What is precocious (early onset) puberty, including its definition, epidemiology, etiology (central and peripheral causes), evaluation, and management?

Early Onset (Precocious) Puberty: Comprehensive Overview

Definition

Precocious puberty is defined as the appearance of secondary sexual characteristics before age 8 years in girls or age 9 years in boys. 1, 2, 3

Key diagnostic markers include:

• Girls: Breast development (thelarche) is the first sign of true precocious puberty—not pubic hair, which represents adrenarche and should not be confused with true precocious puberty 1, 4
• Boys: Testicular enlargement ≥4 mL volume 3

Epidemiology

• Precocious puberty occurs more frequently in girls than boys 5, 3
• In boys, precocious puberty is more often associated with identifiable organic disorders of the central nervous system, adrenal glands, or testes 5
• Girls under age 6 have the highest risk (>90%) of CNS abnormalities causing central precocious puberty 1
• For girls aged 6-8 years, the likelihood of identifying a CNS lesion is lower (2-7%) 4

Etiology

Central Precocious Puberty (Gonadotropin-Dependent)

Results from premature activation of the hypothalamic-pituitary-gonadal (HPG) axis 6, 7:

• CNS pathology: Hypothalamic hamartomas, gliomas, arachnoid cysts 4, 2
• Idiopathic: Most common in girls, with genetic mutations in MKRN3 and DLK1 genes identified 3
• Exposure to exogenous sex steroids 2
• Familial constitutional variants 2
• History of chemotherapy with alkylating agents or radiotherapy 1

Peripheral Precocious Puberty (Gonadotropin-Independent)

Characterized by increased sex steroid production without HPG axis activation 6, 7:

• Testotoxicosis: Constitutive activating mutations in LH-receptor gene 7
• McCune-Albright syndrome: Activating mutations in Gs protein α-subunit gene 6, 7
• Congenital adrenal hyperplasia 6
• Adrenal and gonadal tumors 6, 7

Evaluation

Clinical Assessment

Document the precise age when secondary sexual characteristics first appeared and assess the rate of pubertal progression 1:

• Tanner staging for breast development and pubic hair 1, 4
• Growth velocity and height measurements 4
• Timing of menarche in girls 1
• Family history of pubertal timing 4
• Exposure to exogenous hormones 4
• Neurological symptoms: severe headaches, visual changes, seizures 4

Laboratory Workup

Measure baseline gonadotropins (FSH, LH) and estradiol to distinguish central from peripheral precocious puberty 1, 4, 2:

• Central precocious puberty: Elevated gonadotropins with pubertal estradiol/testosterone levels 4
• GnRH stimulation test: Peak LH >10 IU/L confirms HPG axis activation and central precocious puberty 4
• Prolactin level: Normal range rules out hyperprolactinemia, which occurs in 65% of cases with true pituitary pathology 4

Radiologic Assessment

Obtain bone age X-ray to assess skeletal maturation and predict impact on final adult height 1, 4:

Brain MRI with gadolinium contrast is mandatory for:

• All girls under age 6 years (>90% risk of CNS abnormalities) 1, 4
• Girls aged 6-8 years based on clinical presentation 4
• Any patient with neurological symptoms 4
• The American College of Radiology recommends MRI of the sella and hypothalamic-pituitary axis as the preferred imaging modality 4

Consider pelvic ultrasound in girls to rule out ovarian tumors or cysts 4

Management

Treatment Algorithm for Central Precocious Puberty

GnRH analogs are the standard treatment for central precocious puberty 4, 3:

Treatment indications:

• Girls with progressive central precocious puberty diagnosed before age 8 years should be treated to preserve final adult height and prevent psychosocial complications 1
• Treatment is particularly beneficial for girls diagnosed before age 6 years 1, 4

Mechanism and goals:

• GnRH analogs work through continuous pituitary stimulation, desensitizing gonadotrophs and reducing LH release, effectively halting ovarian/testicular stimulation 4
• Treatment goals: preserve final adult height, delay further pubertal progression, optimize secondary sex characteristics development, and promote psychosocial well-being 4, 8
• Treatment typically continues until the normal age of puberty 4
• A 6-month subcutaneous injection preparation is now available 3

Monitoring:

• Clinical examination with Tanner staging 4
• Hormonal evaluation to confirm adequate suppression 3
• Serial bone age assessments 4

Treatment for Peripheral Precocious Puberty

Management depends on the underlying etiology 7, 3:

• Drugs blocking sex steroid action: cyproterone, tamoxifen 7
• Drugs blocking sex steroid synthesis: ketoconazole, medroxyprogesterone, aromatase inhibitors 7
• Surgical intervention for tumors 6

Special Considerations and Pitfalls

Do not confuse isolated adrenarche (pubic/axillary hair alone) with true precocious puberty—this is a common pitfall 1, 4

Refer to pediatric endocrinology after obtaining baseline LH, FSH, and estradiol if Tanner stage 2 breast development occurs before age 8 years 4

Patients with premature ovarian insufficiency from cancer treatment require hormone replacement therapy for pubertal induction, not GnRH suppression 1

Evaluate for behavioral problems, mood symptoms, and psychosocial adjustment, as early puberty is associated with increased risk of behavioral problems, obesity, metabolic disorders, psychological distress, cardiovascular disease, and breast cancer 9, 1

Provide contraceptive counseling as appropriate, since fertility may be present despite young age 4