eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hypopituitarism

Author: Lawrence A Wetterau, MD, Assistant Professor, Section of Endocrinology, Children's Hospital Central California
Contributor Information and Disclosures

Updated: May 5, 2009

Introduction

Background

Hypopituitarism is a partial or complete insufficiency of pituitary hormone secretion, which may derive from pituitary or hypothalamic disease. Onset can occur in children or adults; underlying causes and clinical presentation vary considerably with age. The focus of this article is childhood-onset hypopituitarism.

A brief review of pituitary anatomy, development, and physiology facilitates comprehension of childhood-onset hypopituitarism.

The pituitary gland, located at the base of the brain, is comprised of anterior (ie, adenohypophysis) and posterior (ie, neurohypophysis) regions. The anterior pituitary is an ectodermal structure that derives from the pharynx as the Rathke pouch. The anterior pituitary synthesizes and releases the following hormones into systemic circulation:

• Growth hormone (GH)
• Adrenocorticotropic hormone (ACTH)
• Thyroid-stimulating hormone (TSH)
• Luteinizing hormone (LH)
• Follicle-stimulating hormone (FSH)
• Prolactin (PRL)

The anterior pituitary is primarily regulated by neuropeptide-releasing and release-inhibiting hormones produced in the hypothalamus. These regulatory hormones are transported to the anterior pituitary via the pituitary portal system circulation. The release-stimulating hormones include growth hormone–releasing hormone (GHRH), corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH). In some instances, other peptides may also have a regulatory influence as is the case for antidiuretic hormone (ADH), which acts synergistically with CRH to promote ACTH release. PRL secretion is regulated by dopamine, which inhibits its release.

Additionally, a negative feedback loop occurs such that the hormones produced in the target glands inhibit the release of their respective regulatory pituitary and hypothalamic factors. For example, hypothalamic TRH stimulates TSH release, which, in turn, stimulates the thyroid gland resulting in increased serum levels of thyroxine (T4) and triiodothyronine (T3). When they have reached sufficient levels, T3 and T4 suppress further TRH and TSH release.

The posterior pituitary consists of neural tissue that descends from the floor of the third ventricle. In contrast to the anterior pituitary hormones, the posterior pituitary hormones (ie, ADH, oxytocin) are synthesized by cell bodies in the hypothalamus and transported along the neurohypophyseal tract of the pituitary stalk. Release of these hormones occurs in response to neurohypophyseal stimuli.

Intrinsic pituitary disease (or any process that disrupts the pituitary stalk or damages the hypothalamus) may produce pituitary hormone deficiency.

The clinical presentation of hypopituitarism widely varies, depending on patient age and on the specific hormone deficiencies that may occur singly or in various combinations. As a general rule, diagnosis of a single pituitary hormone deficiency requires evaluating the other hormone axes.

Pathophysiology

Hypopituitarism has multiple possible etiologies; the pathophysiology depends on the underlying cause (see Causes). The common endpoint is disrupted synthesis or release of one or more pituitary hormones, resulting in clinical manifestations of hypopituitarism.

Frequency

United States

Multiple pituitary hormone deficiency (MPHD) is rare in childhood, with a possible incidence of fewer than 3 cases per million people per year. The most common pituitary hormone deficiency, growth hormone deficiency (GHD), is much more frequent; a United States study reported a prevalence of 1 case in 3480 children.

International

A Scottish survey of 48,000 school-aged children reported a prevalence of 1 case of GHD in 4000 children.

Mortality/Morbidity

Morbidity and mortality generally relate to the underlying cause of hypopituitarism. Morbidity and mortality are minimal when pituitary insufficiency is recognized properly and appropriate hormone replacement (including stress doses of hydrocortisone, when indicated) is instituted. However, failure to recognize and treat clinical manifestations of hypopituitarism can result in significant sequelae.

• Hypoglycemia can cause convulsions; persistent severe hypoglycemia can cause permanent CNS injury.
• During periods of significant stress, an untreated ACTH deficiency can lead to profound hypotension, severe shock, and death.
• Short stature caused by hypopituitarism can have significant psychosocial consequences.
• Hypopituitarism appears to shorten life expectancy. In 1990, Rosen and Bengtsson reported a series of 333 consecutive cases of hypopituitarism diagnosed from 1956-1987 in patients who received routine hormone replacement.¹ Overall mortality was significantly increased in age-matched and sex-matched populations and was attributed to cardiovascular causes. GHD was believed to be an important contributing factor.

