Precocious Puberty
Marta Satin Smith
INTRODUCTION
Normal Pubertal Development
Girls
In girls, puberty usually begins at 10.5 to 11 years with a range of 9 to 11 years. Breast development (thelarche) is usually the first sign of normal sexual development; however, in a small number of girls, pubic hair development may precede breast development by 6 months. Pubic hair development (adrenarche) usually follows thelarche by 6 months and axillary hair 12 to 18 months later. The growth spurt occurs early in pubertal development in girls at a mean age of 11.5 years (between Tanner stages 2 to 3; see Chapter 2, “The Physical Examination,” Table 2-6). Menses (menarche) begin 18 to 24 months after thelarche and become ovulatory in most girls within 18 months. Puberty is completed within 1.5 to 6 years. Pubertal growth in girls contributes 25 cm to overall height.
Breast development and cornification of the vaginal mucosa are controlled primarily by ovarian estrogens, which are influenced by follicle-stimulating hormone (FSH). Pubic and axillary hair growth is stimulated primarily by adrenal androgens, although there may also be an ovarian contribution.
Boys
In boys, puberty usually begins at 11.5 to 12 years with a range of 10 to 14 years. Testicular enlargement occurs first, followed by the development of pubic hair ˜6 months later. Phallic enlargement usually begins 12 months after testicular size begins to increase. The pubertal growth spurt in boys occurs between Tanner stages 3 and 4, with progression of male pubertal development occurring over 2 to 4.5 years (see Chapter 2, “The Physical Examination,” Table 2-5). The average growth during puberty is 28 cm. Onset of spermatogenesis occurs early in puberty with the mean age of conscious ejaculation of 13.5 years (range 12.5 to 15.5 years).
The virilizing changes seen at puberty are mainly the result of testosterone secretion from the testes. Growth of the penis and pubic hair are stimulated primarily by testicular androgens; however, adrenal androgens also contribute. Luteinizing hormone (LH) stimulates Leydig cell production of testosterone, whereas FSH supports spermatogenesis. It is now clear that peripheral conversion of testosterone to estrogen is important in bone growth and maturation in males.
Precocious Puberty
Precocious puberty is defined as the development of secondary sexual characteristics at <6 years of age in African-American girls and at <7 years of age in white American girls, and at <9 years of age in boys regardless of race. These age limits in girls are based on a large study completed in 1997 within the Pediatric Research in the Office Setting network. This recommendation has been somewhat controversial because Tanner staging of breast development was done visually and not by palpation. With increasing obesity in the pediatric population, it has been argued that their data may have been skewed because of the inability to distinguish fat from true breast tissue by inspection only. Two recently published longitudinal studies have confirmed these data (see Suggested Readings). Many experts still recommend evaluation, including magnetic resonance imaging (MRI) of the head, in girls with premature onset of puberty at >6 years of age if the tempo of pubertal progression is unusually rapid, bone age is advanced by >2 years of age, or predicted height is <150 cm; or if neurologic signs or symptoms are detected. Precocious puberty is classified as either central (gonadotropin-dependent) precocious puberty (CPP), which is caused by an elevation of FSH and LH, or peripheral (gonadotropin-independent) precocious puberty (PPP), which is caused by an elevation of sex steroids.
DIFFERENTIAL DIAGNOSIS LISTCentral (Gonadotropin-Dependent) Precocious Puberty (CPP)
Infectious Causes
Brain abscess
Meningitis—viral or bacterial
Encephalitis
Granulomatous disease
Tuberculosis, sarcoidosis, or histiocytosis
Toxic Causes
Chronic exogenous androgen or estrogen exposure (initially presenting as PPP)
Brain Tumor
Glioma
Astrocytoma
Ependymoma
Hypothalamic hamartoma
Brain Injury
Head trauma
Brain surgery
Cranial irradiation
Hemorrhage and stroke
Congenital Causes
Central nervous system (CNS) malformation
Suprasellar cyst
Hydrocephalus
Idiopathic precocious puberty
Constitutional precocious puberty
Peripheral (Gonadotropin-Independent) Precocious Puberty (PPP)
Toxic Causes
Exogenous estrogens—face creams, breast-enlarging creams, contraceptive pill, and vaginal creams
Excess ingestion of phytoestrogens in soy products
Exogenous androgens—transdermal testosterone gel and anabolic steroid abuse
Neoplastic Causes
Boys
Human chorionic gonadotropin (hCG)-secreting tumors—brain and liver choriocarcinomas
Leydig cell tumor
Virilizing adrenal tumor
Girls
Ovarian tumors
Adrenal tumors
Congenital Causes
Congenital adrenal hyperplasia (CAH)
Familial gonadotropin-independent Leydig cell maturation—testotoxicosis
McCune-Albright syndrome
Ovarian follicular cysts
DIFFERENTIAL DIAGNOSIS DISCUSSION
Central (Gonadotropin-Dependent) Precocious Puberty
Etiology
Central precocious puberty, or true precocious puberty, refers to sexual precocity secondary to elevations in the gonadotropins (FSH and LH). CPP arises from early activation of the hypothalamic-pituitary-gonadal axis. CPP is investigated five times more often in girls than in boys.
In most cases of CPP, especially in girls, no cause is identified (idiopathic precocious puberty). The younger the onset, the more likely an etiological factor will be found. Other cases involve various forms of CNS pathology, including malformations and benign or malignant tumors. Hamartomas of the tuber cinereum are the CNS tumors most frequently identified as causing precocious puberty. These tumors contain ectopic gonadotropin-releasing hormone (GnRH) neurosecretory cells. The pulsatile release of GnRH from these cells stimulates the pituitary gland. These hamartomas may be associated with gelastic (involving emotional features) seizures. CPP has also developed after cranial irradiation therapy for CNS tumors and after head trauma. Children with malformations of the CNS, such as septo-optic dysplasia and hydrocephalus, also have an increased incidence of precocious puberty.
Clinical Features
As with children progressing through normal puberty, the first physiologic change is an increase in the amplitude and frequency of hypothalamic GnRH pulses. This causes increased FSH and LH secretion from the pituitary gland, maturation of the gonads, and increased release of sex steroids.
Evaluation
Boys have pubertal FSH and LH levels, a pubertal response to GnRH, and a pubertal value of testosterone. Girls have pubertal FSH and LH levels, a pubertal response to GnRH, and a pubertal value of estradiol (see Tables 61-1 and 61-2). The diagnosis of CPP in boys is almost always serious and necessitates a search for a CNS tumor. Unfortunately, GnRH, which was considered the gold standard stimulation test for diagnosis of CPP, is no longer available. Alternative methods of diagnosis include stimulation tests using nafarelin or leuprolide, ultrasound evidence of ovarian and uterine enlargement, and ultrasensitive assays for LH and estradiol.
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