Hypophysitis 240310 174929

Hypophysitis 26/03/2023 18:00
Hypophysitis
Overview and Recommendations

Background
● Hypophysitis is a rare condition characterized by in!ammation of the pituitary gland
that typically results in pituitary enlargement and/or hypopituitarism.
● Types of hypophysitis include primary and secondary hypophysitis (such as immune
checkpoint inhibitor-induced hypophysitis).
⚬ Primary hypophysitis is characterized by in!ammation con"ned to the pituitary
gland that is caused by autoimmune-mediated destruction of the pituitary gland or
an unknown etiology.
⚬ Secondary hypophysitis is pituitary in!ammation that develops secondary to
autoimmune, in!ammatory, infectious, vascular and neoplastic conditions or as an
adverse e#ect of a medication (mostly due to immune checkpoint inhibitors).
● Clinical presentation can vary from asymptomatic to a life-threatening condition
(primarily due to adrenal crisis resulting from central adrenal insu$ciency).
● Prognosis varies by type of hypophysitis.
⚬ Some patients with primary hypophysitis may have complete remission, while
others continue to have persistent hypopituitarism.
⚬ For patients with immune checkpoint inhibitor-induced hypophysitis,
adrenocorticotropic hormone de"ciency is typically permanent, while thyroid-
stimulating hormone (TSH) and gonadotropin de"ciencies may be reversible in
patients with immune checkpoint inhibitor-induced hypophysitis due to cytotoxic T
lymphocyte-associated protein 4 (CTLA-4) inhibitors.
Evaluation
● Suspect hypophysitis in patients presenting with compressive signs and symptoms
(such as headache or visual defects) and/or hypopituitarism.
● Testing for suspected hypophysitis:
⚬ Perform blood tests to assess for pituitary hormone abnormalities, including
pituitary hormonal de"ciencies and hyperprolactinemia.
– Diagnostic tests to con"rm pituitary hormonal de"ciencies include:
● basal secretion of pituitary and peripheral hormones in the morning, after the
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patient has fasted (can be used to diagnose most pituitary hormone

de"ciencies, except for growth hormone [GH] and adrenocorticotropin
hormone [ACTH] de"ciency)
● dynamic hormone stimulation tests if there is suspected GH or ACTH de"ciency
or if there are unclear results on basal hormone tests
– Measure serum prolactin in the fasting state to con"rm diagnosis of
hyperprolactinemia (Strong recommendation).
⚬ Obtain gadolinium-enhanced pituitary magnetic resonance imaging to assess for
mass e#ect and to rule out other suprasellar or sellar mass lesions.
● Additional blood testing based on clinical suspicion includes assessing for
immunoglobulin (Ig) levels (particularly IgG4 levels) if there is suspected IgG4
hypophysitis.
● Consider additional imaging to help identify other sites of disease in patients suspected
of having secondary hypophysitis due to systemic pathology.
● Consider performing pituitary biopsy if diagnosis of primary hypophysitis is uncertain.
Management
● Management of hypophysitis includes:
⚬ reduction in in!ammatory pituitary enlargement associated with mass e#ect
consequences
⚬ replacement of any pituitary hormone de"ciencies
● Management of signs and symptoms of mass e#ect:
⚬ Consider surgical decompression by transsphenoidal hypophysectomy (preferred)
or administering glucocorticoids as the "rst-line treatment for patient with
hypophysitis who has severe signs and symptoms of mass e#ect.
⚬ If patient with severe mass e#ect signs and/or symptoms is refractory to
glucocorticoid therapy, glucocorticoids are not tolerated or cause unacceptable
adverse e#ects, or patient has recurrent hypophysitis, consider either of:
– other immunosuppressive agents or monoclonal antibodies
– stereotactic radiation therapy
● If hypopituitarism is present, provide hormone replacement therapy.
⚬ Speci"c treatment for hypopituitarism depends on the speci"c endocrine de"ciency.
⚬ Management of adrenal insu$ciency:
– Treat ACTH de"ciency with glucocorticoid hormone replacement therapy using
either hydrocortisone or prednisone. Mineralocorticoid replacement is not

needed in patients with central hypoadrenalism.
– In patients who also require thyroid hormone replacement therapy,
glucocorticoid replacement should begin before thyroid hormone replacement
(rather than the other way around) due to the increased rate of glucocorticoid
metabolism caused by thyroid hormone and the subsequent risk of precipitating
an acute adrenal crisis.
– Treat patients with suspected adrenal crisis due to secondary adrenal
insu$ciency immediately with a hydrocortisone 50-100 mg parenteral injection
followed by appropriate !uid resuscitation (Strong recommendation).
⚬ Management of thyroid hormone de"ciency:
– Use levothyroxine in doses su$cient to achieve serum free thyroxine (T4) levels in
the mid to upper half of the reference range. Appropriate doses are usually up to
1.6 mcg/kg/day, with dose adjustments based on clinical context, age, and free T4
levels (Strong recommendation).
– Evaluate patients for adrenal insu$ciency before starting levothyroxine therapy.
Consider prescribing empiric glucocorticoid therapy in patients starting
levothyroxine therapy until there is a de"nitive evaluation for adrenal
insu$ciency (Weak recommendation).
⚬ Management of gonadotropin de"ciency:
– Use gonadal hormone replacement therapy (estrogen and progestin) in
premenopausal patients with central hypogonadism, assuming no
contraindications are present (Strong recommendation).
– Consider testosterone replacement for patients with central hypogonadism and
no contraindications in order to (Weak recommendation):
● prevent anemia related to testosterone de"ciency
● reduce fat mass
● improve bone mass density, libido, sexual function, energy levels, sense of
well-being, and muscle mass and strength
⚬ Management of GH de"ciency:
– O#er GH replacement to patients with proven GH de"ciency and no
contraindications. Recommended starting dose is (Strong recommendation):
● 0.2-0.4 mg/day for patients < 60 years old
● 0.1-0.2 mg/day for patients > 60 years old
– Titrate GH doses and maintain insulin growth factor-1 levels below the upper limit
of normal, and reduce the dose if side e#ects manifest (Strong recommendation).
⚬ Management of antidiuretic hormone de"ciency:

– Consider an individualized therapeutic schedule for desmopressin (DDAVP), a
synthetic analogue of arginine vasopressin.
– Desmopressin should ideally be initiated at bedtime, but some patients may also
require morning (twice daily) and, rarely, midday (3 times daily) doses.
– To reduce hyponatremia, educate all patients receiving DDAVP about the risks of
overdosing.
● If the patient has symptomatic hyperprolactinemia, treat with a dopamine agonist
(such as cabergoline and bromocriptine) with the dosage adjusted based on prolactin
levels.
● Consider treating patients with primary hypophysitis who do not have severe
compressive signs and symptoms or hypopituitarism with conservative management
(observation with long-term clinical and radiological follow-up). The exception is
patients with IgG4 hypophysitis who require prompt treatment to prevent "brosis.
Related Topics
● Hypopituitarism
● Toxicities of Immune Checkpoint Inhibitors
● Adrenal Insu$ciency in Adults
● Central Diabetes Insipidus
● Hyperprolactinemia
General Information
Description
● hypophysitis is a rare condition characterized by in!ammation of the pituitary gland
that typically results in pituitary enlargement and/or hypopituitarism 1 , 2 , 3
Definitions
● primary hypophysitis
⚬ characterized by in!ammation con"ned to the pituitary 2
⚬ comprises some autoimmune forms of hypophysitis with distinctive immunological
pro"les and histopathological features and idiopathic forms with unknown etiologies
and pathogenesis 1
● secondary hypophysitis - forms of hypophysitis that develop secondary to

autoimmune, in!ammatory, infectious, vascular, and neoplastic conditions or as an
adverse e#ect of a medication (mostly due to immune checkpoint inhibitors) 1 , 5
● autoimmune hypophysitis - results from autoimmune-mediated pituitary gland
destruction (includes most forms of primary hypophysitis and within the secondary
category, forms caused by autoimmune polyendocrinopathies and systemic
autoimmune diseases) 1
● immunoglobulin (Ig)G4-related disease - systemic disease characterized by in"ltration
of IgG4-positive cells into multiple organs 1 , 4
● immune checkpoint inhibitors - monoclonal antibodies that bind to and inhibit the
action of immune checkpoint proteins (including cytotoxic T lymphocyte-associated
protein 4 [CTLA-4], programmed cell death protein-1 [PD-1], and programmed death
ligand-1 [PD-L1]), which allows T cells to detect cancer cells, resulting in immune-
mediated tumor lysis 1
Types
● types of hypophysitis include primary and secondary hypophysitis 1 , 2 , 3
⚬ classi"cation of subtypes of primary hypophysitis is ongoing as there is debate
regarding whether these variants represent distinct, idiopathic forms or are varying
expressions of the same autoimmune process due to the fact that mixed forms can
occur 2
⚬ primary hypophysitis can be classi"ed according to histology
Table 1. Histologic Subtypes of Primary Hypophysitis and Reported Patient

Characteristics
Subtype of Histopatho Female to Mean Age Association

Primary logy Male Ratio of With
Hypophysit Presentati Pregnancy
is on and/or
Postpartu
m
Lymphocyti – Focal or about 3:1 – 40-50 Yes (about

c di#use years in 70% of
hypophysiti lymphocy women cases in
s te – 50-60 women
in"ltratio years in present
n men during late
(primarily pregnancy
T cells) of or
the postpartum)
pituitary
gland
– Lymphoc
ytes can
be
arranged
in
lymphoid
follicles
with
germinal
centers
– Occasion
ally
plasma
cells,
"broblast
s, and
eosinophi
ls are
present
– Pituitary
"brosis
and
atrophy
might
occur in
later
stages of
disease
Idiopathic – Numerou 2.6:1 44 years No

granulomat s
ous multinucl
hypophysiti eated
s giant cells
and
histiocyte
s
arranged
in the
form of
granulom
as
– Areas of
"brosis
possible
Xanthomato – Foamy 3:1 40-50 years No

us histiocyte
hypophysiti s (lipid-
s rich
macroph
ages)
– Absence
of
granulom
as,
plasma
cells, or
small,
round
mature
lymphocy
tes
– Pituitary
"brosis
possible
in later
stages of
disease
IgG4 – Mononuc 1:3 – 56.4 No

hypophysiti lear years in
s* in"ltratio women
n with – 67.5
abundant years in
lymphocy men
tes and
plasma
cells
– ≥ 10
IgG4-
positive
cells per
high-
power
"eld
– Storiform
"brosis is
observed
– Pituitary
"brosis
and
atrophy
might
occur in
later
stages of
disease
Necrotizing – Di#use 1:3 NA No

hypophysiti nonhemo
s rrhagic
necrosis
surround
ed by
lymphocy
tes,
plasma
cells, and
eosinophi
ls
– Fibrosis
(if chronic
in!amma
tion)
Mixed-form – Lymphog NA NA NA
hypophysiti ranuloma
s tous
hypophys
itis can
contain
features
of both
lymphocy
tic and
granulom
atous
forms
– Xanthogr
anulomat
ous
hypophys
itis
presents
with
foamy
xanthom
a cells
and
multinucl
eated
giant
cells;
cholester
ol clefts,
and
hemoside
rin
deposits
may also
be
present
Abbreviations: Ig, immunoglobulin; NA, not available.
* Information presented is for both isolated IgG4 hypophysitis (primary hypophysitis) and
IgG4 hypophysitis in the context of IgG4-related disease (secondary hypophysitis).
Reference - Best Pract Res Clin Endocrinol Metab 2019 Dec;33(6):101371 full-text ,
Neuroendocrinology 2020;110(9-10):822 , Endotext 2018 .
– histology-based classi"cation is not possible for all patients as it requires

neurosurgical biopsy, which can involve signi"cant morbidity 3
⚬ primary hypophysitis can also be classi"ed by pattern of pituitary involvement
– subtypes of primary hypophysitis based on pattern of pituitary involvement
include 1 , 4
● adenohypophysitis (in!ammation of the anterior pituitary)
● infundibuloneurohypophysitis (in!ammation of the posterior pituitary and the
stalk)
● panhypophysitis (in!ammation of the entire pituitary)
– for example, subtypes of lymphocytic hypophysitis further classi"ed based on
pituitary involvement include 1 , 3 , 4
● lymphocytic adenohypophysitis
● lymphocytic infundibuloneurohypophysitis
● lymphocytic panhypophysitis
– classi"cation by pattern of pituitary involvement does not relate to a particular

etiology, but may be helpful describing pituitary hormone de"ciencies that may
arise 3
● secondary hypophysitis includes forms of hypophysitis that develop secondary to
adverse e#ect of a medication (such as immune checkpoint inhibitor-induced
hypophysitis) 1 , 5
Table 2. Examples of Forms of Secondary Hypophysitis and Associated

