ ˆ ¼50% of affected boys have idiopathic central precocious puberty.
Genetics
Genetic causes include the following:
Familial male precocious puberty (testotoxicosis): sex-limited, autosomal dominant inheritance of luteinizing hormone (LH) receptor activating mutation
McCune-Albright syndrome: sporadic, postzygotic, somatic mutation in the stimulatory subunit of G-protein receptor; precocious puberty more common in girls
Pathophysiology
Central precocious puberty can be associated with CNS disorders.
Peripheral precocious puberty
Arises from peripheral sex hormone sources, including gonadal and adrenal disorders, abdominal or pelvic tumors, or exogenous sex steroids
Can progress to central precocious puberty due to maturation of the hypothalamic " “pituitary axis by sex steroids
Etiology
Central precocious puberty (gonadotropin-releasing hormone [GnRH] dependent)
Associated with gonadotropin (LH and/or follicle-stimulating hormone [FSH]) levels that are elevated beyond the normal prepubertal range. Results from activation of hypothalamic " “pituitary " “gonadal axis.
Physical changes are typically those of normal puberty for a child of that sex.
Peripheral sex hormone effects (peripheral precocious puberty or GnRH-independent; less common)
Gonadotropin-independent elevation of sex steroids arising (i) directly from gonads and/or adrenals, (ii) through stimulation of gonads by GnRH-independent mechanism, or (iii) from an exogenous source
Physical changes reflect predominant excess hormones (estrogenic or androgenic) and are often markedly discordant from normal pubertal development.
Diagnosis
Signs & Symptoms
Careful chronology: physical changes, growth spurt, onset of menses
Neurologic, visual, or behavioral changes suggest a CNS lesion.
History
Family history of early puberty (e.g., menarche before age 10 years) or hyperandrogenic disorders (e.g., congenital adrenal hyperplasia)
Presence of exogenous sex steroid medications or creams in the home
Physical Exam
Plot accurate height (using wall-mounted stadiometer), weight, and growth velocity. Growth acceleration within the past year may be strong evidence for puberty.
Careful inventory of early estrogenic and androgenic effects
Estrogenic effects
Girls: careful staging of breasts and color of vaginal mucosa
Boys: gynecomastia in prepubertal child (gynecomastia is common and normal part of puberty in pubescent male.)
Androgenic effects
Girls: careful staging of pubic hair, clitoromegaly
Boys: careful staging of testicular volume (with Prader gonadometer or by measuring testicular length), penile size, and pubic hair
Examine skin for acne and cafe au lait spots.
Perform comprehensive neurologic evaluation to assess for possible CNS pathology.
Diagnostic Tests & Interpretation
Lab
Labs should be selected based on inventory of estrogenic and/or androgenic effects and drawn in early morning.
Estrogenic effects
Girls: FSH and LH (ultrasensitive, pediatric, immunochemiluminometric [ICMA] or electrochemiluminescent [ECL]) (LH is most accurate) and estradiol
Boys: ultrasensitive LH and FSH, estradiol, human chorionic gonadotropin (hCG) level
Androgenic effects
Total testosterone by assay designed to measure low concentrations, adrenal steroids including 17-hydroxyprogesterone (17-OHP) to evaluate for late-onset congenital adrenal hyperplasia and dehydroepiandrosterone sulfate (DHEA-S) to exclude or confirm adrenarche, and ultrasensitive LH to evaluate for central puberty
Other tests
Prolactin: may be elevated with CNS tumors
Thyroid-stimulating hormone (TSH) and free thyroxine (T4)
Avoid lower yield tests, such as total estrogens, nonultrasensitive LH, free testosterone levels (more helpful in adolescent girls with testosterone levels above 30 ng/dL), and other adrenal steroids such as 17-hydroxypregnenolone and DHEA.
Provocative stimulation tests should be done when the aforementioned tests are abnormal or equivocal:
GnRH test (typically leuprolide stimulation) for central precocious puberty; prepubertal GnRH response is predominantly FSH, whereas pubertal response is predominantly LH.
Adrenocorticotropic hormone (ACTH) stimulation test for adrenal abnormalities. Exogenous corticosteroid therapy will interfere with ACTH test but does not interfere with GnRH test of pituitary " “gonadal axis.
Imaging
Bone age x-ray of left hand and wrist: if advanced, further studies, guided by history and physical examination, warranted. If not advanced, or if only early breast or pubic hair development (but not both), premature thelarche or premature adrenarche, respectively, most likely diagnoses.
MRI of head: In the absence of specific clues to CNS disease, the probability of an intracranial abnormality depends primarily on age of onset of puberty, rate of progression, and the sex of the child. MRI is almost always done in boys because they are less likely than girls to have idiopathic precocious puberty.
Ultrasound of gonads/adrenals: as indicated by examination and studies. Evaluates for tumors in both sexes; in girls, ultrasound can also evaluate ovarian/uterine maturity.
Alert
Obese children often have advanced bone ages.
Palpation of breast tissue (buds) can be difficult due to adiposity.
