Reactivation of the hypothalamic-pituitary-gonadal axis initiates puberty. Several neurotransmitters, including kisspeptin, stimulate the hypothalamic secretion of gonadotropin-releasing hormone (GnRH) in pulses during sleep and eventually during waking hours as well. GnRH pulses stimulate the pituitary gland to secrete pulses of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), of which there is an LH predominance. In response to the increased secretion of gonadotropins, increased secretion of gonadal hormones leads to the progressive development of secondary sexual characteristics and gametogenesis. In both sexes, puberty requires maturation of gonadal function and increased secretion of adrenal androgens.

Sexual maturity is determined by physical examination and is described in a scale devised by John Tanner in 1969 (Table 43-1). Because of the distinct actions of adrenal androgens and gonadal steroids, it is important to distinguish between pubic hair and breast development in girls and between pubic hair and testicular development in boys. In all cases, Tanner stage I is prepubertal and Tanner stage V is complete maturation. In addition to the physical examination, the tools to assess pubertal development may include determination of bone age, growth velocity, growth pattern, and specific endocrine studies.

Adrenarche refers to the time during puberty when the adrenal glands increase their production and secretion of adrenal androgens. Plasma concentrations of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), the most important adrenal androgens, begin to increase in children by approximately 6 to 8 years. However, the signs of adrenarche, such as pubic hair, axillary hair, acne, and body odor do not typically occur until early puberty to midpuberty. The control of adrenal androgen secretion is not clearly understood, but it appears to be separate from GnRH and the gonadotropins.

In both boys and girls, the pubertal growth spurt is primarily controlled by the gonadal steroid estrogen. In both sexes, gonadal (and adrenal) androgens are aromatized to estrogens. Estrogens augment growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion. Estrogens also suppress osteoclast activity and prolong the life span of osteoblasts and osteocytes. Androgens have a small independent role in maintenance of adequate bone mineral density. At the end of puberty, linear growth is nearly complete as a result of the effects of gonadal steroids on skeletal maturation and epiphyseal fusion.

The mean age of puberty onset in boys is 11.8 years, with a range of 9 to 14 years. Black boys may start puberty as early as 8 years of age. The first evidence of puberty in the majority of boys is enlargement of the testes to a volume greater than 4 mL or a length greater than 2.5 cm. It is not until midpuberty, when testosterone levels are rapidly rising, that boys experience voice change, axillary hair, facial hair, and the peak growth spurt. Spermatogenesis is mature at a mean age of 13.3 years.

Girls normally begin puberty between age 8 and 13 years (mean age: 10.4 years for white girls, 9.8 years for Hispanic girls, and 9.5 years for black girls). The initial pubertal event is typically the appearance of breast buds, although a small percentage of girls will develop pubic hair first. In an even smaller percentage of girls, menstrual cycling may appear first. Initial breast development often occurs asymmetrically and should not be of concern. Breast development is primarily under the control of estrogens secreted by the ovaries, whereas growth of pubic hair and axillary hair results mainly from adrenal androgens. Unlike in boys, the pubertal growth spurt in girls occurs at the onset of puberty. Menarche usually occurs 18 to 24 months after the onset of breast development (mean age: 12.5 years). Although most girls have reached about 97.5% of their maximum height potential at menarche, this can vary considerably. Consequently, age of menarche is not necessarily a good predictor of final adult height.

Precocious puberty is defined as pubertal development occurring below the limits of age set for normal onset of puberty. In girls, this is puberty before 8 years in white girls, 6.6 years in black girls, and 6.8 years in Hispanic girls. For boys, precocious puberty is development occurring before 9 years in white and Hispanic boys and 8 years in black boys. Girls showing signs of puberty between 6 and 8 years often have a benign, slowly progressing form that requires no intervention. Consequently, evaluation and treatment of girls who start puberty between 6 and 8 years should depend on factors such as family history, rapidity of development, the presence of central nervous system (CNS) symptoms, and family concern. Girls who are short and start puberty between 6 and 8 years may also benefit from evaluation. In children who present with early pubertal signs, precocious puberty must be distinguished from normal variants of puberty, such as benign premature thelarche and benign premature adrenarche.

Benign premature thelarche is defined as isolated breast development in girls without other signs of puberty such as linear growth acceleration and signs of adrenarche, such as pubic hair, axillary hair, body odor, and acne. Benign premature adrenarche, which occurs in both sexes, is defined as the early development of pubic hair with or without axillary hair, body odor, and acne. There are no signs of gonadarche in benign premature adrenarche; girls have no breast development, and boys have no testicular enlargement.

Several characteristics of benign premature thelarche distinguish it from the breast development that occurs in precocious puberty. First of all, benign premature thelarche is most common in girls who are either less than 2 years old or between 6 and 8 years of age. Girls with benign premature thelarche may have a history of slowly progressing breast development or waxing and waning of breast size. Growth rate and bone age are not accelerated, and on physical examination, the breast tissue rarely develops beyond Tanner stage II or III. GnRH stimulation may provoke an FSH-predominant response, as opposed to the typical LH-predominant response seen in true central puberty.

The natural course of benign premature thelarche is for the breast tissue to regress or fail to progress. Because of the benign nature of this condition, treatment is not necessary except for reassurance and follow-up. Follow-up is critical because premature thelarche occasionally is the first sign of what later becomes apparent as central precocious puberty. Measurement of breast tissue diameter during the clinic visit can be helpful for comparison at a later visit.

