What is the recommended evaluation and management approach for a patient suspected of having hypophysitis?

Evaluation and Management of Suspected Hypophysitis

For suspected hypophysitis, immediately obtain morning pituitary axis hormones (ACTH, cortisol, TSH, free T4, LH, FSH, sex hormones, IGF-1, prolactin) before administering steroids, perform MRI of the sella with pituitary cuts, and initiate physiologic hormone replacement as the cornerstone of treatment—reserving high-dose corticosteroids only for severe mass effect symptoms such as visual disturbances or severe headache. 1, 2

Diagnostic Workup

Clinical Presentation to Recognize

• Headache occurs in 85% of patients and is the most common presenting symptom 3
• Fatigue is present in 66% of cases 3
• Visual disturbances from mass effect require immediate evaluation to exclude cerebral metastases 1
• Central hypothyroidism (low TSH with low free T4) is seen in >90% of patients 1
• Central adrenal insufficiency occurs in >75% of patients 1
• Panhypopituitarism (adrenal insufficiency + hypothyroidism + hypogonadism) develops in approximately 50% of cases 1

Mandatory Laboratory Evaluation

Obtain these tests preferably at 8-9 AM before administering any steroids: 1, 3

• Adrenal axis: ACTH and cortisol (or 1 mcg cosyntropin stimulation test)
• Thyroid axis: TSH and free T4
• Gonadal axis: testosterone (men), estradiol (premenopausal women), FSH, LH
• IGF-1 and prolactin 1, 2

Imaging Requirements

• MRI of the sella with pituitary cuts is mandatory for all suspected cases 1, 3
• Characteristic findings include: symmetrical pituitary enlargement, stalk thickening, suprasellar convexity, heterogeneous enhancement, and increased gland height 1, 3
• Loss of posterior pituitary bright spot on T1-weighted images may be present 4
• MRI abnormalities can precede clinical symptoms 1

Diagnostic Confirmation Criteria

Two pathways exist for non-invasive diagnosis: 1, 3

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

Management Approach

Severity-Based Treatment Algorithm

Grade 1 (Asymptomatic or Vague Symptoms):

• Await pituitary axis results to confirm diagnosis 1
• Continue immune checkpoint inhibitor if applicable 1
• Initiate hormone replacement if cortisol <250 nmol/L (9 AM) or <150 nmol/L (random): hydrocortisone 20/10/10 mg 1
• Monitor thyroid function tests every 1-2 weeks initially 1

Grade 2 (Moderate Symptoms - Headache Without Visual Changes, Fatigue but Hemodynamically Stable):

• Oral prednisolone 0.5-1 mg/kg once daily after sending pituitary axis assessment 1
• If no improvement in 48 hours, escalate to Grade 3 treatment 1
• Withhold immune checkpoint inhibitor 1
• Refer to or consult endocrinologist 1
• Do not stop steroids 1

Grade 3-4 (Severe Symptoms - Visual Disturbances, Severe Headache, Hypotension, Severe Electrolyte Disturbance):

• Initiate IV (methyl)prednisolone 1 mg/kg (or hydrocortisone 50-100 mg Q6-8 hours) after sending bloods 1
• Consider hospitalization or emergency department referral 1
• Normal saline (at least 2L) for volume repletion 1
• Formal visual field assessment if visual changes present 1
• Withhold immune checkpoint inhibitor 1
• Taper to oral prednisolone over 4 weeks to 5 mg maintenance 1

Critical Hormone Replacement Principles

Always start cortisol replacement before thyroid hormone to prevent adrenal crisis—this is non-negotiable. 1, 2

Cortisol Replacement:

• Hydrocortisone 20/10 mg (or 20/10/10 mg) for physiologic replacement 1, 2
• Start if 9 AM cortisol <250 nmol/L or random cortisol <150 nmol/L 1

Thyroid Replacement:

• Levothyroxine 0.5-1.5 mcg/kg (start low in elderly or cardiac history) 1
• Must wait at least 1 week after starting cortisol replacement 2
• Goal free T4 in upper half of reference range (TSH is not accurate in central hypothyroidism) 1

Sex Hormone Replacement:

• Testosterone or estrogen therapy if needed in those without contraindications (prostate cancer, breast cancer, DVT history) 1

Steroid Tapering Strategy

• Convert IV to oral prednisolone over 5-7 days 1
• Taper over 4 weeks to 5 mg prednisolone maintenance 1
• Do not stop steroids completely—transition to physiologic maintenance doses 1
• Consider lower average doses (7.5 mg daily over two months) due to reports of reduced survival on higher doses 1

Essential Patient Safety Measures

All patients with adrenal insufficiency must receive: 1, 2

• Medical alert bracelet for adrenal insufficiency
• Education on "sick day rules" and stress dosing
• Prescription for emergency injectable steroid (IM hydrocortisone)
• Instructions on when to seek urgent medical attention for impending adrenal crisis

Long-Term Considerations

• Both adrenal insufficiency and hypothyroidism are typically permanent, requiring lifelong hormone replacement in most cases 1, 2
• Pituitary enlargement commonly resolves on follow-up MRI after 2 months 1
• ACTH stimulation testing can give false-negative results early in hypophysitis; when uncertain, opt for replacement and retest at 3 months 1

Common Pitfalls to Avoid

• Never start thyroid hormone before ensuring adequate cortisol replacement—this can precipitate fatal adrenal crisis 1, 2
• Do not attempt laboratory confirmation of adrenal insufficiency in patients on high-dose corticosteroids for other conditions until ready to discontinue treatment 1
• High-dose steroids do not reverse hormonal deficiencies—they only address mass effect symptoms 2
• Mineralocorticoid replacement is rarely necessary in hypopituitarism 1