Rudolph's Pediatrics, 22nd Ed.

CHAPTER 541. Abnormal Pubertal Development

Dennis M. Styne and Leonna Cuttler

SEXUAL PRECOCITY AND EARLY PUBERTY

Sexual precocity is the general term for early puberty. Isosexual precocity refers to a girl who feminizes or a boy who virilizes early. Central precocious puberty or true precocious puberty is a term reserved for children with gonadotropin-releasing hormone (GnRH)-dependent early puberty that follows the normal pubertal pattern and the normal control mechanisms through GnRH. The only difference from normal puberty is the earlier age at onset. Central precocious puberty can be idiopathic or caused by organic conditions such as a brain tumor or a hamartoma of the tuber cinereum. GnRH-independent isosexual precocity is caused by excessive estrogen secretion in girls or androgen secretion in boys from sources other than the GnRH-gonadotropin axis (such as the gonads, the adrenal glands, ectopic human chorionic gonadotropin (hCG) secretion, and exogenous sources of sex steroids). Gonadotropins are suppressed by negative feedback in all forms of GnRH-independent isosexual precocity because sex steroid secretion is autonomous. Contrasexual (or heterosexual) precocity refers to girls who virilize and boys who feminize.

Onset of puberty among Caucasian girls as early as 7 years of age or among African American girls as early as 6 years of age can be considered normal if there are no neurologic symptoms or signs of increased intracranial pressure, if there is not a rapid advancement in pubertal development or bone age, and if menses is after at least age 9 years. If there is a family history of a pattern of early pubertal development, the child is even more likely to have a variant of normal puberty rather than a pathologic condition causing sexual precocity. Among boys the earliest limit of normal puberty is 9 years of age. Onset earlier than these limits is considered sexual precocity.1 The classification schema and causes of precocious puberty are outlined in Table 541-1.

All children with sexual precocity show the effects of increased sex steroids such as secondary sexual characteristics, excessive growth for chronologic age, and rapid bone age advancement. Although some children progress rapidly through precocious puberty, some follow a waxing and waning course. The more severely affected children have tall stature and a bone age that advances faster than height velocity. If untreated, these patients achieve a severely decreased adult height because of premature epiphyseal closure. Historically, girls not treated for sexual precocity reached a mean adult height of 151 to 152 cm compared with a mean adult height in the United States of 164 cm. Boys not treated for sexual precocity reached an adult height of 161 cm compared with an average adult height in the United States of 178 cm.

Some children start puberty somewhat early compared with current standards but not strikingly so and may be manifesting a family tendency toward early puberty. The milder cases (ie, without marked advancement of bone age, without marked elevation of the serum level of IGF-I, and among girls, without marked elevation of the serum level of estrogen) may not need treatment and still achieve an acceptable adult height as may those with unsustained precocious puberty that may wax and wane over a period of time. In both situations, there should be careful follow-up, as slowly progressive puberty can convert to rapidly progressive true precocious puberty. The psychological stress of early sexual development and menarche among girls can influence a parental decision toward therapy. While boys may exhibit hyperactivity or aggression and masturbation due to early puberty, girls do not necessarily change their behavior.

Table 541-1. Causes and Classification of Sexual Precocity

CNS, central nervous sytem; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin.

Copyright © 2002 by The McGraw-Hill Companies, Inc. All rights reserved.

TRUE CENTRAL PRECOCIOUS PUBERTY (GNRH DEPENDENT)

True central precocious puberty results from an increase in GnRH secretion at a younger age than normal. Most cases are idiopathic, but because organic causes include brain tumors, further evaluation is usually indicated. Precocious puberty occurs more frequently among girls than among boys, but central nervous system tumor as a cause of precocious puberty is more common among boys than among girls.

Signs of central precocious puberty in boys include the development of secondary sexual characteristics, and an increase in testicular diameter to greater than 2.5 cm in longest measurement or a volume greater than 4 mL. Girls with precocious puberty have an increased growth rate even before development of the breasts, but the breast development is more easily detected. Breast development is noticed among girls with all types of isosexual precocity, but true menarche occurs only in GnRH-dependent precocious puberty. Fertility can be achieved early in children with central precocious puberty. There is a report of a 6-year-old girl delivering a child by Caesarian section due to the combination of precocious puberty and sexual abuse, emphasizing the importance of ensuring the safety of girls with early puberty.

Central Nervous System Causes of Precocious Puberty

The most common central nervous system (CNS) abnormality causing central precocious puberty is hamartoma of the tuber cinereum.2 These nonmalignant congenital masses of heterotopic tissue, composed of GnRH-synthesizing neurons, are derived from the embryonic hypothalamus and escape regulation by the central nervous system, so they cause pulsatile secretion of gonadotropins with stimulation of the gonads during childhood. They do not grow so that they are not associated with a mass effect, but they can be associated with gelastic or laughing seizures, petit mal seizures, or grand mal seizures. Hamartoma of the tuber cinereum has a characteristic appearance on magnetic resonance (MR) images of a sessile or pedunculated mass attached to the posterior hypothalamus between the tuber cinereum and the mamillary bodies projecting into the suprasellar cistern.3 Biopsy is not needed for diagnosis due to the classic radiographic findings. Surgical management is not usually indicated, as the lesion is responsive to GnRH agonists as discussed below. However, if seizures are not responsive to treatment, surgery may be necessary.

