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Hypophysitis

Hypophysitis is a rare inflammatory condition affecting the pituitary gland, often leading to hypopituitarism through compression and destruction of pituitary tissue, and it can be primary (idiopathic or autoimmune in origin) or secondary to systemic diseases, infections, tumors, or medications such as immune checkpoint inhibitors.^[1]^[2] The condition encompasses various histopathologic variants, including the most common lymphocytic hypophysitis (characterized by lymphocytic infiltration, often T-cell predominant and associated with pregnancy), granulomatous hypophysitis (featuring granulomas and giant cells), IgG4-related hypophysitis (a systemic fibroinflammatory disorder with IgG4-positive plasma cells), xanthomatous hypophysitis (rare, lipid-laden histiocytes typically post-Rathke's cleft cyst rupture), and necrotizing hypophysitis (involving extensive necrosis and acute mass effect).^[1]^[3] Epidemiologically, hypophysitis has an estimated annual incidence of about 1 in 9 million people, though this is likely underestimated due to improved diagnostics and the rising use of immunotherapies, with over 1,300 cases reported in the literature and immune checkpoint inhibitor-induced forms affecting 0.5–12% of treated patients.^[1]^[2] Clinically, it presents with symptoms such as headaches (in about 48% of cases), visual disturbances from mass effect (32%), adrenal insufficiency (38%), and diabetes insipidus (34%), alongside fatigue, hormonal deficiencies (e.g., in ACTH, TSH, or gonadotropins), and in severe cases, life-threatening endocrine crises.^[1] Diagnosis typically relies on magnetic resonance imaging (MRI) showing pituitary enlargement or stalk thickening, combined with endocrine testing for hormone levels and, in select cases, biopsy for histologic confirmation, as clinical features often mimic pituitary tumors.^[2]^[3] Management focuses on hormone replacement therapy for deficiencies, high-dose glucocorticoids to reduce inflammation and mass effect, and in refractory or secondary cases, immunosuppressive agents like rituximab, surgical decompression, or addressing underlying causes, with recent advances highlighting the expanding spectrum due to immunotherapy-related and paraneoplastic forms.^[1]^[2]

Overview and Classification

Definition

Hypophysitis is defined as inflammation of the pituitary gland, also known as the hypophysis, which can result in varying degrees of pituitary dysfunction.^[2] This inflammatory process may lead to hypopituitarism, characterized by deficiencies in one or more pituitary hormones, as well as mass effects from glandular enlargement that can cause headaches and visual disturbances.^[4] Additionally, involvement of the posterior pituitary or stalk can precipitate diabetes insipidus due to antidiuretic hormone deficiency.^[5] The pituitary gland is situated within the sella turcica, a bony depression in the sphenoid bone at the base of the skull, where it functions as the central regulator of the endocrine system by producing hormones that control other glands and diverse physiological processes.^[6] Through its anterior lobe, it secretes tropic hormones such as adrenocorticotropic hormone, thyroid-stimulating hormone, and growth hormone, while the posterior lobe releases antidiuretic hormone and oxytocin, all essential for maintaining homeostasis.^[7] Hypophysitis can manifest in acute, subacute, or chronic forms, distinguished primarily by the rapidity of onset and progression of symptoms, with acute presentations often mimicking pituitary apoplexy due to sudden glandular swelling.^[8] Subacute forms may develop over weeks to months with gradual endocrine deficits, whereas chronic cases involve prolonged inflammation leading to persistent hypopituitarism.^[9] One common variant is lymphocytic hypophysitis, an autoimmune-mediated form affecting the gland's parenchyma.^[10]

Types

Hypophysitis is categorized histologically into distinct variants based on microscopic features observed in pituitary tissue. The most prevalent form is lymphocytic hypophysitis, accounting for approximately 68% of primary cases, characterized by dense lymphocytic infiltration and considered autoimmune in etiology, often linked to pregnancy or postpartum periods in women.^[1] Other histological subtypes include granulomatous hypophysitis, which comprises about 19% of primary cases and features non-caseating granulomas, frequently associated with systemic conditions like sarcoidosis; xanthomatous hypophysitis, a rare variant (around 4% of primary cases) marked by lipid-laden foamy histiocytes and possible rupture of Rathke's cleft cysts; IgG4-related plasmacytic hypophysitis, representing 8% of primary cases and involving IgG4-positive plasma cell infiltration as part of a multi-organ IgG4-related disease, more common in older males; and necrotizing hypophysitis, the rarest (<1% of primary cases), defined by extensive pituitary necrosis leading to high rates of hypopituitarism.^[1]^[5] Hypophysitis can also be classified anatomically based on the extent of glandular involvement: adenohypophysitis (inflammation limited to the anterior pituitary, ~65% of cases), infundibulo-neurohypophysitis (involving the pituitary stalk and posterior lobe, ~10%), and panhypophysitis (affecting the entire gland, ~25%).^[1] Clinically, hypophysitis is further classified as primary or secondary based on etiology and extent of involvement. Primary hypophysitis refers to idiopathic inflammation confined to the pituitary gland without identifiable systemic causes, encompassing most histological variants like lymphocytic and IgG4-related forms. In contrast, secondary hypophysitis arises from broader systemic diseases, infections, vascular issues, or external triggers, resulting in pituitary involvement as part of a larger pathological process.^[1]^[11] An emerging subtype is immune checkpoint inhibitor (ICI)-induced hypophysitis, often secondary and triggered by anticancer therapies targeting PD-1/PD-L1 pathways, with incidence rates of 0.5% to 3% in patients on anti-PD-1 monotherapy such as nivolumab or pembrolizumab, though higher rates (up to 13%) occur in combination regimens with anti-CTLA-4 agents.^[1]^[12] Recent reports as of 2024 have also described paraneoplastic autoimmune hypophysitis and specific autoantibody-mediated forms, such as anti-PIT-1 hypophysitis, associated with immunotherapy, further expanding the spectrum of secondary hypophysitis.^[13]