Histopathological Characteristics
Form of Secondary Hypophysitis Histopathology
Immune checkpoint inhibitor-induced ⚬ T-cell in"ltration

hypophysitis ⚬ IgG4-dependent complement
"xation and phagocytosis
Hypophysitis secondary to sarcoidosis Noncaseating granulomas
Hypophysitis secondary to ⚬ Necrotizing granulomas

granulomatous polyangiitis ⚬ Vasculitis in small and medium-sized
blood vessels
Hypophysitis secondary to Langerhans Pituitary in"ltration with Langerhans

cell histiocytosis cells, neutrophils, eosinophils, small
lymphocytes, and histiocytes
Hypophysitis secondary to Erdheim- Histiocytes with non-Langerhans

Chester disease features
Anti-PIT-1 hypophysitis Pituitary in"ltration with CD8+ cells
Hypophysitis secondary to Rosai- ⚬ Plasma cell in"ltration, mixed with

Dorfman disease lymphocytes
⚬ Large histiocytes with foamy
cytoplasm
⚬ Touton giant cells
Hypophysitis secondary to Tolosa-Hunt Nonspeci"c granulomatous or

syndrome nongranulomatous in!ammation
Hypophysitis secondary to Cogan Granulomatous in"ltration

syndrome
Hypophysitis secondary to pituitary B-cell in"ltration

lymphoma
Abbreviations: anti-PIT-1, antipituitary speci"c transcription factor 1; Ig, immunoglobulin.
Reference - Neuroendocrinology 2020;110(9-10):822 , Endocr Rev 2020 Apr

1;41(2):doi:10.1210/endrev/bnz003 .
Epidemiology
Who Is Most A!ected

● primary hypophysitis subtypes (with the exception of necrotizing hypophysitis) are
more common in women than men, while immune checkpoint inhibitor-induced
hypophysitis and immunoglobulin (Ig)G4 hypophysitis in the context of IgG4-related
disease are more common in men than women 1
● lymphocytic hypophysitis (a subtype of primary hypophysitis and the most common
form of hypophysitis) most often a#ects women during the last month of pregnancy to
≤ 2 months post partum 5
Incidence/Prevalence
● hypophysitis is relatively rare
⚬ 0.2%-0.88% reported overall prevalence in the general population 1
⚬ < 1% of sella and suprasellar lesions referred to neurosurgical centers reported to
be hypophysitis, although hypophysitis is likely to be underrepresented in surgical
case series since surgery often only occurs if a signi"cant mass e#ect is present 3
● incidence and prevalence has increased in last decade and is likely to increase further
due to 1
⚬ more awareness in medical community of condition

⚬ improved imaging techniques
⚬ increased occurrence of types such as immunoglobulin (Ig)G4 and immune
checkpoint inhibitor-induced hypophysitis
⚬ identi"cation of novel forms such as antipituitary-speci"c transcription factor-1
hypophysitis and isolated adrenocorticotropic hormone de"ciency
● prevalence of primary hypophysitis
Table 3. Reported Prevalence of Subtypes of Primary Hypophysitis
Subtype of Primary Hypophysitis Prevalence of Subtype*
Lymphocytic hypophysitis 68%
Idiopathic granulomatous hypophysitis 20%
Xanthomatous hypophysitis 3%
IgG4 hypophysitis (both isolated and in 4%

the context of IgG4-related disease)
Necrotizing hypophysitis 0.6%
Mixed-form hypophysitis 4%
Abbreviation: Ig, immunoglobulin.
* Prevalence of subtype given as percentage of total cases of primary hypophysitis.
Endotext 2018 .
● reported prevalence of immune checkpoint inhibitor-induced hypophysitis 1

⚬ 11%-13.6% of patients receiving cytotoxic T-lymphocyte associated protein 4 (CLTA-
4) inhibitors
⚬ 0.5% of patients receiving programmed cell death protein-1 (PD-1) or programmed
death ligand-1 (PD-L1) inhibitors
Risk Factors
● risk factors for primary hypophysitis include
⚬ pregnancy and postpartum period (for lymphocytic hypophysitis) 1 , 3 , 4
⚬ Rathke cleft cyst (for xanthomatous hypophysitis) 1 , 3
● risk factors for secondary hypophysitis
⚬ medications
1,3
– immune checkpoint inhibitors, including
● cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, such as
ipilimumab
● programmed cell death protein-1 (PD-1) inhibitors, such as pembrolizumab
and nivolumab
● programmed death ligand-1 (PD-L1) inhibitors, such as atezolizumab,
avelumab, and durvalumab
– interferon alfa-2a and alfa-2b 1 , 3
– ustekinumab 1
⚬ autoimmune conditions
– autoimmune endocrinopathies
● autoimmune polyglandular syndromes 1 , 3
● Hashimoto thyroiditis 1
● Graves disease 1
● type 1 diabetes mellitus 1 (
● Addison disease (primary adrenal insu$ciency) 1
– systemic autoimmune conditions
● systemic lupus erythematosus 1 , 3
● Sjogren syndrome 1
● Behcet disease 1
● primary biliary cholangitis 1
● optic neuritis 1
● atrophic gastritis 1
● myocarditis 1
● Crohn disease 1 , 3
● idiopathic thrombocytopenic purpura 1
● autoimmune hepatitis 1
– vasculitides
● temporal arteritis 1
● Takayasu arteritis 1 , 3
● granulomatosis with polyangiitis 1 , 3
● microscopic polyangiitis 1
● Cogan syndrome 1
⚬ in!ammatory and proliferative disorders
– sarcoidosis 1 , 3
– immunoglobulin (Ig)G4-related diseases, such as 1 , 3
● autoimmune pancreatitis
● Mikulicz disease
● Riedel thyroiditis
● retroperitoneal "brosis
● in!ammatory pseudotumor
● hypertrophic pachymeningitis
– Langerhans cell histiocytosis 1 , 3
– Erdheim-Chester disease 1 , 3
– Tolosa-Hunt syndrome 1
– Rathke cleft cyst rupture 1 , 3
– Castleman disease 3
– hemochromatosis 2
⚬ neoplastic lesions of sellar and suprasellar regions
– pituitary adenoma 1
– germinoma 1 , 3
– craniopharyngioma 1
– meningioma 1
– glioma 1
– chordoma 1
– pituicytoma 1
– pituitary lymphoma 1
– dermoid 1
– epidermoid 1
⚬ infections
– tuberculosis 1 , 3
– syphilis 1 , 3
– fungal infection (nocardiosis, aspergillosis) 1 , 3
– pituitary abscess 1
– viruses (coxsackie, herpes simplex, varicella zoster) 1
– toxoplasma 1
⚬ novel risk factors for secondary hypophysitis 1
– thymoma or another malignant neoplasm may increase risk for antipituitary
speci"c transcription factor 1 (anti-PIT1) hypophysitis
– large-cell neuroendocrine carcinoma or other malignancies (such as gastric
cancer and acute myeloid leukemia) may increase risk for isolated
adrenocorticotropic hormone (ACTH) de"ciency (might represent a novel form of
autoimmune hypophysitis)
EVIDENCE SYNOPSIS
Immune checkpoint inhibitors (particularly CTLA-4 inhibitors) may be associated with

