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Any girl of 13 or boy of 14 years of age without signs of pubertal development falls more than 2.5 SD above the mean and is considered to have delayed puberty (Table 15–2). By this definition, 0.6% of the healthy population is classified as having delay in growth and adolescence. These normal patients need reassurance rather than treatment and ultimately progress through the normal stages of puberty, albeit later than their peers. The examining physician must make the sometimes difficult decision about which patients older than these guidelines are constitutionally delayed and which have organic disease.
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Constitutional Delay in Growth and Adolescence
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A patient with delayed onset of secondary sexual development, whose stature is shorter than that of age-matched peers but who consistently maintains a normal growth velocity for bone age and whose skeletal development is delayed more than 2 SD from the mean, is likely to have constitutional delay in puberty (Figure 15–5). These patients are at the older end of the normal distribution curve describing the age at onset of puberty. A family history of a similar pattern of development in a parent or sibling supports the diagnosis. The subject is usually thin as well. In many cases, even if they show no physical signs of puberty at the time of examination, the initial elevation of gonadal sex steroids has already begun, and their basal LH concentrations measured by ultrasensitive third-generation assays or their plasma LH response to intravenous GnRH or GnRH agonist is pubertal. In boys, an 8 am serum testosterone value above 20 ng/dL (0.7 mmol/L) also indicates that secondary sexual development will commence within a period of months.
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In some cases, observation for endocrine or physical signs of puberty must continue for a period of months or years before the diagnosis is made. Generally, signs of puberty appear after the patient reaches a skeletal age of 11 years (girls) or 12 years (boys), but there is great variation. Patients with constitutional delay in adolescence almost always manifest secondary sexual development by 18 years of chronologic age, although there is one reported case of spontaneous puberty occurring at 25 years of age. Reports of patients with Kallmann syndrome and others with constitutional delay in puberty within one family suggest a possible relationship between the two conditions (see later and Chapter 4). Adrenarche is characteristically delayed—along with gonadarche—in constitutional delay in puberty.
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Hypogonadotropic Hypogonadism
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The absent or decreased ability of the hypothalamus to secrete GnRH or of the pituitary gland to secrete LH and FSH leads to hypogonadotropic hypogonadism. This classification suggests an irreversible condition requiring replacement therapy. If the pituitary deficiency is limited to gonadotropins, patients are usually close to normal height for age until the age of the pubertal growth spurt, in contrast to the shorter patients with constitutional delay. Bone age is usually not delayed in childhood but does not progress normally after the patient reaches the age at which sex steroid secretion ordinarily stimulates maturation of the skeleton. Patients may reach taller stature than expected. However, if GH deficiency accompanies gonadotropin deficiency, severe short stature will result.
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Central Nervous System Disorders
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Tumors—A tumor involving the hypothalamus or pituitary gland can interfere with hypothalamic-pituitary-gonadal function as well as control of GH, adrenocorticotropic hormone (ACTH), thyrotropin (TSH), prolactin (PRL), and vasopressin secretion. Thus, delayed puberty may be a manifestation of a central nervous system tumor accompanied by any or all of the following: GH deficiency, secondary hypothyroidism, secondary adrenal insufficiency, hyperprolactinemia, and diabetes insipidus. The combination of anterior and posterior pituitary deficiencies acquired after birth makes it imperative that a hypothalamic-pituitary tumor be considered as the cause.
Craniopharyngioma is the most common type of hypothalamic-pituitary tumor leading to delay or absence of pubertal development. This neoplasm originates in Rathke pouch but may develop into a suprasellar tumor. The peak age incidence of craniopharyngioma is between 6 and 14 years. Presenting symptoms may include headache, visual deficiency, growth failure, polyuria, and polydipsia; presenting signs may include visual defects (bitemporal hemianopsia is classic), optic atrophy, or papilledema. Clinical manifestations and laboratory evaluation may reflect endocrinopathies (found in 70%-75% including GH, axis abnormalities in 75%, hyperprolactinemia 48%, hypothyroidism in 25%, adrenal insufficiency in 25%, diabetes insipidus (DI) in 4.%, as well as gonadotropin deficiency in 40% in one series. Bone age is often retarded at the time of presentation.
Calcification in the suprasellar region is the hallmark of craniopharyngiomas; 80% of cases have calcifications on lateral skull x-ray, and a higher percentage show this on computed tomography (CT); however, calcifications cannot be seen on magnetic resonance imaging (MRI). The tumor often presents a cystic appearance on CT or MRI scan and at the time of surgery may contain dark, cholesterol-laden fluid. The rate of growth of craniopharyngiomas is quite variable—some are indolent and some are quite aggressive. Small intrasellar tumors may be resected by transsphenoidal surgery; larger ones require partial resection and radiation therapy (see Chapter 4). Recurrence of this tumor after apparent complete removal is noted and lends support to the use of radiation therapy in addition to surgery.
Extrasellar tumors that involve the hypothalamus and produce sexual infantilism include germinomas, gliomas (sometimes with neurofibromatosis), and astrocytomas (see Chapter 4). However, depending on endocrine secretory activity or location, these tumors may alternatively produce central precocious puberty. Intrasellar tumors such as chromophobe adenomas are quite rare in children compared with adults. Hyperprolactinemia—with or without a diagnosed microadenoma or galactorrhea—may delay the onset or progression of puberty; with therapy to decrease PRL concentrations, puberty progresses.
Other acquired central nervous system disorders—These disorders may lead to hypothalamic-pituitary dysfunction. Granulomatous diseases such as Hand-Schüller-Christian disease or histiocytosis X, when involving the hypothalamus, most frequently lead to diabetes insipidus, but any other hypothalamic defect may also occur, including gonadotropin deficiency. Tuberculous or sarcoid granulomas, other postinfectious inflammatory lesions, vascular lesions, and trauma more rarely cause hypogonadotropic hypogonadism.
