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(September 2007)
Aditi Agarwa, MD
Mark P. Trolice, M.D., FACOG, FACS
Board Certified, Reproductive Endocrinology And Infertility
Director, Fertility C.A.R.E.
Puberty is defined as the biological transition between immature and adult reproductive function. Children who begin this transition at a premature are considered to have Precocious Puberty (PP). Although PP may be a benign, albeit alarming, variant of normal development, a complete work-up is necessary to exclude pathological conditions with resultant morbidity and mortality.
Normal Puberty
Puberty averages 4.5 years and starts with thelarche (breast development) followed by adrenarche (pubic hair growth), peak growth velocity, ending with menarche. In the early 1990s, the American Academy of Pediatrics estimates these milestones to occur at ages 9, 10, 11, and 12 years, respectively. However, recently the Academy realized a substantial number of girls develop puberty 6 months to 1 year earlier than previously documented. On average, black American girls begin puberty between ages 8 and 9, and white American girls by age 10. In addition, thelarche and/or adrenarche can occur normally in black girls as early as age 6 and in white girls as early as age 7. Consequently, it is recommended that all children presenting with signs of secondary sexual characteristics younger than age 8 receive careful evaluation.
Precocious Puberty
Precocious puberty affects 0.2% of girls and is equally distributed between its two classifications: GnRH-Dependent or Central Precocious Puberty (CPP), and GnRH-Independent or Peripheral Precocious Puberty (PPP).
CPP is defined by an early activation of the normal pubertal process mediated by the hypothalamic-pituitary-gonadal axis. The sequence of pubertal events remains normal and 75% of cases are idiopathic. While most girls demonstrate a normal reproductive life, a full evaluation is vital to exclude a pathologic cause. Hamartomas of the tuber cinereum of the hypothalamus are the most frequent CNS tumor. Seven percent of causes, CNS tumors results in puberty during the first few years of life. Other CNS tumors include astrocytomas, ependymomas, pineal tumors, and optic gliomas, often found in patients with neurofibromatosis. Primary hypothyroidism can cause CPP by excess TSH stimulating the FSH receptor increasing the production of gonadotropins. Though reversible with thyroxine, hypothyroidism manifests as short stature, early breast development, galactorrhea, and early vaginal bleeding.
PPP results from an extrapituitary/exogeneous secretion of hCG or sex steroids derived from gonads. Patients often present with pubertal developments outside the normal sequence. Comprising 11% of cases, ovarian tumors are the most common cause of PPP usually enlarge and involute, causing vaginal bleeding. Other ovarian tumors are gonadoblastomas, teratomas, lipoid cell tumors, cystadenomas, and ovarian neoplasms.
An ovarian tumor is more likely if a child demonstrates accelerated growth but no symptoms of virilization as opposed to an adrenal tumor having the latter. Since 80% of these tumors are palpable on physical exam, a complete abdominal and pelvic assessment is vital. McCune-Albright Syndrome, also known as polyostotic fibrous dysplasia, makes up 5% and consists of the triad of multiple bony lesions, café-au-lait spots, and sexual precocity.
Diagnosis
With CPP, FSH and LH levels are elevated but not hCG. PPP patients have low GnRH, FSH, and LH but elevated serum estradiol and hCG. All PP patients require testing for thyroid function, DHEA, DHA-S, estradiol, and progesterone levels. Finally, a definitive distinction may be made between central and peripheral precocious puberty with GnRH testing. In the GnRH dependent CPP, LH and FSH levels will increase with administration of exogenous GnRH. Contrarily, in PPP patients, LH and FSH levels will remain low or unchanged with GnRH stimulation.
Treatment
The decision to treat PP depends on the underlying cause and prognosis for the patient. An intracranial disease needs to be addressed either surgically or with medications. Tumors of the testis, adrenal glands, and ovaries should also be resected if possible. HCG-secreting tumors like teratomas and chorioepitheliomas may require chemo and radiation in addition to surgery. The prognosis depends on the tumor; resections of small, benign tumors obviously have a better prognosis than malignant, slow-growing ones.
Medications are used in PP for two reasons: to maximize adult height and to facilitate the avoidance of abuse and emotional problems in adolescence. Children who present with CPP close to normal pubertal age usually have minimal problems and do not require treatment. However, to cause reversal of pubertal characteristics and allow for appropriate height, GnRH analogues are the treatment of choice. Regression of pubertal events, amenorrhea, and reduction in growth velocity usually occur within 1 year. Studies have shown that the best results occur when treatment is initiated early before bone age exceeds the age of 12.
Since PPP is GnRH-Independent, patients will not respond to GnRH analogues but require treatment of the underlying disorder. Defects in adrenal steroidogenesis require treatment with glucocorticoids and mineralocorticoids. Patients with McCune Albright Syndrome may require multiple medications to inhibit estrogen and heal bony lesions. Testolactone is helpful in inhibiting the conversion of androgens to estrogen which decreases the recurrence of ovarian cysts. Tamoxifen can also be used to reduce vaginal bleeding. Pamidronate is the drug of choice for improving bony fibrous dysplasia. Finally, if an endocrinopathy such as acromegaly is present, Pegvisomant can serve as an inhibitor of growth hormone.
Conclusion
PP is a phenomenon that affects a small population of young girls but can lead to serious consequences if left untreated. A careful history and physical exam in conjunction with a select laboratory and radiology exams can make an accurate diagnosis. Aggressive treatment of the disorder may then facilitate a young girl’s transition from childhood to adulthood.
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