Delayed puberty is defined as the lack of pubertal development at two standard deviations above the mean age for the general population. In practical terms, this is a chronological age of 14 years for boys and 13 years for girls.30 In addition, an abnormality may be present if there is lack of the appropriate progression of puberty, more than 4 years between the first signs of puberty and menarche in girls or the onset and the completion of genital growth in boys. The goal of the assessment is to determine whether the delay or lack of development is due to a lag in normal pubertal maturation or represents an abnormality that must be investigated. Etiologies include (1) constitutional delay of growth and development; (2) secondary or functional hypogonadotropic hypogonadism caused by chronic illness or malnutrition; (3) primary hypogonadotropic hypogonadism; and (4) hypergonadotropic hypogonadism.
Constitutional Delay of Growthand Development
Constitutional delay of growth and development (CDGD) represents an exaggerated delay of puberty in an otherwise healthy boy or girl. It is often referred to as “late-blooming” and is usually diagnosed in boys, reflecting an ascertainment bias in referral patterns. In these children, puberty occurs spontaneously and progresses normally beginning at an age later than the average.
CDGD is considered a variant of normal. The exact etiology of CDGD is not currently known, but familial factors are paramount. There is often a family history in up to 50% of cases, with one or both parents having had a similar pattern of development. Recently, genetic analyses have been applied to children with CDGD. A series of patients with CDGD have been reported with heterozygous point variations in the GH secretagogue receptor; the exact significance of this finding requires validation. In addition, a sequence variant within the leptin gene has been reported in a mother and her son with reduced BMI and CDGD. Last, an association with CDGD has been shown with a locus on chromosome 2.
Diagnosis, evaluation, and natural history.
Typically children with CDGD have a normal length and weight at birth, and after a period of normal growth, there is a decline in growth velocity and weight gain beginning as early as 6 months and lasting up to 2 to 3 years of age. Growth then returns to a normal rate and continues along a lower percentile than would be expected for the family height genetics for the remainder of the prepubertal years. At the expected time of puberty, the height of children with CDGD begins to drift further from the normal growth curve because of delay in the onset of the pubertal growth spurt. Confounding the issue, the natural slowing of linear growth just before the onset of puberty (often accompanied by an apparent decline in GH secretion) may be exaggerated, magnifying the difference in size from peers who are beginning to show acceleration in their growth.
At the expected age of pubertal onset, children with CDGD demonstrate delayed bone ages and prepubertal levels of gonadotropins, initially making it difficult to distinguish this condition from primary or secondary gonadotropin deficiency. GnRH agonist and/or hCG stimulation may have better discriminatory value, but suggestive studies have had small numbers of subjects, lack of replication of diagnostic thresholds, and involve prolonged testing protocols that limit clinical application.31 In recent studies, a single inhibin B level has demonstrated good discrimination between groups (for more detail, see section Hypogonadotropic Hypogonadism, later).32 Periodic evaluation of height, weight, and stage of sexual maturation helps differentiate this normal variant from a pathologic entity, eliminating the need for laboratory testing. Because timing and tempo of sexual development appear to be delayed in accordance with the biological state of maturity (bone age), the height of a child with CDGD should be more or less appropriate for his or her genetic target height range when the height is plotted against bone age rather than chronological age (Figure 3-18). There is a poorly understood subset of children with CDGD who have a blunted pubertal growth spurt relative to their peers and may not reach their genetic target height.33 Unfortunately, it is not possible to anticipate which children with CDGD will fall into this category. As a result, it is important to monitor children with CDGD closely during puberty as they may require expedient intervention to attain a normal adult height.
Constitutional delay of growth and development (CDGD). (A) The infant-toddler male growth chart (birth to 36 months) demonstrates the early height pattern of children with CDGD; that is, they have a normal length in the first few months of life, after which there is a steady decline in growth velocity between 6 months and 2 to 3 years of age. (Continued)
Some would argue that, if delayed puberty were a physiologic variation, there is no proven medical necessity for initiating sex steroid replacement. However, there are adolescent boys with CDGD who are very short, significantly underdeveloped, and who are psychologically compromised. These boys frequently request and will profit from a short course of testosterone therapy. The administration of testosterone to adolescent boys with CDGD has been recommended for years, but it remains controversial because of the possibility of premature epiphyseal closure and reduced final height. However, if administered in low doses for a short duration, testosterone therapy is effective and does not appear to compromise final adult height. Intramuscular testosterone enanthate or cypionate ester is typically provided at 50 to 100 mg every 3 to 4 weeks, for a course of 3 to 18 months, depending on the needs of the patient. Transdermal preparations have been used off-label for this indication, but their safety and efficacy have yet to be demonstrated. A pediatric endocrinologist comfortable with prescribing testosterone is essential, as short-term doses higher than appropriate may result in an accelerated advancement in skeletal maturity and significantly short adult stature. Patients require close follow-up, at 3- to 6-month intervals, regarding height, weight, growth velocity, and pubertal and epiphysial maturation to ensure normal growth and development.