Epidemiology and Risk Factors

Incidence and Prevalence

Hypophysitis is a rare condition, with an estimated annual incidence of approximately 1 in 9 million individuals.^[14] This low rate reflects its infrequent occurrence in the general population, where over 1,000 cases of primary hypophysitis had been reported globally as of 2016.^[15] The disease's rarity has historically limited large-scale epidemiological studies, with most data derived from case series and pathology registries rather than population-based surveys.^[2] The prevalence of hypophysitis has increased in recent years, particularly due to the expanded use of immune checkpoint inhibitors (ICIs) in cancer therapy following their approval and wider adoption after 2015.^[15] Among patients receiving ICI therapy, such as anti-CTLA-4 or anti-PD-1/PD-L1 agents, the incidence of hypophysitis ranges from less than 1% for single-agent PD-1 inhibitors to up to 13% for combination regimens, affecting an estimated 1% or more of treated cancer patients overall.^[16]^[17] As of 2023, literature reviews have documented over 900 cases of ICI-related hypophysitis, contributing to a total exceeding 2,000 reported cases overall. Rare associations with COVID-19 infection have also emerged, with at least 7 cases reported by 2024.^[18]^[19] This rise is attributed to the immunogenic mechanisms of these therapies, which can trigger pituitary inflammation as an immune-related adverse event.^[20] Geographic variations in reporting are notable, with higher detection rates in developed countries such as the United States and Japan, where advanced neuroimaging and access to ICI treatments facilitate earlier diagnosis.^[15] In contrast, underreporting is likely in regions with limited diagnostic resources. Lymphocytic hypophysitis, the most common subtype, has been briefly associated with pregnancy in some cases.^[14]

Demographic Patterns

Hypophysitis exhibits distinct demographic patterns, with primary forms showing a marked female predominance, accounting for approximately 70-80% of cases.^[1]^[21] This skew is particularly evident in lymphocytic hypophysitis, the most common primary subtype, where around 70% of affected women present during late pregnancy or within six months postpartum.^[22] In contrast, secondary hypophysitis, often linked to immunotherapy, demonstrates a male predominance of about 60-70%.^[20] The age distribution of hypophysitis displays a bimodal pattern, with peaks reflecting etiological differences. Primary autoimmune cases predominantly affect younger individuals, peaking between 20 and 40 years of age, often aligning with reproductive years in women.^[1]^[21] Secondary forms, particularly those induced by immune checkpoint inhibitors, occur more frequently in older adults, with a peak between 50 and 70 years.^[23] Comorbidities are more prevalent in specific subgroups of hypophysitis patients. Up to 38% of those with primary hypophysitis have preexisting autoimmune conditions, such as thyroiditis or polyglandular autoimmune syndromes.^[24]^[1] Secondary hypophysitis is notably higher among patients with malignancies receiving immune checkpoint inhibitor therapy, including those with melanoma or lung cancer.^[25] Cases in oncology populations have risen with the expanded use of such therapies.^[12]

Pathophysiology and Etiology

Inflammatory Mechanisms

Hypophysitis involves an inflammatory process primarily driven by autoimmune mechanisms, where T lymphocytes infiltrate the pituitary gland, leading to targeted destruction of pituitary cells. This infiltration is mediated by antigen-specific T cells that recognize pituitary autoantigens, resulting in the release of pro-inflammatory cytokines such as interferon-gamma (IFN-γ), interleukin-17 (IL-17), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α).^[26]^[27] In the lymphocytic form, these cytokines amplify the immune response, promoting further recruitment of immune cells and contributing to glandular inflammation.^[27] The inflammatory cascade typically progresses in phases: an acute stage characterized by edema and cellular infiltration that causes pituitary enlargement, followed by a chronic phase involving fibrosis and eventual atrophy of hormone-producing cells. This progression leads to selective loss of pituitary cell types, such as lactotrophs and gonadotrophs, resulting in hypopituitarism.^[27]^[28] Enlargement of the pituitary during the acute inflammatory phase can exert a mass effect, compressing adjacent structures like the optic chiasm or pituitary stalk, which disrupts the release of antidiuretic hormone (ADH) and manifests as central diabetes insipidus.^[27]^[28] In primary forms, autoantibodies against pituitary hormones or transcription factors, such as anti-growth hormone or anti-PIT-1 antibodies, may contribute to the autoimmune targeting, though their precise role remains under investigation.^[27]

