Normal Physiology of Puberty and Adrenarche

Puberty is the transitional period between the juvenile state and adulthood, characterized by attainment of secondary sex characteristics and reproductive capability. The control center of puberty is comprised of hypothalamic GnRH neurosecretory neurons (pulse generator) located in the medial basal hypothalamus [King et al., 1985]. Kisspeptin (product of the KISS 1 gene) and the kisspeptin receptor (KISS1R), also known as GPR54 (a member of the rhodopsin family of G protein coupled receptors), have emerged as key regulators of the hypothalamic-pituitary-gonadal (HPG) axis [de Roux et al., 2003; Seminara et al., 2003]. Kisspeptin neurons found in the hypothalamus directly innervate and stimulate GnRH neurons. Kisspeptin neurons also express the estrogen receptor and the androgen receptor, which enable negative feedback action of sex steroids. Kisspeptin signaling in the brain is critical for triggering and guiding the tempo of sexual maturation at puberty [Oakley et al., 2009]. In addition, the tachykinin neurokinin B (encoded by TAC3) and its receptor NK3R (encoded by TACR3) also serve as central regulators for normal gonadatropin secretion and pubertal development [Topaloglu et al., 2009].

Puberty is not a sudden event, but rather reflects a milestone on a continuum that begins before birth. The GnRH pulse generator becomes pulsatile by midgestation, and remains active in early infancy until about 6 months of age in boys and 12–24 months in girls [Grumbach, 2002]. Between late infancy and the onset of puberty, the GnRH pulse generator becomes relatively quiescent as a consequence of an as yet poorly defined central nervous system (CNS) inhibitory mechanism. After a quiescent period of approximately 10 years, the GnRH pulse generator is disinhibited, leading to increased amplitude and frequency of LH and FSH secretion, and resulting in increased sex steroid production (principally, estradiol and testosterone) and attainment of physical puberty [Grumbach, 2002].

Adrenarche refers to the prepubertal rise of adrenal androgen precursors – in particular, dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) – as a consequence of maturation of the zona reticularis of the adrenal cortex. DHEA can be converted peripherally to testosterone; thus, adrenarche is typified clinically by mild androgenic effects, such as a change in body odor and the appearance of axillary and pubic hair and acne. The mechanisms that regulate adrenarche are not well understood. Adrenache is independent of the maturation of the hypothalamic-pituitary-gonadal axis, preceding the onset of puberty by about 2 years [Miller, 1999].

The normal age of onset of secondary sexual characteristics (defined as 2.5 SD on either side of the mean, or where approximately 99 percent of the population falls) is 6–13 years in girls and 9–14 years in boys. The appearance of secondary sexual characteristics, acceleration of growth, and the capacity of reproduction are hallmarks of puberty. The development of puberty is characterized by sequential events that are specific for each gender. In females, secondary sexual characteristics include breast development, the appearance of pubic and axillary hair, maturation of the labia, and estrogenization of the vaginal mucosa. The development of pubic and axillary hair is influenced by androgens produced in both the adrenal cortex (adrenarche) and the ovary. Menarche usually occurs 2–3 years after initiation of breast development. The pubertal growth spurt, which normally occurs in the early stages of puberty for girls, can result in a gain in height of 25 cm or more. In males, puberty begins with testicular enlargement (≥ 2.5 cm in the longest dimension) followed by the appearance of sexual hair and phallic enlargement. The growth spurt occurs during midpuberty, which results in an average 28 cm gain in height [Grumbach and Styne, 2003]. Abnormalities of puberty include sexual precocity and delayed or arrested puberty, each with a broad differential diagnosis. While pubertal disorders can arise from defects at the level of the hypothalamus, pituitary, or gonads, the focus of this discussion is on hypothalamic and pituitary causes of sexual precocity and delayed puberty.

Sexual Precocity

Sexual precocity is usually defined as the development of secondary sexual characteristics before 6–7 years of age in girls [Herman-Giddens et al., 1997], and before 9 years of age in boys. In all cases thus far described, sexual precocity results from an increase in circulating sex steroids. An endocrine approach to the differential diagnosis of sexual precocity would include consideration of exogenous and endogenous sources of these steroids. Endogenous sources include the gonads and adrenal cortex, either of which may secrete sex steroids inappropriately as the result of a primary process intrinsic to these tissues, or secondary to a circulating stimulatory factor. As previously noted, this chapter will focus only on hypothalamic/pituitary causes of sexual precocity.

