Precocious puberty

Precocious puberty is the appearance of secondary sexual characteristics before 8 years of age in girls and 9 years of age in boys. Precocious puberty is classified as central precocious puberty, resulting from early gonadotropin-releasing hormone (GnRH) secretion causing activation of the hypothalamic-pituitary-gonadal axis, or peripheral precocious puberty, resulting from sex hormone production that is not driven by GnRH secretion. Central precocious puberty may be idiopathic or caused by CNS pathology or genetic syndromes. Causes of peripheral precocious puberty include increased sex hormone production from adrenal or gonadal tumors, functional ovarian cysts, exogenous steroid use, and hypothyroidism. Clinical evaluation involves a focused history and physical examination, including a pediatric growth assessment and sexual maturity rating, to distinguish precocious puberty from benign pubertal variants. Initial diagnostic evaluation includes laboratory testing (gonadotropin and sex hormone levels) and a bone age assessment. Targeted testing to determine the underlying cause is based on clinical presentation and initial results. Management is based on the underlying cause. GnRH analogs may be considered in some patients with central precocious puberty.

By location ^[1][2]

Central precocious puberty

• Caused by early onset of GnRH secretion
• Early activation of the hypothalamic-pituitary-gonadal axis → abnormally early initiation of pubertal changes → early development of secondary sexual characteristics
• ♀ > ♂ (10:1) ^[1]
• The sequence and rate of progression of pubertal development are symmetrical and align with those in normal puberty, but puberty occurs at an early age. ^[1][3]

Peripheral precocious puberty

• Early development of secondary sexual characteristics caused by an increase in sex hormones that is not driven by GnRH secretion
• The sequence and rate of progression of pubertal development may be incomplete, asymmetrical, or discordant from those in normal puberty. ^[1][3]

By phenotype ^[4]

Isosexual precocious puberty

• Early development of secondary sexual characteristics that match the individual's biological sex
• Can occur in central and peripheral precocious puberty

Heterosexual precocious puberty

• Early development of secondary sexual characteristics that are discordant with the individual's biological sex
• Can occur in peripheral precocious puberty (e.g., McCune-Albright syndrome, Leydig cell tumors, congenital adrenal hyperplasia)

Etiology of central precocious puberty ^[1][4][5]

• Idiopathic (most common cause in girls)
• CNS lesions
  • Intracranial tumors (e.g., hypothalamic hamartoma, optic pathway glioma)
  • Hydrocephalus
  • Brain injury (e.g., traumatic brain injury, radiation injury)
  • Intracranial infections (e.g., encephalitis, meningitis)
• Genetic syndromes: neurofibromatosis type 1, tuberous sclerosis

Boys are more likely than girls to have an identifiable cause of central precocious puberty (e.g., CNS lesions). ^[1][4]

Hypothalamic hamartoma is the most common CNS lesion in central precocious puberty. ^[4]

Etiology of peripheral precocious puberty ^[1][2][4]

• Increased androgen production
  • Congenital adrenal hyperplasia
  • Adrenocortical tumors
  • Androgen-producing gonadal tumors (e.g., Sertoli-Leydig cell tumor, Leydig cell tumor)
• Increased estrogen production
  • McCune-Albright syndrome
  • Functional ovarian cyst
• Tumors that produce β-hCG ^[4][6]
  • Embryonal carcinoma
  • Testicular choriocarcinoma
• Primary hypothyroidism
• Exposure to exogenous steroids (e.g., OCPs, estrogen-containing creams, testosterone gel)

Central precocious puberty has a central cause (e.g., hypothalamic lesions) and high GnRH levels, while peripheral precocious puberty has a peripheral cause (e.g., germ cell tumors) without elevated GnRH levels.

Obesity is associated with early pubertal development. See "Factors affecting timing and progression of puberty." ^[7][8]

The clinical presentation depends on the underlying condition.

Focused history ^[1][2]

• Pubertal development
  • Age of onset of secondary sexual characteristic development, e.g.:
    • Pubic and axillary hair
    • Body odor
    • Breast development
    • Testicular development
  • Sequence and pattern of development
  • Symmetry in development of breasts and testes
  • Complete vs. incomplete development (e.g., isolated premature thelarche, adrenarche, or menarche)
  • Additional signs of puberty (e.g., voice change, acne, vaginal bleeding)
• Associated features of an underlying cause
  • Neurological symptoms (e.g., headache, vision changes)
  • Symptoms of hypothyroidism or clinical features of thyrotoxicosis
  • Abdominal pain
• Personal medical history
  • History of brain tumor or head trauma
  • Cancer treatments (e.g., chemotherapy, radiation)
  • Sex steroid use (e.g., OCPs, topical estrogen or testosterone)
• Family history: timing of parental puberty ^[2]
• Environmental exposures: endocrine-disrupting chemicals (e.g., lavender oil, phthalates)

Focused examination ^[1][2]