Developmental defects—Developmental defects of the central nervous system may cause hypogonadotropic hypogonadism or other types of hypothalamic dysfunction. Cleft palate or other midline anomalies may also be associated with hypothalamic dysfunction. Optic dysplasia is associated with small, hypoplastic optic disks and, in some patients, absence of the septum pellucidum on CT or MRI (septo-optic dysplasia); associated hypothalamic deficiencies are often present (see Chapters 4 and 6) (Hesx-1 homeodomain, HESX-1 *601802. Homeobox gene expressed in ES cells; HESX-1 #182230, septooptic dysplasia).
Optic hypoplasia or dysplasia must be differentiated from optic atrophy; optic atrophy implies an acquired condition and may indicate a hypothalamic-pituitary tumor. Both anterior and/or posterior pituitary deficiencies may occur with either congenital midline defects or acquired hypothalamic-pituitary defects. Early-onset GH deficiency or early onset of a combination of anterior and posterior pituitary deficiencies suggests a congenital defect. Patients who have isolated deficiency of gonadotropins tend to be of normal height until the teenage years but lack a pubertal spurt. They have eunuchoid proportions of increased span for height and decreased upper to lower segment ratios. Their skeletal development is delayed for chronologic age during the teenage years, they continue to grow after an age when normal adolescents stop growing. Adult height is often increased in hypogonadotropic hypogonadal individuals.
Radiation therapy—Central nervous system radiation therapy involving the hypothalamic-pituitary area can lead to hypogonadotropic hypogonadism with onset at 6 to 18 months (or longer) after treatment. GH is more frequently affected than gonadotropin secretion, and GH deficiency occurs with exposure to as little as an 18-Gy dose. Other hypothalamic deficiencies such as gonadotropin deficiency, hypothyroidism, and hyperprolactinemia occur more often with higher doses of radiation.
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Isolated Gonadotropin Deficiency
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Kallmann syndrome 1 is the most common genetic form of isolated gonadotropin deficiency (Figure 15–6). Gonadotropin deficiency in these patients is associated with hypoplasia or aplasia of the olfactory lobes and olfactory bulb causing hyposmia or anosmia. Remarkably, patients may not notice that they have no sense of smell, although olfactory testing reveals the finding. GnRH-containing neurons fail to migrate from the olfactory placode (where they originate) to the medial basal hypothalamus in Kallmann syndrome. This is a familial syndrome of variable manifestations in which anosmia may occur with or without hypogonadism in a given member of a kindred. X-linked Kallmann syndrome is due to gene deletions in the region of Xp22.3 (+308700.KAL1), causing the absence of the KAL1 gene which codes for anosmin, which appears to code for an adhesion molecule that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus. There is an association of Kallmann syndrome 1 with X-linked ichthyosis due to steroid sulfatase deficiency, developmental delay, and chondrodysplasia punctata, probably due to a microdeletion. Associated abnormalities in Kallmann syndrome 1 may affect the kidneys and bones, and patients may have undescended testes, gynecomastia, and obesity. Mirror hand movements (bimanual synkinesia) are reported, with MRI evidence of abnormal development of the corticospinal tract. Adult height is normal, although patients are delayed in reaching adult height. Kallmann syndrome 2 is inherited in an autosomal dominant pattern and is due to a mutation in the FGFR1 (fibroblast growth factor receptor 1 [*136350]) gene. Kallmann syndrome 3 (*607002) exhibits an autosomal recessive pattern and appears to be related to mutations in PROKR2 (*607123) and PROK2 (PROK2 *607002), encoding pokineticin receptor-2 and prokineticin-2. FGF8 may also be involved.
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While kisspeptin and GRP54 (G protein–coupled receptor 54) play roles of importance in the onset of puberty, only rare patients have been reported with defects in the kisspeptin-GPR54 axis due to a mutation in the gene for the GRP54 receptor. The first human beings with defects in these molecules were reported in several kindreds, some consanguineous, presenting with hypogonadotropic hypogonadism. Other cases of hypogonadotropic hypogonadism may occur sporadically or in an autosomal recessive pattern without anosmia. The GnRH gene would seem a likely candidate for the cause of the condition, but while mutations of the GnRHreceptor gene, GnRHR, were noted years ago, not until 2009 were mutations in the GnRH1 gene demonstrated. Other mutations causing hypogonadotropic hypogonadism without anosmia include the GPR56, SF-1 (steroidogenic factor 1), HESX-1 (Hesx-1 homeodomain), 3 LHX3 (*600577) (LIM homeobox gene 3) PROP-1 (prophet of PIT1) (*601538) genes. X-linked congenital adrenal hypoplasia is associated with hypogonadotropic hypogonadism (DAX1 #300200). Adrenal hypoplasia, congenital AHC, glycerol kinase deficiency, and muscular dystrophy have also been linked to this syndrome. The gene locus is at Xp21.3-p21.2 and involves a mutation in the DAX1 gene in many but not all patients. An autosomal recessive form of congenital adrenal hypoplasia is reported. Some hypogonadal patients lack only LH secretion and have spermatogenesis without testosterone production (fertile eunuch syndrome); others lack only FSH (see Chapters 12 and 13). While a specific genetic diagnosis for hypogonadotropic hypogonadism suggests a permanent defect, long-term studies do not bear this out. Men with a variety of mutations followed for years are reported to revert to normal or near-normal gonadotropin function in some cases. Thus, long-term follow-up is indicated.