Primary and Secondary Causes

Hypophysitis is classified into primary and secondary forms based on its etiology. Primary hypophysitis refers to idiopathic inflammation confined to the pituitary gland, often driven by autoimmune processes. The most common subtype is lymphocytic hypophysitis, which accounts for approximately 68% of primary cases and predominantly affects women, with a notable association to pregnancy or the postpartum period.^[1] This condition involves autoimmune infiltration of the pituitary, frequently linked to specific human leukocyte antigen (HLA) alleles such as DQ8 (present in 87% of sporadic cases) and DR53 (present in 80%).^[29] Rare genetic variants also contribute to primary hypophysitis, including mutations in the AIRE gene, which are associated with autoimmune polyendocrine syndrome type 1 and can lead to pituitary autoimmunity. Secondary hypophysitis arises from identifiable external triggers or systemic conditions that extend inflammation to the pituitary. Infectious causes include bacterial agents like Mycobacterium tuberculosis and fungal pathogens such as Aspergillus species, which can directly invade or indirectly affect the gland through dissemination.^[1] Systemic diseases represent another major category, with sarcoidosis involving the pituitary in about 0.5% of cases through granulomatous infiltration, and IgG4-related disease causing plasma cell-rich inflammation, often as part of multi-organ involvement.^[1] Neoplastic causes, such as sellar tumors (e.g., pituitary adenomas or craniopharyngiomas) or metastases, can lead to secondary hypophysitis through direct infiltration or reactive inflammation.^[2] Iatrogenic factors are increasingly recognized secondary causes, particularly immune checkpoint inhibitors (ICIs) used in cancer immunotherapy. Agents like ipilimumab (anti-CTLA-4) carry a higher risk, with hypophysitis incidence reaching up to 12%, compared to less than 1% for nivolumab (anti-PD-1); combination therapy elevates rates to around 19%.^[23] ICI-induced hypophysitis typically manifests 6-12 weeks after initiation, often mimicking isolated hypopituitarism—particularly adrenocorticotropic hormone deficiency—without pituitary mass effect on imaging in approximately 50% of cases. Additionally, radiation therapy to the sellar region can induce secondary hypophysitis through direct tissue damage and subsequent inflammatory response.^[15]

Clinical Presentation

Signs and Symptoms

Hypophysitis primarily presents with symptoms attributable to the mass effect of pituitary enlargement and deficiencies in pituitary hormone production. The most common manifestations include headache and visual disturbances due to compression of adjacent structures such as the optic chiasm.^[2] Headache occurs in approximately 49% of patients with lymphocytic hypophysitis, often serving as an initial symptom of mass effect from glandular inflammation and swelling. Visual field defects, such as bitemporal hemianopsia, affect about 26% of cases and result from optic chiasm compression, potentially leading to reduced visual acuity or diplopia if the inflammation extends to the cavernous sinus.^[30] Hormonal deficiencies from anterior pituitary involvement produce a range of systemic symptoms. Secondary adrenal insufficiency, seen in 49% of lymphocytic hypophysitis cases, manifests as fatigue, weakness, and hypotension due to adrenocorticotropic hormone (ACTH) loss. Secondary hypothyroidism, occurring in 43% of patients, leads to fatigue, cold intolerance, and weight gain from thyroid-stimulating hormone (TSH) deficiency. Hypogonadotropic hypogonadism, the most frequent anterior deficit at 54%, causes amenorrhea, infertility, or low libido in women and erectile dysfunction or reduced fertility in men owing to gonadotropin loss. Growth hormone deficiency, present in 22% of cases, may result in growth retardation and delayed development in affected children.^[30] Posterior pituitary dysfunction often presents as central diabetes insipidus in 45% of patients, characterized by polyuria exceeding 3 liters per day, polydipsia, and hypernatremia secondary to antidiuretic hormone (ADH) deficiency.^[30] Hyperprolactinemia arises in some cases from pituitary stalk compression disrupting dopamine inhibition, leading to symptoms such as galactorrhea and further contributing to low libido or menstrual irregularities.^[14]

Associated Complications

Hypophysitis can precipitate acute crises, most notably through secondary adrenal insufficiency, which manifests as adrenal crisis characterized by hypotension, shock, and potentially fatal outcomes if untreated. In primary hypophysitis, ACTH deficiency occurs in approximately 60% of cases, while it affects up to 96% in immune checkpoint inhibitor (ICI)-induced forms, heightening the risk of this life-threatening emergency. Untreated adrenal crisis carries a mortality rate of up to 20% in patients presenting with shock. Severe hyponatremia may also arise, often mimicking syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to cortisol deficiency or posterior pituitary involvement, with an incidence of 62% reported in ICI-related hypophysitis treated with anti-PD-1/PD-L1 agents.^[1]^[1]^[31]^[1] Chronic complications frequently include permanent hypopituitarism, necessitating lifelong hormone replacement in over 70% of primary hypophysitis cases and 89-90% of ICI-induced instances. Optic neuropathy represents another serious concern, resulting from compression of the optic chiasm by pituitary enlargement, leading to visual disturbances in about 32% of primary cases and potential irreversible vision loss if not addressed promptly.^[1]^[1] In secondary hypophysitis, such as that caused by sarcoidosis, systemic effects often stem from the underlying multisystem condition, which involves granulomatous infiltration of multiple organs including the pituitary. For ICI-associated forms, discontinuation of therapy—required in up to 41% of anti-CTLA-4 cases—may compromise cancer control, though studies show mixed impacts on overall survival, with some patients experiencing improved outcomes despite endocrine disruption.^[3]^[1]^[32]

