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A. Definition navigator

  1. Puberty beginning before 7.5 years in girls or 9.5 years in boys
  2. Requires breast and/or pubic hair development
  3. Increased gonadal steroid secretion increases growth and bone maturation
  4. True precocious puberty: isosexual and driven by pituitary hormones
  5. Pseudoprecious puberty: isosexual or heterosexual and mediated by non-pituitary hormones

B. Epidemiologynavigator

  1. Data include both precocious and pseudoprecocious puberty
  2. Overall incidence between 1:500 and 1:10000
  3. More common in girls than boys
  4. Girls
    1. Idiopathic (80-90%)
    2. Ovarian (5%)
    3. CNS (3-5%)
  5. Boys
    1. CNS (40-50%)
    2. Adrenal (25%)
    3. Idiopathic (10-20%)
    4. Testicular (8-10%)

C. Clinical Considerations [1]navigator

  1. Is pubertal development really occurring outside normal temporal range ?
  2. What is underlying mechanism (LHRH dependent or not) and is an intracrnial lesion likely ?
  3. Is pubertal development likely to progress, and will this affect normal physical and psychosocial development ?

D. True Precocious Puberty navigator

  1. LHRH dependent or central
  2. Causes
    1. Idiopathic
    2. Cerebellar Dysfunction
    3. Tumors (see below)
    4. Hydrocephalus (persists with shunting)
    5. Congenital malformations: ventricular cysts, empty sella syndrome
    6. Trauma
    7. Post-infection
    8. Severe hypothyroidism
    9. Other Syndromes: McCune Albright, tuberous sclerosis, neurofibromatosis,
  3. Tumors
    1. Craniopharyngioma
    2. Optic or hypothalamic glioma (NF-type1)
    3. Astrocytoma
    4. Pinealoma
    5. Hypothalamic hamartoma
  4. Pathogenesis
    1. Premature reactivation of hypothalamic-pituitary gonadrotropjn gonadal axis
    2. Resulting pulsatile LH release has a pubertal pattern
    3. Growth hormone levels comparable to pubertal levels
    4. Increased risk for development after previous cranial radiation
  5. Presentation
    1. Rapid progression of pubertal development
    2. Normal pattern of development

E. Pseudoprecocious Pubertynavigator

  1. Independent of pituitary gonadotropins
  2. Causes in girls
    1. 0varian (benign or malignant)
    2. Adrenal feminizing tumors
  3. Ovarian: granulosa theca cell tumor
    1. High estrogen levels with low LH and FSH levels
    2. Bone age advanced
    3. 30% malignant
  4. Ovarian: luteoma
    1. High estrogen and progesterone
    2. High urine pregnanediol
  5. Ovarian: follicular cyst
    1. Most common estrogen-secreting mass in children
    2. Associated with abdominal pain and acyclic vaginal bleeding
  6. Adrenal feminizing tumors - secreting sex steroids [4]
  7. Causes in boys
    1. Testotoxicosis
    2. CAH (late onset)
    3. Adrenal virilizing tumor
    4. Leydig cell tumor
  8. Familial Testotoxicosis
    1. Sex-limited autosomal dominant disorder
    2. Gonadotropin independent premature Leydig and germ cell maturation
    3. Concurrent maturation of Sertoli cells with spermatogenesis
    4. Results in penile growth and testes enlargement
  9. Congenital adrenal hyperplasia (CAH, late onset) [6]
    1. 21-hydroxylase mutations (90% of cases)
    2. 11-beta-hydroxylase (~10% of cases)
    3. Overall, ~1:15,000 births
  10. Virilizing Adrenal Tumor [4]
  11. Leydig cell adenoma
  12. Causes in both sexes
    1. McCune Albright
    2. Hypothyroidism
    3. Peutz-Jegher's syndrome
  13. McCune Albright Syndrome
    1. Sporadic genetic condition
    2. Cafe-au-lait spots (hyper-pigmented macules)
    3. Polyostotic fibrous dysplasia
    4. Pituitary independent precious puberty
    5. In girls, autonomously functioning follicular cysts of the ovaries produce estrogen
    6. In boys, asymmetric enlargement of testes produces testosterone
  14. Severe Hypothyroidism
    1. Elevated TRH increases prolactin release
    2. FSH response to TRH is augmented which can result in precocious puberty
    3. Associated with skeletal and growth delay
    4. Responds to thyroid hormone replacement
  15. Peutz-Jegher's syndrome
    1. Mucocutaneous pigmentation
    2. Gastrointestinal polyposis
    3. Increased risk of rare sex cord tumor of ovary or testes
    4. Regular screening pelvic ultrasounds needed in this syndrome
  16. Iatrogenic (exposure to exogenous steroids)

