Anterior Pituitary Insufficiency

HYPOTHALAMIC AND ANTERIOR PITUITARY INSUFFICIENCY

Hypopituitarism results from impaired production of one or more of the anterior pituitary trophic hormones. Reduced pituitary function can result from inherited disorders; more commonly, it is acquired and reflects the mass effects of tumors or the consequences of inflammation or vascular damage. These processes may also impair synthesis or secretion of hypothalamic hormones, with resultant pituitary failure

DEVELOPMENTAL AND GENETIC CAUSES OF HYPOPITUITARISM

Pituitary Dysplasia

Pituitary dysplasia may result in aplastic, hypoplastic, or ectopic pituitary gland development. Because pituitary development requires midline cell migration from the nasopharyngeal Rathke’s pouch, midline craniofacial disorders may be associated with pituitary dysplasia. Acquired pituitary failure in the newborn can also be caused by birth trauma, including cranial hemorrhage, asphyxia, and breech delivery.

Septo-Optic Dysplasia

Hypothalamic dysfunction and hypopituitarism may result from dysgenesis of the septum pellucidum or corpus callosum. Affected children have mutations in the HESX1 gene, which is involved in early development of the ventral prosencephalon. These children exhibit variable combinations of cleft palate, syndactyly, ear deformities, hypertelorism, optic atrophy, micropenis, and anosmia. Pituitary dysfunction leads to diabetes insipidus, GH deficiency and short stature, and, occasionally, TSH deficiency.

Tissue-Specific Factor Mutations

Several pituitary cell–specific transcription factors, such as Pit-1 and Prop-1, are critical for determining the development and function of specific anterior pituitary cell lineages. Autosomal dominant or recessive Pit-1 mutations cause combined GH, PRL, and TSH deficiencies. These patients present with growth failure and varying degrees of hypothyroidism. The pituitary may appear hypoplastic on magnetic resonance imaging (MRI). Prop-1 is expressed early in pituitary development and appears to be required for Pit-1 function. Familial and sporadic PROP1 mutations result in combined GH, PRL, TSH, and gonadotropin deficiency. Over 80% of these patients have growth retardation; by adulthood, all are defi- cient in TSH and gonadotropins, and a small minority later develop ACTH deficiency. Because of gonadotropin defi- ciency, they do not enter puberty spontaneously. In some cases, the pituitary gland is enlarged. TPIT mutations result in ACTH deficiency associated with hypocortisolism.

Developmental Hypothalamic Dysfunction

Kallmann Syndrome

This syndrome results from defective hypothalamic gonadotropin-releasing hormone (GnRH) synthesis and is associated with anosmia or hyposmia due to olfactory bulb agenesis or hypoplasia. The syndrome may also be associated with color blindness, optic atrophy, nerve deafness, cleft palate, renal abnormalities, cryptorchidism, and neurologic abnormalities such as mirror movements. Defects in the KAL gene, which maps to chromosome Xp22.3, prevent embryonic migration of GnRH neurons from the hypothalamic olfactory placode to the hypothalamus. Genetic abnormalities, in addition to KAL mutations, can also cause isolated GnRH deficiency, as autosomal recessive (i.e., GPR54) and dominant (i.e., FGFR1) modes of transmission have been described. GnRH deficiency prevents progression through puberty. Males present with delayed puberty and pronounced hypogonadal features, including micropenis,probably the result of low testosterone levels during infancy. Female patients present with primary amenorrhea and failure of secondary sexual development. Kallmann syndrome and other causes of congenital GnRH deficiency are characterized by low LH and FSH levels and low concentrations of sex steroids (testosterone or estradiol). In sporadic cases of isolated gonadotropin deficiency, the diagnosis is often one of exclusion after eliminating other causes of hypothalamic-pituitary dysfunction. Repetitive GnRH administration restores normal pituitary gonadotropin responses, pointing to a hypothalamic defect.

Long-term treatment of men with human chorionic gonadotropin (hCG) or testosterone restores pubertal development and secondary sex characteristics; women can be treated with cyclic estrogen and progestin. Fertility may also be restored by the administration of gonadotropins or by using a portable infusion pump to deliver subcutaneous, pulsatile GnRH..