Diagnosis

Clinical Evaluation

Clinical evaluation of hypophysitis begins with a thorough history taking to identify potential risk factors and symptom patterns suggestive of pituitary inflammation. Clinicians inquire about recent pregnancy, particularly in the third trimester or postpartum period, as lymphocytic hypophysitis is associated with approximately 70% of cases occurring during late gestation or within the first few months after delivery.^[1] Other key historical elements include exposure to immunotherapy, such as immune checkpoint inhibitors targeting CTLA-4 or PD-1/PD-L1 pathways, which can precipitate hypophysitis in 0.5–18% of treated patients (higher rates with CTLA-4 inhibitors like ipilimumab); a personal or family history of autoimmune disorders, present in 20-50% of cases; and recent infections like tuberculosis or syphilis that may trigger secondary forms.^[23]^[14] The symptom timeline is critical, often revealing a subacute onset over weeks to months, with headache typically emerging first, followed by fatigue, visual changes, or symptoms of hormonal imbalance such as amenorrhea or dizziness.^[14]^[1] Physical examination focuses on detecting signs of pituitary compression and hormonal deficiencies. Visual acuity and field testing are essential to assess for defects or bitemporal hemianopsia due to optic chiasm involvement, along with evaluation for ophthalmoplegia or diplopia from cavernous sinus compression.^[14] Manifestations of hormone deficiencies include orthostatic hypotension and fatigue indicating adrenal insufficiency, dry skin and bradycardia suggesting hypothyroidism, and loss of libido or secondary sexual characteristics pointing to hypogonadism.^[14]^[1] These findings, combined with general signs like weight changes or polyuria, heighten suspicion for hypophysitis in the appropriate clinical context. Differential diagnosis during evaluation emphasizes distinguishing hypophysitis from other sellar masses through historical and symptomatic clues. Rapid symptom onset over weeks favors inflammatory processes over the slower progression typical of pituitary adenomas, while a history of malignancy or immunotherapy raises concern for metastasis, though the absence of systemic cancer symptoms may support primary hypophysitis.^[14] Pattern recognition, such as prominent headache and endocrine dysfunction without focal neurological deficits, helps narrow considerations away from tumors like adenomas, which more commonly present with insidious mass effects.^[1] Hormonal testing is often pursued next to confirm deficiencies and guide further management.^[14]

Imaging and Laboratory Tests

Magnetic resonance imaging (MRI) with gadolinium contrast is the primary imaging modality for diagnosing hypophysitis, typically revealing symmetrical enlargement of the pituitary gland, often exceeding 10 mm in vertical dimension, along with stalk thickening greater than 3 mm and heterogeneous or intense homogeneous enhancement.^[2] The loss of the posterior pituitary bright spot on T1-weighted images may indicate involvement of the neurohypophysis, while dynamic contrast-enhanced MRI sequences can help exclude microadenomas by demonstrating uniform early enhancement of the anterior pituitary without focal defects characteristic of adenomas.^[1] In chronic cases, imaging may show pituitary atrophy or an empty sella syndrome. Recent advances as of 2025 include predictive scoring systems combining clinical, radiologic, and hormonal data to aid early diagnosis, particularly in immune checkpoint inhibitor-related cases.^[33] Laboratory evaluation focuses on assessing pituitary hormone deficiencies through basal measurements and dynamic stimulation tests. Common findings include low morning cortisol and adrenocorticotropic hormone (ACTH) levels, reduced thyroid-stimulating hormone (TSH) with low free thyroxine (T4), decreased insulin-like growth factor-1 (IGF-1), and impaired gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), often accompanied by mild hyperprolactinemia.^[2] Stimulation tests, such as the ACTH (cosyntropin) stimulation test, evaluate adrenal reserve by measuring cortisol response, which may be blunted in up to 90% of cases, particularly those induced by immune checkpoint inhibitors.^[1] For suspected diabetes insipidus (DI), serum electrolytes are checked, with hypernatremia and elevated plasma osmolality in the setting of polyuria suggesting posterior pituitary involvement, alongside low urine osmolality.^[2] Pituitary biopsy is rarely performed and reserved for cases where imaging and laboratory findings are equivocal or to differentiate from neoplasms like adenomas or metastases, revealing characteristic lymphocytic infiltrates or other inflammatory patterns on histopathology.^[1] In immune checkpoint inhibitor-related hypophysitis, biopsy is generally avoided due to procedural risks, including worsening hypopituitarism or infection, as diagnosis is typically supported by clinical context and non-invasive tests.^[2]

Management

Pharmacological Treatments

Pharmacological management of hypophysitis primarily targets the underlying inflammation and addresses resulting hormone deficiencies through targeted therapies. Corticosteroids form the cornerstone of treatment for acute inflammatory cases with mass effect, particularly in autoimmune hypophysitis, to reduce pituitary enlargement and alleviate symptoms such as headache and visual disturbances. High-dose intravenous hydrocortisone is recommended for severe presentations with mass effect or adrenal crisis, typically administered as 100 mg every 8 hours initially, followed by a taper to oral prednisone at 1 mg/kg/day (approximately 60-80 mg daily for an average adult) over 2-6 weeks, with gradual reduction based on clinical and radiographic response.^[34]^[1]^[35] This regimen yields a response rate of 75-87% in reducing pituitary enlargement, with visual field improvement in up to 91% of severe cases treated intravenously, though relapse occurs in about 38-41% of patients requiring prolonged or repeated courses.^[1]^[36]^[34] For ICI-induced hypophysitis, high-dose corticosteroids are reserved for cases with significant mass effect, visual symptoms, or endocrine crisis; otherwise, physiologic hormone replacement is the mainstay, as high-dose therapy does not improve long-term outcomes and may increase risks. The immunotherapy is typically withheld temporarily for high-grade (3-4) toxicity but can often be resumed if symptoms resolve and oncologic benefits justify continuation.^[37]^[38]^[1] For refractory autoimmune hypophysitis or cases unresponsive to corticosteroids, immunosuppressants such as rituximab (typically 375 mg/m² weekly for 4 weeks) or azathioprine (1-2.5 mg/kg/day) are employed to modulate the immune response, particularly in lymphocytic or IgG4-related subtypes.^[1]^[28] These agents show benefit in select patients, with case series reporting pituitary size reduction and hormone recovery in up to 50% of glucocorticoid-resistant cases, though data remain limited to small cohorts.^[9] Hormone replacement therapy is essential for correcting hypopituitarism, which affects over 70% of patients long-term, and is titrated based on symptoms, laboratory values, and dynamic testing. Hydrocortisone is used for secondary adrenal insufficiency at 15-25 mg/day in divided doses (e.g., 10 mg morning, 5-10 mg afternoon, 0-5 mg evening) to mimic physiologic cortisol rhythms, with stress dosing during illness.^[1]^[39] Levothyroxine replaces thyroid hormone deficiency at 1.6 mcg/kg/day (typically 75-125 mcg daily), initiated after glucocorticoid stabilization to avoid precipitating adrenal crisis.^[1] For central diabetes insipidus, desmopressin is administered intranasally (10-40 mcg/day) or orally (0.1-0.8 mg/day), adjusted to maintain urine osmolality and serum sodium within normal limits.^[1] Gonadal axis replacement with estrogen/progesterone in women or testosterone in men is added as needed, with recovery of anterior pituitary function occurring in only 45% despite therapy.^[1]^[9]