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Idiopathic Hypopituitary Dwarfism (Growth Hormone Deficiency in the Absence of Defined Anatomic or Organic Defects)
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Patients with congenital GH deficiency have early onset of growth failure (Figure 15–7); this feature distinguishes them from patients with GH deficiency due to hypothalamic tumors, who usually have late onset of growth failure. Even without associated gonadotropin deficiency, untreated GH-deficient patients often have delayed onset of puberty associated with their delayed bone ages. With appropriate human growth hormone (hGH) therapy; however, onset of puberty occurs at a normal age. Patients who have combined GH and gonadotropin deficiency do not undergo puberty even when bone age reaches the pubertal stage. Idiopathic hypopituitarism is usually sporadic, but may follow an autosomal recessive or X-linked inheritance pattern due to one of the gene defects listed earlier.
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The syndrome of microphallus (penile length <2 cm at birth due to congenital gonadotropin or GH deficiency) and neonatal hypoglycemic seizures (due to congenital ACTH deficiency or GH deficiency) must be diagnosed and treated early to avoid central nervous system damage due to hypoglycemia (these findings may occur in septo-optic dysplasia). Patients with this syndrome do not undergo spontaneous pubertal development. Testosterone in low doses (testosterone enanthate, 25 mg intramuscularly every month for three doses) can increase the size of the penis in infants diagnosed with congenital hypopituitarism without significantly advancing the bone age. Males with isolated GH deficiency can also have microphallus; the penis enlarges with hGH therapy in these patients. It is important to note that microphallus due to hypopituitarism may be successfully treated with testosterone leading to adult male sexual function, and sex reversal should not be considered (see Chapter 14).
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Birth injury, asphyxia, or breech delivery is more common in the neonatal history of patients with idiopathic hypopituitarism, especially affected males. While some subjects with breech delivery have central nervous system MRI abnormalities including interrupted pituitary stalk and ectopic posterior pituitary gland, cause and effect is not established as some individuals with breech delivery and hypopituitarism have no such MRI findings.
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Miscellaneous Disorders
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Prader-Willi syndrome—Prader-Willi syndrome (#176270) occurs sporadically and is associated with fetal and infantile hypotonia, short stature, poor feeding in infancy but insatiable hunger later, leading to remarkable obesity, characteristic facies with almond-shaped eyes, small hands and feet after infancy, mental retardation, and emotional instability in patients of either sex. Delayed menarche in females and micropenis and cryptorchism in males is common; while there is hypothalamic hypogonadism, there is also testicular dysfunction in males. Osteoporosis is common in these patients during the teenage years, but sex steroid replacement, when indicated, may increase bone density, although the effects are not proven to be long lasting if sex steroids administration cease. Behavioral modification may improve the usual pattern of rampant weight gain, but the constant vigilance of caregivers is necessary. Patients have deletion or translocation of chromosome 15q11-13 derived from their fathers. If an abnormality in this area derives from the mother, Angelman syndrome results. Fluorescent in situ hybridization for this area of the chromosome is available commercially for diagnosis.
Laurence-Moon and Bardet-Biedl syndromes—These autosomal recessive conditions are characterized by obesity, short stature, mental retardation, and retinitis pigmentosa. Hypogonadotropic hypogonadism and primary hypogonadism have variously been reported in affected patients. A distinction between Bardet-Biedl syndrome (#209900) a disorder thought to be linked to a defect in the basal body of ciliated cells) and Laurence-Moon syndrome has been made, with the latter demonstrating polydactyly and obesity and the former being characterized by paraplegia. Recently it has been suggested that these two syndromes really represent a single entity, as was the case in the past.
Chronic disease and malnutrition—A delay in sexual maturation may be due to chronic disease or malnutrition. For example, children with intractable asthma have delayed pubertal development leading to short stature during the teenage years, although they ultimately reach an appropriate adult height for family. Children with other chronic diseases may not fare so well in long-term follow-up; for example, HIV infection in adolescence causes poor growth and pubertal progression. Weight loss to less than 80% of ideal body weight, caused by disease or voluntary dieting, may result in gonadotropin deficiency; weight gain toward the ideal usually restores gonadotropin function.
Chronic disease may have effects on sexual maturation separate from nutritional state. For example, there is a high incidence of hypothalamic hypogonadism in thalassemia major, even with regular transfusion and chelation therapy.
Anorexia nervosa—Anorexia nervosa involves weight loss associated with a significant psychologic disorder. This condition usually affects girls who develop a disturbed body image and exhibit typical behavior such as avoidance of food and induction of regurgitation after ingestion. Weight loss may be so severe as to cause fatal complications such as immune dysfunction, fluid and electrolyte imbalance, or circulatory collapse. Primary or secondary amenorrhea is a classic finding in these patients and has been correlated with the degree of weight loss, although there is evidence that patients with anorexia nervosa may cease to menstruate before their substantial weight loss is exhibited. Other endocrine abnormalities in anorexia nervosa include elevated serum GH and decreased IGF-I (these are characteristic of other types of starvation), decreased serum triiodothyronine, decreased serum 1,25-dihydroxyvitamin D and elevated 24,25-hydroxyvitamin D levels. Weight gain to the normal range for height, however, does not ensure immediate resumption of menses. There is an increased incidence of anorexia nervosa in ballet dancers or ballet students; the incidence of scoliosis and mitral valve insufficiency is also increased in these patients. Functional amenorrhea may also occur in women of normal weight, some of whom demonstrate evidence of psychologic stress. Decreased LH response to GnRH administration, impaired monthly cycles of gonadotropin secretion, and retention of a diurnal rhythm of gonadotropin secretion are found in anorexia nervosa patients, patterns that indicate a reversion to an earlier stage of the endocrine changes of puberty.