Craniopharyngioma, astrocytoma, ependymoma, and optic or hypothalamic glioma and ependymoma all interfere with the normal juvenile pause and can cause central precocious puberty, as can optic glioma or neurofibroma in the hypothalamic area associated with neurofibromatosis type 1 (von Recklinghausen disease). These tumors can cause other symptoms, such as headache, abnormalities of vision, optic atrophy, and diabetes insipidus.

Central nervous system radiation therapy may also cause central precocious puberty even if the treated tumor does not cause precocious puberty. When radiation causes central precocious puberty, the resultant growth acceleration can mask radiation-induced growth hormone (GH) deficiency (see Chapter 521). When both occur, treatment with combined GH and GnRH agonist is necessary to achieve more normal adult height.

High intracranial pressure caused by hydrocephalus or a subarachnoid cyst can cause precocious puberty, which is reversed solely by means of release of the elevated intracranial pressure. Fetal or childhood central nervous system infections of any type, such as tuberculosis and brain abscess, can cause precocious puberty, as can cerebral vascular accidents and central nervous system trauma. Developmental delay of various causes, including static cerebral encephalopathy, can cause precocious adrenarche (see below) or complete central precocious puberty. Congenital defects of the central nervous system such as septooptic dysplasia may cause central precocious puberty.

Those who have no hamartoma or other definable cause of central precocious puberty have idiopathic precocious puberty.

Androgen Exposure

Exposure to high serum concentrations of androgens, as seen with virilizing congenital adrenal hyperplasia, causes early maturation of the hypothalamus with central precocious puberty even after the primary cause of increased androgens is treated, and the androgen levels have reverted to normal levels. Often children diagnosed with congenital adrenal hyperplasia require treatment with a GnRH agonist, in addition to the standard treatment of glucocorticoid and mineralocorticoid, to prevent early puberty. Likewise, children with androgen-secreting tumors that are removed after years of virilization can subsequently have central true precocious puberty.

Children Adopted from Developing Countries

Girls adopted into Western families after an infancy in the Third World may develop central precocious puberty.4 This is postulated to be linked to early malnutrition followed by normal or excessive nutrition with both effects tending to advance the age of puberty.

GNRH-INDEPENDENT SEXUAL PRECOCITY (INCOMPLETE ISOSEXUAL PRECOCITY)

Sexual precocity occurring in the absence of an increase in GnRH is caused by either autonomous secretion of sex steroids in both sexes or, among boys, to production of hCG, which stimulates testicular testosterone secretion. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are suppressed to nondetectable concentrations in the face of elevated (often extremely elevated) sex steroid concentrations. Agonists of GnRH have no effect on these conditions, although as noted above, exposure to sex steroids may stimulate early hypothalamic maturation that persists following treatment for the virilizing condition.

Causes of GnRH-Independent Sexual Precocity among Boys

Germ cell tumors secrete hCG, which in high concentrations stimulates the Leydig cells to produce testosterone. Human chorionic gonadotropin does not stimulate the seminiferous tubules, so these boys have only slight enlargement of the testes (to a degree far less than occurs in central precocious or normal puberty). The penis enlarges; the serum hCG concentration is elevated, but levels of FSH and LH are not. (It is essential to use assays that can differentiate hCG from LH, usually a beta-hCG assay.) The lesion responsible can be teratoma, chorioepithelioma, dysgerminoma, or a mixed germ cell tumor, which can be located in the hypothalamus, the mediastinum, the lungs, the gonads, or the retroperitoneal cavity. Hepatoblastoma also can be causative. The tumors may secrete -feto protein as well as hCG. Boys with 47,XXY Klinefelter syndrome have an increased incidence of hCG-secreting mediastinal germ cell neoplasms.5

Virilizing congenital adrenal hyperplasia can be caused by 21-hydroxylase deficiency, which can be associated with the salt-loss of mineralocorticoid deficiency, or can be caused by 11β-hydroxylase deficiency, which can be accompanied by hypertension because of excess mineralocorticoid secretion. In boys, these conditions cause virilization without testicular enlargement, because the androgen originates from the adrenal glands. Because gonadotro-pins are suppressed, the testes can be small for age or small for the degree of virilization. The classical form manifests during infancy as salt loss and normal genital appearance. Without salt loss, the condition can manifest as GnRH-independent isosexual precocity in boys later in infancy (see Chapter 533). Virilizing adenoma and carcinoma of the adrenal gland secrete large amounts of dehydroepiandrosterone (DHEA) (and dehydroepiandrosterone sulfate [DHEAS]), which is peripherally converted to more potent androgens. When the adrenal gland is the cause of the virilization, the testes remain prepubertal in size. Leydig cell tumors are rare among boys but manifest as asymmetrically enlarged testis or testes.