Bardet-Biedl Syndrome

This is a rare, genetically heterogeneous disorder characterized by mental retardation, renal abnormalities, obesity, and hexadactyly, brachydactyly, or syndactyly. Central diabetes insipidus may or may not be associated. GnRH deficiency occurs in 75% of males and half of affected females. Retinal degeneration begins in early childhood, and most patients are blind by age 30. Ten subtypes of Bardet-Biedl syndrome (BBS) have been identified with genetic linkage to nine different loci. Several of the loci encode genes involved in basal body cilia function, which may account for the diverse clinical manifestations.

Leptin and Leptin Receptor Mutations

Deficiencies of leptin, or its receptor, cause a broad spectrum of hypothalamic abnormalities including hyperphagia, obesity, and central hypogonadism. . Decreased GnRH production in these patients results in attenuated pituitary FSH and LH synthesis and release.

Prader-Willi Syndrome

This is a contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN gene, the NECDIN gene, and possibly other genes on chromosome 15q. Prader-Willi syndrome is associated with hypogonadotropic hypogonadism, hyperphagiaobesity, chronic muscle hypotonia, mental retardation, and adult-onset diabetes mellitus. Multiple somatic defects also involve the skull, eyes, ears, hands, and feet. Diminished hypothalamic oxytocin- and vasopressinproducing nuclei have been reported. Deficient GnRH synthesis is suggested by the observation that chronic GnRH treatment restores pituitary LH and FSH release.

ACQUIRED HYPOPITUITARISM

Hypopituitarism may be caused by accidental or neurosurgical trauma; vascular events such as apoplexy; pituitary or hypothalamic neoplasms such as pituitary adenomas, craniopharyngiomas, lymphoma, or metastatic tumors; inflammatory diseases such as lymphocytic hypophysitis; infiltrative disorders such as sarcoidosis, hemochromatosis, and tuberculosis; or irradiation.

Increasing evidence suggests that patients with brain injury including trauma, subarachnoid hemorrhage, and irradiation have transient hypopituitarism and require intermittent long-term endocrine follow-up, as permanent hypothalamic or pituitary dysfunction will develop in 25–40% of these patients.

Hypothalamic Infiltration Disorders

These disorders—including sarcoidosis, histiocytosis X, amyloidosis, and hemochromatosis—frequently involve both hypothalamic and pituitary neuronal and neurochemical tracts. Consequently, diabetes insipidus occurs in half of patients with these disorders. Growth retardation is seen if attenuated GH secretion occurs before pubertal epiphyseal closure. Hypogonadotropic hypogonadism and hyperprolactinemia are also common.

Inflammatory Lesions

Pituitary damage and subsequent dysfunction can be seen with chronic infections such as tuberculosis, with opportunistic fungal infections associated with AIDS, and in tertiary syphilis. Other inflammatory processes, such as granulomas or sarcoidosis, may mimic the features of a pituitary adenoma. These lesions may cause extensive hypothalamic and pituitary damage, leading to trophic hormone deficiencies..

Cranial Irradiation

Cranial irradiation may result in long-term hypothalamic and pituitary dysfunction, especially in children and adolescents, as they are more susceptible to damage following whole-brain or head and neck therapeutic irradiation. The development of hormonal abnormalities correlates strongly with irradiation dosage and the time interval after completion of radiotherapy. Up to two-thirds of patients ultimately develop hormone insufficiency after a median dose of 50 Gy (5000 rad) directed at the skull base. The development of hypopituitarism occurs over 5–15 years and usually reflects hypothalamic damage rather than primary destruction of pituitary cells.Although the pattern of hormone loss is variable, GH deficiency is most common, followed by gonadotropin and ACTH deficiency.When deficiency of one or more hormones is documented, the possibility of diminished reserve of other hormones is likely. Accordingly, anterior pituitary function should be evaluated over the long term in previously irradiated patients, and replacement therapy instituted when appropriate.

Lymphocytic Hypophysitis

This often occurs in postpartum women; it usually presents with hyperprolactinemia and MRI evidence of a prominent pituitary mass often resembling an adenoma, with mildly elevated PRL levels. Pituitary failure caused by diffuse lymphocytic infiltration may be transient or permanent but requires immediate evaluation and treatment.Rarely,isolated pituitary hormone deficiencies have been described, suggesting a selective autoimmune process targeted to specific  cell types. Most patients manifest symptoms of progressive mass effects with headache and visual disturbance.The erythrocyte sedimentation rate is often elevated. As the MRI image may be indistinguishable from that of a pituitary adenoma, hypophysitis should be considered in a postpartum woman with a newly diagnosed pituitary mass before embarking on unnecessary surgical intervention. The inflammatory process often resolves after several months of glucocorticoid treatment, and pituitary function may be restored,depending on the extent of damage.