Surgical and Supportive Interventions

Surgical interventions for hypophysitis are typically reserved for cases where pharmacological approaches, such as high-dose glucocorticoids, prove insufficient, particularly when there is severe mass effect causing visual impairment or neurological compromise. Transsphenoidal decompression is the preferred surgical approach, aimed at relieving pressure on the optic chiasm and surrounding structures, and has been shown to improve vision in approximately 80% of affected patients.^[40] Biopsy via transsphenoidal surgery may be performed concurrently in atypical presentations to confirm the diagnosis and exclude malignancy, though it is not routinely recommended due to procedural risks including postoperative meningitis, cerebrospinal fluid rhinorrhea, and recurrence rates of 11% to 25%.^[14] Overall, surgery is pursued in fewer than 20% of hypophysitis cases, as it accounts for only about 0.4% of all pituitary surgeries, reflecting its role as a last-resort option amid potential endocrine complications and the disease's inflammatory nature.^[41] Supportive care plays a crucial role in managing hypophysitis symptoms and preventing complications, often involving a multidisciplinary team comprising endocrinologists, neurosurgeons, ophthalmologists, and radiologists to address pituitary dysfunction and mass effects holistically.^[42] For patients developing central diabetes insipidus (DI), a common sequela, fluid and electrolyte management is essential, including vigilant monitoring of serum sodium and osmolality with desmopressin replacement to maintain balance and avert hypernatremic dehydration.^[14] Ophthalmology consultation is indicated for those with vision loss or field defects, enabling timely assessment and intervention to preserve visual function. Hormone replacement therapy is tailored to specific deficiencies, such as cortisol for adrenal insufficiency or levothyroxine for hypothyroidism, supporting overall physiological stability without addressing the underlying inflammation directly.^[14] Monitoring protocols are vital for tracking disease progression and guiding interventions in hypophysitis patients. Serial gadolinium-enhanced MRI of the pituitary is recommended every 3 to 6 months initially, with intervals extended if stable, to evaluate mass size, stalk thickening, and resolution of inflammation.^[5] Regular hormone assays, including ACTH, cortisol, TSH, free T4, IGF-1, prolactin, LH, FSH, testosterone (in males), and assessments for ADH via osmolality, inform the need for adjustments in replacement therapy and detect evolving deficiencies.^[14] In immune checkpoint inhibitor (ICI)-associated hypophysitis, routine pituitary biopsy is avoided due to the risks outweighing diagnostic benefits, favoring clinical and imaging surveillance instead.^[43]

Prognosis and Outcomes

Short-Term Prognosis

In the short term, following diagnosis and initiation of glucocorticoid therapy, hypophysitis often demonstrates favorable outcomes, with mass reduction observed in 65-84% of cases overall and up to 88% when the disease duration is less than 6 months.^[1]^[44] Symptom improvement, including relief from headache and mass effect, typically accompanies these radiological changes within a few weeks of high-dose steroid treatment.^[1] In immune checkpoint inhibitor (ICI)-induced hypophysitis, pituitary enlargement resolves on MRI in nearly all patients (up to 100%) within a median of 11 weeks, though full hormonal recovery remains variable across axes; however, high-dose glucocorticoids in ICI-induced cases, particularly ipilimumab-treated melanoma patients, may be associated with reduced overall survival.^[43]^[38]^[42] Mortality risk in the acute phase is low, estimated at 5-6%, and is predominantly associated with untreated adrenal crisis due to secondary adrenal insufficiency.^[45] Visual disturbances, when present due to suprasellar extension, show recovery rates exceeding 90% with early glucocorticoid intervention, emphasizing the importance of timely diagnosis.^[46] Key factors influencing short-term prognosis include early diagnosis and prompt steroid initiation, which enhance responsiveness and reduce complications; steroid-refractory cases are less common but may require escalation.^[47] Additionally, the absence of fibrotic changes on initial MRI correlates with better mass resolution and functional improvement, as fibrosis may indicate a more established inflammatory process.^[48] While many patients achieve initial stabilization, a subset may require ongoing hormone replacement in the first year to prevent crises.