Familial gonadotropin-independent sexual precocity with premature Leydig and germ cell maturation (or “testotoxicosis”) is a rare, sex-limited dominant condition that manifests clinically only among boys.1It is due to an activating mutation in the luteinizing hormone receptor, rendering it constitutionally activated, so that it constantly stimulates testosterone production. Affected boys have enlargement of the penis and virilization but only minimal enlargement of the testes because there is predominant stimulation of Leydig cells and relatively less enlargement of the seminiferous tubules. The boy grows rapidly, but adult height is markedly decreased; affected girls are normal. Fertility is normal at adulthood. These patients have elevated testosterone levels with low gonadotropin concentrations. Spironolactone, an antimineralocorticoid and antiandrogen agent used to limit androgen effect, has been combined with testolactone, an inhibitor of aromatase that limits bone age advancement, as treatment for these boys. An alternative is cyproterone acetate, a powerful antiandrogen that blocks the androgen receptor, can be used alone. Ketoconazole, an inhibitor of steroidogenesis, has also been employed effectively in males with testotoxicosis. Later in life, central precocious puberty often develops, and these patients become responsive to GnRH, although they were not responsive in childhood. This phenomenon appears similar to the hypothalamic-pituitary-gonadal maturation that occurs among patients with premature puberty after therapy for other virilizing disorders and is responsive to a GnRH agonist.

Familial cortisol resistance syndrome leads to a compensatory increase in corticotropin (ACTH) secretion which increases glucocorticoid secretion; because there is resistance to glucocorticoids, there is no manifestation of excess glucocorticoid effect in spite of elevated circulating glucocorticoids.7 However, because there is an increase in ACTH, adrenal androgen secretion rises causing premature adrenarche and virilization as well as hypertension and hypokalemia due to increased mineralocorticoid secretion. Occasionally, testosterone topically applied by the father may be transferred to his young son resulting in virilization of the child.

Causes of GnRH-Independent Sexual Precocity among Girls

Gonadotropin-independent isosexual precocity among girls can be caused by ovarian cysts or neoplasms, exposure to exogenous estrogens, or abnormalities of the adrenal glands. Prepubertal girls normally have small ovarian cysts, but some cysts enlarge and secrete sufficient estrogen to cause breast development and even withdrawal bleeding.8 The estrogen levels are usually only at pubertal values, but occasionally very high levels, characteristic of tumors, are encountered. Most cysts do not recur, but repetitive cyst formation can occur. Affected girls secreted more FSH than normal prepubertal girls which may explain the pathogenesis of this condition.

Several neoplasms can cause gonadotropin-independent isosexual precocity among girls. Granulosa cell tumors of the ovary are rare, being discovered by bimanual examination in 80% of cases.9Antimüllerian hormone and inhibin are useful tumor markers for postoperative follow-up evaluation of these tumors. Gonadoblastomas can arise in streak gonads and secrete estrogen or even testosterone. These tumors are benign but can harbor malignant ovarian tumors. Estrogen-secreting adrenal neoplasms are infrequent compared with those that secrete androgens. Tumors that secrete human chorionic gonadotropin (hCG) cause no physical pubertal changes in girls due to endocrine effects alone. Girls and boys can be exposed to estrogens through ingestion of their mothers’ oral contraceptives or contact with estrogen-containing ointment; lavender oil and tea tree oil contain estrogen and exert these effects. Feminization also has been attributed to estrogen contamination of milk, meat, or even vitamins prepared on machinery previously used to package estrogen.

Causes of GnRH-Independent Sexual Precocity among Boys and Girls

McCune-Albright syndrome is a disorder including irregular café-au-lait spots (“Coast of California pattern”), polyostotic fibrous dysplasia (cysts in the long bones and thickening of the skull), and autonomous endocrine function, usually manifesting as GnRH-independent sexual precocity. Patients may have autonomous hyperactivity of the somatotropes (acromegaly or gigantism), thyroid cells (thyrotoxicosis), parathyroid glands, or adrenal glands (Cushing syndrome). The widespread endocrine activity is caused by activating mutations of the stimulatory G-protein subunit of the adenyl cyclase system attached to the membrane receptor of the affected cells. Because these are somatic cell mutations that are not in the germline, the disease affects some organs while skipping others, leading to the variable manifestations.

This syndrome is most common among girls but can affect boys. The skin and skeletal manifestations develop after birth. The sexual precocity of the McCune-Albright syndrome is initially autonomous, but exposure to the endogenous estrogens or androgens eventually can mature the hypothalamic-pituitary-gonadal axis and cause GnRH-dependent precocious puberty. Therapy in girls typically includes the use of an antiestrogen, and treatment options in boys include an antiandrogen in combination with an aromatase inhibitor.10,11 Agonists of GnRH have been effective later in childhood in managing secondary central precocious puberty, which occurs after maturation of the hypothalamic-pituitary-gonadal axis.

