The pituitary gland is comprised of two parts with distinct origins. The anterior pituitary is derived embryonically from Rathke’s pouch of oral ectoderm, while the posterior pituitary is of neuroectoderm origin. The pituitary gland regulates endocrine target organs, such as the adrenal gland, ovary, testis, and thyroid gland. Disorders of the pituitary and hypothalamus may therefore result in disruption of any of these hypothalamic-pituitary–target organ axes. Abnormalities in end-organ hormone release caused by pituitary dysfunction are considered “secondary,” and those caused by a hypothalamic abnormality are considered “tertiary.” For example, abnormal thyroid function caused by a decrease in pituitary thyroid stimulated hormone is considered “secondary hypothyroidism” while hypothyroidism due to deficient thyrotropin-releasing factor from the hypothalamus is “tertiary hypothyroidism.” Failure of growth and failure of sexual maturation are two common presentations of hypothalamic-pituitary disease in the pediatric population. Pituitary disorders may be genetic or acquired.

The hypothalamus secretes releasing factors that travel via the portal circulation to the anterior pituitary gland and include growth-hormone releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and gonadotropin releasing hormone (GnRH). These factors stimulate or inhibit release of the six peptide hormones produced by the five distinct cell types of the anterior pituitary gland: growth hormone (GH) from somatotropes, prolactin by lactotropes, thyroid-stimulating hormone (TSH) from the thyrotropes, adrenocorticotropic hormone (ACTH) via corticotropes, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH), secreted by gonadotropes.

The posterior pituitary gland releases arginine vasopressin, also known as antidiuretic hormone (ADH), and oxytocin. The neurons that produce vasopressin originate in the paraventricular and supraoptic nuclei of the hypothalamus. For this reason, diabetes insipidus (DI) can occur with hypothalamic disease, but may not always occur with pituitary disease, even if the stalk has been transected (depending on the level of transection).

GENETIC CAUSES OF PITUITARY HORMONE DEFICIENCY

Several genetic causes of multiple pituitary hormone deficiency have been described (see online eTable 70-1), including mutations in transcription factors integral to the embryonic development of the pituitary. However, known genetic defects still explain less than 20% of hypopituitarism in humans. Congenital malformations involving the midline of the central nervous system (CNS) are associated with pituitary deficiencies. Midline defects elsewhere may alert clinicians to screen for pituitary deficiency (i.e. single central incisor, cleft lip and palate, tracheo-esophageal fistula, omphalocele and gastroschisis, and extrophy of the bladder). In the newborn, pituitary deficiency may present as hypoglycemia (due to GH and/or ACTH deficiency), micropenis (combination of GH and gonadotropin deficiency), or hyperbilirubinemia. Septo-optic-dysplasia, with optic nerve hypoplasia, is often associated with pituitary deficiencies as is holoprosencephaly and absence of the septum pellucidum. Findings on magnetic resonance imaging may include a small or absent anterior pituitary gland, an absent or ectopic posterior pituitary “bright spot,” or a transected pituitary stalk.¹

ACQUIRED CAUSES OF PITUITARY HORMONE DEFICIENCY

Mass-occupying lesions in the hypothalamic area may result in disruption of pituitary function. Tumors such as craniopharyngioma and, less commonly, germinoma and astrocytoma may first present during childhood with growth failure, DI, or visual complaints (or any combination of these). Even in cases when the tumor does not cause loss of pituitary function, surgery may render these children with panhypopituitarism. Hypothalamic hamartomas and pineal tumors are associated with precocious pubertal development during childhood.

Pituitary adenomas are rare in childhood and may or may not actively produce peptide hormones. When active, they most often secrete prolactin (50%) or GH (20%).²

Langerhans cell histiocytosis is a rare disorder that most often presents with DI, but it may also affect the production of other pituitary hormones. Inflammatory, postinfectious, and traumatic lesions of the CNS may cause hypopituitarism as well. CNS irradiation predisposes to the loss of pituitary function, depending on the dose received. Higher doses may precipitate precocious pubertal development.

Clinical signs directly related to pituitary deficiency in children include poor linear growth (GH deficiency), fatigue and malaise (TSH and ACTH deficiency), delayed pubertal development, amenorrhea, or sexual dysfunction (LH and FSH deficiency), hypotension or hypoglycemia (ACTH deficiency). Inability to regulate temperature, appetite, thirst, and vital signs may be seen in hypothalamic dysfunction. Indirect signs of central nervous system lesions, including headaches, vision changes, and other neurological disturbances, may be seen.

DIAGNOSTIC EVALUATION

Diagnosis of anterior pituitary dysfunction typically requires a combination of random hormone measurements and stimulation tests with known secretagogues specific for the pituitary hormone in question.

TSH deficiency can be diagnosed by observing low thyroid hormone (T4) with low or inappropriately normal TSH levels (distinguished from primary hypothyroidism in which TSH is elevated).

Random GH measurements can be diagnostic in the newborn period prior to establishment of the diurnal and pulsatile secretion pattern at 2 to 4 weeks of life. Levels greater than 20 ng/mL are unequivocally sufficient. After this point, or when the diagnosis is not clear, stimulation tests must be performed. Commonly used secretagogues include arginine, clonidine, and glucagon; insulin-induced hypoglycemia was considered a gold standard but is rarely used due to safety concerns. Stimulated growth hormone peaks >10 ng/mL are normal.

Diagnosis of gonadotropin deficiency can be made in the first 6 months for males and before 2 to 3 years of life for females, when the gonadotropin axis is active by measuring random LH and FSH.³ Otherwise diagnosis is generally left until pubertal age.

Secondary or tertiary adrenal insufficiency is diagnosed by observing ACTH and cortisol rise after administration of CRH (1 ug/kg intravenously). Samples for ACTH and cortisol are drawn at baseline and 30, 45, 60, and 120 min after CRH.

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  Normal: Basal ACTH increases 2- to 4-fold after CRH; peak cortisol >19 μg/dL

  
  
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  Secondary adrenal insufficiency: Basal ACTH <10 pg/mL, no response to CRH; peak cortisol <19 μg/dL

  
  
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  Tertiary adrenal insufficiency: Basal ACTH <10 pg/mL, response to CRH (60-min >10 pg/mL, 120-min >20 pg/mL)

Alternatively a low dose of ACTH (1 μg) with cortisol levels at 0, 30, and 60 minutes can be used to diagnose secondary adrenal insufficiency. Peak cortisol levels of <19 μg/dL are consistent with adrenal insufficiency.⁴

MANAGEMENT

Treatment of anterior pituitary deficiency consists of replacement of the pituitary or target gland hormone. Levothyroxine orally is used for thyroid hormone replacement, subcutaneous growth hormone for GH deficiency, testosterone or estrogen (usually during puberty, though testosterone may be given in neonates to correct micropenis) for gonadotropin deficiency. For secondary adrenal insufficiency, maintenance doses of hydrocortisone may be used, though some have sufficient function to not require daily steroid supplementation. Mineralocorticoid replacement is not needed in secondary adrenal insufficiency, as ACTH does not control the zona glomerulosa. Cortisol replacement should be undertaken prior to thyroid hormone replacement, as this may precipitate adrenal crisis.