Clinical Manifestations

Sexual development can begin at any age and generally follows the sequence observed in normal puberty. In girls, early menstrual cycles may be more irregular than they are with normal puberty. The initial cycles are usually anovulatory, but pregnancy has been reported as early as 5.5 yr of age (Fig. 556-1). In boys, testicular biopsies have shown stimulation of all elements of the testes, and spermatogenesis has been observed as early as 5-6 yr of age. In affected girls and boys, height, weight, and osseous maturation are advanced. The increased rate of bone maturation results in early closure of the epiphyses, and the ultimate stature is less than it would have been otherwise. Without treatment, approximately 30% of girls and an even larger percentage of boys achieve a height less than the 5th percentile as adults. Mental development is usually compatible with chronological age. Emotional behavior and mood swings are common, but serious psychological problems are rare.

Figure 556-1 Natural course of idiopathic central precocious puberty. Patient (A) at , (B) at , and (C) at yr of age. Breast development and vaginal bleeding began at yr of age. Bone age was yr at and 14 yr at 8 yr of age. Intelligence and dental age were normal for chronological age. Growth was completed at 10 yr; ultimate height was 142 cm (56 in). No effective therapy was available at the time this patient sought medical attention.

Although the clinical course is variable, 3 main patterns of pubertal progression can be identified. Most girls (particularly those <6 yr of age at the onset) and a large majority of boys have rapidly progressive puberty, characterized by rapid physical and osseous maturation, leading to a loss of height potential. Some girls (>6 yr of age at the onset with an idiopathic form) have a slowly progressive variant, characterized by parallel advancement of osseous maturation and linear growth, with preserved height potential. A small percentage of girls have spontaneously regressive or unsustained central precocious puberty. This variability in the natural course of sexual precocity underscores the need for longitudinal observation at the onset of sexual development, before treatment is considered.

Laboratory Findings

Sex hormone concentrations are usually appropriate for the stage of puberty in both sexes. Serum estradiol concentrations in girls are low or undetectable in the early phase of sexual precocity, as they are in normal puberty. In boys, serum testosterone levels are detectable or clearly elevated by the time the parents seek medical attention, particularly if an early morning blood sample is obtained.

Sensitive immunometric (including immunoradiometric, immunofluorometric, and chemiluminescent) assays for luteinizing hormone (LH) have replaced the traditional LH radioimmunoassays and offer greater diagnostic sensitivity using random blood samples. With sensitive assays, serum LH concentrations are undetectable in prepubertal children but become detectable in 50-75% of girls and a higher percentage of boys with central sexual precocity. Measurement of LH in serial blood samples obtained during sleep has greater diagnostic power than measurement in a single random sample, and it typically reveals a well-defined pulsatile secretion of LH.

Intravenous administration of gonadotropin-releasing hormone (GnRH stimulation test) or a GnRH agonist (leuprolide stimulation test) is a helpful diagnostic tool, particularly for boys, in whom a brisk LH response (LH peak >5-10 IU/L) with predominance of LH over follicle-stimulating hormone (FSH) tends to occur early in the course of precocious puberty. In girls with sexual precocity, however, the nocturnal LH secretion and the LH response to GnRH or GnRH agonist may be quite low at breast stages II to early III (immunometric LH peak <5IU/L), and the LH : FSH ratio can remain low until mid-puberty. In such girls with “low” LH response, the central nature of sexual precocity can be proved by detecting pubertal levels of estradiol (>50 pg/mL), 20-24 hr after stimulation with leuprolide.

Osseous maturation is variably advanced, often more than 2-3 standard deviations (SD). Pelvic ultrasonography in girls reveals progressive enlargement of the ovaries, followed by enlargement of the uterus to pubertal size. An MRI scan usually demonstrates physiologic enlargement of the pituitary gland, as seen in normal puberty; it may also reveal CNS pathology (Chapter 556.2).

Differential Diagnosis

Organic CNS causes of central sexual precocity should be ruled out by MRI scans. They are more likely in girls with rapid breast development, girls with estradiol >30 pg/mL, girls <6 yr of age, and in all boys, but specific criteria for ordering brain imaging are still lacking. Some authorities recommend MRI scans for all children with central precocious puberty.

Gonadotropin-independent causes of isosexual precocious puberty must be considered in the differential diagnosis (see Table 556-1). For girls, these include tumors of the ovaries, autonomously functioning ovarian cysts, feminizing adrenal tumors, McCune-Albright syndrome, and exogenous sources of estrogens. In boys, congenital adrenal hyperplasia, adrenal tumors, Leydig cell tumors, chorionic gonadotropin–producing tumors, and familial male precocious puberty should be considered.