F. Contrasexual Precocious Pubertynavigator

  1. Feminization in Boys
    1. Adrenal tumors
    2. Congenital adrenal hyperplasia
    3. Testicular tumors
    4. Iatrogenic (exposure to exogenous steroids)
    5. Massive extraglandular aromatization to make estrogen
  2. Virilization in Girls
    1. Congenital adrenal hyperplasia
    2. 5-alpha reductase deficiency

G. Historynavigator

  1. Rate of pubertal progression
  2. Presence of acne and oiliness of skin
  3. Body odors
  4. In boys, erections and nocturnal emissions
  5. In girls, vaginal discharge or bleeding
  6. Family history of unexplained death of male sibling (suggests CAH)

H. Laboratory and Radiological Studiesnavigator

  1. LH and FSH levels
  2. Bone age (left wrist)
  3. GnRH stimulation test
    1. Intravenous GnRH (100 mg)
    2. LH and FSH levels are measured at 30 and 60 minutes
    3. Pubertal response is LH predominant
  4. Central Precocious Puberty
    1. Head MRI is standard and highly sensitive for small hypothalamic tumors
    2. Head CT scan was previously recommended
  5. Girls
    1. Estrogen and progesterone levels
    2. Thyroxine (T4) and TSH
    3. Pelvic ultrasound for uterine and ovarian anatomy and size (including cysts)
    4. Androgens and hCG if heterosexual precocity
  6. Boys
    1. Testosterone, DHEA-S, and androstenedione
    2. 17-OH progesterone
    3. ACTH stimulation tests for suspected CAH
    4. Estrogens if heterosexual precocity

I. Treatmentnavigator

  1. LHRH Dependent Precious Puberty [5]
    1. Synthetic GnRH (LHRH) analogues such as leuprolide or deslorelin are used
    2. Leuprolide (Lupron®) dose IM 0.3 mg/kg q 3-4 weeks or 30-100 mg/kg SC or intranasally qd
    3. Deslorelin (Suprelorin®) dose 4µg/kg qd sc (usually at night) [5]
    4. Continuous administration of a normally pulsatile GnRH suppresses LH and FSH release
    5. Monitor treatment GnRH test on 3 months after initiation of therapy
    6. Return to prepubertal growth and bone maturation
    7. Therapy shown to improve adult height but leads to osteoporosis [5]
    8. Discontinuation of therapy at the appropriate time will induce puberty
    9. Other side effects include recurrent hot flashes and moodiness
    10. Inadequate treatment or poor compliance allows continued progression of bone age
    11. Osteoporosis is of sufficient magnitude to prevent routine recommendation
    12. Strongly consider osteoporosis prophylaxis with bisphosphonates during GnRH therapy
    13. Surgery rarely needed
  2. Familial male testotoxicosis
    1. Testolactone - blocks conversion of androgen to estrogen
    2. Spironolactone - blocks action of androgens
    3. Ketoconazole - inhibits biochemical synthesis of testosterone by inhibiting p450c17
    4. LHRH independent precious puberty
  3. McCune Albright Syndrome
    1. Testolactone - 40 mg/kg/day divided tid (improves sexual development) [3]
    2. Treatment effect may only last 1-3 years
    3. LHRH independent precious puberty
  4. Congenital Adrenal Hyperplasia
    1. Hydrocortisone 12-15 mg/m2/day
    2. Fludrocortisone 0.1-0.2 mg/day if associated salt wasting
    3. Surgery and possible chemotherapy needed for hormone secreting tumors

References navigator

  1. Carel JC and L©ger J. 2008. NEJM. 358(20):2366
  2. Styne DM. 1997. Pediatric Endocrinology. 44(2)505 abstract
  3. Feuillan PP, Foster CM, Pescovitz OH, et al. 1985. NEJM. 315:1115
  4. Bornstein SR, Stratakis CA, Chrousos GP. 1999. Ann Intern Med. 130(9):759 abstract
  5. Yanovski JA, Rose SR, Municchi G, et al. 2003. NEJM. 348(10):908 abstract
  6. Speiser PW and White PC. 2003. NEJM. 349(8):776 abstract