Precocious Puberty

Precocious puberty is the appearance of secondary sexual characteristics before age 8 in girls and before age 9 in boys. It is more common in girls (about 10 to 20 times), and in most girls (over 90%) is idiopathic, whereas in boys a pathological cause is found in 25 to 90%.

Classification:

• Central (gonadotropin-dependent, true) precocious puberty: early activation of the hypothalamic-pituitary-gonadal axis. Isosexual and follows the normal sequence of puberty.
• Idiopathic (most girls), genetic (MKRN3 loss of function, the commonest monogenic cause, with paternal imprinting; DLK1, KISS1, KISS1R), hypothalamic hamartoma (gelastic seizures), CNS tumours (optic glioma in NF1, astrocytoma, germinoma), hydrocephalus, cranial radiotherapy (at low doses), infection, trauma, and septo-optic dysplasia.
• Secondary central precocity after long-standing peripheral exposure (congenital adrenal hyperplasia, late diagnosis).
• Peripheral (gonadotropin-independent) precocious puberty: sex steroid excess from gonadal, adrenal or exogenous sources, with suppressed LH and FSH.
• Girls: ovarian cysts (autonomous follicular cysts), McCune-Albright syndrome (GNAS activating mutation: café-au-lait macules with jagged border, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies), granulosa cell tumours, adrenal tumours, hypothyroidism (Van Wyk-Grumbach syndrome), exogenous oestrogens.
• Boys: familial male-limited precocious puberty (testotoxicosis, LHCGR activating mutation), hCG-secreting tumours (germ cell tumours, hepatoblastoma), Leydig cell tumours, congenital adrenal hyperplasia (21-hydroxylase and 11-beta-hydroxylase deficiency), adrenal tumours, McCune-Albright syndrome, and exogenous androgens.
• Variants: premature thelarche, premature adrenarche and premature menarche (isolated).

Consequences:

• Advanced skeletal maturation with premature epiphyseal fusion and reduced adult height (loss of 4 to 10 cm if untreated, more with early onset), psychosocial difficulties, early menarche in young girls, and possible behaviour problems. Underlying CNS pathology may be serious.
• Risk factors for the recent rise: obesity, endocrine-disrupting chemicals, and recent evidence of acceleration of onset of puberty following social stressors.

Girls:

• Breast development (usually the first sign), pubic hair, rapid growth, vaginal discharge or bleeding, adult body odour, acne. Menarche may occur early.
• Slowly progressive forms (common in girls aged 6 to 8) often do not impair adult height. Rapidly progressive forms (progression by more than one Tanner stage within 3 to 6 months, onset before age 6) are more likely pathological.

Boys:

• Testicular enlargement (4 mL or more, a sign of central precocity, whereas small testes with a large phallus suggest adrenal or exogenous causes), penile growth, pubic hair, erections, deep voice, acne, aggressive behaviour.
• Asymmetric testicular enlargement suggests a Leydig cell tumour. Bilateral prepubertal testes with a pubertal phallus suggest adrenal source.

General:

• Growth acceleration (height velocity above 6 cm/year), tall for age in childhood but short as an adult.
• Neurological features (headache, visual change, seizures) point to intracranial lesions, and gelastic seizures to hypothalamic hamartoma. Café-au-lait spots suggest NF1 or McCune-Albright syndrome. Hypothyroid symptoms, abdominal masses, testicular masses and virilisation in girls (clitoromegaly, suggest adrenal source) are clues.

Differential diagnosis: premature thelarche (isolated breast tissue without growth acceleration), premature adrenarche (pubic hair and odour without breast or testicular enlargement), exogenous exposure (oestrogen creams, oral contraceptives, anabolic steroids, soy and lavender or tea tree oils), obesity-related lipomastia, and gynaecomastia.

Red flags: onset before age 6 in girls, any pubertal onset in boys under 9 with small testes, rapid progression, neurological symptoms, signs of virilisation, and café-au-lait pigmentation.

Aims: confirm precocious puberty, distinguish central from peripheral, and identify the cause.

History and examination:

• Age at onset and sequence, growth chart, family history (early puberty, MKRN3), exposure to exogenous hormones, headaches and visual symptoms, seizures, and pubertal stage (Tanner). Visual fields, fundoscopy, skin (café-au-lait, jagged edges), neurological, thyroid and abdominal examination.