Differential Diagnosis
Causes of central precocious puberty:
Often idiopathic (girls >> boys)
Any cause of peripheral precocious puberty
CNS tumors
Hypothalamic hamartoma: most common CNS mass causing precocious puberty; benign (nonprogressive) congenital malformation of GnRH-secreting neurons
Hypothalamic " “chiasmatic glioma: often associated with neurofibromatosis
Astrocytoma
Ependymoma
Post-CNS trauma or damage
Surgery
Radiation: may occur after 18-Gy exposure
Hydrocephalus/other CNS malformations
Infections: brain abscess, meningitis, encephalitis, granuloma. Lesions may result in stimulation or lack of inhibition of GnRH-secreting area of the hypothalamus, resulting in early pituitary activation.
Environmental: exogenous estrogens (creams and oral forms) and/or exogenous androgens (anabolic steroids or testosterone formulations)
Congenital adrenal hyperplasia: Poorly controlled congenital adrenal hyperplasia can activate the hypothalamic " “pituitary " “gonadal axis in either gender.
McCune-Albright syndrome: triad of precocious puberty, cafe au lait spots, and polyostotic fibrous dysplasia
Familial male precocious puberty (testotoxicosis)
Refeeding after severe malnutrition during early development (such as adopted children who had kwashiorkor)
Incomplete pubertal development
Premature thelarche
Premature adrenarche
Premature menarche
Treatment
Medication
Central precocious puberty: GnRH agonists are the treatment of choice. Adjunctive therapy with growth hormone may be needed to optimize final adult height.
Calcium supplementation may assist bone mass accretion during GnRH agonist therapy.
Peripheral sex hormone effects: aromatase inhibitors and antiandrogens (spironolactone or ketoconazole), glucocorticoids for congenital adrenal hyperplasia
Ongoing Care
When to expect improvement:
Depends on cause. For example, sexual changes of McCune-Albright syndrome are due to autonomously functioning ovarian cysts, which regress variably over time.
Treatment of central precocious puberty with a GnRH agonist usually results in cessation of menses within 2 months, slowing or nonprogression of pubertal changes over 4 " “6 months, and decreased rate of bone age acceleration within 12 months.
Typically, GnRH agonists such as leuprolide (Lupron) are administered in a depot form every 28 days. Some children require shortening of the interval, often prompted by incomplete pubertal suppression. A longer acting formulation of leuprolide is sometimes used as an every 3-month injection. A 12-month duration implantable formulation (histrelin) is also available.
The length of treatment is highly individualized but typically continues until the age of normal pubertal onset.
Prognosis
With treatment, improvement in predicted height may be achieved. Earlier treatment results in improved final height, but most children do not reach target height predicted by mid-parental height measurements.
Treatment may decrease psychosocial distress.
Long-term effects of central precocious puberty and GnRH agonists on fertility have not been fully elucidated.
Complications
Short stature
Psychosocial stresses of early puberty
Additional Reading
Carel ‚ JC, Eugster ‚ EA, Rogol ‚ A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009;123(4):e752 " “e762. ‚ [View Abstract]
Carel ‚ JC, Leger ‚ J. Clinical practice. Precocious puberty. N Engl J Med. 2008;358(22):2366 " “2377. ‚ [View Abstract]
Herman-Giddens ‚ ME, Slora ‚ EJ, Wasserman ‚ RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research Office in Settings network. Pediatrics. 1997;99(4):505 " “512. ‚ [View Abstract]
Kaplowitz ‚ PB. Treatment of central precocious puberty. Curr Opin Endocrinol Diabetes Obes. 2009;16(1):31 " “36. ‚ [View Abstract]
Kaplowitz ‚ P, Oberfield ‚ SE. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics. 1999;104(4, Pt 1):936 " “941. ‚ [View Abstract]
Nathan ‚ BM, Palmert ‚ MR. Regulation and disorders of pubertal timing. Endocrinol Metab Clin North Am. 2005;34(3):617 " “641. ‚ [View Abstract]
Oostdijk ‚ W, Rikken ‚ B, Schreuder ‚ S, et al. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child. 1996;75(4):292 " “297. ‚ [View Abstract]
Codes
ICD09
259.1 Precocious sexual development and puberty, not elsewhere classified
253.1 Other and unspecified anterior pituitary hyperfunction
ICD10
E30.1 Precocious puberty
E22.8 Other hyperfunction of pituitary gland
E30.8 Other disorders of puberty
SNOMED
400179000 Precocious puberty (disorder)
237816004 Central precocious puberty (disorder)
19911007 Precocious female puberty (disorder)
190291004 Premature puberty due to hypothyroidism (disorder)
102889008 Premature development of the breasts (finding)
FAQ
Q: If my child is treated with a GnRH agonist, will he or she go through puberty when we stop the medication?
A: Yes. Children on GnRH agonist treatment proceed through normal puberty when the medication is stopped. Effects on fertility have not been fully studied long-term.
Q: If my child already has some pubertal changes, can they be reversed?
A: If GnRH agonists are used, menses will cease and breast tissue and pubic hair will often partially or completely regress.