Long-Term Effects

One of the most significant long-term consequences of hypophysitis is the development of permanent hypopituitarism, affecting approximately 70% or more of patients with primary autoimmune forms, who require lifelong hormone replacement therapy. Recent 2025 analyses affirm glucocorticoid benefits in primary forms but highlight ongoing controversy regarding optimal dosing and long-term outcomes.^[1]^[49] This is particularly pronounced in the adrenocorticotropic hormone (ACTH) and growth hormone (GH) axes, with ACTH deficiency persisting in up to 60% of primary cases and 96% of immune checkpoint inhibitor (ICI)-induced cases, while GH deficiency occurs in 37% of primary and 19% of ICI-related instances.^[1] Gonadotropin deficiencies, impacting follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in 55% of primary and 59% of ICI-induced hypophysitis, can lead to infertility, especially in women, where reproductive axis impairment affects up to 20-50% depending on the extent of involvement.^[1] In ICI contexts, the rate of enduring hormone deficits approaches 89-90%, underscoring the need for ongoing endocrine monitoring post-diagnosis.^[1] Recurrence risk varies by etiology, with autoimmune primary hypophysitis showing relapse rates of up to 38% following glucocorticoid therapy, higher than the near-zero recurrence observed in secondary forms like those induced by ICI.^[1] Untreated or inadequately managed deficiencies, particularly in cortisol and thyroid hormones, contribute to increased cardiovascular morbidity, including higher rates of ischemic heart disease and overall mortality due to metabolic dysregulation and endothelial dysfunction in hypopituitarism.^[50] Patients with autoimmune variants face a 10-20% risk of disease flare, often necessitating vigilant surveillance to prevent progression to panhypopituitarism.^[1] Long-term quality of life is notably impaired in hypophysitis survivors, primarily due to persistent fatigue, cognitive complaints, and psychological effects such as anxiety and depression stemming from chronic hormone replacement and residual pituitary dysfunction.^[51] In ICI-treated cancer patients, ongoing monitoring for secondary malignancies remains essential alongside endocrine assessments, as the inflammatory milieu may influence tumor dynamics or incite additional immune-related adverse events.^[12] Overall, while initial treatment can stabilize acute symptoms, these enduring impacts highlight the importance of multidisciplinary follow-up to mitigate morbidity.^[1]

Historical and Emerging Perspectives

Historical Development

Hypophysitis, particularly its lymphocytic form, was first described in 1962 by Goudie and Pinkerton through an autopsy of a 22-year-old postpartum woman who presented with adrenal insufficiency and exhibited extensive lymphocytic infiltration of the anterior pituitary gland.^[52] This seminal case highlighted the inflammatory nature of the condition, distinguishing it from other pituitary pathologies like tumors or infections, and marked the initial recognition of primary hypophysitis as a distinct entity often linked to the peripartum period.^[14] During the 1970s and 1980s, the autoimmune basis of lymphocytic hypophysitis gained recognition, with early reviews such as that by Bottazzo and Doniach in 1978 synthesizing the limited cases and proposing pituitary autoimmunity as a key mechanism, building on broader endocrine autoimmunity discoveries from the 1950s.^[52] By the 1990s, the condition was increasingly documented in peripartum women, with symptoms including headache, visual disturbances, and hypopituitarism due to glandular enlargement and infiltration. Approximately 300 cases of primary lymphocytic hypophysitis had been reported worldwide by 2000, underscoring its rarity and female predominance.^[15] A key milestone in understanding the autoimmune etiology came in 1998, when De Bellis et al. identified circulating autoantibodies against human pituitary cytosol proteins in patients with hypopituitarism, including those with biopsy-proven lymphocytic hypophysitis, providing serological evidence of an immune-mediated process.^[53] Early management options were limited, primarily involving high-dose corticosteroids to reduce inflammation and pituitary enlargement, alongside surgical decompression via transsphenoidal hypophysectomy for cases with significant mass effect threatening vision or causing severe compression.^[14] These interventions aimed to alleviate symptoms and preserve pituitary function, though long-term hormone replacement was often necessary due to irreversible glandular damage.

Recent Advances

In the 2010s, the recognition of IgG4-related hypophysitis as a distinct subtype expanded the classification of hypophysitis, characterized by its responsiveness to steroid therapy and frequent involvement of multiple organs.^[54] This subtype, often confirmed by elevated serum IgG4 levels and histopathological findings of lymphoplasmacytic infiltration, has been increasingly documented in retrospective cohorts, with pituitary involvement occurring in approximately 4-5% of IgG4-related disease cases.^[5] Concurrently, immune checkpoint inhibitor (ICI)-induced hypophysitis emerged as a significant subtype, particularly associated with anti-CTLA-4 and anti-PD-1/PD-L1 therapies, frequently manifesting as isolated adrenocorticotropic hormone (ACTH) deficiency.^[12] In the 2020s, clinical trials and meta-analyses reported an incidence of 5-10% for ICI-hypophysitis in patients receiving combination ICI regimens, higher than monotherapy rates of 1-2%, underscoring its growing prevalence in oncology practice.^[17]^[55] Diagnostic advancements in the 2020s have enhanced early detection of hypophysitis, with hybrid imaging modalities like 18F-FDG PET/CT demonstrating utility in identifying ICI-induced pituitary inflammation before overt clinical symptoms.^[56] These techniques reveal pituitary hypermetabolism and stalk thickening, aiding differentiation from other sellar pathologies.^[57] Additionally, genetic studies have linked rare polymorphisms in PD-1 and CTLA-4 genes to increased susceptibility for ICI-hypophysitis, with specific HLA alleles such as HLA-DQB1*06:01 associated with anti-PD-1-related cases.^[58] A 2023 narrative review highlighted these immune pathway variants as potential biomarkers, informing risk stratification in patients undergoing ICI therapy.^[58] Therapeutic innovations from 2022 to 2025 have addressed refractory hypophysitis, with trials exploring infliximab, a TNF-α inhibitor, showing efficacy in granulomatous cases unresponsive to glucocorticoids. For instance, case series reported pituitary mass reduction and hormone recovery in patients with Crohn's-associated hypophysitis treated with infliximab, offering an alternative to prolonged steroids.^[59] Additionally, paraneoplastic hypophysitis has emerged as a rare but distinct form, often associated with anti-pituitary antibodies in patients with underlying malignancies, expanding the differential diagnosis. Recent reviews emphasize balancing oncologic benefits with endocrine risks through hormone replacement and, where possible, continuing ICI therapy. This approach, supported by meta-analyses, prioritizes multidisciplinary management to mitigate long-term hypopituitarism.^[60]