an increased risk of hypophysitis.
STUDY
⚬ SUMMARY
programmed cell death 1 inhibitors associated with increased incidence of
immune checkpoint inhibitor-induced hypophysitis
SYSTEMATIC REVIEW: BMJ 2018 Mar 14;360:k793 | Full Text
Details
– based on systematic review limited by clinical heterogeneity
– systematic review of 13 randomized trials comparing immune-related adverse
events in 3,803 patients receiving PD-1 or PD-L1 inhibitors and 2,873 controls
– clinical heterogeneity included di#erences in
● cancer type (3 trials included patients with melanoma, 7 trials included
patients with metastatic non-small cell lung cancer, and 1 trial each included
patients with renal cell carcinoma, bladder cell carcinoma, and head and neck
squamous cell carcinoma)
● type of immune-checkpoint inhibitor (6 trials evaluated nivolumab [PD-1
inhibitor], 5 trials evaluated pembrolizumab [PD-1 inhibitor], and 2 trials
evaluated atezolizumab [PD-L1 inhibitor])
● comparator (11 trials used chemotherapy, 1 trial used targeted therapy, and 1
trial used both)
– incidence of immune checkpoint inhibitor-induced hypophysitis due to PD-1
inhibitor exposure
● overall 0.3%
● serious 0.2%
– compared to control, PD-1 inhibitor therapy associated with increased incidence
of immune checkpoint inhibitor-induced hypophysitis (odds ratio 3.38, 95% CI
1.03-11.08) in analysis of 13 trials
– Reference - BMJ 2018 Mar 14;360:k793 full-text
STUDY
⚬ SUMMARY
CTLA-4 inhibitors associated with increased incidence of hypophysitis
compared to programmed cell death 1 inhibitors and programmed death ligand-
1 inhibitors
SYSTEMATIC REVIEW: Ann Oncol 2017 Oct 1;28(10):2377 | Full Text
Details
– based on systematic review without assessment of trial quality
– systematic review of 48 trials evaluating immune-related adverse events in 6,938
patients receiving CTLA-4 and/or PD-1 or PD-L1 inhibitors
– 26 trials evaluated CTLA-4 inhibitor, 17 trials evaluated PD-1 inhibitor, 2 trials
evaluated PD-L1 inhibitor, and 3 trials evaluated combination of CTLA-4 and PD-1
or PD-L1 inhibitor
– comparing CTLA-4 inhibitors vs. PD-1 or PD-L1 inhibitors, CTLA-4 inhibitors
associated with increased incidence of hypophysitis (odds ratio 6.5, 95% CI 3-
14.3)
– Reference - Ann Oncol 2017 Oct 1;28(10):2377 full-text , commentary can be
found in Ann Oncol 2018 Apr 1;29(4):1067 , Am J Respir Crit Care Med 2018 Oct
1;198(7):951
STUDY
⚬ SUMMARY
combination immunotherapy with ipilimumab plus nivolumab appears to
increase risk of hypophysitis compared to ipilimumab alone in patients treated
with immune checkpoint inhibitors
SYSTEMATIC REVIEW: JAMA Oncol 2018 Feb 1;4(2):173 | Full Text

Details
– based on systematic review without assessment of study quality

– systematic review of 38 randomized trials evaluating immune-related endocrine
toxicities in 7,551 patients treated with immune checkpoint inhibitors
– 85 cases of hypophysitis observed among 6,472 patients (0.5% of cases were
classi"ed as grade 3 or higher)
– overall incidence of hypophysitis
● 6.4% with combination therapy (ipilimumab plus nivolumab)
● 3.2% with CTLA-4 inhibitors (ipilimumab monotherapy)
● 0.4% with PD-1 inhibitors (nivolumab or pembrolizumab monotherapy)
● < 0.1% with PD-L1 inhibitors (atezolizumab monotherapy)
– compared to ipilimumab monotherapy
● combination therapy associated with increased incidence of hypophysitis
(odds ratio 2.2, 95% CI 1.39-3.6)
● PD-1 inhibitors associated with decreased incidence of hypophysitis (odds
ratio 0.29, 95% CI 0.18-0.49)
– Reference - JAMA Oncol 2018 Feb 1;4(2):173 full-text , commentary can be
found in JAMA Oncol 2018 Sep 1;4(9):1295
STUDY
● SUMMARY
human leukocyte antigen class II marker DQ8 might be associated with increased
sporadic lymphocytic hypophysitis in adults
CASE-CONTROL STUDY: J Clin Endocrinol Metab 2015 Nov;100(11):4092 | Full Text

Details
⚬ based on case-control study
⚬ 20 adults (mean age 46 years) with hypophysitis were compared to 54 adult controls
(no age reported) without hypophysitis
– of cases, 15 were patients with sporadic lymphocytic hypophysitis, 4 with immune
checkpoint inhibitor-induced hypophysitis, and 1 with hypophysitis secondary to
sarcoidosis
– of controls, 50 had other sellar abnormalities and 4 had been treated with
immune checkpoint inhibitors but did not develop hypophysitis
– immune checkpoint inhibitors used were CTLA-4 inhibitors ipilimumab or
tremelimumab
⚬ all adults were assessed for human leukocyte antigen (HLA) class II markers DQ8 and
DRW53
Table 4. Percentage of HLA Class II Markers
Patient Group HLA-DQ8 HLA-DR53
Sporadic lymphocytic 87% 80%

