Precocious Puberty

After completing this article, readers should be able to:Isosexual precocious puberty is the appearance of physical signs of sexual development in keeping with the phenotypic gender of the child prior to the earliest accepted age of sexual maturation. Precocious puberty is of concern because of the underlying disorders that may cause premature sexual development, the short adult stature that may result from rapid skeletal maturation attributable to early secretion of sex hormone, and the psychosocial difficulties that the sexually precocious child may encounter.The Sexual Maturity Rating (SMR)(Tanner) stages of sexual development are described in Tables 1 and 2. In girls, breast budding (thelarche) is usually the first sign of puberty;pubic hair growth (pubarche) is the initial pubertal sign in 15% of girls. Menarche occurs an average of 2 years after thelarche (range, 1 to 5 y), and peak height velocity(PHV) is reached at 12 years in girls immediately prior to menarche. Pelvic ultrasonography demonstrates a progressive increase in uterine length and ovarian volume during sexual maturation, correlating with breast growth and serum estradiol concentrations, although these stages overlap substantially. In addition to an increase in volume, the ovarian echogenic pattern varies with advancing puberty as multiple,initially small and then somewhat larger, follicular cysts appear and regress; in the late adolescent female, a multicystic ovarian sonographic pattern is common.In boys, the earliest physical sign of puberty is testicular enlargement(long diameter >2.5 cm, volume>4 mL). Pubertal development progresses at a relatively slow pace through SMR stage III male genital development and then accelerates;approximately 4 years elapse between genital stages II and V. PHV is achieved at the average age of 14 years.There is substantial variation in the onset and duration of puberty for both genders. Those in whom the timing and progression of sexual maturation are “shifted to the left”experience early puberty, at times a familial characteristic. When sexual development begins before the youngest accepted age, that child has precocious puberty.In girls, the age before which pubertal onset has been considered precocious long has been 8 years. However, new data indicate that breast development before 6 to 7 years in Caucasian girls and before 5 to 6 years in African-American girls is a more appropriate criterion. Thus, it recently has been reported that at 3 years of age, 3%of African-American and 1% of Caucasian girls have either thelarche or pubarche, with the percentages increasing to 5.7% and 1.9% at 5 years and to 27.2% and 6.7% at 7 years, respectively (Fig. 1). At each age, the sexual maturation of African-American females is more advanced than that of Caucasian females. Menarche occurs in 2.3%of African-American females by 7 years of age compared with 0.2%of Caucasian females; by 11 years the percentages are 27.9% and 13.4%, respectively. However, mean menarcheal age has not changed(African-American, 12.2 y;Caucasian, 12.9 y). On the other hand,African-American and Caucasian males appear to mature at comparable ages. Sexual development before 9 years of age is considered precocious in boys of either ethnic background.Skeletal maturation (bone age) and increase in bone mineralization parallel the progression of chronologic age under the influence of growth and thyroid hormones, estrogens,and androgens. Estrogen is responsible for epiphyseal fusion and attainment of adult bone mineral density. As measured by magnetic resonance imaging, the height of the anterior pituitary lobe increases during sexual maturation to a maximum of 7 mm as its superior border changes from concave to convex. After intense activity of the hypothalamic-pituitary-gonadal (HPG) axis in the mid-fetal, neonatal, and early infancy periods, there is an interlude between 2 and 8 years of age during which the HPG is relatively quiescent due to the inhibitory influences exerted by higher central nervous system (CNS) centers. Even during this interval, however, there is pulsatile release of low amounts of hypothalamic gonadotropin-releasing hormone (GnRH), measurably increased nocturnal secretion of luteinizing hormone (LH), and GnRH-stimulated secretion of LH and follicle-stimulating hormone(FSH) in both genders.The onset of puberty is characterized hormonally by an increase in the frequency and amplitude of the GnRH “pulse generator” that is reflected by a rise in basal serum LH and FSH concentrations,augmentation of nocturnal LH secretion,and an increase in the LH secretory response to exogenous GnRH. In females, the FSH secretory response to GnRH declines with advancing pubertal development, and the GnRH-stimulated peak LH/FSH ratio increases (Tables 3 and 4). Gonadarche is manifested by increased secretion of estradiol in girls and testosterone in boys. In females, the cyclic pattern of HPG function develops as the processes of ovarian oogenesis and ovulation mature. There is also a peripubertal increase in the secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and its sulfate(DHEAS), with adrenarche usually beginning between 6 and 8 years in both genders. Adrenarche and gonadarche may be dissociated in several disorders of puberty, including primary hypogonadism (Turner syndrome) and isosexual precocity. During puberty there is a marked