Other therapeutic approaches that have been tried in patients with CDGD include oxandrolone, aromatase inhibitors, GnRH agonists, and growth hormone. None of the medications has achieved evidence-based or FDA-approved status.
More than 30% of adolescents at one time suffer from a chronic illness. Medical illnesses have a tremendous impact on normal sexual development. In the face of poorly controlled or undiagnosed illness, children may not develop secondary sexual characteristics until the condition is identified and/or treated appropriately. These children are classified as having functional (or reversible) hypogonadotropic hypogonadism.
Any underlying chronic illness, prolonged medical treatment requiring glucocorticoids, excessive emotional stress, intense physical activity, or inadequate nutritional state can result in reversible hypogonadism (Table 3-6). If the underlying problem can adequately be treated, normal gonadotropin secretion is expected to follow.
Table 3-6.Functional Hypogonadotropic Hypogonadism ||Download (.pdf) Table 3-6. Functional Hypogonadotropic Hypogonadism
Chronic glucocorticoid use
Virtually every adolescent child with a serious chronic disease can have or sometimes present with delayed puberty (due to recurrent infections, immunodeficiency, gastrointestinal disease, cardiac disease, renal disturbances, respiratory illnesses, chronic anemia, endocrine disease, eating disorders, and/or excessive energy expenditure). Pubertal delay associated with chronic illness is accompanied by a delay in growth and by an absent or blunted pubertal growth spurt. The degree to which growth and pubertal development are affected in chronic illness depends on the type of disease and individual factors, as well as on the age at illness onset and its duration and severity. The earlier the onset and the longer and more severe the illness, the greater the repercussions for growth and pubertal development. The basis of abnormal puberty in children with chronic illness is multifactorial. Nutritional deficiency may contribute through insufficient food supply and/or malabsorption of nutrients. Moreover, increased energy supplies are often needed in patients with lung disease, infection, or inflammation. More specific factors due to the disease itself may be involved in growth and pubertal disorders. Abnormalities of the GH-IGF-1 axis and gonadotropin secretion have been described in patients with chronic renal failure, cystic fibrosis, and Crohn disease (see Chapter 2). More recently, it has been shown that cytokines produced during chronic diseases such as juvenile idiopathic arthritis may inhibit the normal function of the GH-IGF-1 axis. Finally, concomitant medications, such as glucocorticoids, which are often given to these patients, may contribute to delayed puberty and poor pubertal growth. Therefore, early diagnosis is essential and appropriate and disease-specific therapy fundamental.
Malnutrition (as may occur in malabsorption, anorexia nervosa, bulimia, and intense exercise), chronic pain, and psychosocial factors can all disrupt the HPG axis. The pituitary gland’s affinity for iron deposition explains the high incidence of hypogonadism, pubertal delay, and growth retardation in hemochromatosis and patients hypertransfused for chronic anemias. Hypogonadism in males with HIV infection is an ongoing concern, even among patients whose viral replication is under control and who have normalized CD4+ cell counts. Elevated serum lead levels have been shown to be associated with pubertal delay.
Endocrinopathies such as hypothyroidism, hyperprolactinemia, and hypercortisolemia may also result in functional hypogonadotropic hypogonadism. Thyroid hormone deficiency impairs growth and development, perhaps through induction of transient reversible GH deficiency. Adolescents with poorly treated or undiagnosed hypothyroidism may also have significantly delayed sexual maturation. Prolactin is naturally synthesized and secreted by lactotrophs in the anterior pituitary gland. Its primary function is during pregnancy to enhance breast development and induce lactation, but there is evidence that it also decreases gonadotropin secretion. Therefore, hyperprolactinemia should be considered in any teenager, male or female, with delayed sexual development and galactorrhea. Adolescents with hypercortisolemia demonstrate arrested pubertal development. Glucocorticoid excess suppresses gonadotropin release and also directly inhibits sex steroid secretion from the gonads.
Diagnosis, evaluation, and natural history
The initial approach in the diagnosis of delayed puberty requires a careful medical history, detailed growth history, complete family history, and physical examination. The medical history should include a detailed search for a reversible etiology for delayed sexual development. A history of competitive athletics or dance should be a red flag for excessive energy expenditure and the likelihood of hypothalamic dysfunction. Children with cardiac, gastrointestinal, rheumatologic, renal, or pulmonary disease need no further examination. If significant medical history is absent, a simple laboratory search for occult chronicillness is appropriate. Initial testing should include comprehensive chemistry panel, complete blood count and erythrocyte sedimentation rate, urinalysis, tissue transglutaminase antibody, TSH, and free T4 (preferably by direct dialysis). The chemistry panel and complete urinalysis help assess hepatic and renal function, respectively, in addition to glucose status. The complete blood count evaluates bone marrow function. The erythrocyte sedimentation rate is helpful to identify inflammatory disorders, such as systemic lupus erythematosus, juvenile rheumatoid arthritis, and inflammatory bowel disease. The tissue transglutaminase antibody assay is specific for the identification of celiac disease. Free T4 and TSH identify thyroid dysfunction.