Precocious puberty (sometimes referred to as “true” or “central” precocious puberty) is defined as early puberty specifically resulting from premature reactivation of the GnRH pulse generator. Precocious puberty most commonly is idiopathic, but can result from a broad range of abnormalities, including CNS tumors, hamartoma of the tuber cinereum, congenital malformations, subarachnoid cysts, CNS infection, irradiation, and trauma. The incidence of precocious puberty is significantly higher in females. In studies of girls with precocious puberty, idiopathic precocious puberty ranges from 63 to 74 percent [Pescovitz et al., 1986; Cisternino et al., 2000]. In contrast, only 6 percent of boys with precocious puberty are idiopathic [Pescovitz et al., 1986]. Idiopathic precocious puberty is a diagnosis of exclusion and it is, thus, essential to search for underlying neurological causes. Tumors involving in the posterior hypothalamus, such as glioma, germinoma, and teratoma, can cause precocious puberty. Most of these tumors are thought to trigger early puberty by interfering with mechanisms that normally inhibit the GnRH pulse generator. Few LH/FSH-secreting adenomas have been reported [Demura et al., 1977]. Hamartoma of the tuber cinereum, a congenital malformation, can cause central precocious puberty. Hamartomas are small lesions (4–25 mm), may be sessile or pedunculated, and usually do not enlarge with time (Figure 97-2). Histologically, they appear to be composed of normal brain tissue and contain GnRH secretory neurons, which may serve as an “ectopic pulse generator” [Mahachoklertwattana et al., 1993]. In some hypothalamic harmatomas, the production of transforming growth factor (TGF)-α can initiate early puberty by activating the normal GnRH pulse generator [Jung et al., 1999]. Hamartomas of the tuber cinereum are often associated with gelastic (laughing) seizures. Recently, an autosomal-dominant activating mutation in GPR54 was found in a girl with central precocious puberty [Teles et al., 2008].

Fig. 97-2 Hamartoma of the tuber cinereum in a 3-year-old girl by magnetic resonance imaging.

Note a small (6-mm × 6-mm), pedunculated and isointense hypothalamic mass in the sagittal view. The patient had midpubertal breast development, and an advanced bone age of 6 years at a chronologic age of 3 years.

Ectopic human chorionic gonadotropin (hCG)-secreting tumors in the CNS (and elsewhere), e.g., hypothalamic germinomas, can cause sexual precocity in boys [Sklar et al., 1981]. Such patients do not have central precocious puberty, in that they do not have premature reactivation of the hypothalamic GnRH pulse generator. Rather, the ectopic hCG interacts with the LH/hCG receptor on testicular Leydig cells, resulting in increased testosterone secretion and virilization. In girls, ovarian estrogen secretion requires both LH and FSH. Thus, ectopic secretion of hCG alone causes sexual precocity only in boys [Grumbach and Styne, 2003]. The accurate diagnosis of precocious puberty and its cause requires a detailed history, physical examination, hormonal testing, and imaging studies of the CNS. Idiopathic precocious puberty is often familial, exhibiting autosomal-dominant inheritance [de Vries et al., 2004]. The occurrence of early breast and pubic hair development is often seen in girls with precocious puberty, while testicular enlargement and other signs of virilization are seen in boys with precocious puberty. Hormonal analysis demonstrates increased amplitude and frequency of LH and FSH pulsatile secretion, resulting from increased pulsatile secretion of GnRH. This finding can be demonstrated either by serial sampling of LH and FSH or by single LH/FSH measurements using highly sensitive immunochemiluminescent assays. Dynamic testing using GnRH or a GnRH agonist is also used routinely to diagnose precocious puberty. Magnetic resonance imaging (MRI), with particular attention to the hypothalamic-pituitary area, should be carried out in any child diagnosed with precocious puberty.

Delayed or Arrested Puberty

Delayed puberty may be defined, in boys, by the absence of testicular enlargement by 14 years of age, and in girls, by the absence of breast development by 13 years of age. The differential diagnosis of delayed puberty can be divided into three major categories: constitutional delay in growth, hypogonadotropic hypogonadism, and hypergonadotropic hypogonadism. Constitutional delay in growth, the most common cause of delayed puberty, is a normal variant, and is thought to result from a prolonged quiescent period of the GnRH pulse generator. Such patients often have a family history of delayed puberty and have delayed skeletal maturation without evidence of endocrinopathy or other organic diseases. Hypergonadotropic hypogonadism, which indicates a defect at the level of the gonads, will not be reviewed in this section. Hypogonadotropic hypogonadism indicates a defect at the level of the hypothalamus or pituitary, and may result from a variety of CNS disorders that can lead to delayed or absent puberty. Hypogonadotropic hypogonadism can be congenital or acquired, can occur alone or in association with multiple hypothalamic and pituitary hormone deficiencies, and may be organic or functional in etiology.

Hypogonadotropic Hypogonadism Associated with Multiple Hypothalamic/Pituitary Hormone Deficiencies

Hypogonadotropic hypogonadism can also present in combination with other hypothalamic/pituitary hormone deficiencies. Human mutations of pituitary transcription factors known to cause delayed puberty include Prop-1 and Lhx3. Prop-1 (prophet of Pit-1) is a paired-like homeodomain transcription factor expressed only in the anterior pituitary. Combined pituitary hormone deficiencies caused by mutations in Prop-1 occur with an incidence of about 1 in 8000 births. Patients with mutations in Prop-1 have combined pituitary hormone deficiencies, which may include deficiencies of GH, PRL, TSH, and gonadotropins. Such patients have hypogonadotropic hypogonadism in association with short stature and hypothyroidism [Wu et al., 1998]. Lhx3 is a LIM-type homeodomain protein. Mutations in Lhx3 have been associated with anterior pituitary hypoplasia and complete deficits of GH, PRL, TSH, and gonadotropins. Lhx3 mutations are also associated with decreased range of motion in the cervical spine [Netchine et al., 2000].