Severe, uncontrolled hypothyroidism can be associated with incomplete sexual precocity of both boys and girls. The extremely high levels of TSH caused by hypothyroidism can stimulate gonadotropin receptors (hormonal overlap syndrome). Plasma level of prolactin is elevated, and galactorrhea can occur, especially among girls. Growth is impaired as for any child with hypothyroidism, so there is no pubertal growth spurt. Girls may have breast development, menstrual flow, and estrogen effects on the vaginal mucosa. In boys, the size of the testes may increase because of enlargement of the seminiferous tubules. The pituitary gland may enlarge and erode the sella turcica in a manner incorrectly suggesting a tumor because of increased TSH secretion and thyrotroph hyperplasia. Once hypothyroidism is controlled, sexual precocity reverts and the sella turcica becomes smaller.

Peutz-Jeghers syndrome is an autosomal dominant condition characterized by nasal polyps, hyperpigmentation of the lips, and macules of the buccal mucosa; affected boys can have gynecomastia and precocious puberty with Sertoli cell tumors, and girls can develop ovarian cysts.

FIGURE 541-1. Diagnostic algorithm for breast development before 7 years among white girls and 6 years among African American girls. CNS, central nervous system; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; MRI, magnetic resonance imaging.

DIAGNOSIS OF SEXUAL PRECOCITY

The approach to diagnosis of the cause of sexual precocity is shown in Figures 541-1541-2, and 541-3. The goal in diagnosis of sexual precocity is first to eliminate the possibility of life-threatening tumors or other central nervous system conditions and second to determine optimal therapy to suppress pubertal development and bone age advancement.1 In girls with breast development before age 7 in Caucasians, and age 6 in African Americans, evaluation begins with measurement of basal or gonadotropin-releasing hormone (GNRH) stimulated levels of luteinizing hormone (LH) (Fig. 541-1). If they are pubertal, central causes of precocious puberty are considered, and cranial MR imaging is usually indicated. If not, serum estradiol levels are measured. If these are not elevated, a diagnosis of premature thelarche is made. If elevated, an ultrasound of the uterus and ovary should be performed. In cases presenting with pubic hair before age 7 years in white girls and age 6 years in African American girls, the evaluation begins with determination of DHEAS levels. If elevated, virilizing adrenal tumors need to be considered. If normal, other diagnosis need to be considered as outlined in Figure 541-2. The diagnostic approach to boys with puberty before age 9 years is outlined in Figure 541-3. The possibility of exogenous androgen or hCG needs to be considered. Then testicular size is determined. Based upon the size, and adrenal etiology, or androgen or hCG-secreting tumor, or testotoxicosis are considered prior to making a diagnosis of idiopathic precocious puberty. Idiopathic central precocious puberty is a diagnosis of exclusion in both sexes. All aspects of the pubertal process mirror the normal condition, albeit at an early age. Children can enter puberty even before their first birthday without a sign of an organic condition as the cause.

FIGURE 541-2. Diagnostic algorithm for pubic hair before 7 years among white girls and 6 years among African American girls. ACTH, adrenocorticotrophic hormone; DHEAS, dehydroepiandrostenedione sulfate; 17OHP, 17α-hydroxyprogesterone.

FIGURE 541-3. Diagnostic algorithm for precocious puberty among boys before 9 years of age. ACTH, adrenocorticotropin hormone; DHEAS, dehydroepiandrostenedione sulfate; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; 17OHP, 17α-hydroxyprogesterone.

Patients with true precocious puberty have many laboratory findings similar to the results obtained in normal puberty. Alkaline phosphatase is elevated for chronologic age but not for bone age. Resting concentrations of gonadotro-pins are elevated to the pubertal range when measured with sensitive third-generation assays. Nocturnal episodic gonadotropin secretion increases, as does the gonadotropin secretory response to administration of GnRH. Laboratories have their own standards, and if LH level increases more than the standard prepubertal value after GnRH or GnRH agonist is administered, the response is considered pubertal. Baseline LH values in new third-generation assays can also help establish the diagnosis.12

Management of Precocious Puberty

Central precocious puberty is best managed with administration of GnRH agonists that have a strong binding affinity for the GnRH receptor and resist enzymatic degradation.13 After a brief period of stimulation of LH and FSH secretion, binding of the GnRH agonist to the receptor downregulates the GnRH receptor, which decreases or eliminates further LH and FSH secretion. Levels of sex steroids decrease, bone age advancement decreases, and growth rate decreases. If therapy is started early enough, adult height equals or approximates the genetic potential. Menses ceases in girls, although an initial episode may occur after initiation of therapy. The most widely used preparation, leuprolide acetate, is available as a daily, a once-per-month, or a once per 3 months injection. A new subcutaneous implant of long-acting GnRH agonist provides 1 year of therapy. Agonists of GnRH are used to manage most types of central precocious puberty, including hamartoma of the tuber cinereum (as noted above, these congenital lesions do not necessitate surgery). Agonists of GnRH are not indicated for children with borderline early onset of puberty who are progressing slowly, have not had menarche, and have no central nervous system signs or symptoms.