Table 3-7.Keys to Diagnosis of Absent/Delayed Puberty ||Download (.pdf) Table 3-7. Keys to Diagnosis of Absent/Delayed Puberty
Symptoms suggestive of occult disease
Constitutional delay in growth and development in ~50% of first-degree relatives
Newborn screening abnormalities
Optic nerve evaluation
Evidence of developmental delay or mental retardation
Evaluation of the sense of smell
Evidence of underlying/associated condition
Screening evaluation for occult disease
Estradiol or testosterone
Karyotype if elevated gonadotropins are found
MRI for hypogonadotropic hypogonadism
Pelvic or scrotal ultrasound
Surgical exploration for gonadal tissue
Treatment of the underlying condition is the only therapy necessary.
The lack of any clinical manifestation of puberty by age 13 years in girls and 14 years in boys, along with persistence of low LH and FSH levels, is indicative of hypogonadotropic hypogonadism.
Etiologies of hypogonadotropic hypogonadism are divided by congenital and acquired forms (see Table 3-8). Congenital deficiency states include kisspeptin 1 gene mutations, KISS1 receptor mutations, isolated gonadotropin deficiency, adrenal hypoplasia congenita, and certain genetic syndromes. Acquired deficiency may result from an array of disorders affecting the brain, including tumors, malformations, trauma, surgery, radiation, infections, and infiltrative disease.
Kisspeptin gene and receptor mutations
KISS1 and its receptor are required for normal function of the HPG axis and play an important role in the physiologic regulation of puberty. Evidence supports a role for kisspeptin in stimulating GnRH secretion. Loss-of-function mutations in the KISS1R gene34 and a homozygous inactivating mutation in the KISS1 gene35 have been described in consanguineous families with isolated HH without olfactory abnormalities.
To date, there are too few patients described in the literature to provide an adequate understanding of the clinical presentation. However, the patients who have been reported with KISS1 and KISS1R mutations have presented with lack of onset of pubertal development or stalled pubertal development. Biochemically, patients present with low gonadotropin levels without other pituitary hormonal deficiencies.
GnRH-producing and olfactory neurons migrate together in embryologic development so that disruption of this process can cause either isolated hypogonadotropic hypogonadism or Kallmann syndrome. GnRH is released from neurons in the arcuate nucleus in a pulsatile fashion into the hypophysial-portal circulation, the capillaries perfusing the anterior pituitary gland. GnRH binds to GnRH receptors on the surface of gonadotrophs in the anterior pituitary gland, which, in turn, synthesize and secrete LH and FSH. The gonadotropins are released into the circulation where they stimulate gonadal steroidogenesis and gametogenesis. Gonadal steroids, principally testosterone in boys and estradiol in girls, exert negative feedback upon the hypothalamus and pituitary early in life and during puberty.
Isolated idiopathic HH has clinical and genetic heterogeneity, multiple modes of inheritance, and variable associates with other anomalies. Idiopathic hypogonadotropic hypogonadism and Kallmann syndrome are both characterized by defects in pituitary GnRH secretion.36 Impairment of both GnRH and olfactory neuron migration results in Kallmann syndrome, the key components of which are hypogonadotropic hypogonadism and disordered sense of smell. Normosmic patients are not diagnosed with Kallmann syndrome, but rather idiopathic hypogonadotropic hypogonadism. Both Kallmann syndrome and idiopathic hypogonadotropic hypogonadism can occur in partial or complete forms. Kallmann syndrome and idiopathic hypogonadotropic hypogonadism can occur in multiple generations and can present at any time from the early neonatal period to adulthood, and with varying degrees of gonadotropin deficiency. Male infants may present with cryptorchidism and/or micropenis. Both male and female patients may fail to enter puberty during adolescence. In recent years, adult-onset hypogonadotropic hypogonadism has been reported with loss of libido and decreased fertility after completion of normal pubertal development.37 In addition, there have been reports of spontaneous hypogonadotropic hypogonadism reversal.