Treatment

Virtually all boys and the large subgroup of girls with rapidly progressive precocious puberty are candidates for treatment. Girls with slowly progressive idiopathic central precocious puberty do not seem to benefit in terms of height prognosis from GnRH-agonist therapy. Children who were small for gestational age may be at greater risk of short stature as adults and can require more-aggressive treatment of precocious puberty, possibly in conjunction with human growth hormone (hGH) therapy. Certain patients require treatment solely for psychological or social reasons, including children with special needs and very young girls at risk of early menarche.

The observation that the pituitary gonadotropic cells require pulsatile, rather than continuous, stimulation by GnRH to maintain the ongoing release of gonadotropins provides the rationale for using GnRH agonists for treatment of central precocious puberty. By virtue of being more potent and having a longer duration of action than native GnRH, these GnRH agonists (after a brief period of stimulation) desensitize the gonadotropic cells of the pituitary to the stimulatory effect of endogenous GnRH and effectively halt the progression of central sexual precocity.

Long-acting formulations of GnRH agonists, which maintain fairly constant serum concentration of the drug for weeks or months, constitute the preparations of choice for treatment of central precocious puberty. In the USA, the most commonly used preparation is leuprolide acetate (Lupron Depot Ped), in a dose of 0.25-0.3 mg/kg (minimum, 7.5 mg) intramuscularly once every 4 wk. Other preparations (D-Trp6-GnRH [Decapeptyl], goserelin acetate [Zoladex]) are approved for treatment of precocious puberty in other countries. Recurrent sterile fluid collections at the sites of injections are the most troublesome local side effect and occur in <2-3% of treated patients. Alternatively, histrelin (Supprelin LA), a subcutaneous 50 mg implant with effects lasting 12 mo, is approved by the FDA for use in central precocious puberty. Other available treatment options include subcutaneous injections of aqueous leuprolide, given once or twice daily (total dose 60 µg/kg/24 hr), or intranasal administration of the GnRH agonist nafarelin (Synarel), 800 µg bid. The potential for irregular compliance with daily administration, as well as the variable absorption of the intranasal route for nafarelin, can limit the long-term benefit of the latter preparations on adult height. Preparations of depot-leuprolide with longer duration of action (90 days) are currently not FDA approved for treatment of central precocious puberty. GnRH antagonists are relatively new and have not been investigated sufficiently. Oral GnRH antagonists are also being investigated.

Treatment results in decrease of the growth rate, generally to age-appropriate values, and an even greater decrease of the rate of osseous maturation. Some children, particularly those with greatly advanced (pubertal) bone age, can show marked deceleration of their growth rate and a complete arrest in the rate of osseous maturation. Treatment results in enhancement of the predicted height, although the actual adult height of patients followed to epiphyseal closure is approximately 1 SD less than their mid-parental height.

In girls, breast development can regress in those with Tanner stage II-III development. Most commonly, the size of the breasts remains unchanged in girls with stage III-V development or even increases slightly because of progressive adipose tissue deposition. The amount of glandular tissue decreases. Pubic hair usually remains stable in girls or progresses slowly during treatment, reflecting the gradual increase in adrenal androgens. Menses, if present, cease. Pelvic sonography demonstrates a decrease of the ovarian and uterine size. In boys, there is decrease of testicular size, variable regression of pubic hair, and decrease in the frequency of erections.

Except for a reversible decrease in bone density (of uncertain clinical significance), no serious adverse effects of GnRH analogs have been reported in children treated for sexual precocity. If treatment is effective, the serum sex hormone concentrations decrease to prepubertal levels (testosterone, <10-20 ng/dL in boys; estradiol, <5-10 pg/mL in girls). The serum LH and FSH concentrations, as measured by sensitive immunometric assays, decrease to <1 IU/L in most patients, although almost never does the LH return to truly prepubertal levels (<0.1 IU/L). The incremental FSH and LH responses to GnRH stimulation decrease to <2-3 IU/L. Serum LH and sex hormone levels remain suppressed for as long as therapy is continued, but puberty resumes promptly when therapy is discontinued, typically at a “pubertal” chronological age. In girls, menarche and ovulatory cycles generally appear at an average of 18 mo (range 6-24 mo) of cessation of therapy. The addition of hGH to GnRH agonists has been used in children with precocious puberty, markedly advanced bone age, and prediction of short stature. The available data indicate that combined therapy can increase the adult height.