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BACKGROUND

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).

CLINICAL PRESENTATION

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

eTABLE 70-1Genetic Causes of Multiple Pituitary Hormone Deficiencies...

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