Increased physical activity—Girls who regularly participate in activities such as strenuous athletics and ballet dancing may have delayed thelarche, delayed menarche, and irregular or absent menstrual periods. Increased physical activity and not decreased weight appears to be the cause of the amenorrhea in some girls; such amenorrheic patients may resume menses while temporarily bedridden even though weight does not yet change. Statistical analysis of mothers' ages at menarche and the type of sport pursued by their daughters indicates that late maturation of some gymnasts may be referable to a familial tendency to late menarche, suggesting that gymnastic activity may not be the primary cause of late menarche. On the other hand, there are studies indicating that intensive gymnastics training at an early age leads to a decrease in ultimate stature.
Hypothyroidism—Hypothyroidism can delay all aspects of growth and maturation, including puberty and menarche. Galactorrhea may occur in severe primary hypothyroidism due to concomitant elevation of serum PRL due to TSH stimulation. With thyroxine therapy, catch-up growth and resumed pubertal development and menses occur. Conversely, severe primary hypothyroidism may be associated with precocious puberty and galactorrhea (due to elevated serum PRL) in some patients (Van Wyk-Grumbach syndrome). There is evidence that excessive TSH can stimulate FSH receptors, leading to estrogen secretion and breast development.
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Hypergonadotropic Hypogonadism
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Primary gonadal failure is heralded by elevated gonadotropin concentrations due to the absence of negative feedback effects of gonadal sex steroids and inhibin. The most common causes of hypergonadotropic hypogonadism are associated with chromosomal and somatic abnormalities (see Chapter 14), but isolated gonadal failure can also present with delayed puberty without other physical findings. When hypergonadotropic hypogonadism is present in patients with a Y chromosome or a fragment of a Y chromosome (genetic males or conditions noted later), testicular dysgenesis must be considered in the differential diagnosis. The risk of testicular cancer rises in testicular dysgenesis (testicular cancer in normal boys is rare; eg, the incidence in Scandinavia is rising but still 0.5 per 100,000 in childhood).
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Syndrome of Seminiferous Tubule Dysgenesis (Klinefelter Syndrome)
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A common form of primary testicular failure is Klinefelter syndrome (47,XXY karyotype), with an incidence of 1:1000 males. Before puberty, patients with Klinefelter syndrome have decreased upper segment-lower segment ratios, small testes, and an increased incidence of developmental delay and personality disorders. Onset of puberty is not usually delayed, because Leydig cell function is characteristically less affected than seminiferous tubule function in this condition and testosterone is adequate to stimulate pubertal development. Serum gonadotropin levels rise to castrate concentrations after the onset of puberty; the testes become firm and are rarely larger than 3.5 cm in diameter. After the onset of puberty, there are histologic changes of seminiferous tubule hyalinization and fibrosis, adenomatous changes of the Leydig cells, and impaired spermatogenesis. Gynecomastia is common, and variable degrees of male secondary sexual development are found. Surviving sperm have been found by microdissection of some seminiferous tubules in a few patients leading to successful fertilization of a partner's ovum. Other forms of male hypergonadotropic hypogonadism are found with 46,XX/47,XXY, 48,XXYY, 48,XXXY, and 49,XXXXY karyotypes. Phenotypic males are described with 46,XX karyotypes and some physical features of Klinefelter syndrome; they may have the SRY gene translocated to an X chromosome (see Chapter 14).
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Other Forms of Primary Testicular Failure
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Patients surviving treatment for malignant diseases form a growing category of testicular failure. Chemotherapy—primarily with alkylating agents—or radiation therapy directed to the gonads may lead to gonadal failure. Injury is more likely if treatment is given during puberty than if it occurs in the prepubertal period, but even prepubertal therapy leads to risk. Normal pubertal development may occur in boys treated with chemotherapy before puberty, although they demonstrate elevated peak serum LH and elevated basal and peak serum FSH after GnRH, as well as a high incidence of decreased or absent sperm counts. This indicates that prepubertal status does not protect a child against testicular damage from chemotherapy and that normal physical development may hide significant endocrine and reproductive damage.
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The Sertoli cell only syndrome (germinal cell aplasia) is a congenital form of testicular failure manifested by azoospermia and elevated FSH concentrations but generally normal secondary sexual characteristics, normal testosterone concentrations, and no other anomalies. A mutation in a gene at Yq11.23, the azoospermia factor (AZF) (#415000 spermatogenic failure, nonobstructive, Y-linked) appears to play a role in the lack of production of spermatocytes.
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Patients with Down syndrome may have elevated LH and FSH levels even in the presence of normal testosterone levels, suggesting some element of primary gonadal failure.
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Cryptorchism or Anorchia
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Phenotypic males with a 46,XY karyotype but no palpable testes have either cryptorchism or anorchia. Cryptorchid males should produce a rise in testosterone levels greater than 2 ng/mL 72 hours after intramuscular administration of hCG (3000 U/m2) in the newborn period, although repeated doses are required after the first postnatal months. Testes may also descend during 2 weeks of treatment with hCG given three times a week.
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Patients with increased plasma testosterone levels in response to hCG administration, but without testicular descent, have cryptorchism. Their testes should be brought into the scrotum by surgery to decrease the likelihood of further testicular damage due to the elevated intra-abdominal temperature and to guard against the possibility of undetected tumor formation. Cryptorchid testes may demonstrate congenital abnormalities and may not function normally even if brought into the scrotum early in life. Furthermore, the descended testis in a unilaterally cryptorchid boy may itself show abnormal histologic features; such patients have a 69% incidence of decreased sperm counts. Thus, unilateral cryptorchid patients can be infertile even if they received early treatment of their unilateral cryptorchism. Since both the descended and the undescended testes may be affected, there may be preexisting disease that is manifested by the lack of descent of one testis. Lack of normal descent of the testes is hypothesized to cause the testicular dysgenesis syndrome (TDS), which explains the late occurrence of testicular disease. In addition, patients undergoing orchiopexy may sustain subtle damage to the vas deferens, leading to the later production of antibodies to sperm that may result in infertility. This finding may depend on the surgical technique used.