hypophysitis
Immune checkpoint 0% 25%

inhibitor-induced
hypophysitis
Controls 20% 48%
Abbreviation: HLA, human leukocyte antigen.
⚬ 73% of patients with sporadic lymphocytic hypophysitis had both HLA markers DQ8
and DR53
⚬ comparing patients with sporadic lymphocytic hypophysitis to patients with another
sella mass
– patients with sporadic lymphocytic hypophysitis were more likely to have HLA
class II marker DQ8 (odds ratio [OR] 23.1, 95% CI 5.24-181)
– no signi"cant di#erence in likelihood of having HLA class II marker DR53 (OR 3.5,
95% CI 0.96-17.1)
⚬ Reference - J Clin Endocrinol Metab 2015 Nov;100(11):4092 full-text
Associated Conditions
● in patients with lymphocytic adenohypophysitis, other autoimmune diseases such as
chronic thyroiditis 4
● in patients with antipituitary speci"c transcription factor 1 (anti-PIT1) hypophysitis,
other endocrine conditions (such as type 1 diabetes mellitus) 1
Etiology and Pathogenesis
Causes
● primary hypophysitis is characterized by in!ammation con"ned to the pituitary gland
that is caused by autoimmune-mediated destruction of the pituitary gland or an
unknown etiology 1 , 2 , 3 , 4
● secondary hypophysitis is pituitary in!ammation that develops secondary to
adverse e#ect of a medication (mostly due to immune checkpoint inhibitors) 2 , 5
Pathogenesis
Pathogenesis of Primary Hypophysitis
● primary hypophysitis is thought to be largely an autoimmune condition, although the
exact pathogenesis for each subtype is unclear 1
● lymphocytic hypophysitis
⚬ thought to have an autoimmune etiology due to 5
– evidence of lymphocytic in"ltration of the pituitary
– association with pregnancy and certain human leukocyte antigen (HLA) alleles
– often "nding pituitary antibodies in patients with lymphocytic hypophysitis
– improvement of symptoms with immunosuppressive medications
⚬ possible explanations for the association between lymphocytic hypophysitis and
pregnancy include
– pituitary enlarges during pregnancy, possibly leading to a release of pituitary
antibodies (Indian J Endocrinol Metab 2013 Nov;17(6):996 full-text )
– common antibodies reacting against both pituitary and placenta (Minerva
Endocrinol 2016 Sep;41(3):390 )
– change in the pituitary blood !ow pattern with more from systemic circulation
and less from hypothalamic-pituitary portal system, possibly allowing the pituitary
to become more accessible to the immune system (Indian J Endocrinol Metab
2013 Nov;17(6):996 full-text )
⚬ pituitary antibodies reported in patients with lymphocytic hypophysitis include those
against 2
– alpha-enolase
– gamma-enolase
– pituitary gland speci"c factors 1 and 2
– secretogranin 2
– chorionic somatomammotropin
– corticotroph-speci"c transcription factor (TPIT)
⚬ other antibodies described in patients with lymphocytic hypophysitis include 2
– antihypothalamic antibodies targeting corticotrophin-releasing hormone-
secreting cells
– antibodies against somatotroph, lactotroph, gonadotroph, and corticotroph cells
causing selective hormone de"ciencies
● idiopathic granulomatous hypophysitis may represent a late histopathological
manifestation of lymphocytic hypophysitis, since granulomatous hypophysitis
reportedly occurs about 8 years after lymphocytic hypophysitis 1
● xanthomatous hypophysitis is thought to represent an in!ammatory response to
ruptured Rathke cleft cyst 2 , 5
● pathogenesis for immunoglobulin (Ig)G4 hypophysitis remains unknown, although
autoimmunity is potentially involved due to reported presence of the following in
biopsy-proven IgG4 hypophysitis 4
⚬ autoantigen candidates such as growth hormone and proopiomelanocortin
⚬ antipituitary antibodies
● pathogenesis for necrotizing hypophysitis is unknown, but the condition may represent
a more severe form of other forms of hypophysitis 1
● mixed forms of hypophysitis 1 , 2
⚬ lymphogranulomatous hypophysitis may be transitional phase from initial
in"ltration in lymphocytic hypophysitis to chronic in!ammation of granulomatous
hypophysitis
⚬ xanthogranulomatous hypophysitis may be part of disease spectrum that begins
with xanthomatous form and transitioning to xanthogranulomatous form
Pathogenesis of Immune Checkpoint Inhibitor-induced Hypophysitis

● immune checkpoint inhibitor-induced hypophysitis is thought to occur due to immune
checkpoint inhibitors binding to pituitary cells and triggering 1
⚬ activation of humoral immune response resulting in production of antipituitary
antibodies
⚬ combined type 2 and type 4 hypersensitivity reactions
– type 2 reaction leads to activation of macrophages and complement pathway due
to IgG antibody binding to target antigen on pituicytes
– type 4 reaction is driven by cytotoxic T-lymphocyte activation that results in

granzyme and perforin-mediated toxicity, cytokine release and B lymphocyte and
phagocyte activation
● cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors are more likely than
programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1)
inhibitors to cause immune checkpoint inhibitor-induced hypophysitis, as the latter are
not e$cient at activating cytotoxicity or complement pathway 1
Pathogenesis of Antipituitary Specific Transcription Factor 1 (Anti-PIT-1)

Hypophysitis
● proposed pathogenesis of anti-PIT-1 hypophysitis
⚬ a thymoma or neoplasm ectopically expresses pituitary speci"c transcription factor
1 (PIT-1) protein leading to a breakdown of immune tolerance and the production of
PIT-1-reactive cytotoxic T cells
⚬ in the pituitary, the PIT-1-reactive cytotoxic T cells recognize and attack the PIT-1
presenting cells (lactotrophs, somatotrophs, and thyrotrophs), resulting in cell-
speci"c injury
⚬ Reference - Endocr Rev 2020 Apr 1;41(2):doi:10.1210/endrev/bnz003
History and Physical
Clinical Presentation
● clinical presentation can vary from asymptomatic to a life-threatening condition
(primarily due to adrenal crisis resulting from central adrenal insu$ciency) 1
● patients with any type of hypophysitis may present with
⚬ signs and symptoms of mass e#ect (especially during acute or subacute phase),
including 1 , 2 , 3 , 5
– headache with or without nausea
– visual defects, such as bitemporal quadrantopsia or hemianopsia
– signs and symptoms of hyperprolactinemia (may be due to pituitary stalk
compression or immune-mediated destruction of prolactin-secreting cells), such
as
● galactorrhea (typically in women)
● loss of libido
● oligomenorrhea or amenorrhea in women
● erectile dysfunction in men
– ophthalmoplegia (rare)
– orbital pain (rare)
– facial paresthesia (rare)
⚬ signs and symptoms of anterior hypopituitarism (clinical manifestations depend on
type of hormone de"ciency) 1
Table 5. Anterior Pituitary Deficiencies From Most to Least Frequent in Patients