Recent large-scale molecular genetic studies have highlighted multiple genes responsible for both conditions. Mutations in the following genes have all been implicated in Kallmann syndrome: Kallmann syndrome 1 sequence (anosmin-1 or KAL1), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor 8 (FGF8 or KAL2), prokineticin receptor 2 (PROKR2) and prokineticin 2 (PROK2), nasal embryonic luteinizing releasing hormone factor (NELF), chromodomain-helicase DNA-binding protein 7 (CHD7), heparan sulphate 6-O-sulphotransferase 1 (HS6ST1), and a WD-repeat protein 11 (WDR11).38 Mutations in the genes encoding the GnRH receptor (GnRHR), kisspeptin receptor (KISS1R), LH β-subunit gene (LHβ), FSH β-subunit gene (FSHβ), tachykinin 3 receptor (TAC3R), and TAC3 underlie uncomplicated normosmic hypogonadotropic hypogonadism.36 Genes associated with idiopathic hypogonadotropic hypogonadism in the backdrop of obesity include those encoding leptin (LEP), the leptin receptor (LEPR), and prohormone convertase 1 (PC1). It should be pointed out that Kallmann syndrome and idiopathic hypogonadotropic hypogonadism may not be distinct disorders as these two entities may exist in different relatives within the same family suggesting that they are subtypes of a complex genetic disease that is characterized by variable expression, penetrance, and modes of inheritance. As occurs in other multifactorial complex diseases, the pathogenesis of hypogonadotropic hypogonadism may be linked to environmental factors that may exert epigenetic effects on gene expression and the concurrent involvement of single nucleotide polymorphisms or other genetic defects in two (digenic) or multiple interacting genes.
All patients with Kallmann syndrome have either anosmia or severe hyposmia (reduced sense of smell) and may exhibit symptoms of associated conditions including unilateral renal agenesis, atrial septal defect, colorblindness, metacarpal shortening, and synkinesia (alternating mirror movements) most often seen in patients with KAL1 mutations. The sense of smell can easily be confirmed by testing the recognition for common substances such as alcohol, peppermint, or coffee, or with the use of commercially available smell test kits. Patients with FGFR1 mutations have cleft lip/palate and may have dental agenesis. Those with FGF8 mutations may have involuntary mirror movements, scoliosis, short stature, joint hyperextension, and osteoporosis. Patients with either PROKR2 or PROK2 mutations may often have a sleep disorder, epilepsy, fibrous dysplasia, and/or synkinesia. The CHD7 gene is responsible for CHARGE syndrome, explaining why Kallmann syndrome and CHARGE syndrome have been reported to have overlapping phenotypes. These patients may also have hearing deficits with hypoplasia of their semicircular canals. Kisspeptin regulates GnRH secretion in the hypothalamus via the KISS1R located on the surface of GnRH neurons and its secretion increases just before the start of puberty to promote the pulsatile secretion of GnRH. There are no nonreproductive effects of mutations of either KISS1 or the KISSR known at this time. Patients with mutations of leptin or the leptin receptor have associated obesity.
Transcription factors involved in pituitary development
Mutations of pituitary transcription factors may also result in hypogonadotropic hypogonadism. Gland development is governed by activation of a cascade of transcription factors that orchestrate both pituitary morphogenesis and differentiation of all five cell lineages of the anterior pituitary: corticotrophs, gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. Of those pituitary transcription factors identified so far, defects of HESX1, LHX3, LHX4, PROP1, and POU1F1 (Pit-1) have been found to lead to the phenotype of multiple pituitary hormone deficiency in humans.39 The specific phenotype of mutations of POU1F1 is characterized by a combined deficiency of GH, TSH, and prolactin. In contrast, endocrine phenotypes of mutations of HESX1, LHX3, LHX4, and PROP1 tend to overlap and have been reported to include failure of up to all five cell lineages. To make the understanding of phenotypes even more complex, the influences of these transcription factors on pituitary function seem to be dynamic with the potential to develop hormone deficiencies throughout the human lifespan.
To date, mutations of PROP1 represent the most frequently reported etiology of combined pituitary hormone deficiencies that include early loss of GH, TSH, and gonadotropins, with occasional late ACTH deficiency. The phenotypes of affected children vary widely. The pituitary gland may be hypoplastic, normal, or hyperplastic in size, with subsequent involution over time. The typical child with a PROP1 mutation may present with small genitals and hypoglycemia during the newborn period. Growth velocity, despite congenital GH deficiency, may be normal during the first 6 months of life, but then tapers off considerably. If mild hypoglycemia is not identified during infancy, CNS alterations may develop (delayed development, mental retardation, seizures, and, even neurologic devastation).
Mutations of the HESX1 gene may result in pituitary hormone insufficiency associated with ONH, historically known as septo-optic dysplasia (SOD). This syndrome is characterized by abnormalities of midline brain structures (absence of the septum pellucidum in 50% and, less frequently, agenesis of the corpus callosum), ONH, and pituitary hypoplasia. Newer findings reveal that patients with isolated ONH seem to be equally at risk as those with associated SOD to develop hypopituitarism.40 The spectrum of endocrinopathy associated with ONH ranges from isolated GH deficiency to panhypopituitarism. Evolving endocrinopathies are common with loss of endocrine function over time. Children with ONH/SOD usually come to attention with ophthalmological issues, that is, wandering nystagmus and poor vision. Retinal examination (often requiring fundal photography) reveals unilateral or bilateral hypoplastic optic nerve(s), leading to a further workup for possible ONH/SOD and referral to a pediatric endocrinologist.