Other genetic factors that lead to delayed puberty include mutations of prohormone convertase (PC)1, leptin, and leptin receptor genes. A defect in PC1 has been shown to disrupt GnRH processing, and results in hypogonadotropic hypogonadism and obesity associated with impaired processing of insulin and POMC. Mutations in leptin and the leptin receptor are associated with a similar clinical picture of hypogonadotropic hypogonadism, hyperinsulinemia, and obesity [Kalantaridou and Chrousos, 2002; Beier and Dluhy, 2003]. Congenital midline defects of the CNS, such as septo-optic dysplasia (SOD), empty sella syndrome, and Rathke’s cyst, are often associated with hypothalamic/pituitary dysfunction, which may include hypogonadotropic hypogonadism. The genetics of SOD and its related pituitary hormone deficiencies will be reviewed in detail in the section on hypothalamic/pituitary disorders of statural growth.

Numerous CNS lesions can lead to hypogonadotropic hypogonadism, including CNS tumors (primarily, third ventricular), CNS infection, invasive diseases, cranial irradiation, and trauma. These CNS disorders often present with combined anterior and posterior pituitary hormone deficiencies. CNS tumors of the sella and parasellar region associated with multiple hypothalamic/pituitary hormone deficiencies include craniopharyngioma, pituitary adenomas, optic and hypothalamic gliomas, and germ-cell tumors. Delayed or arrested puberty is the second most common presenting symptom of CNS tumors following headache. Craniopharyngiomas, the most common tumor of the sella and parasellar region in children, are slow-growing, space-occupying tumors (Figure 97-3). Most patients present before their teenage years with headache, visual loss, and multiple hypothalamic/pituitary hormone deficits. Pituitary adenomas in children usually present as microadenomas with pituitary hormone hypersecretion. Nonsecreting adenomas in children are rare, and are usually macroadenomas. Prolactinoma is the most common pituitary adenoma in the pediatric population and frequently is associated with delayed or arrested puberty. Nonsecreting macroadenomas can also cause delayed puberty, at least in part, through elevation of prolactin as a consequence of stalk compression [Kunwar and Wilson, 2001]. Cranial irradiation to the third ventricular area also may be associated with hypogonadotropic hypogonadism.

Fig. 97-3 Craniopharyngioma in a child by magnetic resonance imaging.

Note a large suprasellar mass elevating the floor of the third ventricle.

Normal Biochemistry and Physiology of Prolactin

PRL was identified in humans in the early 1970s after the lactogenic acitivity of GH was blocked by GH antiserum. PRL is a 199-amino-acid peptide synthesized in lactotroph cells, which constitute 15–25 percent of functioning anterior pituitary cells. PRL has homology to GH and placental lactogen in its structure and function. Regulation of prolactin secretion is distinct from that of other anterior pituitary hormones. PRL is the only pituitary hormone that is regulated predominantly by the hypothalamus through an inhibitory mechanism mediated by dopamine via the hypothalamic-pituitary-portal circulation. Other inhibitory factors include TGF-β and endothelin-1, thought to act via paracrine mechanisms. Stimulatory factors include TRH, oxytocin, and vasoactive intestinal polypeptide (VIP). The principal physiologic functions of PRL are enhanced mammary gland development during pregnancy and lactation. PRL may be increased through physiologic and pathologic mechanisms. Physiologic stimuli include pregnancy, lactation, stress, sleep, and exercise. Pathologic causes of hyperprolactinemia include prolactinomas, injury to the hypothalamic-pituitary stalk secondary to tumors or other CNS disease (infiltration, granuloma, irradiation, trauma), a variety of systemic disorders, including chronic renal failure and cirrhosis, and a variety of drugs ranging from dopamine receptor blockers and dopamine synthesis inhibitors to oral contraceptives.

Clinical Features and Management of Hyperprolactinemia

The principal clinical feature of hyperprolactinemia, regardless of the cause, is galactorrhea, which may be unilateral or bilateral. Other clinical features may include delayed or arrested puberty, amenorrhea in females, and gynecomastia in males. Prolactinoma is the most common tumor of the pituitary, comprising about 50 percent of anterior pituitary adenomas. Most prolactinomas are less than 1 cm in diameter, i.e., microprolactinomas, and normally do not cause significant mass effects. However, with macroprolactinoma, headache and visual disturbance can be the first presenting symptoms. Rarely, patients with macroprolactinoma present with hydrocephalus, cranial nerve palsies, and seizures [Colao et al., 1998].

If a prolactinoma is diagnosed, therapeutic options include medical management with dopamine agonists, surgery, and adjunctive radiotherapy. While medical management is often considered the principal intervention, numerous reports indicate that microprolactinomas can be removed surgically, though with variable recurrence rates. Macroprolactinomas are less likely to be cured surgically and often require chronic dopamine agonist treatment. Dopamine agonists are effective and safe pharmacologic interventions for both micro- and macroprolactinoma [Pivonello et al., 2004; Verhelst et al., 1999]. Cabergoline is better tolerated and more effective than bromocriptine [Di Sarno et al., 2001]. Withdrawal of cabergoline after long-term therapy has been safe, although careful monitoring of tumor progression is necessary [Colao et al., 2003]. Nearly all prolactinomas have been reported to respond to cabergoline treatment, irrespective of tumor size and preceding treatment with higher doses (>3 mg/week) [Ono et al., 2008]. Adjunctive radiotherapy has been considered beneficial in some patients with macroprolactinoma. The skill and experience of the surgeon clearly play a role in determining the optimal treatment and outcome.