Race

Hypopituitarism exhibits no specific racial predilection.

Sex

Hypopituitarism exhibits no specific predilection for either sex.

Age

Because hypopituitarism has both congenital and acquired forms, the disease can occur in neonates, infants, children, adolescents, or adults.

Clinical

History

Clinical presentation of hypopituitarism, which widely varies, depends on the patient's age, etiology, and the specific hormone deficiencies, which may occur as isolated deficiencies or in various combinations of multiple pituitary hormone deficiency (MPHD). Presenting signs and symptoms may develop insidiously and can be nonspecific, requiring a high index of suspicion.

• Hypopituitarism in neonates
  • Most neonates with hypopituitarism have normal or even high birth weights and lengths and no history of intrauterine growth retardation.
  • Neonates (particularly those with MPHD) often have histories of breech presentation, although the explanation for this is unclear.
  • Presenting features in newborns may include hypoglycemia, prolonged jaundice, history of a complicated neonatal course, hyponatremia, and small genitalia.
  • Signs of hypoglycemia may be nonspecific and include lethargy, jitteriness, pallor, cyanosis, apnea, and convulsions.
  • Jaundice may be secondary to indirect hyperbilirubinemia (as occurs in thyroid stimulating hormone [TSH] axis deficiency) or to direct hyperbilirubinemia (as occurs in growth hormone [GH] or adrenocorticotropic hormone [ACTH] axis deficiencies).
  • Neonates with hypopituitarism may have undergone several evaluations to exclude sepsis or for unexplained apnea, hypotension, or temperature instability. Consider hypopituitarism as a possible diagnosis when these conditions occur in a full-term infant.
  • Hyponatremia unassociated with hypovolemia and unresponsive to fluid restriction occurs in infants with hypopituitarism. In contrast to the hyponatremia that occurs with the salt-losing crisis of 21-hydroxylase deficiency, serum potassium levels are typically low or within the reference range. The hyponatremia resolves with physiologic corticosteroid replacement.²
  • Microgenitalia may result from a gonadotropin deficiency or from GH deficiency.
• Hypopituitarism in older infants and children
  • Common presenting features include growth failure, disorders of pubertal development, and diabetes insipidus.
  • Hypoglycemia, although less frequent, can also be a presenting sign of hypopituitarism in older infants and children.
  • Growth failure may be the most common presenting symptom in this age group, possibly with an associated delay in tooth development.
  • Patients with acquired or milder forms of gonadotropin deficiency who do not present with microgenitalia in infancy may present later with absent or delayed puberty.
  • Central diabetes insipidus secondary to antidiuretic hormone (ADH) deficiency can be difficult to recognize in infancy because patients often present with nonspecific signs (eg, irritability, unexplained fever).
  • Symptoms of polyuria and polydipsia are more readily obvious in older children.
  • Patients with hypothyroidism secondary to a TSH axis deficiency present with signs and symptoms identical to those of primary hypothyroidism, although typically less severe. These include fatigue, cold intolerance, constipation, dry skin, slow growth, and weight gain.
• Depending on the etiology of the hypopituitarism, associated findings in the neonate, infant, or child may include developmental delay, various visual and neurologic symptoms, and a number of congenital malformation syndromes.
  • Optic nerve hypoplasia warrants careful follow-up of linear growth and consideration of pituitary hormone testing.
  • Anencephaly is associated with variable pituitary hypoplasia and complete absence of the hypothalamus.
  • Various forms of holoprosencephaly may be associated with hypopituitarism.
  • Patients with acquired hypopituitarism, caused by a suprasellar tumor, often present with headaches, visual disturbances, and other neurologic symptoms.

Physical

• Neonates
  • Birth weights and lengths are typically within the reference range.
  • Important physical signs in the neonate that may suggest a diagnosis of hypopituitarism include microgenitalia, jaundice, and physical evidence of possible hypoglycemia (ie, jitteriness, pallor).
  • Microgenitalia includes micropenis (which has a well-documented association with hypopituitarism) and an underdeveloped clitoris. Micropenis is defined as stretched penile length less than 2.5 cm (reference range mean length is 4 cm). Data on normal clitoral size, including that for different gestational ages, are also available.
  • Optic nerve hypoplasia is associated with hypopituitarism; the presence of small pale optic disks or nystagmus should prompt consideration of hypopituitarism.
• Older infants and children
  • Growth failure (see Media file 1) is the most important sign to recognize in hypopituitarism. Growth failure may often exist for a considerable period of time before it is recognized. In addition to short stature and abnormal growth rate, the affected child may show evidence of delayed skeletal maturation (eg, delayed dental development).
    