• Pediatric growth assessment
  • Standard pediatric growth parameters (e.g., height, weight, and BMI)
  • Growth velocity
• Evaluation for physical changes during puberty
  • Sexual maturity rating ^[1]
  • Facial and axillary hair
  • Acne
• Evaluation for underlying cause
  • Abdominal and testicular examination: for gonadal tumors
  • Vaginal examination to assess for signs of:
    • Estrogen exposure (e.g., dull pink vaginal mucosa, vaginal discharge)
    • Virilization (e.g., clitoromegaly)
  • Skin examination: for café au lait macules (seen in McCune-Albright syndrome, neurofibromatosis)
  • Thyroid examination
  • Neurological examination: for suspected CNS pathology

Children with precocious puberty may have accelerated growth in adolescence but typically have shorter than average stature in adulthood due to early closure of the epiphyseal plates. ^[1]

Approach

• Suspected benign pubertal variant : Consider observation for 3–6 months before diagnostic testing.
• Multiple and/or progressive development of secondary sexual characteristics: Obtain initial studies, including gonadotropins and bone age radiography.
  • LH > 0.3 IU/L: targeted testing for etiology of central precocious puberty ^[2]
  • LH < 0.3 IU/L with suspected central precocious puberty: GnRH stimulation test
  • Prepubertal LH levels
    • Suspected peripheral precocious puberty: targeted testing for etiology of peripheral precocious puberty
    • Suspected benign pubertal variant: observation
• Diagnostic uncertainty: Refer to endocrinology for further evaluation.

Patients with normal initial laboratory studies and isolated examination findings suggesting benign pubertal variants can be observed for 3–6 months before further workup. ^[1]

The diagnostic approach to precocious puberty in children with obesity is the same as in children with normal body weight. ^[8]

Initial diagnostic studies ^[1]

Laboratory studies

• LH and FSH
  • Typically increased in central precocious puberty
  • Prepubertal levels suggest peripheral precocious puberty or a benign pubertal variant.
• Testosterone (boys) or estradiol (girls)
  • Typically increased in both central and peripheral precocious puberty
  • Estradiol > 100 pg/ml suggests an ovarian source (e.g., ovarian tumor). ^[1]

Obtaining laboratory studies in the early morning is preferred. ^[9]

Bone age radiography

• Most commonly performed as x-ray of nondominant hand and wrist
• Advanced bone age (> 2 standard deviations) compared to chronological age suggests central or peripheral precocious puberty rather than benign pubertal variant

Advanced bone age is common in children with obesity, which limits the utility of bone age radiography in distinguishing between precocious puberty and benign pubertal variants.^[8]

Additional diagnostic studies ^[1]

Obtain additional testing based on clinical presentation and initial diagnostics. Consult a specialist (e.g., endocrinology) as needed.

Suspected central precocious puberty despite LH < 0.3 IU/L ^[1][2]

• GnRH stimulation test
  • LH elevation after GnRH stimulation: central precocious puberty
  • No LH elevation after GnRH stimulation: peripheral precocious puberty or benign pubertal variant
• Pelvic imaging: Consider in girls to assess uterine and ovarian volume in the case of diagnostic uncertainty.

Targeted testing for underlying cause

• Central precocious puberty and/or suspected CNS pathology: MRI brain ^[2][9]
• Signs of hypothyroidism or signs of hyperthyroidism: TSH
• Signs of hyperandrogenism: serum DHEA-S, 17-hydroxyprogesterone
• Suspected gonadal tumor
  • Ultrasound pelvis or testicles
  • β-hCG in boys with suspected germ cell tumors
• Suspected adrenal tumor: adrenal imaging

CNS imaging is recommended in all boys and in girls < 6 years of age with central precocious puberty. Use shared decision-making to determine the need for imaging in girls 6–8 years of age. ^[2][9]

Manage precocious puberty in consultation with a pediatric specialist as appropriate (e.g., endocrinology, neurology, surgery). ^[1][2]

Management of central precocious puberty ^[1][2][12]

• GnRH agonists (e.g., leuprolide, buserelin, goserelin, histrelin) ^[2][9]
  • Indications
    • Preservation of height potential ^[2]
    • Promotion of psychosocial well-being
    • Prevention of early menarche and sexual maturity ^[2]
  • Duration of therapy: based on patient's height potential and ability to tolerate puberty
• Expectant management may be considered in the absence of indications for GnRH agonists.
• Management of CNS lesions, if present
• Management of associated psychological stress (e.g., anxiety) as necessary

Childhood obesity is not a contraindication to GnRH agonists in children with precocious puberty. ^[8]

Management of peripheral precocious puberty ^[1]

Treat the underlying cause, e.g.:

• Hormone-producing tumor: surgery ^[4]
• Congenital adrenal hyperplasia: cortisol replacement (see “Treatment of congenital adrenal hyperplasia”)
• Ovarian cysts
  • Spontaneous resolution is common.
  • Surgery may be indicated for complications.
  • See “Management of ovarian cysts” for details.

Benign variants of puberty ^[2][13]

• Benign pubertal variants involve isolated development of secondary sexual characteristics and prepubertal pattern of linear growth.
• Observation over 4–6 months is usually appropriate. ^{[2] [1][13]}
• Children with progressive pubertal development and/or rapid linear growth during this period should be evaluated for precocious puberty.