What is hypophysitis?

What is Hypophysitis

Hypophysitis is an inflammatory condition of the pituitary gland that typically results in pituitary hormone deficiencies and pituitary enlargement, requiring lifelong hormone replacement therapy in most cases. 1

Definition and Classification

Hypophysitis represents inflammation of the pituitary gland that can be classified in several ways 2, 3:

• Primary hypophysitis: Most commonly lymphocytic, granulomatous, or xanthomatous disease with an underlying autoimmune etiology 2, 4
• Secondary hypophysitis: Results from systemic diseases, immunotherapy (particularly immune checkpoint inhibitors), infections, or other sellar pathologies 2, 5
• Anatomical classification: Based on which part of the pituitary is affected (adenohypophysitis, infundibuloneurohypophysitis, or panhypophysitis) 3

Clinical Presentation

The most common presenting symptoms include 6, 1:

• Headache: Occurs in approximately 85% of patients 6, 7
• Fatigue: Present in 66% of cases 6, 7
• Visual disturbances: Due to mass effect on the optic chiasm, though less common than headache 6, 1
• Symptoms of hormone deficiencies: Including hypothyroidism, adrenal insufficiency, and hypogonadism 6

A critical pitfall is that visual changes are actually uncommon despite the proximity to the optic chiasm, so their absence should not exclude the diagnosis. 6

Hormonal Deficiencies

Hypophysitis causes various patterns of anterior pituitary hormone deficiency 6, 1:

• Central hypothyroidism: Present in over 90% of cases, characterized by low TSH with low free T4 6
• Central adrenal insufficiency: Found in the majority of patients, often presenting with low cortisol and ACTH 6, 1
• Panhypopituitarism: Occurs in approximately 50% of patients, involving adrenal insufficiency plus hypothyroidism plus hypogonadism 6
• Diabetes insipidus: A less common manifestation, occurring in only about 7% of cases 1

Etiology and Risk Factors

The incidence of hypophysitis has dramatically increased over the past decade, primarily due to 3, 5:

• Immune checkpoint inhibitor therapy: The most significant modern cause, with incidence varying by agent 6, 1:

  • Anti-CTLA-4 monotherapy (ipilimumab): 1-17% depending on dose (1% at 3 mg/kg, up to 17% at 10 mg/kg) 6
  • Combination ipilimumab/nivolumab: 8-13% 6, 1
  • Anti-PD-1/PD-L1 monotherapy: Very rare, approximately 1% 6, 1

• Lymphocytic hypophysitis: The most common histological subtype of primary hypophysitis, primarily affecting pregnant women 1

• IgG4-related hypophysitis: An increasingly recognized form that occurs frequently in men and is associated with systemic IgG4 disease 1, 3

The median time from starting ipilimumab to diagnosis is 8-9 weeks, typically after the third dose, which is crucial for monitoring. 6

Diagnostic Approach

Diagnosis requires a combination of clinical, biochemical, and imaging findings 1, 7:

Mandatory Laboratory Evaluation

• Morning hormonal panel (obtained before administering steroids to avoid interference): ACTH and cortisol at 9 AM, TSH and free T4, LH, FSH, testosterone (in men), estradiol (in premenopausal women), IGF-1, and prolactin 1, 7
• Glucose and HbA1c for glycemic monitoring 7

Imaging Requirements

• MRI of the sella with pituitary cuts is mandatory, showing characteristic findings of symmetrical pituitary enlargement and homogeneous enhancement after gadolinium 7, 5

Diagnostic Confirmation Criteria

The diagnosis can be confirmed without biopsy using two pathways 1, 7:

1. At least one pituitary hormone deficiency (TSH or ACTH deficiency required) plus MRI abnormality, OR
2. At least two pituitary hormone deficiencies (TSH or ACTH deficiency required) plus headache and other symptoms

A common pitfall is that serum anti-pituitary antibodies have limited diagnostic value due to low sensitivity and specificity, and should not be relied upon for diagnosis. 2, 4

Management Principles

Hormone Replacement Therapy

Physiological hormone replacement is the cornerstone of management, not high-dose steroids. 1, 8

• Hydrocortisone 20/10 mg daily should be initiated first if morning cortisol is low 1, 8
• Levothyroxine 50-100 mcg/day should be started only after ensuring adequate cortisol replacement (at least 1 week later) to prevent adrenal crisis 1, 8
• Lifelong hormone replacement is required in most patients, as hormonal deficiencies rarely recover 8, 5

High-Dose Steroids

High-dose steroids are reserved for specific indications 1, 8:

• Severe neurological symptoms: IV methylprednisolone 1 mg/kg daily for severe headache with visual disturbances, hypotension, or severe electrolyte disturbances 8
• Moderate symptoms without mass effect: Oral prednisolone 0.5-1 mg/kg daily 8

A critical caveat is that high-dose steroids help reduce mass effect but do not reverse hormonal deficiencies, which require lifelong replacement. 1, 8

Surgical Intervention

Surgery should be limited to specific cases 1, 9:

• Severe compressive symptoms with progressive deterioration
• Lack of response to medical treatment with progressive visual deterioration
• The standard transnasal approach is preferred 1

Immunosuppressive Therapies

When glucocorticoids and/or surgery fail 1, 9:

• Rituximab is the most commonly used immunosuppressant, with successful response in approximately two-thirds of patients 1
• Other options include azathioprine, methotrexate, cyclosporine A, and mycophenolate 1, 9

Patient Safety Measures

All patients with adrenal insufficiency must 1, 8:

• Obtain and wear a medical alert bracelet
• Receive education on "sick day" rules for stress dosing
• Have a prescription for emergency intramuscular steroid use

Prognosis

Most patients require lifelong hormone replacement therapy, as pituitary function rarely recovers spontaneously. 8, 4 The condition can be fatal if adrenal crisis from central adrenal insufficiency is not recognized and treated promptly 3, 4.