Another cause of hypogonadotropic hypogonadism is adrenal hypoplasia congenita, caused by mutations of the NROB1 gene (formally called DAX1). The NROB1 gene encodes for DAX-1 protein, which is a transcription factor necessary for the development of the hypothalamus, pituitary gonadotrophs, and the adrenal cortex. DAX1 also appears to regulate gonadotropin secretion at both the hypothalamic and pituitary levels.41 Children with NROB1 mutations usually present with primary adrenocortical failure in infancy or childhood. Those adequately treated with gluco- and mineralocorticoids later present with delayed sexual development due to hypogonadotropic hypogonadism.
Syndromes associated with hypogonadotropic hypogonadism
Prader-Willi syndrome (PWS) is a contiguous gene syndrome caused by the sporadic loss of function of genes situated within the 15q11-q13 region, with a prevalence rate of one in 16,000. PWS was the first human disorder attributed to genomic imprinting. In such disorders, genes are expressed differentially based on the parent of origin. An imprinting center has been identified within 15q11-13; gene expression may be regulated by DNA methylation at cytosine bases. PWS results from the loss of imprinted genomic material within the paternal 15q11.2-13 locus. The loss of maternal genomic material at the 15q11.2-13 locus results in Angelman syndrome. The molecular events underlying the disorder include interstitial deletions (70%), uniparental disomy (25%), imprinting center defects (< 5%), and rarely chromosomal translocations (< 1%). PWS is commonly associated with hypogonadotropic hypogonadism and small genitalia, although there are also reports of patients with hypergonadotropic hypogonadism.42 Characteristic facial features include narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, and a downturned mouth. Infants typically have poor tone, delayed development, and failure-to-thrive. By age 2 years, these children develop polyphagia and progressive obesity.
Noonan syndrome is an autosomal dominant, genetically heterogeneous disease. Approximately 50% of cases are caused by gain-of-function mutations in the PTPN11 gene. The incidence of Noonan syndrome is estimated to be 1 per 1000 to 2500 live births and occurs equally in males and females (and, thus, should not be referred to as male Turner syndrome). The cardinal facial features are shown in Figure 3-19; affected individuals also manifest right-sided congenital heart disease (pulmonic stenosis) or atrial septal defect, and short stature. Testes are often small or cryptorchid. Typical patients demonstrate hypogonadotropic hypogonadism, but there are reports of patients with elevated gonadotropins.43 A bleeding diathesis is present in as many as half of all patients with Noonan syndrome, with factor XI deficiency the most frequent abnormality.
The cardinal dysmorphic features of a patient with Noonan syndrome are demonstrated in this figure: triangular-shaped face, hypertelorism, downslanting eyes, ptosis, low-set ears with thickened helices, high nasal bridge, and short webbed neck.
CHARGE syndrome is another autosomal dominant condition with genotypic heterogeneity. Most cases are due to mutation or deletion of the chromodomain helicase DNA-binding protein-7 (CHD7) gene.44 The estimated incidence of CHARGE syndrome is 1 in 8500 to 12,000 live births. It is associated with hypogonadotropic hypogonadism and olfactory bulb abnormalities similar to the abnormalities found in individuals with Kallmann syndrome. Boys with CHARGE syndrome may have micropenis, cryptorchidism, and/or small testes. Girls may have small labia. The cardinal features of coloboma (Figure 3-20), heart anomalies, choanal atresia, pre- and postnatal retardation of growth, genital hypoplasia, and ear anomalies clinically define CHARGE syndrome.
Large coloboma involving the optic nerve in a child with CHARGE syndrome. (Fundus photograph used with permission by Mark Borchert, MD, Children’s Hospital Los Angeles.)
Bardet-Biedl syndrome (BBS) is an autosomal recessive condition with a wide spectrum of clinical features.45 Prevalence rates in North America and Europe range from 1:140,000 to 1:160,000 live births. However, in Kuwait and Newfoundland, the rate is much higher, with an estimated incidence of 1:13,500 and 1:17,500, respectively, suggesting a founder effect. BBS is genetically heterogeneous, with 12 BBS genes identified to date. Although the cellular mechanisms that underlie BBS remain unclear, it is now evident that all of the known BBS proteins are important for ciliary transport. BBS is characterized by early-onset retinal dystrophy, obesity, postaxial polydactyly (Figure 3-21), brachydactyly of the hands and feet, mental retardation, hypogonadism, and renal disease. Hypogenitalism (cryptorchidism and/or microphallus) is reportedly more frequently in BBS boys. Genital abnormalities encompass a wide range in girls, including hypoplastic fallopian tubes, uterus, and ovaries, partial and complete vaginal atresia, absent vaginal orifice, and absent urethral orifice. Hypogonadotropic hypogonadism has only been reported in BBS girls. Primary gonadal failure has been seen in both sexes.