Adrenocorticotropic Excess

Excessive production of ACTH from the pituitary arises either from CRH overproduction or from a primary ACTH-producing adenoma (Cushing’s disease). The first sign of Cushing’s disease in a growing child is often impaired linear growth [Mindermann and Wilson, 1995]. Other classic signs and symptoms of Cushing’s disease include excessive weight gain (central obesity), buffalo hump, plethora, “moon facies,” acne, striae, hypertension, hirsutism, fatigue, pubertal delay or arrest, bruising, and headache [Magiakou et al., 1994; Devoe et al., 1997; Magiakou and Chrousos, 2002]. Usually, at the time of diagnosis, ACTH-producing adenomas are significantly smaller than other pituitary adenomas (Figure 97-4). These tumors are usually not well demarcated, and are often less than 10 mm in diameter (microadenoma).

Fig. 97-4 Adrenocorticotropic hormone-secreting pituitary adenoma in a 15-year-old girl by magnetic resonance imaging.

A, A crescent-shaped, hypodense area is indicated by the arrow in the coronal view. B, A 3-mm × 2-mm hypodense nodule in the inferior aspect of the pituitary is indicated by the arrow in the sagittal view.

The diagnosis of Cushing’s disease can pose significant challenges. Endogenous hypercortisolism is either ACTH-dependent or ACTH-independent. Of the ACTH-dependent causes, a pituitary adenoma (Cushing’s disease) is most common. A less common ACTH-dependent cause is ectopic ACTH production associated with a variety of extrapituitary neoplasms. ACTH-independent causes of hypercortisolism are rare in the pediatric population. Biochemical evidence of hypercortisolism can be demonstrated by 24-hour urine collections for free cortisol. Patients with hypercortisolism will demonstrate loss of normal diurnal variation in plasma cortisol and ACTH. A single midnight serum cortisol value has been reported to distinguish Cushing’s syndrome effectively from a pseudo-Cushing condition (e.g., exogenous obesity, depression, stress) [Papanicolaou et al., 1998]. The principal challenge in the differential diagnosis of Cushing’s syndrome is distinguishing Cushing’s disease from ectopic ACTH production. In general, patients with Cushing’s disease show suppression of cortisol and ACTH with dexamethasone administration (20 μg/kg every 6 hours for 2 days). However, up to 20 percent of patients with Cushing’s disease do not suppress under these conditions. An MRI of the hypothalamic/pituitary area should be obtained if Cushing’s disease is suspected, though small adenomas may not be visualized [Magiakou et al., 1994; Devoe et al., 1997].

Trans-sphenoidal resection of pituitary adenomas has emerged as the treatment of choice for Cushing’s disease [Devoe et al., 1997]. Due to small size, some of these tumors are difficult to identify intraoperatively. The recurrence rate after surgery is about 15–25 percent, even in the hands of skilled neurosurgeons. Radiotherapy has been shown to be effective for unsuccessful trans-sphenoidal surgery [Estrada et al., 1997]. Other therapeutic options for recurrent Cushing’s disease include repeated pituitary exploration, bilateral adrenalectomy, and the use of pharmacologic agents that directly impair cortisol synthesis and secretion.

Adrenocorticotropic Hormone Deficiency

Secondary adrenal insufficiency is defined as hypocortisolism as a consequence of ACTH deficiency. Secondary adrenal insufficiency can be isolated or occur as part of multiple hypothalamic/pituitary deficiencies; such deficiencies can be idiopathic or associated with structural malformations or various CNS diseases, as previously discussed in the section on gonadotropin deficiency. Chronic suppression of CRH and ACTH by long-term glucocorticoid therapy also can result in secondary adrenal insufficiency.

Isolated ACTH deficiency is a rare cause of secondary adrenal insufficiency, due to either CRH deficiency or a primary decrease in ACTH production by corticotrophs. Clinical presentation is highly variable. Neonatal onset of isolated ACTH deficiency usually presents with sudden, severe episodes of hypoglycemia, sometimes with seizure and coma. Neonates may also present with prolonged cholestatic jaundice. Death may occur if treatment is not initiated promptly. Over 70 percent of these patients have a loss-of-function mutation in the TPIT gene, which encodes a transcription factor that is expressed specifically in corticotrophs and is required for expression of POMC, the precursor of ACTH [Pulichino et al., 2003; Vallette-Kasic et al., 2003, 2007]. Other genetic factors leading to isolated ACTH deficiency remain to be elucidated, since later-onset, isolated ACTH deficiency can occur peripubertally [Bremer et al., 2008]. As noted, ACTH deficiency can be associated with multiple hypothalamic/pituitary hormone deficiencies. The genetic basis of some forms of combined pituitary hormone deficiencies has been elucidated. As previously noted, mutations in Prop-1 can present with GH, PRL, TSH, gonadotropin, and ACTH deficiencies [Agarwal et al., 2000]. ACTH deficiency also is found in patients who have mutations in the Lhx4 gene, which is closely related to Lhx3, as described in the section on delayed puberty. Mutations in either Lhx3 or Lhx4 also can lead to deficiencies in both GH and TSH [Machinis et al., 2001]. CNS tumors involving the third ventricular area, such as craniopharyngioma, germinoma, and astrocytoma, can cause multiple pituitary deficiencies, including ACTH deficiency. In addition, ACTH deficiency with other pituitary hormone deficiencies can be seen in a variety of CNS disorders, including infection, invasive disease, irradiation, congenital malformation, and trauma. Long-term glucocorticoid therapy, e.g., in patients with chronic inflammatory and autoimmune diseases, will often suppress the HPA axis.