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It is important to determine if any testicular tissue is present in a boy with no palpable testes, because unnoticed malignant degeneration of the tissue is a possibility. The diagnosis of anorchia due to the testicular regression syndrome may be pursued by ultrasound, MRI, laparotomy, or laparoscopic examination. There are other endocrine evaluations besides the hCG test that may help in diagnosis. The presence of anti-Müllerian factor in a young child indicates the presence of testicular tissue, although during puberty anti-Müllerian factor becomes undetectable, and this test cannot be employed at that stage. Inhibin may be measured as an indication of functioning testicular tissue. Except for the absence of testes, 46 XY patients who are otherwise normal and have the vanishing testes syndrome of late fetal loss of the testes have normal infantile male genital development, including Wolffian duct formation and Müllerian duct regression. The testes were presumably present in these patients early in fetal life during sexual differentiation, but degenerated after the 13th week of gestation for unknown reasons (see Chapter 14). When these boys reach adulthood, they are reported to establish a normal male gender identity. The presence of normal basal gonadotropin levels in a prepubertal boy without palpable testes at least suggests the presence of testicular tissue even if the testosterone response to hCG is low, whereas the presence of elevated gonadotropin levels without any testosterone response to hCG suggests anorchia.
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Syndrome of Gonadal Dysgenesis (Turner Syndrome)
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45,XO gonadal dysgenesis is associated with short stature, female phenotype with sexual infantilism, and a chromatin-negative buccal smear. We do not recommend routinely ordering a buccal smear; it is now difficult for laboratories to perform the test reliably, and it has been replaced with modern karyotyping procedures. Patients have streak gonads consisting of fibrous tissue without germ cells. Other classic but variable phenotypic features include micrognathia, fish mouth (downturned corners of the mouth), ptosis, low-set or deformed ears, a broad shield-like chest with the appearance of widely spaced nipples, hypoplastic areolae, a short neck with low hairline and webbing of the neck (pterygium colli), short fourth metacarpals, cubitus valgus, structural anomalies of the kidney, extensive nevi, hypoplastic nails, and vascular anomalies of the left side of the heart (most commonly coarctation of the aorta associated with hypertension proximal to the coarctation). However, some affected girls can have almost normal female phenotypes. The medical history of patients with the syndrome of gonadal dysgenesis often reveals small size at birth, lymphedema of the extremities most prominent in the newborn period, and loose posterior cervical skin folds. (The terms Bonnevie-Ullrich syndrome and infant Turner syndrome are applied to this neonatal appearance.) Affected patients often have a history of frequent otitis media with conductive hearing loss. There may be frequent urinary tract infections associated with a horseshoe-shaped kidney, duplication of ureters, or other anatomic defects. Intelligence is normal, but there is often impaired spatial orientation, which may lead to difficulty in mathematics, especially geometry. Patients have no pubertal growth spurt, and reach a mean final height of 143 cm. Short stature is a classic feature of Turner syndrome, but not of other forms of hypergonadotropic hypogonadism that occur without karyotype abnormalities. The short stature is linked to the absence of the (short stature homeobox) SHOX homeobox gene of the pseudoautosomal region of the X chromosome (Xpter-p22.32) (OMIM*312865). GH function is usually normal in Turner syndrome. However, exogenous hGH treatment improves growth rate and increases adult stature toward the normal range in affected girls. It improves lipid profiles and decreases diastolic blood pressure (see Chapter 6). Pubic hair may appear late and is usually sparse in distribution owing to the absence of any ovarian secretions; thus, adrenarche progresses in Turner syndrome even in the absence of gonadarche. Autoimmune thyroid disease (usually hypothyroidism) is common in Turner syndrome, and determination of thyroid function and thyroid antibody levels is important in evaluation of these patients.
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Serum gonadotropin concentrations in Turner syndrome are extremely high between birth and about age 4 years. They decrease toward the normal range in prepubertal patients in the juvenile pause and then rise again to castrate levels after age 10 years (see Chapter 14).
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Sex chromatin–positive variants of gonadal dysgenesis include 45,X/46,XX, 45,X/47,XXX, and 45,X/46,XX/47,XXX mosaicism with chromatin-positive buccal smears. Patients with these karyotypes may resemble patients with the classic syndrome of gonadal dysgenesis, or they may have fewer manifestations and normal or nearly normal female phenotypes. Streak gonad formation is not invariable; some patients have had secondary sexual development, and menarche and rare pregnancies have been reported.
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Sex chromatin–negative variants of the syndrome of gonadal dysgenesis have karyotypes with 45,X/46,XY mosaicism. Physical features vary; some patients have the features of classic Turner syndrome, whereas others may have ambiguous genitalia or even the features of phenotypic males. Gonads are usually dysgenetic but vary from streak gonads to functioning testes. These patients are at risk for gonadoblastoma formation; this is a benign tumor that has the potential for malignant transformation and then may metastatize. Because gonadoblastomas may secrete androgens or estrogens, patients with gonadoblastoma may virilize or feminize as though they had functioning gonads, confusing the clinical picture. Gonadoblastomas may demonstrate calcification on abdominal x-ray. Malignant germ cell tumors may arise in dysgenetic testes, and orchiectomy is generally indicated. In some mosaic patients with one intact X chromosome and one chromosomal fragment, it is difficult to determine whether the fragment is derived from an X chromosome or a Y chromosome. Polymerase chain reaction techniques to search for specific Y chromosome sequences may be helpful if a karyotype reveals no Y chromosomal material.