    

    

    The left photograph shows an untreated 21-month-old girl with congenital hypopituitarism. The right panel depicts the same child aged 29 months, following 8 months of growth hormone therapy.

    [ CLOSE WINDOW ]

    

    The left photograph shows an untreated 21-month-old girl with congenital hypopituitarism. The right panel depicts the same child aged 29 months, following 8 months of growth hormone therapy.

  • Weight gain typically is out of proportion to growth, resulting in relative obesity. This obesity is truncal in distribution; skull and head circumference growth are typically preserved, producing the impression of a large head.
  • Craniofacial features of pituitary growth hormone deficiency (GHD) include craniofacial disproportion (ie, normal head circumference, small facies, prominent forehead, frontal bossing). The presence of a central incisor is an important finding because it may represent hypopituitarism in a midline CNS abnormality.
  • During physical examination, pay particular attention to pubertal development because patients with hypopituitarism may present with microgenitalia in infancy or with delayed or absent puberty.
  • Visual and neurologic abnormalities may represent important features associated with hypopituitarism. When not recognized in infancy, optic nerve hypoplasia may be noted in childhood as decreased visual acuity. Signs that may indicate the potential presence of a suprasellar mass include decreased visual acuity, visual field defects, papilledema, and/or optic atrophy.
  • Anosmia, particularly in a patient with delayed or absent puberty, should prompt consideration of Kallmann syndrome (KS).

Causes

Mutations in pituitary transcription factors can cause multiple or isolated pituitary hormone deficiency. Mutations in PIT1 and PROP1 (ie, prophet of Pit-1) were the first shown to cause MPHD. Pit-1 is a homeobox transcription factor expressed in the anterior pituitary during early fetal development and throughout life. Mutations in the PIT1 gene produce a phenotype consisting of deficiencies of GH, prolactin (PRL), and TSH. PROP1 is expressed before Pit-1 and is a prerequisite for the expression of Pit-1. Inactivating mutations of PROP1 cause deficiencies of LH, follicle-stimulating hormone (FSH), GH, PRL, and TSH. Clinical phenotypes of MPHD patients with PROP1 defects, determined by the pattern of hormone deficiency, can vary considerably even among patients with the same mutation.

HESX1 and KAL are two additional genes for which mutations have been found to cause pituitary abnormalities. Homozygous inactivating mutations in HSEX1 produce a complex phenotype with pituitary hypoplasia that resembles septo-optic dysplasia (SOD). Most cases of SOD remain sporadic without a known genetic defect and much remains to be learned about the role of HESX1 in other forms of hypopituitarism.

KAL plays a causative role in some forms of KS. KS is a rare syndrome consisting of hypogonadotropic hypogonadism and anosmia. Cases may be sporadic or familial with X-linked, autosomal recessive, and autosomal dominant forms being reported. The X-linked form is caused by a KAL gene defect and is characterized by failure of gonadotropin-releasing hormone (GnRH) secretion caused by the failure of GnRH neurons to migrate normally from the olfactory bulb to the hypothalamus. KAL gene defects are only responsible for a small percentage of other familial cases as well as some sporadic cases. Defects in autosomal genes that have yet to be identified are thought to be likely to account for most familial (and presumably sporadic) cases of KS.

In the past several years, several novel transcription factor gene alterations have been reported as a cause of congenital pituitary hormone deficiencies. In addition to the above, these include mutations in LHX3, LHX4, TPIT, and PTX2.

Congenital etiologies

• Perinatal insults (eg, traumatic delivery, birth asphyxia)
• Genetic disorders
  • Isolated GHD types IA, IB, II, III
  • MPHD (eg, PIT1, PROP1 gene mutations)
  • Septo-optic dysplasia
  • KS
• Developmental CNS defects
  • Anencephaly
  • Holoprosencephaly
• Pituitary aplasia or hypoplasia
  • Interrupted pituitary stalk
  • Absent or ectopic neurohypophysis
  • Pallister-Hall syndrome

Acquired etiologies

• Cranial irradiation
• Infiltrative disorders
  • Histiocytosis X
  • Tuberculosis
  • Sarcoidosis
  • Lymphocytic hypophysitis
• Hemochromatosis
• Tumors (eg, sellar, suprasellar, pineal)
  • Craniopharyngioma (most common)
  • Germinoma
  • Glioma/astrocytoma
  • Pituitary adenoma (rare prior to adulthood)

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