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Review Diagnosis and classification of autoimmune hypophysitis
LH may present as an acute, subacute or chronic condition. Acute manifestation of LH is similar to that of a non-secretory pituitary tumour with ...
[11]
Hypophysitis - DynaMedex
primary hypophysitis · secondary hypophysitis - forms of hypophysitis that develop secondary to autoimmune, inflammatory, infectious, vascular, and neoplastic ...
[12]
Immune Checkpoint Inhibitor-Induced Hypophysitis and Patterns of ...
Mar 7, 2022 · The incidence of hypophysitis has ranged from 1-18% in patients treated with ipilimumab (8–13), 0.5-1.5% for PD-1 inhibitors (2, 12, 14), and up ...
[13]
Lymphocytic Hypophysitis - StatPearls - NCBI Bookshelf - NIH
Aug 8, 2023 · It causes the pituitary gland to be infiltrated by lymphocytes and can cause hypopituitarism, and thus, diagnosis and management need to be ...
[14]
Hypophysitis: An Update on the Novel Forms, Diagnosis and ...
Hypophysitis is a heterogeneous condition that leads to inflammation of the sella and/or suprasellar region, potentially resulting in hormonal deficiencies ...<|control11|><|separator|>
[15]
The association of hypophysitis with immune checkpoint inhibitors use
Mar 29, 2024 · Prior studies have demonstrated that CTLA-4 inhibitors have a higher prevalence of hypophysitis than PD-1/PD-L1 inhibitors. ... The incidence of ...
[16]
Differences in checkpoint-inhibitor-induced hypophysitis: mono
Jul 28, 2024 · Treatment with anti-PD-(L)1, anti-CTLA-4 or anti-CLTA-4/PD-1 may induce hypophysitis, but little is known about the differences in clinical presentation or ...<|control11|><|separator|>
[17]
Hypophysitis induced by immune checkpoint inhibitors: a 10-year ...
These estimates report an incidence of hypophysitis of 12% after CTLA-4 blocking antibodies, and 0.5% after PD-1 blocking antibodies [66], estimates confirmed ...
[18]
Clinical Characteristics of Primary Hypophysitis – A Single-Centre ...
Results Female sex was predominant (73%). ... 14,17 Our results were consistent with these data with a female predominance of 78% and a median age of 36 years.
[19]
Lymphocytic hypophysitis in the elderly: A case presentation and ...
Another large review of 211 patients with LH found 69% of cases to occur in peripartum women late in pregnancy or early postpartum [3].
[20]
[PDF] Differences between immunotherapy-induced and primary ...
Sep 13, 2021 · We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH). Design Retrospective multicenter ...<|control11|><|separator|>
[21]
Immune Checkpoint Inhibitor-Induced Hypophysitis and Patterns of ...
Mar 8, 2022 · Incidence of hypophysitis on anti-PD-1 monotherapy was 5% (7/129) in ... It is still unclear if PD-1 or PD-L1 is expressed in the pituitary (33, ...
[22]
Adverse effects of immune-checkpoint inhibitors - Nature
May 15, 2019 · Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer.
[23]
In Situ Activation of Pituitary-Infiltrating T Lymphocytes in ... - Nature
Mar 6, 2017 · Autoimmune hypophysitis (AH) is a chronic inflammatory disease characterized by infiltration of T and B lymphocytes in the pituitary gland.
[24]
Unveiling the Etiopathogenic Spectrum of Hypophysitis: A Narrative ...
Jul 30, 2023 · Our objective is to summarize the most recent research on the etiopathogenesis, molecular mechanisms, and genetics of both primary and secondary hypophysitis.
[25]
MECHANISMS IN ENDOCRINOLOGY: Hypophysitis: diagnosis and ...
Jun 7, 2018 · Hypophysitis is a rare condition characterised by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement.
[26]
HLA Markers DQ8 and DR53 Are Associated With ... - PubMed
The HLA markers, DQ8 and DR53, were found to be commonly present in patients with LH. The odds ratio of a patient with LH expressing the HLA-DQ8 marker is ...
[27]
Sheehan Syndrome - StatPearls - NCBI Bookshelf - NIH
Sheehan syndrome which is also called post-partum pituitary necrosis refers to the necrosis of cells of the anterior pituitary gland following significant post ...
[28]
a systematic review with meta-analysis - PMC - PubMed Central
Introduction. Lymphocytic hypophysitis (LYH) is a rare disease of presumed autoimmune etiology characterized by lymphocytic infiltration of the pituitary gland ...
[29]
Adrenal Crisis: Causes, Symptoms, Diagnosis & Treatment
Aug 3, 2022 · Without treatment, up to 20% of people in shock may die from an adrenal crisis. An adrenal crisis may also cause seizures or a coma.Missing: hypophysitis 10-20%
[30]
Lymphocytic Hypophysitis in a Patient With Suspected Syndrome of ...
Oct 11, 2022 · Hypopituitarism has been shown to cause hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH).
[31]
Long-Term Toxicities of Immune Checkpoint Inhibitors | Drugs
Sep 30, 2025 · The impact of hypophysitis on cancer outcomes is mixed, with some studies showing improved overall survival (OS) in patients treated with ...
[32]
Glucocorticoid therapy as first-line treatment in primary hypophysitis
Dec 22, 2022 · High-dose glucocorticoids are associated with improved recovery of deficits in primary autoimmune hypophysitis (PAH), but optimal dosing, route, ...
[33]
Clinical diagnosis and treatment of immune checkpoint inhibitors ...
Therefore, it is recommended to use hydrocortisone (10–30 mg/day) for treatment, divided into several doses. In the event of an adrenal crisis, severe ...
[34]
Treatment of Primary Hypophysitis in Germany - PubMed