Bardet-Biedl syndrome patient with postaxial skeletal malformations: polydactyly (six digits) of both hands, partial syndactyly between fourth and fifth digits of the left hand, fifth digit clinodactyly. (From Karaman A. Bardet-Biedl syndrome: a case report. Dermatol Online J. 2008;14(1):9. With permission.)
CNS lesions such as neoplasms, head trauma, surgery, radiation, infections, and infiltrative disease can disrupt hypothalamic-pituitary function resulting in hypogonadotropic hypogonadism.
Sellar and suprasellar tumors may alter pituitary function directly and/or disrupt the hypothalamic-pituitary stalk, leading to pituitary hormone deficiencies. Craniopharyngiomas are the most common suprasellar tumors identified in children. These tumors have a benign histology with a malignant behavior, having the tendency to invade surrounding structures and to recur after what was thought to be complete resection. They frequently present as cystic structures (single or lobulated) filled with a turbid, proteinaceous material of brownish-yellow color that glitters and sparkles because of a high content of floating cholesterol crystals that has been compared to machinery oil. The tumor frequently arises in the pituitary stalk and projects into the hypothalamus. It extends voraciously along the path of least resistance (anteriorly into the prechiasmatic cistern and subfrontal spaces; posteriorly into the prepontine and interpeduncular cisterns, cerebellopontine angle, third ventricle, posterior fossa, and foramen magnum; and laterally toward the subtemporal spaces). Craniopharyngiomas account for 5% to 10% of intracranial tumors and 56% of suprasellar tumors in children and usually are diagnosed between the ages of 5 and 10 years. Affected patients present with characteristic symptoms of increased intracranial pressure (headache, nausea, and vomiting), pituitary dysfunction, and/or visual disturbance. Most children present with growth failure secondary to GH deficiency. Adolescents present with growth failure and delayed or absent sexual development, which can be overlooked until after symptoms of increased intracranial pressure develop. Some patients also have central hypothyroidism and adrenal insufficiency. The neurologic examination is suggestive of increased intracranial pressure, in the form of papilledema and visual field deficits. The radiologic hallmark of craniopharyngiomas is the appearance of suprasellar calcification on neuroimaging. If hypopituitarism were not present prior to therapy, resection of the tumor will likely disrupt the hypothalamic-pituitary communication fairly acutely. For this reason, children with a history of craniopharyngioma should be followed regularly by a pediatric endocrinologist.
Traumatic brain injury is, unfortunately, common in the adolescent population, especially in males. Necrotic, hypoxic, ischemic, and shearing lesions involving the hypothalamus and/or the pituitary are now being reported more frequently in adolescents with traumatic brain injury. Children at highest risk appear to be those who have suffered moderate or severe trauma. Clinical signs of anterior hypopituitarism are often subtle and may be masked by the sequelae of traumatic brain injury. Therefore, posttraumatic anterior pituitary dysfunction may remain undiagnosed and, possibly, aggravate symptoms of brain injury. Moreover, it may, if undiagnosed, lead to a potentially fatal adrenal crisis.
Leukemia and brain tumors account for 53% of all cancers diagnosed among children younger than 15 years. Although there are obvious differences between leukemia and brain tumors, these two childhood cancers share some important features that influence the long-term health and quality of life of survivors. Both cancers require CNS-targeted therapy. Because the peak incidence for both cancers is during a vulnerable neurocognitive developmental period, CNS-directed therapy, in particular moderate- or high-dose cranial radiotherapy, often has significant long-term consequences. This is especially true for brain tumor survivors. This knowledge has led to efforts to reduce radiation exposure in the treatment of brain tumors and to use other measures of CNS prophylaxis in the treatment of acute lymphoblastic leukemia. Radiation-induced damage to the hypothalamic-pituitary axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormone secretion.46 The frequency, rapidity of onset, and the severity of these abnormalities correlate with the total radiation dose delivered to the axis, as well as to the fraction size, younger age, prior pituitary compromise by tumor and/or surgery, and the length of follow-up. Although the hypothalamus is the primary site of radiation-induced damage, secondary pituitary atrophy evolves with time due to impaired secretion of hypothalamic tropic factors and/or time-dependent direct radiation-induced damage. Abnormalities in gonadotropin secretion are dose-dependent. Precocious puberty can occur after radiation doses less than 30 Gy in girls and in both sexes equally with a radiation dose of 30 to 50 Gy. Gonadotropin deficiency is usually a long-term complication following a minimum radiation dose of 30 Gy. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone-replacement therapy.