increase in the spontaneous secretion of growth hormone (GH) as well as in the GH secretory response to provocative stimuli and in serum concentrations of insulin-like growth factor-I.Isosexual precocious puberty is several-fold more common among girls than boys. Approximately 50%of children who have isosexual precocity have true and complete central precocious puberty (CPP) (Table 5). In CPP, pubertal development is driven by GnRH, as the “restraint”placed on the HPG axis by higher CNS centers is removed, which is the same mechanism that brings about normal sexual development. CPP may be due to congenital anomalies; infectious, neoplastic, or traumatic insults to the CNS; or treatment of long-standing sex hormone exposure due to pseudoisosexual precocity. In females, CPP most often is idiopathic (95%),although frequently an asymptomatic hypothalamic hamartoma with GnRH-synthesizing neurons may be identified by CNS imaging. A CNS insult or structural abnormality may be found in more than 90% of boys who have CPP. Both septo-optic dysplasia and cranial radiation therapy lead to deficiencies of multiple anterior pituitary hormones,including GH; however, paradoxically, in many of these children the HPG axis remains intact and begins to function at a prematurely young age.Hypothalamic, pineal, and mediastinal germinomas secrete human chorionic gonadotropin (hCG),thereby stimulating Leydig cell secretion of testosterone in boys independently of GnRH and LH,examples of pseudoisosexual precocious puberty. Familial male-limited precocious puberty (testotoxicosis) is due to a germ-line mutation in the LH receptor that renders it constitutively active; that is, it behaves as if it were being stimulated by its natural ligand (LH) and, thus, “turns on”Leydig cell testosterone synthesis. The McCune-Albright syndrome is due to a germ-line mutation that leads to a constitutively active G alphas subunit of the guanosine triphosphate binding protein, the membrane-bound signaling molecule linked to the LH receptor, and results in both Leydig cell synthesis of testosterone and granulosa cell production of estradiol. Ovarian cysts, granulosa, and Leydig cell gonadal tumors also secrete sex hormones independently of gonadotropin control and are, at times, due to somatic tissue-specific mutations in the LH receptor or the G alphassubunit of the G-protein.Congenital adrenal hyperplasia due to deficiency of either 21- or 11 beta-hydroxylase leads to excessive secretion of testosterone and pseudoisosexual precocious puberty in males. In some girls who have primary hypothyroidism, thelarche and uterine bleeding occur; in males,macro-orchidism may result,although excessive phallic and pubic hair growth seldom are seen. In this complex, precocious puberty may be due to the hypometabolic state that prolongs LH and FSH biologic activity or, because thyroid-stimulating hormone also binds to LH and FSH receptors, high concentrations of this hormone may simulate gonadotropin function. In females, primary hypothyroidism may be associated with multiple,large ovarian cysts that occasionally twist and infarct the ovary. Primary hypothyroidism is accompanied by hyperprolactinemia and occasionally by galactorrhea in both genders.Incomplete forms of isosexual precocious puberty are relatively benign. As noted, the HPG axis is active even in prepubertal girls; if an ovarian follicle secretes sufficient estrogen, breast and uterine endometrial growth may be stimulated,leading to premature thelarche or uncommonly premature menarche,which are both self-limited and nonprogressive states. Postnatally, in utero breast development usually disappears within several weeks after birth, but occasionally it may persist for as long as 8 months. Approximately 10% of children who have apparent premature thelarche progress to CPP, particularly if breast growth begins after 2 years of age. Premature pubarche, which most often is due to an early increase in adrenal androgen secretion (premature adrenarche), is followed by functional ovarian hyperandrogenism in 20% of affected young women.A thorough historical review and complete physical examination are the first steps in evaluating the child who has precocious puberty (Table 6, Figs. 2 and 3).If the primary concern is early thelarche, it is helpful to determine whether neonatal breast development has persisted or regressed only to recur later; the latter suggests a “new” process. The growth rate in the child who has CPP or pseudoisosexual precocious puberty usually is rapid, and height rises to a higher growth percentile than occupied previously. Children who have incomplete forms of precocious puberty usually continue to grow steadily in an established channel. It is essential to learn if a sibling had ambiguous genitalia(ie, congenital adrenal hyperplasia)or if the father, grandfather, or uncle was sexually precocious (familial male-limited sexual precocity).Height, weight, and head circumference are plotted (increasing head circumference may suggest hydrocephalus); blood pressure is recorded (an elevated blood pressure may suggest congenital adrenal hyperplasia due to deficiency of 11 beta-hydroxylase); sexual maturity is rated; and signs of systemic disease are sought. In girls, it is necessary to distinguish between the dense, irregular consistency of ductal breast tissue and the soft, smooth consistency of increased subcutaneous