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Precocious Puberty

by Andrew Calabria, MD

Precocious puberty is onset of sexual maturation before age 8 in girls or age 9 in boys. Diagnosis is by comparison with population standards, x-rays of the left hand and wrist to assess skeletal maturation and check for accelerated bone growth, and measurement of serum levels of gonadotropins and gonadal and adrenal steroids. Treatment depends on the cause.

In girls, the first pubertal milestone is typically breast development (thelarche), followed soon after by appearance of pubic hair (pubarche) and axillary hair and later by the first menstrual period (menarche), which traditionally occurs 2 to 3 yr after thelarche (see Figure: Puberty—when female sexual characteristics develop.).

In boys, the first pubertal milestone is typically testicular growth, followed by penile growth and appearance of pubic and axillary hair (see Figure: Puberty—when male sexual characteristics develop.).

In both sexes, appearance of pubic and axillary hair is called adrenarche. Adrenarche may occur before gonadarche in about 10% of children (premature adrenarche). Although gonadarche and adrenarche may have overlapping signs, they are regulated independently.

The definition of precocious puberty depends on reliable population standards for onset of puberty (ie, when pubertal milestones occur); because onset seems to be occurring earlier in the US, especially in females, these traditional standards are being reevaluated. Breast development is increasingly occurring at younger ages and this trend is mirroring the obesity epidemic, with a higher body mass index (> 85th percentile) associated with earlier thelarche.

Almost 8 to 10% of white girls, 20 to 30% of black girls, and an intermediate percentage of Hispanic girls reach early puberty at age 8. The lower limit of normal puberty may be 7 yr for white girls and 6 yr for black girls. The mean age for early breast development is about 9.5 to 10 yr for white girls and 8.5 to 9 yr for black girls (range 8 to 13 yr). However, the age of menarche has not lowered as drastically, with a mean decrease of only 3 mo in the past 30 yr (mean age 11.5 yr in black girls and 12.5 yr in white girls). The mean age for pubic hair growth is 9 to 10.5 yr for both groups. These findings imply that guidelines for evaluating disorders that cause precocious puberty can be interpreted more leniently if children are otherwise healthy and are projected to reach their full adult height potential.

Classification

Precocious puberty can be divided into 2 types:

  • Gonadotropin-releasing hormone (GnRH)–dependent (central precocious puberty)

  • GnRH-independent (peripheral sex hormone effects)

GnRH-dependent precocious puberty is more common overall and 5 to 10 times more frequent in girls. In GnRH-dependent precocious puberty, the hypothalamic-pituitary axis is activated, resulting in enlargement and maturation of the gonads, development of secondary sexual characteristics, and oogenesis or spermatogenesis.

GnRH-independent precocious puberty is much less common. Secondary sexual characteristics result from high circulating levels of estrogens or androgens, without activation of the hypothalamic-pituitary axis.

Precocious puberty may also be classified by whether gonadarche or adrenarche occurs. In girls, gonadarche includes breast development, change in body habitus, growth of the uterus, and eventually menarche. In boys, gonadarche includes testicular enlargement; phallic growth; the initial appearance of pubic, facial, and axillary hair; adult body odor; and facial skin oiliness or acne. Adrenarche for both girls and boys involves the development of body hair, body odor, and acne.

Incomplete or unsustained pubertal development is common, most often as isolated premature thelarche or adrenarche. Girls with premature thelarche typically display breast development during the first 2 years of life, but this change is not accompanied by pubertal hormone levels, menarche, advanced bone age on x-ray, androgen effects, or growth acceleration. Isolated premature adrenarche is likewise not associated with progressive pubertal development.

Children with premature adrenarche may have signs of adrenal androgen production (eg, pubic hair, acne, body odor) that progress slowly without acceleration of linear growth. Premature adrenarche may be associated with later development of polycystic ovary syndrome (see Polycystic Ovary Syndrome (PCOS)) in adolescence.

Etiology

GnRH-dependent precocious puberty

Physical changes are typically those of normal puberty for a child of that sex, with the exception of age of onset. In most affected girls, a specific cause cannot be identified. In the absence of specific symptoms or signs of CNS disease, the probability of an intracranial abnormality depends on younger age of onset of puberty (< 4 yr in girls) and sex of the child (more common among boys). Overall, affected boys are more likely (up to 60%) to have an identifiable underlying lesion. Such lesions include intracranial tumors, especially of the hypothalamus or pineal gland region, including hamartomas, gliomas, germinomas, and adenomas. Neurofibromatosis and a few other rare disorders have also been linked to precocious puberty. Central precocious puberty can also arise from iatrogenic causes (eg, surgery, radiation, or chemotherapy for cancer).

GnRH-independent precocious puberty

The etiology depends on the predominant sex hormone effect (estrogenic or androgenic), and physical changes are often markedly discordant from normal pubertal development. Estrogenic effects are most commonly caused by follicular ovarian cysts; other causes include granulosa-theca cell tumors and McCune-Albright syndrome (a triad of follicular cysts, polyostotic fibrous dysplasia, and café-au-lait spots). Adrenal enzyme defects, specifically congenital adrenal hyperplasia (see Overview of Congenital Adrenal Hyperplasia), are the most common pathologic form of androgen excess in children of either sex. Additional causes of GnRH-independent precocious puberty in boys include familial male gonadotropin-independent precocity (due to an activating mutation of the gene for luteinizing hormone [LH] receptors), testosterone -producing testicular tumors, and occasionally McCune-Albright syndrome.