Inflammatory and infectious diseases of the pituitary gland are rare, and diagnosis via imaging may be difficult. They encompass a wide spectrum of pathology, including autoimmune hypophysitis, granulomatous hypophysitis, local manifestations of systemic disease, and a multitude of infectious processes (HIV, herpes simplex virus, and Mycoplasma are just a few reported). Granulomatous hypophysitis is rare, with an estimated incidence of one case per 10 million per year. It is characterized by granulomas with epithelioid histiocytes and multinucleated giant cells. Lymphocyte collections also occur, but they are not the dominant feature. It was initially thought to be a distinct entity occurring in isolation, but newer cases have been described in association with systemic conditions such as Takayasu disease, ruptured intrasellar Rathke cleft cyst, Crohn disease, thyroiditis and adrenalitis, and granulomatosis with polyangiitis (Wegener granulomatosis). Because of their ultrastructural similarity and autoimmune origin, it has been suggested that granulomatous and lymphocytic hypophysitis may have similar pathogenetic backgrounds or even may represent different stages of the same disease. Lymphocytic hypophysitis is a rare disorder predominantly affecting women usually during the ante- or postpartum period. It is characterized by destruction and lymphocytic infiltration of the pituitary gland, probably by an autoimmune process, leading to a pituitary mass lesion and/or various degrees of hypopituitarism. The lesion is usually confined to the adenohypophysis. Posterior pituitary gland or stalk involvement is rare, although patients presenting with diabetes insipidus have been reported. The clinical presentation and radiologic findings may mimic those of a pituitary adenoma, with a firm diagnosis established only after biopsy with histologic examination.
Diagnosis, evaluation, andnatural history
Random measurement of various puberty-related hormones has been attempted to distinguish idiopathic normosmic hypogonadotropic hypogonadism from CDGP, including FSH, LH, and testosterone.31 However, this approach may not be effective because of significant overlap between patients with an immature hypothalamic-pituitary axis and those with permanent gonadotropin deficiencies. A peak serum LH less than 10 mIU/mL after GnRH stimulation (100 μg IV) differentiated patients with hypogonadotropic hypogonadism from those with CDGP with a sensitivity of 82% and a specificity of 98% in adolescents older than 14 years. Recently, however, a baseline serum inhibin Bconcentration of less than 35 pg/mL in males ages 14 to18 years with testicular volumes less than 3 mL was shown to provide 100% sensitivity and specificity in the diagnosis of hypogonadotropic hypogonadism. However, the sensitivity and specificity was lower when evaluating boys with testicular volumes of 3 to 6 mL.
Table 3-8.Hypogonadotropic vs Hypergonadotropic Hypogonadism ||Download (.pdf) Table 3-8. Hypogonadotropic vs Hypergonadotropic Hypogonadism
Isolated GnRH deficiency
KAL1, FGFR1, FGF8, PROKR2, PROK2, NELF, CHD7, HS6ST1, WDR11
Idiopathic hypogonadotropic hypogonadism
GnRH receptor, GPR54, LHB, FSHB, TAC3R, TAC3, NROB1
Leptin, leptin receptor, PC1 (+ obesity)
Adrenal hypoplasia congenita
Pituitary transcription factor deficiency PROP1, HESX1
Suprasellar/sellar solid tumors
Granulomatosis with polyangiitis (Wegener)
X chromosome abnormalities
Turner syndrome (45,X)
Swyer syndrome (46,XY)
Mixed gonadal dysgenesis (46,XX/46,XY)
Pure ovarian agenesis (46,XX)
Fragile X premutation
Blepharophimosis ptosis epicanthus inversus syndrome
FSH β-subunit gene mutation
FSH or LH receptor gene mutations
LH receptor gene mutation
If the patient is found to have permanent hypogonadotropic hypogonadism, the history and physician examination should narrow the differential. A family or patient history of hypogonadism and/or absent or reduced sense of smell might indicate isolated gonadotropin deficiency. An abnormal perinatal history, with any of the following, should alert one to the possibility of a pituitary transcription factor abnormality: micropenis, hypoglycemia, cleft lip/palate, bifid uvula, prolonged jaundice, giant cell hepatitis, hypotension, and/or electrolyte disturbance. History and physical examination identify any of the syndromic etiologies for hypogonadotropic hypogonadism. Low tone with poor feeding during infancy and delayed development, along with rapid weight gain and polyphagia after 2 years, may indicate PWS. Pulmonic stenosis and short stature suggest Noonan syndrome. A perinatal history of choanal atresia or childhood history of coloboma could be indicative of CHARGE syndrome. Progressive vision loss in a child with postaxial polydactyly or renal disease is indicative of BBS. Signs or symptoms of increased intracranial pressure point toward the possibility of an intracranial tumor. A history of traumatic brain injury may result in pituitary insufficiency many years after the event and should alert the physician to the possibility of hypopituitarism. Last, a history of prior brain (especially hypothalamic) cancer and/or radiation to that area of the brain should alert to the possibility of gonadotropin deficiency.