fat and between the reddish, less moist vaginal mucosa and small labia minora of the prepubertal girl compared with the pale, moist appearance of pubertal vaginal mucosa and elongated labia minora. In boys, measurement of phallic and testicular dimensions and careful palpation of the testes are crucial;testicular volume is disproportionately greater than phallic size, as in normal puberty, in males who have CPP (and some who have primary hypothyroidism). In males who have pseudoisosexual precocious puberty,penile dimensions are disproportionately greater than testicular size. Usually the testes are prepubertal in size (long diameter ≤2 cm, volume≤3 mL) and consistency (indicative of an extragonadal source of androgen such as the adrenal or a teratoma). Sometimes they may be modestly and symmetrically enlarged(2.5 to 3.5 cm, 5 to 6 mL) (familial male-limited precocious puberty,hCG-secreting tumors), and rarely they are asymmetrically enlarged,possibly with the presence of a palpable mass (Leydig cell or adrenal rest tumor). In girls who have isolated vaginal bleeding, it is necessary to exclude local causes, such as a foreign body, vaginitis, and neoplasia.The next step in the evaluation is governed by the physical findings and the child’s bone age (hand/wrist radiograph) (Figs. 2 and 3). Advanced skeletal maturation reflects long-standing sex hormone action and possible developmental maturity of the CNS and HPG axis. In most patients who have CPP or pseudoisosexual precocious puberty,the bone age is more than 2 years in advance of the chronologic age. In children who have incomplete forms of precocious puberty, bone age more closely approximates or is only slightly more mature than the chronologic age. When the diagnosis of the McCune-Albright syndrome is suspected, a skeletal survey or technetium bone scan may reveal polyostotic fibrous dysplasia. Thyroid function is assessed in children in whom primary hypothyroidism is suspected.Basal levels of LH, FSH (hCG if a germinoma is suspected), and sex hormones (testosterone in boys,estradiol in girls) are measured in patients who have possible CPP or pseudoisosexual precocity (Table 7). In girls who have isosexual precocity, basal LH levels in excess of 0.3 IU/L are found primarily in CPP. If necessary, the prepubertal or pubertal state of the HPG axis may be assessed further by determining the gonadotropin secretory response to GnRH. A serum LH concentration of 8 IU/L 40 minutes after the subcutaneous administration of 100 mcg of GnRH is consistent with CPP. Suppressed or prepubertal GnRH-stimulated LH secretion is consistent with either pseudoisosexual or incomplete forms of sexual precocity. However, as with all gonadotropin assays, there is overlap between basal and post-GnRH LH and FSH values among prepubertal and early pubertal subjects. Therefore, basal and post-GnRH LH and FSH measurements must be interpreted in relation to the clinical findings, bone age, and sex hormone levels.Basal serum concentrations of estradiol frequently are low(<10 pg/mL) or appropriate for the SMR (Tanner) stage of breast development in girls who have CPP; in those who have estrogen-secreting ovarian cysts or granulosa cell tumors, estradiol levels often exceed 100 pg/mL. Serum concentrations of anti-müllerian hormone often are increased in patients who have ovarian granulosa cell tumors.Ultrasensitive assays for estrogen are being developed that may help distinguish between prepubertal girls and those who have various forms of precocious puberty. In girls who have CPP, pelvic ultrasonography reveals a maturational increase in uterine length and ovarian volume and echogenic pattern (>6 cysts >4 mm in diameter). Ovarian cysts are demonstrated easily by this technique unless the cyst has ruptured and disappeared by the time of the examination. Because it is difficult to interpret pelvic ultrasonograms in prepubertal and pubertal girls, the reader should be experienced. In boys who have CPP, serum testosterone values are appropriate for the SMR (Tanner) stage of male genital development and substantially elevated in those who have testicular neoplasms. Magnetic resonance imaging of the CNS is essential in all patients who have CPP to identify any specifically treatable CNS lesion.Boys who have 21-hydroxylase-deficient congenital adrenal hyperplasia will exhibit elevated serum concentrations of 17 alpha-hydroxyprogesterone that decline after administration of cortisol. In those who have deficiency of 11 beta-hydroxylase, serum levels of 11-deoxycortisol are increased. Patients who have virilizing adrenal tumors have markedly elevated serum levels of DHEA and DHEAS. Those who have familial male-limited precocious puberty often present with a positive family history, symmetrically but only slightly(5 to 6 mL) enlarged testes, pubertal serum testosterone levels that increase further after hCG administration, prepubertal basal and post-GnRH concentrations of LH and FSH, and testosterone secretion that is not suppressible by GnRH agonists. Leydig cell tumors usually are identified as unilateral testicular masses; testosterone concentrations are pubertal and nonsuppressible.In children who have premature thelarche (or rarely, premature menarche), the bone age is similar to or only modestly advanced (<2 y) over chronologic age; serum levels of LH, FSH, and estradiol are within the prepubertal ranges; and