With Any Type of Hypophysitis
De!ciency Signs and Symptoms
ACTH – Fatigue and low stamina

– Arthralgias
– Orthostatic hypotension
– Anorexia and nausea/vomiting
– Hyponatremia
– Weight loss
TSH – Fatigue and low stamina

– Hyponatremia
– Constipation
– Weight gain
– Cold intolerance
– Menstrual
irregularities/amenorrhea in
women
FSH/LH (gonadotropins) – Fatigue and low stamina

– Erectile dysfunction in men
– Menstrual
irregularities/amenorrhea in
women
– Hot !ashes/vaginal dryness in
women
GH – General
● Short stature/reduced growth in
children
● Fatigue
● Impaired sleep quality
● Decreased exercise capacity
– Musculoskeletal
● Decreased muscle mass and
strength
● Osteoporosis
● Fractures
– Cardiovascular/metabolic
● Hypertension
● Decreased lean body mass
● Increased fat mass
● Hyperlipidemia
● Insulin resistance
● Impaired glucose tolerance
● Impaired cardiac function
● Premature atherosclerosis
Prolactin Lactation failure in postpartum

women (may indicate lymphocytic
hypophysitis)
Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH,

growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.
Reference - Best Pract Res Clin Endocrinol Metab 2019 Dec;33(6):101371 full-text , J Clin
Endocrinol Metab 2016 Nov;101(11):3888 , J Clin Endocrinol Metab 2016 Feb;101(2):364
full-text .
⚬ signs and symptoms of central diabetes insipidus (more likely to occur in patients
with infundibuloneurohypophysitis or panhypophysitis), such as 1
– polyuria
– polydipsia
– nocturia
– dehydration
⚬ rare "ndings in patients with autoimmune hypophysitis may include 1

– weight gain and disruption of temperature regulation (due to hypothalamic
dysfunction)
– hypercalcemia (in patients with adrenal insu$ciency)
● clinical presentation can vary by type of hypophysitis
⚬ overall, primary hypophysitis is more common in women with a mean age at
presentation of 41 years, while immune checkpoint inhibitor-induced hypophysitis is
more common in men with a mean age at presentation of 59 years 1 , 5
Table 6. Reported Signs and Symptoms of Primary Hypophysitis and Immune

Checkpoint Inhibitor-induced Hypophysitis
Type of Hypophysitis Signs and Pituitary

Symptoms Hormone
Abnormalities
Primary hypophysitis ⚬ Headache in ⚬ ACTH

47% de"ciency in
⚬ Polydipsia/pol 60%
yuria in 35% ⚬ FSH/LH
⚬ Visual de"ciency in
disturbances 55%
in 31% ⚬ TSH de"ciency
in 52%
⚬ ADH
de"ciency in
39%
⚬ GH decreased
in 38%
⚬ Hyperprolacti
nemia in 37%
Immune checkpoint inhibitor-induced ⚬ Headache in ⚬ ACTH

hypophysitis 60% de"ciency in
⚬ Visual 91%*
disturbances ⚬ TSH de"ciency

in 3% in 84%
⚬ Polydipsia/pol ⚬ FSH/LH
yuria in 0.9% de"ciency in
83%
⚬ GH decreased
in 43%
⚬ Hyperprolacti
nemia in 9%
⚬ ADH
de"ciency in
1%
Abbreviations: ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CTLA-4,

cytotoxic T lymphocyte-associated protein 4; FSH, follicle-stimulating hormone; LH, luteinizing
hormone; GH, growth hormone; TSH, thyroid-stimulating hormone; PD-1, programmed cell
death protein-1; PD-L1, programmed death ligand-1.
*Immune checkpoint inhibitor-induced hypophysitis due to PD-1 inhibitors or PD-L1 inhibitors

typically presents as isolated ACTH de"ciency, while immune checkpoint inhibitor-induced
hypophysitis due to CTLA-4 inhibitors often has numerous pituitary de"ciencies.
Reference - Endotext 2018 , Expert Rev Endocrinol Metab 2019 Nov;14(6):381 .
● subtypes of primary hypophysitis may have di#erent clinical presentations
Table 7. Clinical Presentation of Subtypes of Primary Hypophysitis
Primary Hypophysitis Subtype Clinical Presentation
Lymphocytic Lymphocytic ⚬ Signs and symptoms

hypophysitis adenohypophysitis of mass e#ect (such
as headache, visual
"eld disturbance,
galactorrhea)
⚬ Hypopituitarism signs
and symptoms, such
as fatigue and
amenorrhea
⚬ Decreased levels of ≥
1 anterior pituitary
hormones
Lymphocytic ⚬ Thirst
infundibuloneurohypop ⚬ Polydipsia and
hysitis polyuria
⚬ ADH de"ciency and
other laboratory
"ndings consistent
with central diabetes
insipidus
Lymphocytic ⚬ Signs and symptoms

panhypophysitis of mass e#ect (such
as headache, visual
"eld disturbance,
galactorrhea)
and symptoms
(including symptoms
of central diabetes
insipidus), such as
– Fatigue
– Amenorrhea
– Thirst
– Polydipsia and
polyuria
⚬ Decreased levels of ≥
1 anterior pituitary
hormones
⚬ ADH de"ciency and
other laboratory
"ndings consistent
with central diabetes
insipidus
Other types of primary Idiopathic ⚬ Headache

hypophysitis granulomatous ⚬ Visual disturbances
hypophysitis ⚬ Polyuria/polydipsia
and cranial nerve
palsies each reported
in about 25% of cases
Xanthomatous ⚬ Anterior pituitary is

hypophysitis most a#ected area
(but less severe than
in lymphocytic type)
⚬ Gonadotropin and
growth hormone
de"ciencies more
common than in
lymphocytic type
⚬ Rare signs and
symptoms include
– Visual disturbances
– Ophthalmoplegia
– Signs and
symptoms of
central diabetes
insipidus
IgG4 hypophysitis ⚬ Headache