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Patients with Turner syndrome who desire fertility can be treated with in vitro fertilization techniques. After exogenous hormonal preparation, a fertilized ovum (possibly a sister's ovum fertilized by the patient's male partner, or an extra fertilized ovum from another couple undergoing in vitro fertilization) can be introduced into the patient's uterus, and the pregnancy is then brought to term by support with exogenous hormone administration. A serious possible complication is uterine rupture.
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Other Forms of Primary Ovarian Failure
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Ovaries appear to be more resistant to damage from the chemotherapy used in the treatment of malignant disease than are testes. Nonetheless, ovarian failure can occur with medical therapy. Damage is common if the ovaries are not surgically tacked out of the path of the beam or shielded by lead in abdominal radiation therapy. Normal gonadal function after chemotherapy does not guarantee normal function later. Late-onset gonadal failure has been described after chemotherapy. Bone marrow transplantation with whole-body irradiation for acute lymphoblastic leukemia or non–Hodgkin lymphoma appear to cause the most damage to endocrine function.
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Premature menopause has also been described in otherwise healthy girls owing to the presence of anti-ovarian antibodies. Patients with Addison disease may have autoimmune oophoritis as well as adrenal failure. A sex steroid biosynthetic defect due to 17α-hydroxylase deficiency (P450c17) manifests as sexual infantilism and primary amenorrhea in a phenotypic female (regardless of genotype) with hypokalemia and hypertension (see Chapter 14). A patient with 17α-hydroxylase deficiency may have ovaries or testes and still present as a phenotypic female.
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Noonan Syndrome (Pseudo–Turner Syndrome, Ullrich Syndrome, Male Turner Syndrome (Omim#163950 Noonan Syndrome 1; NS1)
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Noonan syndrome is associated with phenotypic manifestations of Turner syndrome such as webbed neck, ptosis, short stature, cubitus valgus, and lymphedema, but other additional clinical findings such as a normal karyotype, triangular facies, pectus excavatum, right-sided heart disease, and an increased incidence of developmental delay differentiate these patients from those with Turner syndrome. Males may have undescended testes and variable degrees of germinal cell and Leydig cell dysfunction. Noonan syndrome follows an autosomal dominant pattern of inheritance with incomplete penetrance (gene locus 12q24). hGH is approved by the FDA to increase stature in these patients.
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Familial and Sporadic Forms of 46,XX or 46,XY Gonadal Dysgenesis
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These forms of gonadal dysgenesis are characterized by structurally normal chromosomes and streak gonads or partially functioning gonads. They do not have the physical features of Turner syndrome. If there is some gonadal function, 46,XY gonadal dysgenesis may present with ambiguous genitalia or virilization at puberty. If no gonadal function is present, patients appear as phenotypic sexually infantile females. Patients with 46,XY gonadal dysgenesis and dysgenetic testes should undergo gonadectomy to eliminate the possibility of malignant germ cell tumor formation.
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Primary Amenorrhea Associated with Normal Secondary Sexual Development
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If a structural anomaly of the uterus or vagina interferes with the onset of menses but the endocrine milieu remains normal, the patient presents with primary amenorrhea in the presence of normal breast and pubic hair development. A transverse vaginal septum may seal the uterine cavity from the vaginal orifice, leading to the retention of menstrual flow—as may an imperforate hymen. The Rokitansky-Küster-Hauser syndrome (OMIM #277000) combines congenital absence of the vagina with abnormal development of the uterus, ranging from a rudimentary bicornuate uterus that may not open into the vaginal canal to a virtually normal uterus; surgical repair may be possible in patients with minimal anatomic abnormalities, and fertility has been reported. Associated abnormalities include major urinary tract anomalies and spinal or other skeletal disorders. The rarest anatomic abnormality in this group is absence of the uterine cervix in the presence of a functional uterus.
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46,XY disorder of sexual development (DSD), previously called male pseudohermaphroditism, is an alternative cause of primary amenorrhea if a patient has achieved thelarche. The syndrome of complete androgen resistance leads to female external genitalia and phenotype without axillary or pubic hair development in the presence of pubertal breast development (syndrome of testicular feminization; see Chapter 14).
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Differential Diagnosis of Delayed Puberty
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Patients who do not begin secondary sexual development by age 13 (girls) or age 14 (boys) and patients who do not progress through development on a timely basis (girls should menstruate within 5 years after breast budding; boys should reach stage 5 pubertal development 4½ years after onset) should be evaluated for hypogonadism. The yield of diagnosable conditions is quite low in children younger than these ages, but many patients and families request evaluation well before these limits. Without significant signs or symptoms of disorders discussed above, it is best to resist evaluation and offer support until these ages in most cases.
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A patient with constitutional delay may have a characteristic history of short stature for age with normal growth velocity for bone age and a family history of delayed but spontaneous puberty. The patient's mother may have had late onset of menses, or the father may have begun to shave late or continued growing after high school. Not all patients with constitutional delay are so classic, and gonadotropin-deficient patients may have some features similar to those of constitutional delay in adolescence. Indeed, patients with Kallmann syndrome and others with constitutional delay are occasionally found in the same kindred.