Gonadotropin-independent sexual precocity is managed in an individual manner depending upon the etiology as described above.

VARIATIONS OF EARLY PUBERTAL DEVELOPMENT

PREMATURE THELARCHE

Premature thelarche occurs most frequently among girls by 2 years of age and almost always before 4 years. In most cases, breast development regresses within 6 months of onset, but in some cases it remains for years after diagnosis.14 Ultra-sensitive bioassays have described higher estrogen levels in these girls compared to controls. Breast-feeding with maternal estrogen exposure may foster some cases. Recently, it has been shown that some girls with exaggerated or fluctuating thelarche may have an activating mutation in the GNAS gene, which codifies for alpha subunit of G stimulating protein (Gsalpha). Occasionally, girls with premature thelarche may also exhibit increased growth velocity and bone age, despite prepubertal gonadotropin secretion. This may represent an intermediate state between benign premature thelarche and precocious puberty.

Results of long-term follow-up studies suggest no untoward effects of premature thelarche on later health or development. Some girls with apparently classic premature thelarche later progress to central precocious puberty, so continued follow-up care of girls is essential, even if therapy is not initially indicated. In most cases, premature thelarche is a benign, self-limited disorder that is managed with reassurance.

PREMATURE ISOLATED MENARCHE

There are rare reports of girls who have menarche at an early age with no breast development. This can occur as an isolated incident or over a period of years. These girls then have normal pubertal development later in childhood. They must be differentiated from girls who have vaginal bleeding due to a foreign body, a local tumor, or vaginal trauma possibly caused by child abuse. The cause of premature isolated menarche is unknown.

PREMATURE ADRENARCHE

Some children have elevated levels of adrenal androgens years before the normal age of onset of adrenarche and have pubic and axillary hair development and acne years before the normal age of onset of normal puberty. Premature adrenarche must be differentiated from nonclassic 21-hydroxylase deficiency. In premature adrenarche, the serum level of DHEAS is elevated to early midpubertal levels, whereas in nonclassic adrenal hyperplasia, serum levels of 17OHP and DHEAS may be elevated in the basal state and hyperrespond after ACTH stimulation to concentrations higher than normal in puberty. Bone age in premature adrenarche usually is not advanced over chronologic age, and growth velocity is similarly minimally increased or normal for age. Small-for-gestational-age (SGA) birth is a risk factor for premature adrenarche.15 Some girls with premature adrenarche have mild insulin resistance and are at increased risk of polycystic ovary syndrome in adulthood.16 Premature adrenarche requires careful follow-up due to these potential risks.

ADOLESCENT GYNECOMASTIA

Adolescent gynecomastia is discussed in Chapter 64.

DELAYED PUBERTY

Causes of delayed puberty are shown in Table 541-2. A boy who has not initiated spontaneous secondary sexual development by 14 years of age or a girl who has not done so by 13 years of age has delayed puberty. This can be caused by constitutional delay in adolescence, usually considered a normal variant, or by a pathologic condition as serious as a brain tumor. Because 0.6% of the healthy population enter puberty spontaneously at an age outside these ranges, even these age cutoffs include normal children with late spontaneous puberty. In some pathologic conditions, abnormalities of the hypothalamic-pituitary-gonadal axis are associated with a normal age of puberty onset followed by cessation in the progression of puberty. Thus, patients who do not progress in secondary sexual development also require evaluation.

CONSTITUTIONAL DELAY IN GROWTH AND ADOLESCENCE: TEMPORARILY DELAYED PUBERTY

Patients who are healthy but have a slower rate of physical development than average have constitutional delay in growth and puberty.17 This entity is described further in Chapter 522. These patients often have a history of stature shorter than their age-matched peers throughout childhood, but their height is appropriate for bone age, and skeletal development is delayed by more than 2.5 SD. They often seek evaluation when classmates or friends undergo pubertal development and growth, thereby accentuating their delay; sometimes the normal earlier growth spurt in girls makes these boys more obviously short, leading to request for evaluation. A family history of delay is common, so mothers should be asked their age at onset of menarche or other aspects of puberty, and fathers their age at shaving or at reaching adult height. Permanent gonadotropin deficiency is most likely if a patient does not start puberty spontaneously by 18 years of age as spontaneous pubertal development is rare after 18 years of age. Before that age, in the absence of a classic presentation of constitutional delay in puberty, central nervous system disease, or other diagnostic characteristics, it is difficult to differentiate the temporary condition, constitutional delay in puberty, from permanent hypogonadotropic hypogonadism. The most common reason for treating constitutional delay in growth and puberty, usually with androgens, is for psychological difficulties and for loss of bone mineralization.18