⚬ Visual disturbances
⚬ Galactorrhea
and symptoms
(including signs and
symptoms of central
diabetes insipidus),
such as
– Fatigue
– Amenorrhea
– Thirst
– Polydipsia and
polyuria
⚬ Reported laboratory
"ndings
– 50% with
panhypopituitaris
m
– 25% with anterior
pituitary de"ciency
– 18% with isolated
central diabetes
insipidus
Necrotizing hypophysitis Likely to present with

more acute symptoms
of mass e#ect such as
⚬ Eye pain
⚬ Visual defects
⚬ Headache, sti# neck,
and photophobia
(may indicate aseptic
meningitis)
Abbreviations: ADH, antidiuretic hormone; Ig, immunoglobulin.
Neuroendocrinology 2020;110(9-10):822 , Endocr J 2020 Apr 28;67(4):373 full-text ,
Endotext 2018 .
● patients with secondary hypophysitis may also present with the features associated
with underlying conditions 1
History
History of Present Illness (HPI)
● onset of symptoms for patients with hypophysitis can be insidious, subacute, or acute
(potentially mimicking pituitary apoplexy) (Clin Diabetes Endocrinol 2016;2:15 full-
text )
● for immune checkpoint inhibitor-induced hypophysitis, time to onset varies according
to type of immune checkpoint inhibitor; onset of immune checkpoint inhibitor-induced
hypophysitis reported to be about
⚬ 6-12 weeks for cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor
(ipilimumab, tremelimumab)
⚬ 14-36 weeks for programmed cell death protein-1 (PD-1) inhibitor (nivolumab,
pembrolizumab)
⚬ 52-56 weeks for programmed death ligand-1 (PD-L1) inhibitor (atezolizumab)
⚬ 10 weeks for CTLA-4 plus PD-1 combination therapy (ipilimumab plus nivolumab or
ipilimumab plus pembrolizumab)
⚬ Reference - Future Oncol 2019 Sep;15(27):3159 full-text
Medication History
● ask about medications that are risk factors for hypophysitis, such as
⚬ immune checkpoint inhibitors, including 1 , 2 , 3 , 4
– CTLA-4 inhibitors, such as ipilimumab
– PD-1 inhibitors, such as pembrolizumab and nivolumab
– PD-L1 inhibitors, such as atezolizumab, avelumab, and durvalumab
⚬ interferon alfa-2a and alfa-2b 1 , 3
⚬ ustekinumab 1 , 2
Past Medical History (PMH)

● ask about conditions that are potential risk factors for primary and secondary
hypophysitis
Family History (FH)

● ask about family history of autoimmune disease (patients with lymphocytic
hypophysitis often have a family history of autoimmune conditions) (Pituitary 2016
Dec;19(6):625 full-text )
Physical
General Physical
● general physical "ndings may include
⚬ weight gain (may indicate thyroid-stimulating hormone de"ciency)
⚬ weight loss (may indicate adrenocorticotropin hormone [ACTH] de"ciency)
⚬ Reference - Endocrine Society clinical practice guideline on hormonal replacement in

hypopituitarism in adults (J Clin Endocrinol Metab 2016 Nov;101(11):3888 )
Skin
● assess for skin manifestations of hypopituitarism
⚬ dry skin, thinning of hair, and loss of body hair may be seen in patients with ACTH or
thyroid-stimulating hormone (TSH) de"ciencies (loss of body hair can also occur with
severe gonadotropin de"ciency of long duration)
⚬ pallor may be seen in patients with ACTH de"ciency or in men with luteinizing
hormone/follicle-stimulating hormone de"ciencies
⚬ see Hypopituitarism for additional information
HEENT
● look for signs of mass e#ect, including
⚬ visual defects, such as
– bitemporal quadrantopsia or hemianopsia due to compression of the optic
chiasm 1 , 3
– reduction in visual acuity due to compression of the optic apparatus 3
– pupillary defects due to compression of the ocular motor (third, fourth, and sixth
cranial) nerves 1 , 3
⚬ rarely
– orbital pain or facial paresthesia due to compression of the trigeminal ("fth
cranial) nerve 1
– ophthalmoplegia due to compression of the ocular motor (third, fourth, and sixth
cranial) nerves, which may present as diplopia 1 , 3
● assess for hoarseness (may be present in severe TSH de"ciency) (Endocrinol Metab
(Seoul) 2015 Dec;30(4):443 full-text )
Cardiac
● assess for
⚬ postural hypotension and tachycardia (may be seen in ACTH de"ciency) (J Clin
Endocrinol Metab 2016 Nov;101(11):3888 )
⚬ bradycardia (may be seen in TSH de"ciency) (Endocrinol Metab (Seoul) 2015
Dec;30(4):443 full-text )
Neuro
● assess ocular motor (third, fourth, and sixth cranial) nerves
⚬ pupil examination
– examine size, shape, and symmetry of pupils
– elicit direct (constriction when exposed to light) and indirect (constriction when
opposite pupil exposed to light) pupillary responses
– test accommodation of pupils (patient looks in distance then focuses on tip of
nose)
● absent light re!ex with intact accommodation may suggest midbrain or ciliary
ganglion lesion
● accommodation failure rarely occurs with midbrain lesion or cortical blindness
⚬ eye muscle function and movement
– look for failure in eye movement and ask about diplopia; diplopia is early sign of
extraocular muscle weakness
● horizontal diplopia suggests sixth nerve involvement (lateral rectus muscle)
● predominantly torsional diplopia suggests fourth nerve involvement (superior
oblique muscle)
● vertical diplopia suggests third and/or fourth nerve involvement (vertical recti
and oblique muscles)
– with diplopia, establish eye movement position where image separation is
maximal
● image separation should be greatest in direction of movement is maximally
mediated by weak muscle
● individually cover eyes at maximal image separation; false image disappears
when a#ected eye covered
– for sixth cranial nerve, test each eye independently; pseudorestrictive e#ects of
alternating monocular "xation and vergence occur when both eyes open
⚬ Reference - Clin Anat 2014 Jan;27(1):25
⚬ see Cranial Neuropathies for additional information
● evaluate trigeminal ("fth cranial) nerve
⚬ test trigeminal divisions sequentially on forehead, malar eminence, and lower face
over mandible (comparing both sides of face) for hypoalgesia using blunt tip needle
or hypoesthesia using cotton wool ball; loss of pain sensation will result in feeling of
dullness, which should be mapped to area
⚬ test corneal re!ex using wisp of cotton to touch cornea
– ask about corneal sensation and look for blink response (in both eyes)
– blinking occurring in contralateral eye alone may indicate ipsilateral facial (VII)
nerve palsy
⚬ test motor function of trigeminal nerve by assessing temporalis, masseteric, and
pterygoid muscles
– palpate temporalis and masseteric muscles for tone and bulk while jaw clenched
– test temporalis and masseteric muscle strength by assessing depth of bite marks
after bite on wooden tongue depressor
– test pterygoid muscle strength by attempting to force mouth shut while held
open
– test jaw re!ex placing index "nger on chin and tapping with tendon hammer;
slight or no jaw closure normal, exaggerated closure may indicate upper motor
neuron lesion
⚬ Reference - Clin Anat 2014 Jan;27(1):25
⚬ see Cranial Neuropathies for additional information
● cognitive defects may be seen in TSH and ACTH de"ciencies (J Clin Endocrinol Metab
2016 Nov;101(11):3888 )
Diagnosis
Making the Diagnosis
● suspect hypophysitis in patients presenting with
⚬ signs and symptoms of mass e#ect (especially during acute or subacute phase), such
as 1 , 2 , 3 , 5
– headache with or without nausea
– visual defects, such as bitemporal quadrantopsia or hemianopsia
– signs and symptoms of hyperprolactinemia, such as
● galactorrhea (typically in women)
● loss of libido
● oligomenorrhea or amenorrhea in women
● erectile dysfunction in men
⚬ signs and symptoms of anterior hypopituitarism (clinical manifestations depend on
type of hormone de"ciency) 1
⚬ signs and symptoms of central diabetes insipidus, such as 1
– polyuria
– polydipsia
– nocturia
– dehydration
● diagnosis of primary or secondary hypophysitis is based on clinical, biochemical, and
gadolinium-enhanced magnetic resonance imaging "ndings 2 , 5
● de"nitive diagnosis of primary hypophysitis requires pituitary biopsy and
histopathological evaluation, but this invasive procedure is only performed if
management outcome of biopsy outweighs its risks 2
● some subtypes of primary hypophysitis (such as lymphocytic and immunoglobulin
([Ig]G4 hypophysitis) have diagnostic criteria
CLINICIANS' PRACTICE POINT
IgG4 hypophysitis can be both isolated IgG4 hypophysitis (primary hypophysitis)