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If the diagnosis is not obvious on the basis of physical or historical features, the differential diagnostic process begins with determination of whether plasma gonadotropins are (1) elevated due to primary gonadal failure or (2) decreased due to secondary or tertiary hypogonadism or constitutional delayed puberty. Gonadotropins must be measured in a third generation assay with pediatric standards as the customary gonadotropin determinations are too insensitive to reveal the small changes of puberty. A single ultrasensitive, third-generation determination of serum LH concentration in the pubertal range suggests that puberty is progressing. Determination of the rise in LH after administration of GnRH or GnRH agonist is helpful in differential diagnosis; secondary sexual development usually follows within months after conversion to a pubertal LH response to GnRH. Because it is difficult, if not impossible, to obtain GnRH presently, GnRH agonists are more frequently used for diagnosis with serum LH values measured 2 hours after administration. Frequent nighttime sampling (every 20 minutes through an indwelling catheter) to determine the amplitude of peaks of LH secretion during sleep is an alternative to GnRH or GnRH agonist testing but is too cumbersome for most clinical settings. Unfortunately, the results of GnRH infusions or nighttime sampling are not always straightforward. Patients may have pubertal responses to exogenous GnRH but may not spontaneously secrete adequate gonadotropins to allow secondary sexual development. In females with amenorrhea, the frequency and amplitude of gonadotropin secretion may not change to allow monthly menstrual cycles. The retention of a diurnal rhythm of gonadotropin secretion (normal in early puberty) into late puberty is a pattern linked to inadequate pubertal progression. In males, a morning serum testosterone concentration over 20 ng/dL (0.7 mmol/L) indicates the likelihood of pubertal development within 6 months. Measurement of testosterone or estradiol must be done in an ultrasenstivie assay with pediatric standards or, as with gonadotropin assays, the small changes of pubertal development will be missed. Presently highly sensitive high performance liquid chromatography tandem mass spectroscopy (HPLC MS/MS) assays are available at national laboratories for this purpose.
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Other methods of differential diagnosis between constitutional delay and hypogonadotropic hypogonadism have been proposed but are complex or are not definitive. Clinical observation for signs of pubertal development and laboratory evaluation for the onset of rising levels of sex steroids may have to continue until the patient is 18 years of age before the diagnosis is definite. In most cases, if spontaneous pubertal development is not noted by 18 years of age, the diagnosis is gonadotropin deficiency. Of course, the presence of neurologic impairment or other endocrine deficiencies should immediately lead to investigation for central nervous system tumor or congenital defect in a patient with delayed puberty. CT or MRI scanning is helpful in this situation.
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Treatment of Delayed Puberty
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Constitutional Delay in Growth and Adolescence
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Teenagers who are so embarrassed about short stature and lack of secondary sexual development that they have significant psychologic problems may require psychological evaluation and therapy if they have passed the ages of 13 years for girls or 14 years for boys. Patients with constitutional delay in growth and adolescence should be counseled that normal pubertal development will occur spontaneously. Peer pressure and teasing can be oppressive. Although the majority of these patients do quite well, severe depression must be treated appropriately, because short patients with pubertal delay have become suicidal. In some cases, it helps to excuse the patient from physical education class, because the lack of development is most apparent in the locker room. In general, boys feel more stress than girls when puberty is delayed.
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New preparations of topical sex steroids, that have different systemic effects and length of action than parenteral or oral sex steroids, have enlarged the therapeutic armamentarium for delayed puberty. The classic recommendation for girls has been a 3-month course of conjugated estrogen (0.3 mg) or ethinyl estradiol (5-10 μg) given orally each day. Topical estrogen is said to carry less risk of hypertension, gallstones, increased fat mass, decreased insulin sensitivity, and increased triglycerides (topical estrogen does not, however, increase HDL cholesterol and decrease low-density lipoprotein [LDL] cholesterol, as does oral estrogen). Estrogen-impregnated patches are available and might be used to initiate puberty, but the lowest dose available leads to serum estrogen values higher than physiologic levels found in early puberty. They might be used for only a few days each week to reduce the delivered dose. Alternatively, 17-beta estradiol patches (0.025 mg/patch; Vivelle Dot matrix patch) may be cut into fragments the size of one-eighth to one-fourth of a patch fragments to initiate pubertal development with more physiologic estrogen values. However, the use of such topical estrogen preparations is not approved by the Food and Drug Administration (FDA).
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The classic recommendation for boys is a 3-month course of testosterone enanthate or cypionate (50 mg) given intramuscularly once every 28 days for three doses. The possibility that a higher dose will cause priapism limits the initial dose to 50 mg. New patch or testosterone gel preparations could be used to initiate puberty, but the dose in manufactured packets is too high to mimic the physiologic levels found in early puberty. These preparations are made for full replacement in adult males. The entire gel packet or lowest-dose patch could be used every other day over the 3-month period of treatment, although this leads to variable daily dosage. The gel is available in a pump but even one pump dose is too high for the initial therapy. The testosterone patches are not impregnated like the estrogen patches and cannot be cut down in size. Thus, to date, the low-dosage injection of testosterone or the use of an estimated one-half or less of the 5 mg testosterone gel packet are the only methods of reaching appropriate dosage. The topical use of testosterone is not approved by the FDA for such purposes. Therapy with oxandrolone has been suggested as a method of increasing secondary sexual development and increasing growth without advancing skeletal development. This method is not widely preferred. Furthermore, testosterone, which can be aromatized, increases the generally low endogenous GH secretion in constitutional delayed puberty to normal, whereas oxandrolone, which cannot be aromatized, does not increase GH secretion.
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Hormonal treatment of boys or girls elicits noticeable secondary sexual development and a slight temporary increase in stature. The low doses recommended do not advance bone age substantially and do not significantly change adult height if used for 3 months. Low-dose sex steroid treatment has been reported to promote spontaneous pubertal development after sex steroid therapy is discontinued, although responding individuals may include those boys who are on the brink of further pubertal development and are, therefore, most likely to achieve a growth response to androgen therapy. However, a short course of therapy may improve patients' psychologic outlook and allow them to await spontaneous pubertal development with greater confidence. Continuous gonadal steroid replacement in these patients is not indicated, because it advances bone age and leads to epiphyseal fusion and a decrease in ultimate stature. After a 3- to 6-month break to observe spontaneous development, a second course of therapy may be offered if no spontaneous pubertal progression occurs during observation.
