Hypophysitis: A Contemporary Clinical Review for the Modern Internist

Dr Neeraj Manikath , claude.ai

Abstract

Hypophysitis represents a diagnostically challenging group of inflammatory disorders affecting the pituitary gland. With the advent of immune checkpoint inhibitors in oncology, the landscape of hypophysitis has fundamentally shifted, making recognition of this condition increasingly critical for internists. This review synthesizes current understanding of hypophysitis etiology, clinical presentation, diagnostic approach, and management strategies, with emphasis on practical clinical pearls for the astute clinician.

Introduction

Hypophysitis, literally inflammation of the pituitary gland, encompasses a heterogeneous spectrum of inflammatory conditions affecting the anterior pituitary, posterior pituitary, or infundibulum. Once considered exceedingly rare, the true incidence has risen dramatically in recent years, paralleling the widespread adoption of immune checkpoint inhibitors (ICIs) in cancer therapeutics. While lymphocytic hypophysitis was historically the prototypical form, our contemporary understanding now recognizes multiple etiologic subtypes with distinct clinical characteristics and implications.

For the practicing internist, hypophysitis presents a diagnostic conundrum: symptoms are often nonspecific, imaging findings can mimic pituitary adenomas or other sellar masses, and the condition frequently masquerades as other endocrine or neurological disorders. Early recognition is paramount, as delayed diagnosis may result in life-threatening adrenal crisis or permanent hypopituitarism.

Classification and Etiology

Primary Hypophysitis

Lymphocytic hypophysitis represents the most common form of primary hypophysitis, characterized by lymphocytic infiltration of pituitary tissue. This autoimmune condition demonstrates remarkable female predominance (approximately 3:1), with peak incidence during pregnancy and the postpartum period. The association with late pregnancy and early postpartum period is so strong that hypophysitis should be considered in any woman presenting with headache, visual disturbances, or endocrine dysfunction during these periods.

IgG4-related hypophysitis has emerged as a recognized entity within the broader IgG4-related disease spectrum. This fibroinflammatory condition may present with isolated pituitary involvement or as part of multiorgan disease. Key distinguishing features include male predominance, chronic indolent course, and responsiveness to glucocorticoid therapy.

Granulomatous hypophysitis presents the greatest diagnostic challenge, as it may occur in isolation or secondary to systemic granulomatous diseases including sarcoidosis, tuberculosis, or Wegener's granulomatosis (granulomatosis with polyangiitis).

Xanthomatous hypophysitis is exceedingly rare, characterized by foamy histiocytes and cholesterol clefts, typically presenting with mass effects.

Secondary Hypophysitis

Immune checkpoint inhibitor-induced hypophysitis (ICI-hypophysitis) has revolutionized our understanding and clinical encounter with this condition. ICIs, particularly anti-CTLA-4 antibodies (ipilimumab), but also anti-PD-1 and anti-PD-L1 agents, have created a new population at risk. Incidence ranges from 0.5-17% depending on the specific agent and combination therapy used. Unlike primary lymphocytic hypophysitis, ICI-hypophysitis demonstrates male predominance (reflecting cancer demographics) and typically occurs 6-12 weeks after treatment initiation, though onset may occur after a single dose or following prolonged therapy.

Other secondary causes include infections (syphilis, tuberculosis, fungal), infiltrative disorders (Langerhans cell histiocytosis, hemochromatosis), and drug-induced hypophysitis from agents beyond ICIs.

Clinical Presentation: The Art of Suspicion

Classical Triad (Often Incomplete)

The classical presentation comprises headache, visual disturbances, and hypopituitarism—yet this complete triad appears in only 40-50% of cases, contributing to diagnostic delays.

Headache occurs in 60-90% of patients, typically described as retro-orbital or frontal, sometimes severe enough to mimic intracranial hypertension. The mechanism relates to stretching of the diaphragma sellae and dural irritation.

Visual symptoms arise from compression of the optic chiasm by the enlarged pituitary gland. Patients may report bitemporal hemianopsia, visual field defects, or decreased visual acuity. Any patient with unexplained visual field defects and headache warrants pituitary imaging.

Hypopituitarism represents the most consequential manifestation. The pattern and severity vary based on the extent of inflammation:

• ACTH deficiency: Most critical and potentially life-threatening. Patients present with fatigue, weakness, hypotension, hyponatremia, and risk of adrenal crisis. In ICI-hypophysitis, this is often the predominant or isolated finding.
• TSH deficiency: Manifests as central hypothyroidism with fatigue, cold intolerance, weight gain, but with inappropriately normal or low TSH levels.
• Gonadotropin deficiency: Amenorrhea in women, erectile dysfunction and decreased libido in men.
• GH deficiency: Subtle in adults, causing decreased quality of life, altered body composition.

Pearl #1: In ICI-hypophysitis, the presentation may be remarkably subtle—persistent fatigue in a cancer patient receiving immunotherapy should always prompt evaluation of adrenal function before attributing symptoms to cancer burden or other causes.