Investigations:

• Bone age (advanced by more than 1 year compared with chronological age supports hormone exposure).
• Basal LH and FSH (ultrasensitive assays) and sex steroids (oestradiol, testosterone). Basal LH above 0.3 IU/L (or above 0.2 to 0.3 in some assays) suggests central activation.
• GnRH agonist stimulation test (leuprolide 20 micrograms/kg SC or GnRH 100 micrograms IV, LH measured at 30 to 60 minutes or 3 hours): peak LH above 5 IU/L (above 3.3 to 3.5 IU/L with GnRH agonist) with LH/FSH ratio above 0.6 confirms central precocious puberty. Suppressed LH indicates peripheral.
• Pelvic ultrasound: uterine length above 3.5 cm, uterine volume, ovarian volume above 2 mL, follicular cysts, and a thick endometrium support oestrogen exposure.
• Peripheral workup: 17-hydroxyprogesterone, DHEAS, androstenedione, testosterone, cortisol, hCG and AFP (boys), TSH and free T4, and adrenal imaging (ultrasound or CT).
• MRI of the brain and hypothalamic-pituitary region with contrast: indicated in all boys with central precocious puberty, girls under 6, rapid progression, neurological features, or high LH and oestradiol. Girls aged 6 to 8 with slow progression may avoid imaging.
• Genetic testing: MKRN3, GNAS (McCune-Albright, mosaic), LHCGR, CYP21A2 and CYP11B1, as relevant. Skeletal survey or bone scan for fibrous dysplasia.
• Testicular ultrasound for asymmetry or a mass.

Central precocious puberty

• Indications to treat: onset at young age, rapid progression, advanced bone age with predicted adult height loss, early menarche, and psychological distress. Slowly progressive disease at ages 7 to 8 with normal predicted height may be observed.
• GnRH analogues (continuous stimulation desensitises gonadotropes), first line:
• Leuprolide acetate depot 7.5 to 15 mg IM every 4 weeks, or 11.25 to 30 mg every 12 weeks (also 45 mg every 24 weeks).
• Triptorelin 3 mg every 4 weeks or 11.25 mg every 3 months (22.5 mg every 6 months).
• Histrelin acetate subcutaneous implant 50 mg (arm) every 12 months.
• Dose by weight, and titrate to suppress LH to prepubertal levels (peak stimulated LH below 4 IU/L or basal LH below 1 IU/L) and oestradiol or testosterone to prepubertal levels.
• Monitor: height velocity, Tanner stage, bone age every 6 to 12 months, LH at 3 to 6 months, and injection site reactions. A transient initial flare and sterile abscesses may occur.
• Treatment continues until chronological age of about 10 to 11 years (girls) and 11 to 12 (boys), or bone age about 12 to 12.5 (girls) and 13 to 13.5 (boys), after which puberty resumes within 3 to 12 months, and menses usually within 2 years. Fertility is preserved.
• Outcomes: growth deceleration, bone age slowing, and improved final height particularly when started before age 6 (gain 4 to 10 cm). Bone density is preserved. Obesity may modestly worsen, and weight needs monitoring.
• Treatment of the cause: neurosurgical resection or radiotherapy for tumours, hypothalamic hamartoma (observation, GnRH analogue, or surgery and radiosurgery for refractory gelastic seizures), hydrocephalus shunting, and levothyroxine for hypothyroidism-induced precocity.
• If growth is poor despite suppression, add growth hormone (0.033 to 0.05 mg/kg/day) in selected children with adult height prediction concerns.

Peripheral precocious puberty

• McCune-Albright syndrome (girls): aromatase inhibitors (letrozole 1.5 to 2.5 mg daily, anastrozole 1 mg daily) or antioestrogens (tamoxifen 20 mg daily, fulvestrant 4 mg/kg monthly) to reduce oestrogen action and bleeding. GnRH analogue added if secondary central puberty ensues. Treat fibrous dysplasia (pamidronate 1 mg/kg IV, orthopaedic care), hyperthyroidism (methimazole 0.2 to 0.5 mg/kg/day), growth hormone excess (octreotide, pegvisomant), Cushing syndrome (adrenalectomy), and phosphate wasting (phosphate with calcitriol 20 to 50 ng/kg/day).
• Testotoxicosis (boys): antiandrogen (bicalutamide 12.5 to 50 mg daily, spironolactone 2 to 4 mg/kg/day) with aromatase inhibitor (anastrozole 1 mg daily, letrozole 2.5 mg daily), and GnRH analogue if central puberty develops.
• Congenital adrenal hyperplasia: hydrocortisone 10 to 15 mg/m2/day in 3 divided doses, with fludrocortisone 0.05 to 0.2 mg daily in salt-wasting. Add GnRH analogue if secondary central puberty develops.
• Tumours: surgical excision (adrenal, ovarian, Leydig cell, germ cell), with chemotherapy for malignant germ cell tumours (BEP: bleomycin, etoposide, cisplatin) and hepatoblastoma (cisplatin, doxorubicin).
• Ovarian follicular cyst: observation, as most resolve spontaneously.
• Exogenous exposure: remove the source.
• Hypothyroidism: levothyroxine 2 to 4 micrograms/kg/day.

Supportive care

• Psychological support for child and family, age-appropriate education, and school liaison. Discuss menstrual hygiene for young girls and consider menstrual suppression.
• Ensure adequate nutrition and avoid excess weight gain. Calcium and vitamin D for bone health.
• Monitor for polycystic ovary syndrome and metabolic effects in adolescence.

Follow-up

• Review every 3 to 6 months during treatment, then after stopping to confirm resumption of puberty. Long-term follow-up for adult height, reproductive function and cause-related issues.