Table 541-2. Causes and Classification of Delayed Puberty

PERMANENT CONDITIONS OF SEXUAL INFANTILISM

Hypogonadotropic Hypogonadism

Abnormalities of the hypothalamus or pituitary gland cause absence of pubertal development associated with low serum concentrations of gonadotropins. Unlike patients with constitutional delay in puberty and those with growth hormone (GH) deficiency, patients with isolated gonadotropin deficiency are of normal height until the adolescent age range, when, because of an absent pubertal growth spurt, they fall behind healthy peers. Because of delayed epiphyseal closure, they may continue to grow and reach a normal adult height albeit with characteristic eunuchoid proportions consisting of long legs and long arms and an upper-to-lower-segment ratio well below the normal adult values.

Kallmann Syndrome

This is the most common genetic disorder of gonadotropin deficiency and combines disordered development of the olfactory system and the gondadotropin-releasing hormone neurons leading to hyposmia or anosmia combined with hypogonadism.19 Within a family, patients may have disorders of the sense of smell with normal gonadal function, and others may have abnormal gonadal function and a normal sense of smell. Some kindreds contain members with Kallmann syndrome and others that appear to have constitutional delay in puberty that suggests an etiologic relation between the 2. Various gene mutations are associated with Kallman syndrome.20 In some cases, the disorder is caused by a mutation in a gene on Xp22.3 for an adhesion molecule that participates in normal migration of hypothalamic GnRH-secreting cells from the fetal volmeronasal organ (primitive nose) to the mediobasal hypothalamus. An autosomal dominant type of Kallmann syndrome is caused by mutations in the fibroblast growth factor receptor-1 gene and an autosomal recessive form is also reported. More than 80% of patients have absence of the olfactory sulci or olfactory bulbs on MR images, demonstrating the associated disordered development of the olfactory system.

Other Forms of Isolated Hypogonadotropic Hypogonadism

Although no human being has been determined to have a mutation in the gonadotropin-releasing hormone (GnRH) gene, there are kindreds exhibiting mutations in the GnRH receptor gene. Leptin and leptin receptor deficiencies cause another form of hypogonadotropic hypogonadism. Recently a gene coding for a metastasis-suppressing peptide, known as metastin or kisspeptin, and its receptor, GPR54, were shown to play an important role in the secretion of gonadotropins via GnRH; mutations in GPR54 lead to absence of pubertal development and infertility.20 The GPR54 mutation is rare but instructive in understanding the process of puberty.

ABNORMALITIES OF THE CENTRAL NERVOUS SYSTEM: GONADOTROPIN DEFICIENCY WITH OTHER PITUITARY HORMONE DEFICIENCIES

Idiopathic Hypopituitarism

Congenital absence of any or all of the pituitary hormones is found in idiopathic hypopituitarism. Because GH deficiency can delay the onset of puberty in an untreated patient, it may be difficult to determine which patient also has gonadotropin deficiency until the teenage years. Hypopituitarism is discussed in Chapter 523.

Disorders of the Central Nervous System

Patients with congenital midline defects may have gonadotropin deficiency as well as other types of hypothalamic-pituitary disorders that usually manifest during the neonatal period but require treatment in adolescence to promote sexual development. Central nervous system tumors, particularly those involving the hypothalamic-pituitary region, can delay puberty or facilitate precocious puberty depending upon their location, as discussed above. Prolactin-secreting tumors can delay puberty because of an inhibitory effect of prolactin on gonadotropin release or because of a mass effect of the tumor. Dopaminergic agents suppress progression of the tumor and prolactin secretion in some cases, but larger tumors necessitate surgical removal. Langerhans histiocytosis can cause isolated diabetes insipidus but can affect other hypothalamic-pituitary hormones as well. Granuloma of tuberculosis or sarcoid, postinfectious inflammation, and vascular lesions of the central nervous system all can impair hypothalamic-pituitary function, as can hydrocephalus, trauma caused by accidents, child abuse, or surgery. Radiation treatment can affect hypothalamic-pituitary function long after therapy is completed; this can include gonadotropin deficiency that delays puberty as well as precocious puberty as described above.

OTHER DISORDERS WITH DELAYED PUBERTY

Malnutrition or Weight Loss

Weight loss to less than 80% of ideal body weight can cause hypogonadotropic hypogonadism. This occurs in various chronic diseases, malnutrition states, and with psychiatric disorders such as anorexia nervosa. Gonadotropin secretion patterns revert to prepubertal, low-amplitude pulsatile secretion. The pattern only returns to normal months after weight regain. Increased physical activity in the presence of weight loss, as among ballerinas, or even in the maintenance of normal body weight, such as among swimmers or ice skaters, can cause cessation of menses.21 When increased activity ceases, as after an injury, menses recurs. Extreme exercise and weight control programs, such as those of young girls in competitive gymnastics, have been linked with a decrease in adult height and a decrease in bone density if puberty is delayed.