Cortisol (hydrocortisone) replacement is based on studies of the cortisol secretory rate in the pediatric population [Linder et al., 1990; Kerrigan et al., 1993; Metzger et al., 1993]. During periods of significant stress, such as febrile illness and surgery, such patients are managed routinely with a temporary increase in glucocorticoids (given orally or parenterally) at doses up to 50 mg/m²/day of hydrocortisone.

Growth Hormone Deficiency

The incidence of GH deficiency is estimated to be as high as 1:3480 in the United States [Lindsay et al., 1994]. Children with congenital GH deficiency are of normal size at birth. However, after approximately 6 months of life, growth failure becomes apparent when linear growth becomes GH-dependent. Usually, children with GH deficiency are short and cherubic, with a doll-like appearance. Approximately 10–20 percent of G- deficient patients present with severe hypoglycemia in addition to short stature. In the neonatal period, hypoglycemia and microphallus strongly suggest GH deficiency.

While abnormalities can occur at any level of the GHRH-GH-IGF-I axis, the majority of these abnormalities occur at the hypothalamic/pituitary level. In fact, most patients with GH deficiency (80–90 percent) are GHRH-deficient, and are capable of secreting GH in response to exogenous GHRH. As with gonadotropins or ACTH, a deficiency of GH may be isolated or associated with other hypothalamic/pituitary hormone abnormalities. GH deficiency may be idiopathic, genetic, or associated with a variety of CNS disorders (midline developmental defect syndrome, tumors, infection, irradiation, and trauma), and may occur in association with significant emotional deprivation.

Isolated GH deficiency is rarely due to a GH gene deletion. About 3–30 percent of cases with isolated GH deficiency (IGHD) have a genetic etiology. Most of these genetic defects remain elusive, with 11 percent of the mutations being reported in GH1 and GHRHR genes [Alatzoglou et al., 2009]. Mutations in the homeobox gene Rpx/Hesx1 are associated with septo-optic dysplasia, also known as de Morsier’s syndrome, a common midline malformation. This syndrome is characterized by the classical triad of optic nerve hypoplasia, midline malformations (such as agenesis of the corpus callosum and absence of the septum pellucidum), and pituitary hypoplasia with consequent panhypopituitarism. Mutations in Rpx/Hesx1 also can cause isolated GH deficiency. However, more commonly, these mutations found in pituitary transcription factors cause multiple hormonal deficiencies and congenital midline defects. The phenotypes of mutations in the Rpx/Hesx1 gene are highly variable, ranging from isolated GH deficiency without any midline defects, to the complete spectrum of the disease with panhypopituitarism [Thomas et al., 2001].

Evaluation of a child with suspected GH deficiency includes a thorough history, physical examination, and careful review of growth charts and laboratory studies. Severe neonatal hypoglycemia is suggestive of GH deficiency. Most children with GH deficiency will have not only short stature, but also a subnormal height velocity with relative preservation of weight and head circumference. The diagnosis of GH deficiency is often difficult to make with a single blood test, in view of the pulsatile nature of GH secretion. GH-dependent IGF-I, and IGF binding protein (BP) 3 levels, and provocative tests of GH secretion have been used widely to evaluate GH status. If a diagnosis of GH deficiency is made, it is essential to evaluate all anterior and posterior pituitary hormones, and to obtain a cranial MRI with particular attention to the third ventricular area.

The principal treatment of children with GH deficiency is recombinant synthetic GH. Typically, GH is administered as a daily subcutaneous injection, though long-acting preparations either are already prescribed or are in clinical trials in some parts of the world. Some children with GH deficiency on the basis of GHRH deficiency have been treated successfully with GHRH. Adequacy of treatment is determined by assessment of growth velocity and serum IGF-I and IGF-BP3 levels. Recent studies demonstrate beneficial effects of continued GH treatment (at lower doses) after final height is reached in adolescents with permanent GH deficiency. GH treatment occasionally is associated with side effects, such as increased intracranial pressure, hyperglycemia, and slipped femoral capital epiphysis.

