Why is it necessary to administer steroids, such as hydrocortisone (corticosteroid), before thyroxine (T4) in patients with central hypothyroidism or suspected hypophysitis, particularly those with a history of pituitary or hypothalamic disease?

Why Steroids Must Be Administered Before Thyroxine in Central Hypothyroidism

In patients with central hypothyroidism or suspected hypophysitis, steroids must always be started prior to thyroid hormone replacement to prevent life-threatening adrenal crisis. This is because initiating or increasing thyroid hormone accelerates cortisol metabolism, and if the patient has concurrent adrenal insufficiency, this can precipitate acute adrenal decompensation 1.

The Critical Pathophysiology

Why This Sequence Matters

• Central hypothyroidism frequently coexists with central adrenal insufficiency because both conditions arise from pituitary or hypothalamic dysfunction 1.
• In hypophysitis, more than 75% of patients present with both central hypothyroidism and central adrenal insufficiency, and approximately 50% have panhypopituitarism 1.
• When thyroid hormone is administered to a patient with unrecognized adrenal insufficiency, it increases the metabolic clearance of cortisol, effectively lowering already-insufficient cortisol levels and triggering adrenal crisis 1.

The Clinical Presentation That Should Raise Suspicion

• Hypophysitis is most commonly seen with anti-CTLA-4 antibody therapy (ipilimumab), occurring in up to 17% at higher doses, and with combination ipilimumab/nivolumab (up to 13%) 1.
• The median time from starting ipilimumab to diagnosis is 8-9 weeks, typically after the third dose 1.
• Clinical findings include headache (85%), fatigue (66%), and biochemical evidence showing low free T4 with low/normal TSH—the hallmark of central hypothyroidism 1.
• Visual changes are uncommon but when present suggest more severe pituitary involvement 1.

Diagnostic Confirmation Before Treatment

Essential Testing Sequence

• All patients with suspected hypophysitis require morning (8 AM) testing of TSH, free T4, ACTH, and cortisol before any hormone replacement is initiated 1.
• A 1 mcg cosyntropin stimulation test should be performed if baseline cortisol is equivocal 1.
• MRI of the sella with pituitary cuts is recommended to identify pituitary enlargement, stalk thickening, or suprasellar convexity 1.
• Gonadal hormones (testosterone in men, estradiol in women, FSH, LH) should also be measured to assess the full extent of pituitary dysfunction 1.

Diagnostic Criteria for Hypophysitis

• Confirmation requires either ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, or ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) with headache and symptoms 1.
• The TSH level in central hypothyroidism is inappropriately low or normal relative to the low free T4, distinguishing it from primary hypothyroidism where TSH would be markedly elevated 1, 2.
• In some cases, TSH may even be in the high-normal range due to production of biologically inactive TSH 2.

The Correct Treatment Sequence

Step 1: Initiate Corticosteroid Replacement First

• Start physiologic steroid replacement with hydrocortisone approximately 10 mg/m² (typically 15 mg in the morning and 5 mg at 3 PM) for central adrenal insufficiency 1.
• For severe or life-threatening symptoms such as adrenal crisis, severe headache, or visual field deficiency, use high-dose corticosteroids (prednisone 1 mg/kg/day or equivalent methylprednisolone), followed by taper over 1 month 1.
• Adrenal crisis should be managed per standard guidelines with IV hydrocortisone 100 mg bolus and 0.9% saline infusion 1, 3.

Step 2: Wait Before Starting Thyroid Hormone

• Corticosteroids should be started several days before initiating thyroid hormone replacement 3.
• This waiting period allows stabilization of cortisol levels and prevents the metabolic stress of increased cortisol clearance that occurs when thyroid hormone is introduced 1.

Step 3: Initiate Levothyroxine After Steroid Coverage

• Start levothyroxine 1 mcg/kg once central adrenal insufficiency is adequately treated 1.
• Repeat thyroid function testing 6-8 weeks after initiation, then periodically (every 3 months in the first year, every 6 months thereafter) to assess recovery 1.
• In central hypothyroidism, monitor free T4 levels rather than TSH, as TSH is an unreliable marker of thyroid status in these patients 1, 4, 5, 6.

Critical Pitfalls to Avoid

Never Start Thyroid Hormone First

• Starting thyroid hormone before ruling out and treating adrenal insufficiency can precipitate life-threatening adrenal crisis 1, 3.
• This is the single most important safety consideration in managing central hypothyroidism 1.
• Even in patients without obvious symptoms of adrenal insufficiency, the risk is substantial because central adrenal insufficiency often presents with subtle or nonspecific symptoms 1, 3.

Don't Rely on Electrolytes Alone

• The absence of hyperkalemia cannot rule out adrenal insufficiency, as it is present in only about 50% of cases 3.
• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases but can be indistinguishable from SIADH if adrenal function is not specifically assessed 3.
• Central adrenal insufficiency typically does not cause hyperkalemia because the renin-angiotensin-aldosterone system remains intact (only glucocorticoid deficiency, not mineralocorticoid deficiency) 3.

Recognize the Long-Term Nature

• Both adrenal insufficiency and hypothyroidism from hypophysitis appear to represent long-term sequelae, and lifelong hormonal replacement is needed in most cases 1.
• All patients with adrenal insufficiency should obtain and carry a medical alert bracelet 1.
• Periodic assessment (every 3 months in the first year, every 6 months thereafter) with clinical monitoring and repeat hormone levels is necessary to assess for potential recovery 1.

Special Considerations in Immune Checkpoint Inhibitor Therapy

Monitoring Protocol

• Before each cycle of immune checkpoint inhibitor therapy, thyroid testing (TSH and free T4) should be repeated, along with baseline metabolic panel 1.
• Routine monitoring with early morning ACTH and cortisol should be considered every month for 6 months, then every 3 months for 6 months, then every 6 months for 1 year 1.
• Patient education about signs and symptoms of endocrinopathies is essential 1.

When to Hold Immunotherapy

• Hold immune checkpoint inhibitors if grade ≥2 endocrine adverse event occurs until workup is completed and appropriate hormone replacement is started 1.
• Once hormone replacement is established, immunotherapy can typically be resumed, as endocrine toxicities rarely require permanent discontinuation 1.