The initial response to glucocorticoid pulse therapy was most favorable, with early failure in only 3%. However, the overall failure and recurrence rate was 41% ...
[35]
Managing Ipilimumab-Induced Hypophysitis - PubMed Central - NIH
Oct 2, 2020 · The management of ipilimumab-induced hypophysitis involves primarily the replacement of deficient hormones and/or treatment with high-dose ...Pathophysiology · Clinical Presentation And... · Treatment
[36]
Case series and review of the literature on the surgical management ...
Surgery resulted in visual improvement in about 80% cases. Non-endocrine complications remains rare but could be severe (5%). Neuropathology was contributive in ...
[37]
Hypophysitis: Evaluation and Management
Sep 6, 2016 · Hypophysitis is the acute or chronic inflammation of the pituitary gland. The spectrum of hypophysitis has expanded in recent years with the addition of two ...Background · Diagnosis · Treatment
[38]
Hypophysitis - Endocrine Practice
Jun 29, 2022 · Additionally, recurrence has been reported in approximately 42% (3 of 7) of patients who had surgery as the first-line therapy.
[39]
Immune checkpoint inhibitor related hypophysitis: diagnostic criteria ...
Hypophysitis is rare with an annual incidence of about 1 in 9 million (Hunn et al. 2014). Lymphocytic hypophysitis was the most common histologic variant ( ...Introduction · Methods · Results · Discussion<|separator|>
[40]
Corticosteroids in the management of lymphocytic hypophysitis
The study reported a 50% rate of reduction in the size of the mass; and if the disease duration was for <6 months, 88% of the patients showed improvement in the ...
[41]
Immune Checkpoint Inhibitors and Endocrine Disorders: A Position ...
Dec 26, 2022 · In nearly all patients with ICI-related hypophysitis, pituitary enlargement resolves within weeks to months [33,39]. It is possible that ...<|separator|>
[42]
Adrenal Crisis - StatPearls - NCBI Bookshelf
An adrenal crisis should be suspected in patients who exhibit acute refractory shock despite receiving adequate fluid resuscitation and vasopressor support.
[43]
Glucocorticoid therapy as first-line treatment in primary hypophysitis
Very high-dose glucocorticoids by i.v. route and cumulative longer duration (>6.5 weeks) lead to better outcomes and could be considered as first-line treatment ...
[44]
Hypophysitis Outcome and Factors Predicting Responsiveness to ...
Glucocorticoid treatment of hypophysitis improves pituitary secretion and should be encouraged in accordance with the evaluation of endocrine-, immunological-, ...
[45]
Neuroimaging of hypophysitis: etiologies and imaging mimics - PMC
Apr 3, 2023 · In this article, we will review the types of hypophysitis and summarize clinical and imaging features of both hypophysitis and its mimickers.Missing: tests | Show results with:tests
[46]
Hypopituitarism and Cardiovascular Risk
Apr 29, 2025 · Hypopituitarism, resulting from a partial or complete deficiency of anterior or posterior pituitary hormones, is associated with increased cardiovascular (CV) ...
[47]
Neurocognitive Function, Psychosocial Outcome, and Health ...
Jul 21, 2020 · Three survivors experienced hypophysitis; all suffered from persistent fatigue and cognitive complaints 5 years after onset.
[48]
Pituitary autoimmunity: 30 years later - PMC - NIH
In 1962 Goudie and Pinkerton described the autopsy of a young woman ... , first described in 1937, is an ischemic necrosis of the anterior pituitary ...
[49]
Pituitary autoantibodies in patients with hypopituitarism and their ...
Abstract. Autoantibodies to human pituitary cytosol proteins were determined by immunoblotting in sera from patients with hypopituitarism and their relatives.
[50]
IgG4-Related Hypophysitis: A New Addition to ... - Oxford Academic
We describe the first Caucasian patient with biopsy-proven IgG4-related hypophysitis and provide classification criteria for this disease.
[51]
https://onlinelibrary.wiley.com/doi/10.1155/2020/2192480
[52]
18 F-FDG PET/CT for Detection of Immunotherapy-Induced ...
Dec 1, 2024 · This study evaluates the diagnostic accuracy FDG PET/CT in detecting ICI-induced hypophysitis in a cohort of melanoma patients.Missing: 2020s | Show results with:2020s
[53]
Imaging for assessment of cancer treatment response to immune ...
Nov 28, 2023 · Detection of early onset of hypophysitis by (18)F-FDG PET-CT in a patient with advanced stage melanoma treated with ipilimumab. Clin Nucl ...Missing: 2020s | Show results with:2020s
[54]
Unveiling the Etiopathogenic Spectrum of Hypophysitis: A Narrative ...
Moreover, hypophysitis can be classified histologically into various forms: lymphocytic, granulomatous, xanthomatous, IgG4-related, and necrotizing hypophysitis ...3.4. Autoantigens Of Primary... · 4.3. Paraneoplastic Syndrome... · 5. Sars-Cov-2 And...
[55]
https://www.e-enm.org/journal/view.php?number=2626
[56]
Pituitary Complications of Checkpoint Inhibitor Use | Endocrine Society
Oct 8, 2024 · Immune checkpoint inhibitors have revolutionized cancer therapy but are associated with a risk of endocrine immune-related adverse events, including pituitary ...Missing: ICI | Show results with:ICI
[57]
Risk and Incidence of Endocrine Immune-Related Adverse Effects ...
May 7, 2024 · We showed that risk, independent from cancer type, and incidence of eirAEs are substantially increased with ICI therapy. Combination of ICIs ...