Pearl #2: Diabetes insipidus occurs in approximately 20-40% of lymphocytic hypophysitis but is rare in ICI-hypophysitis. The presence of polyuria and polydipsia should raise suspicion for lymphocytic or granulomatous forms.

Atypical Presentations and Diagnostic Pitfalls

Hypophysitis occasionally presents with isolated pituitary hormone deficiency without mass effect, particularly isolated ACTH deficiency in ICI-hypophysitis. The clinician must maintain vigilance even when imaging appears unremarkable or shows only subtle abnormalities.

Some patients present primarily with neuropsychiatric symptoms—confusion, lethargy, or personality changes—related to severe hypocortisolism or hyponatremia. These symptoms may lead to initial psychiatric or neurological consultation before endocrine etiology is recognized.

Oyster #1: Not all sellar masses are adenomas. A middle-aged woman presenting in late pregnancy or postpartum with headache and a pituitary mass should be assumed to have hypophysitis until proven otherwise—not a coincidentally discovered adenoma.

Diagnostic Approach: Building the Case

Laboratory Evaluation

The cornerstone of diagnosis involves demonstrating hypopituitarism through comprehensive pituitary function testing:

Morning cortisol (8 AM): Levels <3 μg/dL confirm adrenal insufficiency; >15 μg/dL generally exclude it; intermediate values require dynamic testing. In ambiguous cases or when clinical suspicion is high, proceed with:

• ACTH stimulation test: Standard dose (250 μg) or low dose (1 μg) cosyntropin
• Insulin tolerance test: Gold standard but contraindicated in elderly, cardiac disease, or seizure disorders

Thyroid function: Free T4 with TSH—central hypothyroidism shows low/low-normal free T4 with inappropriately normal or low TSH.

Gonadal axis: Testosterone in men, LH/FSH with estradiol in premenopausal women. Gonadotropins are typically low or inappropriately normal relative to sex hormone levels.

Prolactin: Paradoxically, mild hyperprolactinemia (typically <100 ng/mL) occurs frequently due to stalk compression interrupting dopaminergic inhibition—the "stalk effect."

Posterior pituitary function: Serum and urine osmolality, sodium levels. If diabetes insipidus suspected, water deprivation test or copeptin measurement may be needed.

Pearl #3: A prolactin level >200 ng/mL suggests prolactinoma rather than hypophysitis; levels between 50-200 ng/mL are indeterminate and may occur with either condition.

Additional testing based on suspected etiology:

• IgG4 levels (elevated in IgG4-related disease, but not specific)
• ACE levels (sarcoidosis)
• Infectious serologies when appropriate
• Inflammatory markers (ESR, CRP)—often elevated but nonspecific

Imaging: Reading Between the Lines

MRI of the pituitary with and without gadolinium contrast is the imaging modality of choice.

Characteristic features suggestive of hypophysitis:

• Diffuse, homogeneous pituitary enlargement with intact gland architecture
• Loss of posterior pituitary bright spot on T1-weighted images
• Thickened, enhancing pituitary stalk
• Symmetric enlargement maintaining gland contour
• Enhancement pattern: intense and homogeneous
• Absence of suprasellar extension (usually)

Contrast with adenoma features:

• Focal, asymmetric enlargement
• Preserved posterior bright spot
• Heterogeneous enhancement
• Possible suprasellar extension
• Sellar floor erosion may occur

Hack #1: The "dural tail sign"—enhancement extending along adjacent dura—may be seen in hypophysitis and helps distinguish it from adenoma.

Pearl #4: In ICI-hypophysitis, MRI may appear normal or show only subtle changes in up to 50% of cases. Diagnosis relies heavily on clinical context and biochemical confirmation of hypopituitarism.

Dynamic imaging: Follow-up MRI after 6-12 weeks can be revealing. Adenomas typically persist or grow; hypophysitis often shows regression with or without glucocorticoid therapy.

Histopathologic Diagnosis

While definitive diagnosis requires tissue confirmation, biopsy is rarely performed due to surgical risks and location. Transphenoidal biopsy is reserved for:

• Diagnostic uncertainty with mass effect requiring decompression
• Progressive visual field defects despite medical therapy
• Failure to respond to empiric treatment
• Suspected malignancy or unusual etiology

Pearl #5: Clinical diagnosis combining appropriate presentation, biochemical hypopituitarism, characteristic imaging, and response to therapy is generally sufficient for management decisions.

Management: Treating the Treatable

Acute Management

Adrenal crisis prevention is paramount. Any patient with suspected or confirmed ACTH deficiency requires immediate glucocorticoid replacement before further evaluation.

Initial replacement: Hydrocortisone 15-20 mg daily in divided doses (typically 10 mg morning, 5 mg afternoon) or prednisone 5 mg daily. Stress dosing education is critical.

Visual compromise: Urgent neurosurgical consultation if acute visual deterioration or severe visual field defects present. High-dose glucocorticoids (methylprednisolone 1000 mg IV daily for 3 days) may prevent permanent visual loss.

