Hypopituitarism

Neoplastic

Pituitary adenoma is the most common cause of hypopituitarism in adulthood.[3] These may be non-functional, or secrete one or more anterior pituitary hormones.[13] Classified on size as micro-adenomas (<10 mm) or macro-adenomas (>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.[14]
Craniopharyngiomas account for 1% of all intracranial tumours in adults and 6% to 13% of intracranial tumours in children.[15] Rathke's cleft cysts (benign fluid-filled lesions originating from the remnants of the Rathke's pouch) are more commonly diagnosed in adults than in children.[16]
Other space-occupying para-pituitary tumours associated with hypopituitarism include sellar meningiomas, metastases, plasmacytomas, germ cell tumours, astrocytomas of the optic nerve, and chordomas.[17]
Pituitary metastases from other tumours are rare but can present as anterior hypopituitarism and diabetes insipidus.[18][19]

Vascular

Pituitary apoplexy is the sudden spontaneous development of a haemorrhage into, or infarction of, a pre-existing adenoma. Between 2% and 12% of cases in patients with pituitary adenoma are complicated by apoplexy.[20][21]
Sheehan syndrome is infarction of the pituitary after substantial blood loss with hypotension during childbirth.[22][23]
Intrasellar aneurysms of the carotid arteries may present as sellar or suprasellar masses and lead to hypopituitarism.[24]

Inflammatory and infiltrative lesions

Lymphocytic hypophysitis classically presents as a pituitary mass lesion with partial or progressive hypopituitarism, particularly in the setting of pregnancy or postpartum.[25][26] It is thought to be an autoimmune disease with infiltration of the pituitary by lymphocytes and plasma cells.[27]
Hypophysitis and hypopituitarism has been reported as a complication of immune checkpoint inhibitor immunotherapy (e.g., ipilimumab, tremelimumab).[28][29][30][31]
Haemochromatosis is characterised by iron deposition in pituitary cells.
Sarcoidosis, tuberculosis, and Langerhans cell histiocytosis X have all been associated with the development of hypopituitarism.[17][32][33]

Infection

Pituitary abscess formation is rare and can develop from either haematogenous spread or extension from the sinuses or meningeal sepsis.
Pituitary tuberculomas presenting as sellar masses are very rare.[34][35]
Fungal pituitary disease may occur as a complication of AIDS, but is uncommon.[36]

Congenital

Congenital forms of hypopituitarism may be of either pituitary or hypothalamic origin.
Congenital deficiencies may be of isolated hormones or multiple pituitary hormones.[37]
Transcription factor defects including Pit-1, PROP1, HESX1, LHX3, and LHX4 are associated with multiple hormone deficiencies and varying degrees of inherited hypopituitarism.[38][39]
Mutations in PROP1 gene are the most common cause of familial and sporadic congenital pituitary hormone deficiencies.
Mutations in the TBX19 gene (also known as TPIT) cause isolated adrenocorticotrophic hormone (ACTH) deficiency.[40]

Radiotherapy

Deficiency of one or more pituitary hormones may follow treatment with external radiation when the hypothalamic-pituitary axis lies within the field of radiation.
In patients with pituitary adenoma, radiotherapy is associated with new or worsening pituitary hormone deficits at 5 years in 30% to 50% and 10% to 40% of patients treated with conventional radiotherapy and stereotactic radiosurgery, respectively.[41]

Pituitary surgery

The risk of new hypopituitarism after pituitary adenoma surgery varies from approximately 5% to 25%.[42][43] Aetiology and surgeon experience inform risk.

Other

Traumatic brain injury: deficiency of one or more pituitary hormones may follow a traumatic brain injury and is especially prevalent in younger populations.[44][45][46]
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 opioid use can lead to deficiency of gonadotrophins, ACTH, and growth hormone; use of megestrol has been associated with ACTH deficiency.[47]

The sequential loss of anterior pituitary hormones secondary to a mass effect occurs with the loss of hormones least necessary for survival first, namely, growth hormone and gonadotrophins (luteinising hormone and follicle-stimulating hormone).[47] This is followed by the loss of hormones more critical for survival: namely, adrenocorticotrophic hormone (ACTH) and thyroid-stimulating hormone.[47]

Pituitary adenomas may present with a typical clinical syndrome, such as acromegaly, Cushing, prolactinoma, thyrotrophinoma, or gonadotrophinoma syndromes, resulting from hypersecretion of one or more anterior pituitary hormones. Alternatively, they may present more insidiously with mass effect or tumour 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).[48] Sudden onset of ACTH deficiency and subsequent cortisol deficiency is serious and can cause life-threatening hypotension, hyponatraemia, and hypoglycaemia. Hypopituitarism caused by pituitary infarction may develop immediately or after a delay of several years, depending on the degree of tissue destruction.[22]

Causes of hypopituitarism

This is an informal classification of hypopituitarism based on aetiology.

Neoplastic

Anterior pituitary tumours: functional and non-functional
Posterior pituitary tumours: astrocytomas, ganglioneuromas
Parasellar: craniopharyngiomas, Rathke's cleft cysts, meningiomas, gliomas, metastases, germ cell tumours, chordomas
Lymphoma
Pituitary metastases

Vascular

Pituitary apoplexy
Sheehan syndrome
Vascular anomalies: aneurysms
Subarachnoid haemorrhage

Inflammatory/infiltrative disorders

Lymphocytic hypophysitis (Simmond syndrome)
Hypophysitis related to anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapy
Haemochromatosis, Langerhans cell histiocytosis X
Granulomatosis diseases: granulomatosis with polyangiitis (formerly known as Wegener's 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

Post-radiation

Pituitary, parasellar, nasopharyngeal, craniospinal tumours

Post-surgical

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

Miscellaneous

Traumatic brain injury
Empty sella syndrome
Hypothalamic diseases
Drugs (e.g., opioids, megestrol)

Pathophysiology

Classification

Causes of hypopituitarism