Cancer Therapy

Successful treatment of childhood cancer is common but ovarian toxicity may develop from chemotherapy or radiation therapy reflected by elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations or decreased inhibin B. There appears to be a higher prevalence of premature ovarian failure if cancer therapy is administered during the pubertal years rather than in childhood. Nonetheless, a majority of girls retain fertility after therapy. Radiation therapy that includes the ovaries within the field can cause primary ovarian failure; ovaries can be surgically moved out of the radiation field if they are not the actual target of the therapy, thereby greatly decreasing the dose of radiation to the ovaries and preserving ovarian function. The uterus may also be affected by radiation and may not expand normally during pregnancy.

Testicular failure following treatment during childhood is common but may not become apparent until years following therapy. Radiation of the gonads can cause primary testicular failure; the gonads must be shielded from the treatment, if they are not the focus of the therapy. Sperm preservation by cryopreservation is possible in a boy who will undergo chemotherapy or radiotherapy. Another approach is to freeze testicular tissue to be reimplanted later into the subject’s own testis or to be stimulated to mature for use in intracytoplasmic sperm injection. Careful endocrine follow-up of children and adolescents, boys and girls, treated with chemotherapy or radiotherapy is essential.

Autoimmune Oophoritis

Autoimmune oophoritis can cause ovarian failure most often associated with other autoimmune endocrinopathies, especially autoimmune Addison disease. Premature ovarian failure, often before age 20 years, is common in women with the type I autoimmune polyglandular syndrome (also known as APECED, whose manifestations include hypoparathyroidism, adrenal insufficiency, gonadal failure, diabetes mellitus, pernicious anemia, hypothyroidism, chronic hepatitis, mucocutaneous candidiasis, dystrophic nail hypoplasia, vitiligo, alopecia, keratopathy, and intestinal malabsorption).22

Other Associations

Prader-Willi syndrome and Laurence-Moon or Bardet-Biedl syndrome are also associated with hypogonadotropic hypogonadism. Hypothyroidism can inhibit the onset of puberty and menses, and hypothyroidism that occurs after the onset of puberty may slow the progression of puberty. Hypergonadotropic hypogonadism occurs in individuals with ovarian or testicular failure eliminating negative feedback inhibition and thereby increasing gonadotropin secretion. Both Turner and Klinefelter syndromes have elevated serum gonadotropin concentrations, karyotypic abnormalities, and specific physical findings as do patients with familial and sporadic XX or XY gonadal dysgenesis and their variants, LH resistance, testicular biosynthetic defects, anorchia, and cryptorchidism. Males with Noonan syndrome may have impaired Leydig cell function and delayed puberty (see Chapter 539). Chronic renal failure is combined with gonadal dysgenesis in the Frasier syndrome, which usually presents also with ambiguous genitalia. However, the diagnosis should be considered in any phenotypic female with end-stage renal disease (due to focal segmental glomerulosclerosis) and sexual infantilism.

Resistant ovary is a heterogeneous cause of primary hypogonadism, a syndrome associated with elevated concentrations of plasma FSH and LH and ovaries that contain primordial follicles. Polycystic ovary syndrome or functional ovarian hyperandrogenism does not delay the onset of puberty but often delays menarche or causes menstrual abnormalities (see Chapter 76). Homozygous galactosemia due to mutation in the galactose-1-phosphate uridylyltransferase gene (GALT) is commonly associated with primary ovarian failure (presentation ranging from failure to develop puberty to primary or secondary amenorrhea and premature menopause). Most cases are detected by newborn screening programs. Nephropathic cystinosis in boys also leads to hypergonadotropic hypogonadism. Mumps previously was a frequent cause of testicular failure, but with the advent of universal immunization for mumps, this is now extremely rare.

EVALUATION OF DELAYED PUBERTY

The approach to the evaluation of boys with absence of secondary sexual development by age 14 years, and girls by age 13 years is reason to consider further evaluation as outlined in Figure 541-4. The evaluation of girls with primary or secondary amennorhea with normal secondary sexual development is discussed in Chapter 76). The first step in laboratory diagnosis of delayed puberty is differentiating primary gonadal disease (hypergonadotropic hypogonadism) from hypothalamic-pituitary disease (hypogonadotropic hypogonadism). If gonadotropin levels are high for age, a karyotype is obtained to evaluate the possibility of Turner syndrome, Klinefelter syndrome, or their variants if there are suggestive physical features or laboratory or historical clues. Chronic disease, malnutrition, and excessive voluntary weight loss can delay puberty. Hypothyroidism must be ruled out by measurement of free T4and thyroid-stimulating hormone (TSH) because severe hypothyroidism can cause precocious puberty as well as delay in puberty. Because hyperprolactinemia can delay puberty, prolactin is measured; prolactin levels can also be elevated in cases of severe primary hypothyroidism.