Growth Hormone Excess

GH excess can lead to tall stature (gigantism) in children, who have open epiphyses, and acromegaly in adolescents, who have closed epiphyses. Gigantism is a rare condition caused by GH oversecretion, primarily due to increased GH production from the pituitary [Abe and Ludecke, 1999; Kunwar and Wilson, 1999]. GH-producing adenomas constitute up to 10 percent of pituitary adenomas [Kunwar and Wilson, 2001]. Ectopic GHRH overproduction is a rare cause of GH excess [Thorner et al., 1982]. In addition, McCune–Albright syndrome can present with gigantism. The constitutively active G proteins in somatotrophs can result in a rise in cAMP, leading to increased GH secretion in patients with McCune–Albright syndrome [Geffner et al., 1987; Cuttler et al., 1989].

Accelerated longitudinal growth and acromegalic features (enlarged head, large hands and feet, big tongue, and broad nose) are the most prominent signs of GH excess. In girls, menstrual irregularity is common. Mass effect of the tumor can cause impaired vision and headache due to increased intracranial pressure. Some patients also may have hyperprolactinemia as a result of an adenoma from somatolactotrophs. A diagnosis of pituitary gigantism is made by demonstrating nonsuppressible GH in response to glucose infusion, in association with elevated IGF-I and IGF-BP3 levels. Usually, cranial MRI will reveal a pituitary mass.

The goal of treatment in GH-secreting adenomas is normalization of GH and IGF-I levels. Trans-sphenoidal surgery has resulted in a greater than 80 percent cure rate, and thus remains the first choice of treatment. If surgery is unsuccessful, somatostatin analogs, GH antagonists, and dopamine agonists can be used. Long-term studies have shown a clear advantage to using a long-acting-release somatostatin analog over a slow-release analog, which can be used as first-line treatment should the patient prefer medication over surgery [Colao et al., 2009]. Radiotherapy may be beneficial.

Normal Thyroid Physiology

Under regulation by the hypothalamus and pituitary, the thyroid gland produces thyroxine (T4) and triiodothyronine (T3), which have broad effects on metabolism, general growth, and CNS development [Anderson et al., 2000]. Embryonic development of the hypothalamic-pituitary-thyroid (HPT) axis begins during the first trimester, marked by significant concentrations of TRH in the hypothalamus, the median eminence, and the supraoptic tract. The thyroid gland forms as an invagination of endoderm at the base of the tongue, and descends along the midline to its final position anterior to the second to fourth tracheal cartilage rings [Fisher and Brown, 2000]. Maturation of the human HPT axis is a complex process, involving ontogenesis of hypothalamic TRH, pituitary TSH, and thyroid hormone secretory processes, as well as maturation of their respective receptors, and of pituitary iodothyronine monodeiodinase enzyme activities [Fisher and Brown, 2000]. TSH is a heterodimeric glycoprotein consisting of alpha and beta subunits. The alpha subunit is common to TSH, LH, FSH, and hCG, while the beta subunit confers specificity. TSH acts on the thyroid gland to stimulate thyroid hormone synthesis and secretion. TSH is negatively regulated by thyroid hormones and positively regulated by TRH. Thyroid hormone signaling is mediated by specific nuclear receptors that regulate the expression of target genes at the levels of transcription and protein synthesis [Anderson et al., 2000]. Over 90 percent of circulating T4 and T3 is bound to thyroid binding proteins (thyroid-binding globulin, transthyretin, and albumin) [Refetoff, 1989]. T4 serves largely as prohormone, which is converted peripherally to the more potent T3 [Anderson et al., 2000].

Central Hypothyroidism

Central (hypothalamic/pituitary) hypothyroidism is rare in comparison to primary hypothyroidism, and may be congenital or acquired. Signs and symptoms associated with hypothyroidism may arise insidiously and are often nonspecific. In the neonatal period, newborns may have lethargy, hypotonia, hypothermia, or prolonged jaundice. Untreated hypothyroidism during infancy and early childhood can result in developmental delay, mental retardation, and poor statural growth. Presenting symptoms in older children include weight gain, subnormal height velocity, constipation, cold intolerance, hoarse voice, dry skin, and lethargy.

Congenital TSH deficiency occurs in 1:50,000–150,000 newborns [Fisher and Grueters, 2008]. Underlying etiologies include isolated TSH deficiency, developmental defects of the hypothalamus and pituitary, and familial panhypopituitarism. Patients with congenital TSH deficiency are usually not detected by neonatal screening for hypothyroidism, as most programs are designed to screen for the hyperthyrotropinemia that accompanies the more primary hypothyroidism.

Isolated TSH deficiency is usually autosomal-recessive. Mutations in the TSH beta subunit prevent formation of the active TSH heterodimer [Hayashizaki et al., 1989, 1990; McDermott et al., 2002; Karges et al., 2004]. TSH deficiency in combination with other pituitary hormone deficiencies is seen frequently in patients with HESX1, PIT-1, and PROP-1 mutations. As described previously in the sections on disorders of statural growth and puberty, these genes are pituitary transcription factors that are critical for pituitary development. In addition, isolated central hypothyroidism can result from a loss-of-function mutation in the TRH receptor [Collu et al., 1997].

Acquired central hypothyroidism may result from CNS insults, including tumors invading the third ventricular area, irradiation, infection and trauma. Acquired central hypothyroidism usually is associated with multiple hypothalamic/pituitary hormone deficiencies.