Symptoms and Signs

In girls, breasts develop, and pubic hair, axillary hair, or both appear. Girls may begin to menstruate. In boys, facial, axillary, and pubic hair appears and the penis grows, with or without enlargement of testes, depending on the etiology. Body odor, acne, and behavior changes may develop in either sex.

Pubertal growth spurt is seen in both sexes (with early-mid puberty in females, mid-late puberty in males), but premature closure of the epiphyses results in short adult stature. Ovarian or testicular enlargement occurs in precocious puberty but is absent in isolated precocious adrenarche.

Diagnosis

  • Bone age x-rays

  • Serum hormone measurement

  • Possibly pelvic ultrasonography and brain MRI

Diagnosis is clinical. X-rays of the left hand and wrist are done to check for accelerated skeletal maturation as a result of sex hormone effect. Unless history and examination suggest an abnormality, no further evaluation is required for children with pubertal milestones that are within 1 yr of population standards. Girls and boys with isolated premature adrenarche and girls with premature thelarche also do not require further evaluation as long as x-rays confirm that skeletal maturation is not accelerated.

When further evaluation is necessary, blood tests should be chosen according to the features present. For patients who have mainly androgen effects, the most useful initial tests include measurements of total testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, and luteinizing hormone (LH); all should be measured using high-sensitivity assays designed for pediatric patients. For patients who have only estrogen effects, the most useful screens for girls include ultrasensitive LH and follicle-stimulating hormone (FSH), and estradiol, and, for boys, LH, FSH, β-human chorionic gonadotropin, and estradiol. Pelvic and adrenal ultrasonography may be useful if any of the steroid levels are elevated, and MRI of the brain may be done to rule out intracranial anomalies in younger patients or in males with central precocious puberty.

A GnRH stimulation test may be considered to confirm GnRH-dependent precocious puberty when initial tests are inconclusive. Previously, a 1-h stimulation test with the GnRH agonist gonadorelin was used, but because gonadorelin is no longer available, other GnRH agonists such as leuprolide are used. Leuprolide acetate 10 to 20 mcg/kg sc is given and LH, FSH, testosterone (in boys), and estradiol (in girls) are measured at 0, 1, and 2 h. At 24 h post-leuprolide, estradiol and testosterone may be measured to improve sensitivity of the test. In GnRH-dependent precocious puberty, gonadotropin responses are pubertal. In GnRH-independent precocious puberty, gonadotropin responses to leuprolide are prepubertal.

Treatment

  • GnRH agonist therapy (GnRH-dependant precocious puberty)

  • Androgen or estrogen antagonist therapy (GnRH-independent precocious puberty)

  • Tumor excision as needed

If pubertal milestones are within 1 yr of population standards, reassurance and regular reexamination are sufficient. Treatment is not needed for premature adrenarche or thelarche, but regular reexamination is warranted to check for later development of precocious puberty. For GnRH-dependent precocious puberty, pituitary LH and FSH secretion can be suppressed with GnRH agonists, including leuprolide acetate 7.5 to 15 mg IM q 4 wk or 11.25 mg or 30 mg IM q 12 wk, or histrelin implants (changed annually). Responses to treatment must be monitored, and drug dosages modified accordingly. Treatment may be continued until age 11 yr in girls and age 12 yr in boys.

In girls with McCune-Albright syndrome, aromatase inhibitors, including older drugs such as testolactone and newer drugs such as letrozole and anastrozole, have been used with varying success to reduce estradiol; alternatively, tamoxifen, an estrogen antagonist, may be beneficial.

If GnRH-independent precocious puberty in boys is due to familial male gonadotropin-independent precocity or McCune-Albright syndrome, androgen antagonists (eg, spironolactone) ameliorate the effects of excess androgen. The antifungal drug ketoconazole reduces testosterone in boys with familial male gonadotropin-independent precocity.

If GnRH-independent precocious puberty is due to a hormone-producing tumor (eg, granulosa-theca cell tumors in girls, testicular tumors in boys), the tumor should be excised. However, girls require extended follow-up to check for recurrence in the contralateral ovary.

Key Points

  • Precocious puberty is the onset of sexual maturation before age 8 in girls or age 9 in boys; however, in recent years, puberty has been starting earlier, and traditional standards are being reevaluated.

  • Most commonly, secondary sexual characteristics develop prematurely because the hypothalamic-pituitary axis is activated (GnRH-dependent precocious puberty); often the cause is idiopathic, but some children have a CNS tumor.

  • Less commonly, the cause is high circulating levels of estrogens or androgens (GnRH-independent precocious puberty) caused by congenital adrenal hyperplasia or various gonadal tumors.

  • Diagnosis is made by bone age x-rays and measurement of hormone levels.

  • Treat GnRH-dependent precocious puberty with the GnRH agonists leuprolide or histrelin.

  • Treat GnRH-independent precocious puberty based on the cause, including giving androgen or estrogen antagonists and removing tumors.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • DELATESTRYL
  • LUPRON
  • ESTRADERM, ESTROGEL, VIVELLE
  • No US brand name
  • NIZORAL
  • ARIMIDEX
  • NOLVADEX
  • FEMARA
  • ALDACTONE

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