What is the management and treatment of hypophysitis?

Management and Treatment of Hypophysitis

Immediate Management Priority

The cornerstone of hypophysitis management is physiologic hormone replacement therapy, not high-dose steroids—reserve high-dose steroids exclusively for severe neurological symptoms from mass effect (severe headache, visual disturbances, or adrenal crisis). 1, 2

Diagnostic Confirmation Before Treatment

Required Testing (Morning, ~8 AM)

• Pituitary hormone panel: TSH, free T4, ACTH, cortisol (or 1 mcg cosyntropin stimulation test), FSH, LH, testosterone (men), estradiol (women), IGF-1, prolactin 3, 1
• MRI of sella with pituitary cuts to identify characteristic findings: pituitary enlargement, stalk thickening, suprasellar convexity, heterogeneous enhancement 3
• Complete testing BEFORE administering steroids to avoid masking hormonal deficiencies 3

Diagnostic Criteria

• ≥1 pituitary hormone deficiency (TSH or ACTH required) + MRI abnormality, OR 3, 1
• ≥2 pituitary hormone deficiencies (TSH or ACTH required) + headache/symptoms 3, 1

Treatment Algorithm by Severity

Grade 1-2: Mild to Moderate Symptoms (No Mass Effect)

Physiologic hormone replacement is the primary treatment:

1. Start hydrocortisone 20/10 mg daily FIRST if morning cortisol is low or ACTH deficiency confirmed 1, 2

   • Critical: Always initiate cortisol replacement at least 1 week before thyroid hormone to prevent adrenal crisis 1, 2
   • All patients require medical alert bracelet, "sick day rules" education, and emergency IM steroid prescription 1, 2

2. Add levothyroxine 50-100 mcg/day only after adequate cortisol replacement established 1

   • Monitor TSH and free T4 every 1-2 weeks initially 1

3. Replace other deficient hormones as indicated (testosterone, estradiol) 3

4. Continue immune checkpoint inhibitor therapy in most cases 3

Grade 3-4: Severe Symptoms (Mass Effect or Adrenal Crisis)

Immediate intervention required:

1. IV methylprednisolone 1 mg/kg daily for severe headache with visual disturbances, hypotension, or severe electrolyte disturbances 2

   • Alternative: Oral prednisolone 0.5-1 mg/kg daily for moderate symptoms 2

2. Withhold immune checkpoint inhibitor immediately 2

3. Taper steroids gradually under close monitoring:

   • Grade 2: taper over 2-4 weeks 2
   • Grade 3-4: taper over 4 weeks 2
   • Goal maintenance dose: 5 mg prednisolone 2

4. Initiate physiologic hormone replacement concurrently (hydrocortisone, then levothyroxine) 1, 2

Surgical Intervention

Reserve surgery for specific indications only:

• Severe compressive symptoms with progressive deterioration 1
• Lack of response to medical treatment with progressive visual deterioration 1
• Preferred approach: Standard transnasal route 1

Refractory Cases: Immunosuppressive Therapy

When glucocorticoids and/or surgery fail:

• Rituximab is first-line immunosuppressant with successful response in approximately two-thirds of patients 1
• Alternative agents: azathioprine, methotrexate, cyclosporine A, mycophenolate 1, 4

Long-Term Management

Prognosis and Monitoring

• Lifelong hormone replacement required in most cases—hormonal deficiencies rarely recover 3, 2
• Both adrenal insufficiency and hypothyroidism represent permanent sequelae in the majority of patients 3
• MRI abnormalities typically resolve within 2 months, but hormonal deficiencies persist 3

Follow-up Schedule

• Monitor ACTH and cortisol: monthly for 6 months, then every 3 months for 6 months, then every 6 months for 1 year 3
• Monitor TSH and free T4 before each treatment cycle 3

Critical Pitfalls to Avoid

1. Never start thyroid hormone before cortisol replacement—this precipitates adrenal crisis 1, 2
2. Do not use high-dose steroids routinely—they do not reverse hormonal deficiencies and are only for mass effect symptoms 3, 1, 2
3. Do not delay hormone replacement while awaiting MRI—treat based on clinical and biochemical findings if imaging delayed 3
4. Recognize that low TSH with low free T4 suggests central (pituitary) etiology, not primary thyroid disease 3

Context-Specific Considerations

Immune Checkpoint Inhibitor-Induced Hypophysitis

• Highest incidence with combination anti-PD(L)1/anti-CTLA-4 (9-10%), followed by anti-CTLA-4 alone (2-6%), and anti-PD-1 (1%) 1
• Median onset: 8-9 weeks after starting ipilimumab (typically after third dose) 3
• Most common symptoms: headache (85%), fatigue (66%); visual changes uncommon 3

Lymphocytic Hypophysitis

• Primarily affects pregnant women and is the most common histological subtype 1

IgG4-Related Hypophysitis

• Occurs frequently in men and associated with systemic IgG4 disease 1