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Permanent Hypogonadism
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Once a patient has been diagnosed as having delayed puberty due to permanent primary or secondary hypogonadism, replacement therapy must be considered at the average age of onset of puberty, in most cases when the diagnosis is made in childhood.
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Males with hypogonadism may be treated with testosterone gel, testosterone patches, or testosterone enanthate or cypionate given intramuscularly every month, as described earlier for temporary conditions. Treatment as for constitutional delay should be started and gradually increased to the adult range over months to years to mimic the normal progression of puberty and to avoid abrupt exposure to high-dose androgen and the possibility of frequent erections or priapism. Oral halogenated testosterone and methylated testosterone are never recommended because of the risk of hepatocellular carcinoma or cholestatic jaundice. Testosterone therapy may not cause adequate pubic hair development, but patients with secondary or tertiary hypogonadism may benefit from hCG administration with increased pubic hair growth resulting from endogenous testicular androgen secretion in addition to the exogenous testosterone.
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Testosterone gel or patches, as described earlier, are used for permanent replacement but are not FDA-approved for individuals less than 16 years. Girls may be treated with oral ethinyl estradiol (increasing from 5 μg/d to 10 to 20 μg/d depending on clinical results), or conjugated estrogens (0.3 or 0.625 mg/d). One may start with daily doses with eventual conversion to treatment on days 1 to 21 of the month after several months of daily ingestion. Five to ten milligrams of medroxyprogesterone acetate are then added on days 12 to 21 after physical signs of estrogen effect are noted and breakthrough bleeding occurs (and always within 6 months after initiating estrogen). Neither hormone is administered from day 22 to the end of the month to allow regular withdrawal bleeding (see Chapter 13). Later, the patient may be switched to sequential oral contraceptives to simplify treatment. As described earlier, estrogen patch therapy may have benefits (but these are not proven) over oral estrogen and may be preferable (but these are not FDA-approved for individuals under 16 years of age). Gynecologic examinations should be performed yearly for those on replacement therapy.
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Hypothalamic hypogonadism may be treated with GnRH pulses by programmable pumps to achieve fertility or to promote pubertal development. Likewise, in the absence of a functional pituitary gland, hCG and menotropins (human postmenopausal gonadotropin) may be administered in pulses. These techniques are cumbersome and best reserved for the time when fertility is desired.
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Coexisting GH Deficiency
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The treatment of patients with coexisting GH deficiency requires consideration of their bone age and amount of growth left before epiphyseal fusion. If such a patient has not yet received adequate treatment with GH, sex steroid therapy may be kept at the lower dosage or even delayed to optimize adult height. The goal is to allow appropriate pubertal changes to support psychologic development and to allow the synergistic effects of combined sex steroids and GH without fusing the epiphyses prematurely.
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Constitutional delayed puberty may be associated with decreased GH secretion in 24-hour profiles of spontaneous secretion or in stimulated testing. GH secretion increases when pubertal gonadal steroid secretion rises due to the effects of estrogen, so decreased GH secretion in this condition should be considered temporary. Nonetheless, true GH-deficient patients may have delayed puberty due to the GH deficiency or to coexisting gonadotropin deficiency. Therefore, deciding whether a pubertal patient has temporary or a permanent GH deficiency can be difficult; previous observation may indicate a long history characteristic of constitutional delay in adolescence, whereas a recent decrease in growth rate may suggest the onset of a brain tumor or other cause of hypopituitarism.
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The Syndrome of Gonadal Dysgenesis
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In the past, patients with the syndrome of gonadal dysgenesis were frequently not given estrogen replacement until after age 13 years, for fear of compromising adult height. However, low-dose estrogen therapy (5-10 μg of ethinyl estradiol orally) can be administered to allow feminization and improve psychologic status at 12 to 13 years of age without decreasing final height, as shown in several studies. Low-dose estrogen increases growth velocity, whereas high-dose estrogen suppresses it. Even if growth velocity is increased, however, adult height is not increased with such estrogen treatment. Treatment of Turner syndrome with GH successfully increases adult stature (see Chapters 6 and 14). During childhood these girls must be regularly screened for strabismus, hearing loss, and autoimmune thyroid disease as well as learning difficulties. There are several recommendations for the preparation of these girls to transition to adult care and necessary follow-up for issues that will affect their later life, including monitoring for the development of aortic dilation at 5- to 10-year intervals since this defect may progress to aortic aneurysms. The induction of fertility was described earlier in this chapter.
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After infancy, most bone mass accrual takes place during the second decade of life, and disorders of puberty may affect this process. Delayed puberty in boys causes decreased cross-sectional bone density, when the subjects are tested as young adults, because they have not yet reached peak bone acquisition. Although there is some controversy, it appears likely that normalization of volumetric bone density occurs with maturity and exposure to a normal androgen milieu. A range of defects in girls such as anorexia nervosa, athletics-induced delayed puberty, and Turner syndrome also cause decreased bone density. The use of testosterone in boys and estrogen and progesterone in girls with hypogonadotropic hypogonadism is helpful in increasing bone mass but has not been demonstrated to result in normal adult bone mass. Appropriate ingestion of dairy products containing calcium or calcium supplementation and vitamin D should be encouraged in hypogonadal or constitutionally delayed patients as well as in normal children at least as a common sense measure. No long-term follow-up is yet available, however, to prove the efficacy of this therapy in susceptible subjects.