Commercial genetic analyses may be applied to confirm some of the syndromes associated with hypogonadotropic hypogonadism. For example, DNA methylation analysis is the test of choice for PWS. Additionally, evaluation of the PTPN11 gene, mutations of which are present in approximately 50% of patients with Noonan syndrome, should also be considered at least for uncertain cases.
An MRI of the brain with contrast dye enhancement in a closed-tube system should be obtained in all patients with hypogonadotropic hypogonadism. Abnormalities of the olfactory placode indicate Kallmann syndrome (Figure 3-22). Congenital malformations of the anterior or posterior pituitary, congenital lesions of septum pellucidum and corpus callosum, as well as acquired tumors or infiltrative lesions may also be identified with MRI.
(A) A coronal T1-weighted image of a male with Kallmann syndrome (KS) showing (abnormal) medially oriented olfactory sulci (black arrows) and normal-appearing olfactory bulbs (white arrows). (B) An axial T1-weighted image of the same male with KS showing the presence of olfactory sulci (white arrows). (C) A coronal T1-weighted image of a female with IHH showing normal olfactory bulbs (large arrows) and sulci (small arrows). (D) A coronal T1-weighted image of a female with KS showing lack of olfactory bulbs with shallow olfactory sulci (arrows). (From Quinton R, Duke VM, de Zoysa PA, et al. The neuroradiology of Kallmann’s syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab. 1996;81:3010-3017. With permission.)
The basic principles of hormonal treatment of permanent hypogonadism, either hypo- or hypergonadotropic varieties, are the same.
Therapy for boys is aimed at replacement of testosterone in a stepwise fashion, targeted at mimicking normal physiology. Therefore, in boys with hypogonadism, as well as for those with CDGD, intramuscular testosterone is begun in a similar manner, but for those with permanent hypogonadism, there will need to be continued administration with increases of 50 mg made over a 2- to 3-year period. Using this approach, most adult men receive 200 to 300 mg every 2 to 4 weeks. This dosing is based on the daily adult male testosterone production rate of 6 mg. Once reaching final adult height, older adolescent boys can take testosterone transdermally by patch or gel.
Therapy for girls with permanent hypogonadism is typically initiated with daily low-dose estrogen therapy alone for 1 to 2 years. This can be in the form of any number of equivalent estrogen preparations. Conjugated equine estrogens (eg, Premarin) have traditionally been used at 0.3 mg daily for the first 6 months, 0.625 mg daily for the second 6 months, followed by 0.6 to 1.2 mg starting in the second year. Ethinyl estradiol (eg, Estrace) has also been used with replacement at 0.02 mg for the first 6 months, followed by 0.1 mg daily for the second 6 months, and 0.2 mg thereafter. Transdermal estradiol preparations (eg, Vivelle dot) are also available and are advanced slowly throughout the following 2 years to a total daily dose of 0.025 to 0.1 mg/day. Although it is not clear that cutting patches reliably allow the necessary dose escalation, serum estradiol levels can be measured to guide the clinician with ongoing dosing decisions. The initial duration of unopposed estrogen, if not exceeded, for 1 to 2 years does not appear to expose the uterus to any undue risk for endometrial hyperplasia and/or malignancy. At the end of the first few years, cyclical progesterone must be added. The two options include oral medroxyprogesterone (eg, Provera) and micronized progesterone (eg, Prometrium). Medroxyprogesterone at10 mg or micronized progesterone at 200 mg is provided on days 20 to 30 of the cycle. With this approach, withdrawal bleeding generally occurs in the following 3 to 10 days, although there can be some variability between patients. Another option is to provide progesterone on days 100 to 120 of the cycle to minimize menstruation. Alternatively, at adult dosing, the aforementioned estrogendelivery methods are often abandoned in favor of a more conventional oral contraceptive or substituted with a weekly estrogen patch used in conjunction with oral progesterone. There are also oral contraceptive agents (eg, Seasonale) that decrease the frequency of menstruation to quarterly intervals.
Patients of either sex with hypogonadotropic hypogonadism are potentially fertile, but sex steroid therapy alone will not ordinarily be sufficient to initiate gametogenesis, although there are rare cases in men in which testosterone replacement alone has stimulated spermatogenesis, presumably by local intratesticular action on the seminiferous tubules. Thus, the typical approach to fertility induction is pump-administered GnRH therapy (assuming an intact pituitary gland) or parenteral combination gonadotropin treatment (synthetic LH/hCG and recombinant FSH) if the pituitary is nonfunctioning, supervised by an experienced reproductive endocrinologist.