Benign premature adrenarche is caused by early secretion of the adrenal androgens, primarily DHEA and DHEA-S, and is suspected when clinical signs of androgen exposure are present, such as pubic hair, axillary hair, acne, or body odor. A child who has benign premature adrenarche and Tanner stage II pubic hair development will have adrenal androgen values similar to those normally found in a pubertal child at the same stage of development. As in premature thelarche, growth rate and bone age are typically not accelerated. If signs of puberty are rapidly progressing, or if there is evidence of increased linear growth and advanced bone age, measurement of androgens (DHEA-S, androstenedione, and testosterone) is performed to evaluate for a serious virilizing disorder such as congenital adrenal hyperplasia (CAH) or an adrenal tumor. A 17-hydroxyprogesterone (17-OHP) level may also be drawn as the first screen for late-onset CAH.

The natural course of benign premature adrenarche is a slow progression of the signs of adrenarche with no effect on the timing of true puberty. Because pubic hair development may be the first sign of puberty, follow-up is necessary to evaluate for evidence of gonadarche (i.e., breast development or testicular enlargement).

Precocious puberty, regardless of the cause, is associated with accelerated linear growth and skeletal maturation secondary to elevated sex steroid levels. Children with precocious puberty are often tall for their age during childhood. However, skeletal maturation may become more advanced than stature, thus leading to premature fusion of the epiphyseal growth plates and a compromised final adult height. In addition to the physical consequences of early puberty, social and psychological aspects may need to be considered.

Precocious puberty predominantly affects girls. The disparity in overall prevalence of precocity is explained by the large numbers of girls with central idiopathic precocity, a condition that is less common in boys. At least 80% of all precocious puberty in girls is central idiopathic. The prevalence of organic causes of precocious puberty (CNS lesions, gonadal tumors, and specific underlying diseases) is similar in both sexes.

The diagnosis of precocious puberty requires the appearance of the physical signs of puberty before the defined age limits, as discussed previously. In both boys and girls, a complete history should be taken, with careful consideration of any exposure to exogenous steroids or estrogen receptor agonists (e.g., lavender oil or tea tree oil), onset of pubertal signs and rate of progression, presence or history of CNS abnormalities, and pubertal history of other family members. Height measurements should be plotted on a growth chart to determine growth pattern and growth velocity. A physical examination should be performed with a focus on Tanner staging, the presence of café-au-lait spots, and neurologic signs. One of the early steps in evaluating a child with early pubertal development should be to obtain a radiograph of the left hand and wrist to determine skeletal maturity (bone age). If the bone age is advanced, further evaluation is warranted. Sex steroid levels should be measured, especially in boys, because testosterone levels higher than the prepubertal range (> 10 ng/dL) confirm pubertal status. For girls, estradiol measurements are less reliable indicators of puberty, because most commercial assays are not sufficiently specific or sensitive to demonstrate an increase during early puberty.

It is usually difficult to distinguish GnRH-dependent (central) from GnRH-independent (peripheral) precocity on physical examination. Central precocious puberty involves activation of the GnRH pulse generator, an increase in gonadotropin secretion, and a resultant increase in the production of sex steroids. Consequently, the sequence of hormonal and physical events in central precocious puberty is identical to the progression of normal puberty. Peripheral precocious puberty occurs independent of gonadotropin secretion. Although the possible causes of peripheral precocious puberty are more numerous (Box 43-1), central precocity accounts for most cases.

The GnRH stimulation test is the single most important test to determine whether gonadotropin responses are consistent with central or peripheral precocious puberty. The diagnosis of central precocious puberty is made by demonstrating a pubertal LH response to GnRH. Measurement of random gonadotropins is typically not helpful because of overlap between prepubertal and early pubertal values until at least Tanner stage III. If random gonadotropins are measured, a third-generation assay is recommended because it has better discrimination between prepubertal and pubertal levels.

In girls younger than 6 years, and boys of any age, who are diagnosed with central precocious puberty, an MRI study of the brain should be performed to evaluate for CNS lesions. It is unlikely that an abnormality will be found in girls between 6 and 8 years old, so the need for an MRI in this age group should be assessed individually.

Children with central precocious puberty can be treated with GnRH agonists, such as leuprolide. GnRH agonists disrupt the endogenous pulsatile GnRH, thus downregulating pituitary GnRH receptors and decreasing gonadotropin secretion. The most important clinical criteria for GnRH agonist therapy is documented progression of pubertal development, which is based on the recognition that many girls with central precocious puberty, especially those between 6 and 8 years old, have a slowly progressive form and reach a normal adult height without intervention. With GnRH agonist treatment, physical changes of puberty regress or cease to progress, and linear growth slows to a prepubertal rate. Pubic hair and axillary hair typically do not regress. Projected final adult height often increases because of a slowing of skeletal maturation. GnRH agonists are generally given as a monthly depot intramuscular injection, and side effects are rare. There is also a small hydrogel implant that can be placed under the skin that releases a GnRH agonist (histrelin) continuously for about 1 year. Children receiving GnRH agonists should be monitored every 4 to 6 months to evaluate for pubertal regression or treatment failure. After discontinuation of therapy, pubertal progression resumes, and normal rates of fertility are expected.