pelvic ultrasonography reveals prepubertal uterine and ovarian sizes and echogenic patterns (<3 cysts <5 mm in diameter). Clinical judgment dictates the extent of evaluation of a female infant who has suspected premature thelarche, with watchful observation often being the most appropriate. For girls who have vaginal bleeding for which a local cause cannot be identified readily, pelvic ultrasonography is required to eliminate an intravaginal neoplasm.For children who have premature pubarche, bone age is usually less than 2 years in advance of chronologic age, growth rate is not increased markedly, and DHEA(>50 ng/dL) and DHEAS(>20 mcg/dL) levels are within adrenarchal ranges. Only rarely does a child who has premature pubarche have a nonclassical form of 21-hydroxylase-deficient congenital adrenal hyperplasia. If the growth rate is unduly rapid and the bone age is more than 2 years in advance of chronologic age (particularly if there is clitoral or penile enlargement), it is appropriate to measure the basal concentration and postadrenocorticotropin (intravenous bolus of ACTH 0.25 mg followed by sampling at >60 min) secretory response of 17 alpha-hydroxy-progesterone. Mutations in 3 beta-hydroxysteroid dehydrogenase are extremely rare in patients who have premature adrenarche.Effective management of the child who has isosexual precocious puberty depends on accurate identification of the cause and of its In children who have CPP due to a specifically abnormality of the primary is on management of the underlying the of its treatment on the of CPP then is because this may those who have idiopathic CPP or puberty associated with a hypothalamic hamartoma or other form of CPP for which primary therapy is not the child who has pseudoisosexual precocity that during or after treatment has the pubertal HPG axis may be by the administration of a of GnRH The most is 3 to 4 forms of are more in the HPG than are forms several times by or subcutaneous of to LH and FSH in children who have CPP may because an of GnRH gonadotropin However, GnRH is as a over several gonadotropin secretion is stimulated and then is to of GnRH and in synthesis of the The same occurs is by some girls who have bleeding may 2 weeks after the first of but usually not In the of children who have of HPG function is complete within 4 to 8 weeks after of The of therapy is in growth or of progression of physical signs of sexual maturation, rate or even of bone age and hormonally estradiol or testosterone and post-GnRH peak LH concentrations at HPG function in children who have CPP, it is to identify the child in whom treatment is necessary and appropriate. boys who have CPP therapy with because bone age usually is markedly advanced and pubertal development is For many girls who have maturation progresses bone age is not in advance of chronologic age, the in the height age ratio is growth rate is and adult height is with and does not decline during In such and observation as they puberty are appropriate. it is necessary to all girls who have CPP because occasionally a child who has the progressive form may rapid of skeletal maturation and for treatment with should be considered before the child who has CPP on (Table If the of to these are treatment with should be on the age, skeletal it often is to the girl who has idiopathic CPP for 6 to the rate of pubertal progression before whether therapy is of leads to of in girls and or in the progression of sexual in both genders. The of growth and skeletal maturation the adult height of children who have CPP is 8 to 12 greater than that before the of this of administration of and growth hormone have been with increases in adult of treatment on achieved adult height and psychosocial that it may have to be with usually is between 11 and 12 years of age in girls and 12 and years of age in boys as age pubertal development. After the HPG to the pubertal usually within 6 to after patients who have pseudoisosexual precocious puberty, the primary disease must be and other tumors are patients who have and nonclassical forms of congenital adrenal hyperplasia and those who have hypothyroidism are with Ovarian cysts associated with thelarche and elevated estrogen levels may be the cyst often In boys who have familial male-limited precocious puberty or the McCune-Albright synthesis may be by (an of 17 an be in girls who have due to the McCune-Albright After of sex hormone patients who have pseudoisosexual precocious puberty may have the if bone are in the pubertal children then may be with the of girls who have premature thelarche, breast growth within 4 years after it first However, CPP in 10% of children who have apparent premature who have premature thelarche may have several before In the of these girls may be and the child boys and many girls who have premature adrenarche because of the high frequency of functional ovarian all girls who have premature adrenarche young particularly boys, who have markedly advanced sexual development to be and in the of age and may Because of size and mature physical advanced sexual and maturational may be from such children by However, the and development of these children usually is It is essential to and to and in to the to appropriate It also is to to sexual of the child who has CPP and is There appear to be psychosocial or of isosexual precocity. When pubertal advance is or during some of the also