With respect to laboratory assessment of thyroid function, it is critical to recognize that normal ranges vary significantly with age [Nelson et al., 1993]. In particular, TSH and free T4 are relatively high in newborns in comparison to older infants, children, and adolescents. The principal goals of treating central hypothyroidism are prevention of mental retardation and growth impairment. Thus, thyroxine replacement should be instituted promptly following diagnosis of hypothyroidism, regardless of etiology.

Central Hyperthyroidism

Most cases of hyperthyroidism in the pediatric population are autoimmune and TSH-independent. Central hyperthyroidism as a consequence of a pituitary TSH-secreting adenoma is exceedingly rare [Tolis et al., 1978]. Such patients may have a prominent local mass effect of the tumor, such as loss or partial loss of vision from optic atrophy, and may have hydrocephalus. Other signs and symptoms of hyperthyroidism, such as agitation, tall stature, goiter, tremor, and palpitation, also are manifested in central hyperthyroidism. Biochemically, patients with central hyperthyroidism have elevated concentrations of TSH in the context of elevated T4 and T3. If a pituitary adenoma is not identifiable on imaging studies, rare selective pituitary T3 resistance should be considered. Surgical removal of the tumor is the treatment of choice for TSH-secreting pituitary adenoma. However, the treatment of selective pituitary T3 resistance remains a therapeutic challenge.

Diabetes Insipidus

DI may result from a deficiency of AVP or from nephrogenic causes [Baylis and Cheetham, 1998; Robinson and Verbalis, 2003; Verbalis, 2003]. Nephrogenic DI may be congenital, resulting from inactivating mutations in the V2R gene, or from autosomal-recessive or dominant lesions in the AQP-2 gene; or acquired, resulting from a variety of conditions, including some forms of primary renal disease, obstructive uropathy, hypokalemia, hypercalcemia, sickle cell disease, and a variety of drugs, including lithium and demeclocycline [Baylis and Cheetham, 1998; Morello and Bichet, 2001; Robinson and Verbalis, 2003; Verbalis, 2003; Spanakis et al., 2008]. Prolonged polyuria of any cause can result in some degree of nephrogenic DI secondary to a reduction of tonicity in the renal medullary interstitium and a subsequent decrease in the gradient necessary to concentrate the urine.

Central DI is rarely congenital and more frequently acquired. Congenital central DI may be caused by hypothalamic structural malformations and through both autosomal-dominant and recessive mutations in the AVP/NPII gene. Of the latter, the autosomal-dominant causes are more common, and are thought to be a consequence of heterozygous mutations in the AVP/NPII gene, which lead to misfolding of the precursor AVP/NPII protein [Rutishauser et al., 2002]. The dominant negative effect is thought to occur as a consequence of the misfolded precursor protein, which accumulates in the endoplasmic reticulum of vasopressinergic neurons, ultimately resulting in death of these neurons and gliosis [Rutishauser et al., 2002; Robinson and Verbalis, 2003]. In such patients, clinical DI usually develops several months to years after birth. A rare autosomal-recessive form of central DI has been reported in association with a mutation in the AVP/NPII gene, resulting in a biologically inactive AVP [Willcutts et al., 1999].

Acquired forms of DI occur in association with a variety of disorders in which there is destruction or degeneration of vasopressinergic neurons. Etiologies include primary tumors (e.g., craniopharyngioma, germinoma) or metastases, infection (meningitis, encephalitis), histiocytosis, granuloma, vascular disorders, and autoimmune disorders (lymphocytic infundibuloneurohypophysitis) [Baylis and Cheetham, 1998; Robinson and Verbalis, 2003; Verbalis, 2003]. Acquired DI may occur in association with trauma and surgery. Idiopathic DI is a diagnosis of exclusion, and one that is made with decreasing frequency concurrent with improved sensitivity of MRI of the CNS, and of cerebrospinal fluid and serum tumor markers [Mootha et al., 1997; Maghnie et al., 2000].

The principal presenting sign of DI is polyuria, which, in addition to deficiency or impaired responsiveness to AVP, may result from an osmotic agent (e.g., hyperglycemia in diabetes mellitus) or from excessive water intake (primary polydipsia). Hypernatremia usually does not occur if patients have an intact thirst mechanism, adequate access to fluids, and no additional on-going fluid losses (e.g., diarrhea). Infants with DI, in addition to polyuria and polydipsia, may be irritable and have fever of unknown origin, growth failure secondary to inadequate caloric intake, and hydronephrosis. Older children may also have nocturia and enuresis. DI may not be apparent in patients with coexisting untreated anterior pituitary-mediated adrenal glucocorticoid insufficiency, as cortisol is required to generate a normal free water loss [Robinson and Verbalis, 2003].

