Etiology

1. Neoplastic

  • Pituitary adenoma is the most common cause of hypopituitarism in adulthood.[7]

    It may be nonfunctional or secrete one or more anterior pituitary hormones.[8] Classified on size as microadenomas (<10 mm) or macroadenomas (>10 mm). Occasionally, a pituitary adenoma may appear as an incidental finding on an imaging study and is termed a pituitary incidentaloma. Pituitary incidentalomas need biochemical screening for hormone hypersecretion or hypopituitarism.[9]

  • Craniopharyngiomas account for 1% of all intracranial tumors in adults and 6% to 13% of intracranial tumors in children.[10] Rathke cysts present more often in adults, in contrast to craniopharyngiomas, which present more commonly in children.[11]

  • Other space-occupying para-pituitary tumors associated with hypopituitarism include sellar meningiomas, metastases, plasmacytomas, germ cell tumors, astrocytomas of the optic nerve, and chordomas.[12]

  • Pituitary metastases from other tumors are rare but can present as anterior hypopituitarism and diabetes insipidus.[13]

2. Vascular

  • Pituitary apoplexy is the sudden spontaneous development of a hemorrhage into or infarction of a pre-existing adenoma. Incidence is reported to be 0.6% to 9.1% of all surgically treated pituitary adenomas.[14]

  • Sheehan syndrome is infarction of the pituitary after substantial blood loss with hypotension during childbirth.[15]

  • Intrasellar aneurysms of the carotid arteries may present as sellar or suprasellar masses and lead to hypopituitarism.[16]

3. Inflammatory and infiltrative lesions[17]

  • Lymphocytic hypophysitis classically presents as a pituitary mass lesion with partial or progressive hypopituitarism, particularly in the setting of pregnancy or postpartum.[18] It is thought to be an autoimmune disease with infiltration of the pituitary by lymphocytes and plasma cells.[19]

  • Hypophysitis and hypopituitarism has been reported as a complication of anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapy with ipilimumab and tremelimumab.[20][21]

  • Hemochromatosis is characterized by iron deposition in pituitary cells.

  • Sarcoidosis, tuberculosis, and Langerhans cell histiocytosis X have all been associated with the development of hypopituitarism.[12][22][23]

4. Infection

  • Pituitary abscess formation is rare and can develop from either hematogenous spread or extension from the sinuses or meningeal sepsis.

  • Pituitary tuberculomas presenting as sellar masses are very rare.[24]

  • Fungal pituitary disease may occur as a complication of AIDS but is uncommon.[25]

5. Congenital

  • Congenital forms of hypopituitarism may be of either pituitary or hypothalamic origin. Congenital deficiencies may be of isolated hormones or multiple pituitary hormones.

  • Transcription factor defects including Pit-1, PROP1, HESX1, LHX3, and LHX4 are associated with multiple hormone deficiencies and varying degrees of inherited hypopituitarism.[26][27]

  • Mutations in PROP1 gene are the most common cause of familial and sporadic congenital pituitary hormone deficiencies.

  • Mutations in TPIT gene cause isolated adrenocorticotropic hormone (ACTH) deficiency.[28]

6. Radiation therapy

  • Deficiency of one or more pituitary hormones may follow treatment with external radiation when the hypothalamic-pituitary axis lies within the field of radiation.

7. Pituitary surgery

8. Other

  • Traumatic brain injury: deficiency of one or more pituitary hormones may follow a traumatic brain injury and is especially prevalent in younger populations.[29][30][31]

  • Empty sella syndrome.

  • Hypothalamic damage from mass lesions, infections, radiation to hypothalamus, and infiltrative disorders can all lead to deficiency of antidiuretic hormone and diabetes insipidus.

  • Chronic opiate use can lead to deficiency of gonadotropins, ACTH, and growth hormone; use of megestrol has been associated with ACTH deficiency.[32]

Pathophysiology

The sequential loss of anterior pituitary hormones secondary to a mass effect occurs with the loss of the least important hormones initially, namely, growth hormone and gonadotropins (luteinizing hormone and follicle-stimulating hormone). This is subsequently followed by the loss of more important hormones: namely, adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone.[33] The hormones least needed for survival are lost first and the ones critical for survival are preserved till later.[34]

Pituitary adenomas may present with a typical clinical syndrome, such as acromegaly, Cushing, prolactinoma, thyrotropinoma, or gonadotropinoma syndromes, resulting from hypersecretion of one or more anterior pituitary hormones. Alternatively they may present more insidiously with mass effect or with tumor expansion leading to compression of surrounding structures, including normal pituitary tissue with destruction of hormone-producing cells. Hypopituitarism resulting from pituitary adenomas is thought to be related to impaired blood flow to the normal pituitary tissue, compression of normal tissue, or interference with the delivery of hypothalamic hormones via the hypothalamus-hypophyseal portal system.

Pituitary apoplexy presents with sudden onset of an excruciating headache, visual disturbance, or ophthalmoplegia due to cranial nerve palsies (III, IV, VI).[35] Sudden onset of ACTH deficiency and subsequent cortisol deficiency is serious and can cause life-threatening hypotension, hyponatremia, and hypoglycemia. Hypopituitarism caused by pituitary infarction may develop immediately or after a delay of several years, depending on the degree of tissue destruction.[15]

Classification

Causes of hypopituitarism

This is an informal classification of hypopituitarism based on etiology.

Neoplastic

  • Anterior pituitary tumors: functional and nonfunctional

  • Posterior pituitary tumors: astrocytomas, ganglioneuromas

  • Parasellar: craniopharyngiomas, Rathke cleft cysts, meningiomas, gliomas, metastases, germ cell tumors, chordomas

  • Lymphoma

  • Pituitary metastases

Vascular

  • Pituitary apoplexy

  • Sheehan syndrome

  • Vascular anomalies: aneurysms

  • Subarachnoid hemorrhage

Inflammatory/infiltrative disorders

  • Lymphocytic hypophysitis (Simmond syndrome)

  • Hypophysitis related to anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapy

  • Hemochromatosis, Langerhans cell histiocytosis X

  • Granulomatosis diseases: granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), sarcoidosis

Infections

  • Abscesses

  • Tuberculosis, syphilis, mycoses

Congenital

  • Familial isolated or multiple hormone deficiencies

  • Mutations of transcription factors involved in pituitary gland development (Pit-1, PROP-1, HESX1, LHX3, LHX4, TPIT)

  • Septo-optic dysplasia and other midline syndromes

  • Prader-Willi syndrome, Bardet-Biedl syndrome

Postradiation

  • Pituitary, parasellar, nasopharyngeal, craniospinal tumors

Postsurgical

  • Post-transsphenoidal resection of pituitary adenomas, post-aneurysm repair

Miscellaneous

  • Traumatic brain injury

  • Empty sella syndrome

  • Hypothalamic diseases

  • Medications (e.g., opioids, megestrol)

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