FIGURE 541-4. Evaluation of absence of secondary sexual development among boys at 14 years and girls at 13 years.

If a patient has a low serum concentration of gonadotropin, differentiation between constitutional delay in puberty and permanent hypogonadotropic hypogonadism is challenging. A complete neurologic evaluation is performed to uncover any indication of a central nervous system tumor or abnormalities suggestive of Kallman syndrome (anosmia or hyposmia). If a tumor is being considered, head magnetic resonance imaging is performed. If there is a compelling family history of delayed but ultimately spontaneous puberty, the diagnosis is likely to be constitutional delay in puberty. If the diagnosis still is in doubt, the patient is observed for signs of spontaneous pubertal development or an increase in sex steroid concentrations over time. If a patient has not progressed through the changes of puberty spontaneously by the age of 18 or 19 years, it is unlikely that he or she will do so. No diagnostic methods can yet reliably differentiate constitutional delay in puberty from gonadotropin deficiency, although, if an 8 am serum testosterone value rises above 0.7 nmol/L (20 ng/dL) in a boy, the changes of puberty will likely develop within 12 months.

TREATMENT OF DELAYED PUBERTY

In patients with pubertal delay, their immature appearance may cause social dysfunction, and in the most severe cases it can lead to depression. In general, delayed puberty among boys is said to cause more distress than this condition among girls. Psychological support is often beneficial. In cases of permanent hypogonadism, sex steroids are replaced to assure pubertal development. In constitutional delay they may also be useful. In the frequent situation in which the difference between the 2 cannot be established, short-term low-dose sex steroid therapy may be used to treat patients feeling the pressure of appearing immature, who are not comforted by the thought of “waiting for nature to take its course.” The goal is to cause progression of secondary sexual development without advancing bone age and decreasing final height.

Treament of Boys

After the age of 14 years (the upper age of onset of normal pubertal development), boys can be given 50 mg of testosterone enanthate or cypionate intramuscularly every month for 3 months.23 If no sign of spontaneous puberty occurs within 3 months after treatment is initiated, another course of testosterone can be offered.

Patients with known hypogonadotropic hypogonadism need continuous testosterone therapy in increasing doses until the final dose of 250 to 300 mg per month is reached over 12 months or more. A dermal patch or gel can be used to administer testosterone in lieu of long-acting injections and will offer quicker relief in case of accidental overdose.24 Some teenagers prefer dermal application over injections, but this type of treatment is not approved by the US Food and Drug Administration (FDA). Some men request human chorionic gonadotropin (hCG) injections in addition to testosterone to further pubic hair development and to achieve a more normal adult appearance. If the patient remains quite short or qualifies for GH treatment but has not yet been treated with GH before the teenage years, testosterone therapy can be withheld for a period of time or used at a lower dosage to ensure that maximal growth is reached before epiphyseal fusion eliminates the ability to respond to growth hormone. Those previously treated with GH treatment may receive testosterone therapy to promote pubertal development.

Treatment of Girls

Girls with delayed puberty can be treated with low-dose estrogen therapy. Ethinyl estradiol can be compounded into capsules and administered at 5 μg/day for 3 months or 0.3 mg of conjugated estrogens may be given if that is all that is available. If hypogonadotropic hypogonadism is proved, or if the patient has hypergonadotropic hypogonadism, 10 to 15 μg/day of ethinyl estradiol is administered after feminizing effects appear. There is recent interest in administering estradiol by dermal patch which is thought to provide a more physiologic treatment with less likelihood of side effects such as an adverse lipid profile that is more likely to occur if estrogen directly enters the hepatic portal circulation after oral administration; this treatment is not approved for children or teenagers by the FDA. After several months, estradiol is given only on the first to 21st days of the month. Withdrawal bleeding usually occurs each month after the end of estradiol administration. After several more months, a progestational agent such as medroxyprogesterone acetate (5 to 10 mg) is given on the 12th to 21st day of the monthly cycle.

Because of the suspected increase in risk of uterine carcinoma with exogenous estrogen treatment, it is recommended that a girl taking estrogen therapy undergo yearly pelvic examinations. Breast examinations also are required because of the relation between estrogen and breast cancer. Patients with a family history of breast cancer need even closer observation. Girls with GH deficiency should not receive long-term or high-dose estrogen therapy until growth rate is normalized by administration of GH.

All Patients

All children and teenagers need the recommended daily allowance of calcium, and it is even more important for those with disorders of puberty. All patients with hypogonadism, even those with temporarily delayed puberty, should receive at least the recommended 1500 mg of elemental calcium per day along with an appropriate dose of vitamin D (at least 400 IU/day) to diminish the likelihood of osteoporosis in the future. Sex steroid therapy for the permanent conditions also can decrease the risk of osteopenia or osteoporosis later in life.