Pituitary Apoplexy

Acute intrapituitary hemorrhagic vascular events can cause substantial damage to the pituitary and surrounding sellar structures. Pituitary apoplexy may occur spontaneously in a preexisting adenoma; post-partum (Sheehan’s syndrome); or in association with diabetes, hypertension, sickle cell anemia, or acute shock. The hyperplastic enlargement of the pituitary during pregnancy increases the risk for hemorrhage and infarction. Apoplexy is an endocrine emergency that may result in severe hypoglycemia, hypotension, central nervous system (CNS) hemorrhage, and death. Acute symptoms may include severe headache with signs of meningeal irritation, bilateral visual changes, ophthalmoplegia, and, in severe cases, cardiovascular collapse and loss of consciousness. Pituitary computed tomography (CT) or MRI may reveal signs of intratumoral or sellar hemorrhage, with deviation of the pituitary stalk and compression of pituitary tissue.

Patients with no evident visual loss or impaired consciousness can be observed and managed conservatively with high-dose glucocorticoids. Those with significant or progressive visual loss or loss of consciousness require urgent surgical decompression. Visual recovery after surgery is inversely correlated with the length of time after the acute event.Therefore, severe ophthalmoplegia or visual deficits are indications for early surgery. Hypopituitarism is very common after apoplexy.

Empty Sella

A partial or apparently totally empty sella is often an incidental MRI finding. These patients usually have normal pituitary function, implying that the surrounding rim of pituitary tissue is fully functional. Hypopituitarism, however, may develop insidiously. Pituitary masses may undergo clinically silent infarction with development of a partial or totally empty sella by cerebrospinal fluid (CSF) filling the dural herniation. Rarely, small but functional pituitary adenomas may arise within the rim of pituitary tissue, and these are not always visible on MRI.

PRESENTATION AND DIAGNOSIS

The clinical manifestations of hypopituitarism depend on which hormones are lost and the extent of the hormone deficiency. GH deficiency causes growth disorders in  children and leads to abnormal body composition in adults. Gonadotropin deficiency causes menstrual disorders and infertility in women and decreased sexual function, infertility, and loss of secondary sexual characteristics in men. TSH and ACTH deficiency usually develop later in the course of pituitary failure. TSH deficiency causes growth retardation in children and features of hypothyroidism in children and in adults.The secondary form of adrenal insufficiency caused by ACTH deficiency leads to hypocortisolism with relative preservation of mineralocorticoid production. PRL deficiency causes failure of lactation.When lesions involve the posterior pituitary, polyuria and polydipsia reflect loss of vasopressin secretion. Epidemiologic studies have documented an increased mortality rate in patients with longstanding pituitary damage, primarily from increased cardiovascular and cerebrovascular disease.

LABORATORY INVESTIGATION

Biochemical diagnosis of pituitary insufficiency is made by demonstrating low levels of trophic hormones in the setting of low target hormone levels. For example, low free thyroxine in the setting of a low or inappropriately normal TSH level suggests secondary hypothyroidism. Similarly, a low testosterone level without elevation of gonadotropins suggests hypogonadotropic hypogonadism. Provocative tests may be required to assess pituitary reserve. GH responses to insulin-induced hypoglycemia, arginine, l-dopa, growth hormone–releasing hormone (GHRH), or growth hormone–releasing peptides (GHRPs) can be used to assess GH reserve. Corticotropin-releasing hormone (CRH) administration induces ACTH release, and administration of synthetic ACTH [cosyntropin (Cortrosyn)] evokes adrenal cortisol release as an indirect indicator of pituitary ACTH reserve. ACTH reserve is most reliably assessed during insulininduced hypoglycemia. However, this test should be performed cautiously in patients with suspected adrenal insufficiency because of enhanced susceptibility to hypoglycemia and hypotension. Insulin-induced hypoglycemia is contraindicated in patients with active coronary artery disease or seizure disorders.

Treatment:

HYPOPITUITARISM

Hormone replacement therapy, including glucocorticoids, thyroid hormone, sex steroids, growth hormone, and vasopressin, is usually safe and free of complications. Treatment regimens that mimic physiologic hormone production allow for maintenance of satisfactory clinical homeostasis. Patients in need of glucocorticoid replacement require careful dose adjustments during stressful events such as acute illness, dental procedures, trauma, and acute hospitalization.