A diagnosis of DI can be made if screening laboratory studies reveal serum hyperosmolality concurrent with urine that is inappropriately dilute. However, as most patients with DI do not have hyperosmolality and hypernatremia, as noted above, a standardized water deprivation test is useful to distinguish DI from primary polydipsia. Urine osmolality of >750 mOsm/kg after 7–8 hours of water deprivation is thought to exclude DI [Baylis and Cheetham, 1998]. Urine osmolality in the 300–750 mOsm/kg range may indicate partial DI [Baylis and Cheetham, 1998]. If DI is suspected, a plasma sample should be obtained for AVP radioimmunoassay. AVP or a synthetic analog (desmopressin) should then be administered to distinguish AVP deficiency from AVP unresponsiveness.

Once a diagnosis of central DI is made, a brain MRI, with particular attention to the third ventricular area, should be obtained. An absent posterior pituitary “bright spot” is seen in virtually all patients with central DI. Under normal circumstances, a posterior pituitary bright spot is seen on T1-weighted images due to stored AVP in neurosecretory granules (see Figure 97-1). In patients with DI as a consequence of an autosomal-dominant mutation in the AVP/NPII gene, a posterior pituitary bright spot may be seen in the early stages of the disease [Robinson and Verbalis, 2003]. In central DI patients with an absent posterior pituitary bright spot, an otherwise normal MRI warrants close follow-up with cerebrospinal fluid tumor markers and cytology, serum tumor markers, and serial contrast-enhanced brain MRIs for early detection of an evolving occult hypothalamic-stalk lesion [Mootha et al., 1997].

In addition to treatment of a primary disease causing central DI, the drug of choice for most patients with AVP deficiency is desmopressin. This AVP analog has markedly reduced pressor activity in comparison to native AVP, has a prolonged half-life, and can be administered orally, intranasally, or by subcutaneous injection.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

SIADH is characterized by the inability to excrete a free water load, with inappropriately concentrated urine, and resultant hyponatremia, hypo-osmolality, and natriuresis [Bartter and Schwartz, 1967; Baylis, 2003; Verbalis et al., 2007]. Following from the original criteria established by Bartter and Schwartz, a diagnosis of SIADH is made when the following occur [Bartter and Schwartz, 1967]:

While most patients with SIADH have inappropriately measurable or elevated levels of plasma AVP relative to plasma osmolality, 10–20 percent of patients with SIADH do not have measurable AVP levels. This may reflect issues of assay sensitivity or may indicate a syndrome resembling SIADH, such as the recently described nephrogenic syndrome of inappropriate antidiuresis (NSIAD), associated with an activating mutation in the X-linked G-protein-coupled V2R and unmeasurable circulating levels of AVP [Feldman et al., 2005].

Euvolemia in chronic SIADH is an important distinguishing factor in the evaluation of a patient with serum hypo-osmolality, and has a bearing on treatment issues, as will be discussed subsequently. Euvolemia in chronic SIADH is thought to represent an adaptation to water overload. This adaptation is mediated, in part, at the cellular level through depletion of intracellular electrolytes (potassium) and organic osmolytes [Verbalis et al., 2007]. The loss of brain solutes is thought to allow effective regulation of brain volume during chronic hyponatremia and SIADH. Natriuresis, thought to be mediated in part through secretion of atrial natriuretic peptide, also contributes to volume regulation in chronic SIADH [Cogan et al., 1988]. Cerebral salt wasting, associated with some intracranial diseases (e.g., subarachnoid hemorrhage), is often considered in the differential diagnosis of SIADH. However, the hypo-osmolality, hyponatremia, and natriuresis in cerebral salt wasting are associated with volume contraction, which distinguishes this disorder from the euvolemic condition of SIADH [Verbalis et al., 2007].

A large number of disorders and conditions are associated with SIADH, and can be grouped into five categories:

Therapy for SIADH includes treatment of the underlying disorder (or discontinuation of an offending drug) and fluid restriction. Replacement of lost body sodium also may be necessary but usually can be achieved through normal dietary salt intake. Severe hyponatremia (serum sodium <120 mEq/L) may be associated with CNS abnormalities, including seizures, and may require treatment with hypertonic (3 percent) intravenous sodium chloride solution. Concurrent use of a diuretic, such as furosemide, may be indicated when volume expansion is severe. Other therapeutic approaches include the use of agents that induce nephrogenic DI, such as demeclocycline and lithium, although both are contraindicated, particularly in younger pediatric patients, because of untoward side effects. Urea has been used as an osmotic diuretic in pediatric SIADH and NSIAD [Huang et al., 2006]. A variety of nonpeptide V2R antagonists are currently in various stages of clinical trials or have been approved by the Food and Drug Administration for use in adults [Verbalis et al., 2007].

If SIADH and hyponatremia are acute (<48 hours), it is thought that hyponatremia can be corrected quickly. However, if SIADH and hyponatremia are chronic (>48 hours), overzealous treatment can result in CNS damage, including central pontine myelinolysis [Verbalis et al., 2007]. Brain solute loss, while an important regulatory mechanism in chronic SIADH, may predispose to the development of central pontine myelinolysis with rapid correction of serum osmolality. Generally, it is recommended that plasma sodium be corrected to a “safe” level of approximately 120–125 mEq/L, at a rate of no greater than 0.5 mEq/L per hour, with an overall correction that does not exceed 12 mEq/L in the initial 24 hours and 18 mEq/L in the initial 48 hours of treatment [Verbalis et al., 2007].