PRECOCIOUS PUBERTY

Definition

• Precocious puberty = onset of secondary sexual characteristics before age 8 in girls or before age 9 in boys.
• May be isosexual (appropriate for genetic sex) or contrasexual (virilization in girls, feminization in boys).
• Occurs 10× more often in girls (usually central/true precocious puberty).

GONADOTROPIN-DEPENDENT (CENTRAL) PRECOCIOUS PUBERTY

General

• Also called true precocious puberty.
• Caused by early maturation of the GnRH pulse generator → premature LH, FSH secretion.
• Accounts for ~20× higher incidence in girls than in boys.

Clinical Features

• Girls: Premature thelarche (breast dev.) + pubarche in normal pubertal sequence, advanced bone age, accelerated growth.
• Boys: Early testicular enlargement (gonadarche), plus pubic hair, advanced bone age, accelerated growth.

Etiologies

• Idiopathic (no identifiable CNS lesion):
  • 90% of central precocity in girls.
  • 50% of central precocity in boys (the other 50% have CNS lesion).
• CNS Causes:
  1. Hamartomas of the tuber cinereum (ectopic GnRH pulse generator)
  2. Astrocytoma, ependymoma
  3. Hypothalamic or optic gliomas (e.g., in NF1)
  4. Craniopharyngioma or other tumors near the posterior hypothalamus
  5. Radiation to CNS (e.g., for leukemia)
  6. Hydrocephalus, CNS inflammatory disorders (e.g., sarcoid)
  7. Pineal region neoplasms (e.g., germinoma)
  8. Congenital midline defects
• Rare: Gonadotropin-secreting pituitary tumors, or androgen exposure can secondarily activate GnRH pulses.

Laboratory Findings

• LH, FSH, estradiol/testosterone: Elevated, appropriate to pubertal levels.
• Bone age: Advanced.

Imaging

• Head MRI: Indicated, especially in boys, or if suspicion of CNS lesion in girls.

Treatment

• If CNS lesion: Specific therapy (surgery, radiation, etc.).
• Idiopathic: GnRH agonist therapy (e.g., leuprolide) to arrest early puberty, help attain better adult height.

GONADOTROPIN-INDEPENDENT (PERIPHERAL) PRECOCIOUS PUBERTY

General

• Also called pseudoprecocious puberty.
• Excess sex steroids (estrogens/androgens) from gonadal or adrenal sources, independent of LH/FSH.
• LH and FSH are suppressed due to negative feedback from high sex steroids.

Isosexual vs. Contrasexual

• Isosexual: External characteristics match genetic sex (e.g., girl with estrogen excess).
• Contrasexual: Virilization of girls, feminization of boys.

Causes in Girls (Isosexual)

1. Exogenous Estrogen (e.g., creams)
2. Ovarian Sources: Follicular cysts, granulosa-cell tumors, gonadoblastoma, Leydig cell tumors.
3. Adrenal Estrogen-Secreting Neoplasms
4. McCune-Albright Syndrome (MAS)
   • GNAS somatic mutation → constitutive Gs protein → multiple endocrine hyperfunctions.
   • Triad: Café-au-lait spots (coast-of-Maine), bony fibrous dysplasia, precocious puberty (often early vaginal bleeding <2 yrs).

Causes in Boys (Isosexual)

1. Leydig Cell Tumors (testicular, usually benign)
2. hCG-Secreting Germ Cell Tumors (pineal, retroperitoneum, testes, etc.) → hCG mimics LH.
3. Adrenal Tumors producing androgens.
4. Congenital Adrenal Hyperplasia (e.g., 21-hydroxylase deficiency, 11β-hydroxylase deficiency).
5. Testotoxicosis: Germline activating LH receptor mutation → early testosterone secretion.
6. McCune-Albright Syndrome (less common in boys).

Contrasexual Precocity

• Girls with androgen excess: exogenous androgens, adrenal androgen-secreting tumors, CAH.
• Boys with estrogen excess: exogenous estrogens, adrenal estrogen-secreting neoplasms.

Laboratory Findings

• LH, FSH: Low (suppressed).
• Sex steroids (E2, T): Elevated.
• Bone age: Advanced.

Treatment

• Address primary source of sex steroid (e.g., remove tumor, treat CAH with glucocorticoids).

INCOMPLETE PRECOCIOUS PUBERTY

Definition

• Premature thelarche or Premature adrenarche without full pubertal development.
• Often benign variants; bone age not advanced.
• May precede or evolve into full-blown central precocious puberty in a subset.

Other Causes

• Untreated primary hypothyroidism can cause incomplete precocious puberty (rare).

DIAGNOSTIC EVALUATION AND TREATMENT OF PRECOCIOUS PUBERTY

Clinical Evaluation

1. History: Headaches, vision changes, polydipsia/polyuria (suggest CNS lesion?), prior radiation or medications.
2. Growth Chart: Plot all heights over time.
3. Tanner Staging: Document breast/genital/pubic hair development.
4. Bone Age: Assess advanced skeletal maturation.
5. Lab Tests:
   • LH, FSH, estradiol, testosterone, 17-hydroxyprogesterone, DHEA-S, androstenedione, TSH, ± β-hCG, α-fetoprotein.
   • GnRH stimulation test (if needed) for central puberty diagnosis.
6. Imaging:
   • MRI (head) for central puberty.
   • Abdominal/pelvic imaging for gonadal/adrenal tumor suspicion.

Management

• Central (Gonadotropin-Dependent)
  • If CNS lesion: Specific therapy (e.g., surgical resection of craniopharyngioma, radiation, etc.).
  • Idiopathic: GnRH agonists (leuprolide) to halt progression, preserve height.
• Peripheral (Gonadotropin-Independent)
  • Treat underlying source (e.g., resect androgen-secreting tumor, glucocorticoids for CAH).