Immunosuppressive Therapy

Glucocorticoids represent first-line therapy for primary hypophysitis when mass effect or progressive symptoms present:

• Prednisone 1 mg/kg/day or equivalent
• Continue 4-6 weeks, then taper gradually
• Monitor pituitary function and repeat MRI to assess response

Response patterns:

• Mass effect and inflammation typically improve
• Recovery of pituitary function variable and unpredictable
• Some hormone deficiencies, particularly ACTH, may be permanent

ICI-hypophysitis management: Continuation versus discontinuation of checkpoint inhibitor requires oncology collaboration. Many patients can continue immunotherapy with appropriate hormone replacement. High-dose glucocorticoids are generally not required and do not restore pituitary function.

Other immunosuppressants: Azathioprine, methotrexate, rituximab reserved for steroid-refractory cases or IgG4-related disease.

Hormone Replacement Therapy

Permanent hormone replacement remains the mainstay of long-term management:

• Hydrocortisone/prednisone: Adjust to clinical response; sick-day rules and stress dosing crucial
• Levothyroxine: Start after glucocorticoid replacement established
• Sex hormone replacement: Testosterone in men, estrogen/progesterone in premenopausal women
• Desmopressin: If diabetes insipidus present
• Growth hormone: Consider in younger patients with documented deficiency affecting quality of life

Hack #2: Always replace glucocorticoids before thyroid hormone—starting levothyroxine in untreated adrenal insufficiency may precipitate adrenal crisis by increasing cortisol metabolism.

Pearl #6: Recovery of pituitary function may occur months to years after treatment, necessitating periodic reassessment. Conversely, late-onset hypopituitarism may develop even after apparent resolution.

Monitoring and Follow-Up

• Clinical assessment every 3-6 months initially
• Pituitary hormone panel every 6-12 months
• MRI at 6-12 weeks, then annually or as clinically indicated
• Education on stress dosing and medical alert identification

Special Populations

Pregnancy and Postpartum Period

Pregnancy represents unique challenges and considerations:

• Physiologic pituitary enlargement complicates diagnosis
• Urgent treatment needed if visual compromise
• Glucocorticoid therapy generally safe in pregnancy
• Postpartum monitoring essential; Sheehan's syndrome (pituitary infarction) in differential

Cancer Patients on Immunotherapy

• Maintain high index of suspicion
• Screen cancer patients on ICIs with clinical assessment and consider morning cortisol
• Fatigue is nonspecific but warrants endocrine evaluation
• Early recognition prevents adrenal crisis

Oyster #2: Cancer patients are often followed by oncology teams who may not recognize subtle signs of hypopituitarism. Internists should advocate for endocrine screening in patients receiving checkpoint inhibitors.

Prognosis and Long-Term Implications

Natural history varies by etiology:

• Primary lymphocytic hypophysitis: Spontaneous resolution of mass effect common, but permanent hypopituitarism in 20-60%
• ICI-hypophysitis: Nearly always permanent ACTH deficiency, other axes occasionally recover
• IgG4-related: May respond dramatically to immunosuppression but prone to recurrence

Quality of life considerations are significant. Patients require lifelong medical supervision, carry medication risks, and face psychological burden of chronic disease.

Conclusion: The Contemporary Internist's Role

Hypophysitis has evolved from an obscure pathological curiosity to a condition internists regularly encounter, particularly in the immunotherapy era. The modern internist must maintain clinical suspicion, recognize atypical presentations, coordinate diagnostic evaluation, and initiate appropriate management while collaborating with endocrinology and neurosurgery colleagues.

Key take-home messages:

1. Think hypophysitis in pregnant/postpartum women with headache and pituitary mass
2. Screen all patients on immune checkpoint inhibitors for subtle adrenal insufficiency
3. Not all sellar masses are adenomas—clinical context is crucial
4. ACTH deficiency is life-threatening and requires immediate replacement
5. Imaging may be unremarkable despite significant disease, especially in ICI-hypophysitis
6. Multidisciplinary management optimizes outcomes
7. Long-term monitoring is essential for detecting evolving hormone deficiencies

The diagnostic journey requires synthesis of clinical presentation, biochemical evidence, radiological findings, and therapeutic response. While definitive tissue diagnosis remains the gold standard, practical clinical diagnosis suffices for most cases. As our arsenal of immunotherapies expands, internists must remain vigilant stewards of this increasingly common yet frequently overlooked condition.

References

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7. Chiloiro S, Bianchi A, Giampietro A, et al. Diagnosis of endocrine disease: primary hypophysitis: clinical presentations and management. Eur J Endocrinol. 2017;176(4):R145-R157.

8. Iwama S, De Remigis A, Callahan MK, et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med. 2014;6(230):230ra45.

9. Leporati P, Landek-Salgado MA, Lupi I, et al. IgG4-related hypophysitis: a new addition to the hypophysitis spectrum. J Clin Endocrinol Metab. 2011;96(7):1971-1980.

10. Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317(5):516-524.

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Final Pearl: When encountering unexplained fatigue, headache, or endocrine dysfunction, ask yourself: "Could this be hypophysitis?" This simple question may prevent catastrophic adrenal crisis and guide appropriate investigation.