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 years after thelarche (see Figure: Puberty—when female sexual characteristics develop Puberty—when female sexual characteristics develop ).
Puberty—when female sexual characteristics develop
Bars indicate normal ranges.
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 Puberty—when male sexual characteristics develop ).
Puberty—when male sexual characteristics develop
Bars indicate normal ranges. No mean is available for change in habitus.
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 years for white girls and 6 years for black girls. The mean age for early breast development is about 9.5 to 10 years for white girls and 8.5 to 9 years for black girls (range 8 to 13 years). However, the age of menarche has not lowered as drastically, with a mean decrease of only 3 months in the past 30 years (mean age 11.5 years in black girls and 12.5 years in white girls). The mean age for pubic hair growth is 9 to 10.5 years 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 of Precocious Puberty
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 Polycystic Ovary Syndrome (PCOS) Polycystic ovary syndrome is a clinical syndrome characterized by mild obesity, irregular menses or amenorrhea, and signs of androgen excess (eg, hirsutism, acne). Most patients have multiple... read more in adolescence.
Etiology of Precocious Puberty
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 central nervous system disease, the probability of an intracranial abnormality depends on younger age of onset of puberty (< 4 years 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 Overview of Intracranial Tumors Intracranial tumors may involve the brain or other structures (eg, cranial nerves, meninges). The tumors usually develop during early or middle adulthood but may develop at any age; they are... read more , especially of the hypothalamus or pineal gland region, including hamartomas, gliomas Gliomas Gliomas are primary tumors that originate in brain parenchyma. Symptoms are diverse and vary by location, manifesting as focal neurologic deficits, encephalopathy, or seizures. Diagnosis is... read more , germinomas, and adenomas. Neurofibromatosis Neurofibromatosis Neurofibromatosis refers to several related disorders that have overlapping clinical manifestations but that are now understood to have distinct genetic causes. It causes various types of benign... read more 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). A family history of GnRH-dependent precocious puberty is another risk factor. Mutations have been identified in several genes to date, but testing remains in its infancy.
GnRH-independent precocious puberty
The etiology of GnRH-independent precocious puberty 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 Overview of Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is a group of genetic disorders, each characterized by inadequate synthesis of cortisol, aldosterone, or both. In the most common forms, accumulated hormone precursors... read more , 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, rarely ectopic beta-human chorionic gonadotropin (beta-hCG) production resulting from certain tumors (due to activation of LH receptors in testes), and occasionally McCune-Albright syndrome.
Symptoms and Signs of Precocious Puberty
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 of Precocious Puberty
Bone age x-rays
Serum hormone measurement
Possibly pelvic ultrasonography and brain MRI
Diagnosis of precocious puberty 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 year 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, beta-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-hour 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 subcutaneously is given and LH, FSH, testosterone (in boys), and estradiol (in girls) are measured at 0, 1, and 2 hours. At 24 hours 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.
Genetic testing may be considered in familial cases of GnRH-dependent precocious puberty, but this remains controversial.
Treatment of Precocious Puberty
GnRH agonist therapy (GnRH-dependent precocious puberty)
Androgen or estrogen antagonist therapy (GnRH-independent precocious puberty)
Tumor excision as needed
If pubertal milestones are within 1 year 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 every 4 weeks, 11.25 mg or 30 mg IM every 12 weeks, or 45 mg every 24 weeks, triptorelin 22.5 mg every 6 months, or histrelin implants (changed annually). Responses to treatment must be monitored, and drug dosages modified accordingly. Treatment may be continued until age 11 years in girls and age 12 years in boys.
In girls with McCune-Albright syndrome, aromatase inhibitors, such as letrozole and anastrozole, have been used with varying success to reduce estradiol.
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 (1 Treatment references 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... read more , 2 Treatment references 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... read more ).
1. Aguirre RS, Eugster EA: Central precocious puberty: From genetics to treatment. Best Pract Res Clin Endocrinol Metab 32(4):343–354, 2018. doi: 10.1016/j.beem.2018.05.008
2. Latronico AC, Brito VN, Carel J-C: Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol 4(3):265–274, 2016. doi: 10.1016/S2213-8587(15)00380-0
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 central nervous system 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|
|ESTRADERM, ESTROGEL, VIVELLE|
|No US brand name|