and IgG4 hypophysitis in the context of IgG4-related disease (secondary
hypophysitis). Because diagnosis and management of IgG4 hypophysitis does
not depend on distinction between primary and secondary types, IgG4
hypophysitis is grouped with other subtypes of primary hypophysitis.
⚬ Japan Endocrine Society diagnostic criteria for lymphocytic and IgG4 hypophysitis 4
Table 8. Japan Endocrine Society Diagnostic Criteria for Lymphocytic and IgG4
Hypophysitis
Primary Diagnostic Criteria Additional

Hypophysit Findings
is Subtype De!nitive Probable Possible
Diagnosis Diagnosis Diagnosis
Lymphocyti – Any of – Any of NA – More

c the the common
adenohypo following: following: in
physitis ● Signs ● Signs women,

or or especially
sympt sympt during
oms of oms of pregnanc
mass mass y and
e#ect e#ect postpartu
(such (such m
as as – Hyperpro
heada heada lactinemi
che, che, a
visual visual possible
"eld "eld – Often
disturb disturb accompa
ance, ance, nied by
galacto galacto autoimm
rrhea) rrhea) une
● Signs ● Signs disease
or or (such as
sympt sympt chronic
oms of oms of thyroiditi
hypopi hypopi s)
tuitaris tuitaris – Presence
m m of
(such (such antipituit
as as ary
fatigue fatigue antibodie
, , s possible
ameno ameno – Long-
rrhea) rrhea) term
cases
– PLUS all – PLUS all
may
of the of the
show
following: following:
empty
● Decrea ● Decrea
sella
sed sed
– Cystic
levels levels
changes
of ≥ 1 of ≥ 1
rare
anterio anterio
r r
hormo hormo
ne and ne and
those those
from from
target target
organs organs
● Impair ● Impair
ed ed
anterio anterio
r r
hormo hormo
ne ne
respon respon
se in se in
stimul stimul
ation ation
tests tests
● Di#use ● Di#use
enlarg enlarg
ement ement
of of
pituita pituita
ry ry
● Homo ● Homo
geneo geneo
us and us and
strong strong
enhan enhan
cemen cemen
t of t of
pituita pituita
ry on ry on
postga postga
doliniu doliniu
m MRI m MRI
● Lymph
ocytic
in"ltra
tion of
anterio
r
pituita
ry
Lymphocyti All of the All of the NA – Anterior

c following: following: pituitary
infundibulo- – Thirst, – Thirst, function
neurohypop polydipsi polydipsi usually
hysitis a, and a, and preserve
polyuria polyuria d
– Laborator – Laborator – Enlarged
y "ndings y "ndings pituitary
consisten consisten gland or
t with t with stalk
central central usually
diabetes diabetes resolves
insipidus insipidus in natural
– Enlarged – Enlarged course
pituitary pituitary
gland or gland or
stalk stalk
– Di#use – Di#use
and and
strong strong
enhance enhance
ment of ment of
posterior posterior
pituitary pituitary
and/or and/or
stalk stalk
lesion on lesion on
postgadol postgadol
inium inium
MRI MRI
– Lymphoc
ytic
in"ltratio
n of
lesion
Lymphocyti All of the All of the NA – Hyperpro

c following: following: lactinemi
panhypoph – Signs or – Signs or a
ysitis symptom symptom possible
s of mass s of mass – Pituitary
e#ect or e#ect or and
hypopitui hypopitui hypothal
tarism tarism amus
– Signs and – Signs and dysfuncti
symptom symptom on
s of s of possible
central central – Central
diabetes diabetes diabetes
insipidus insipidus insipidus
– Decrease – Decrease symptom
d levels d levels s may be
of ≥ 1 of ≥ 1 masked if
anterior anterior patient
hormone hormone has
and and secondar
those those y adrenal
from from insu$cie
target target ncy
organs organs
– Impaired – Impaired
anterior anterior
hormone hormone
response response
in in
stimulati stimulati
on tests on tests
– Laborator – Laborator
y "ndings y "ndings
consisten consisten
t with t with
central central
diabetes diabetes
insipidus insipidus
– Di#use – Di#use
enlargem enlargem
ent of ent of
pituitary pituitary
gland gland
and/or and/or
stalk stalk
– Homogen – Homogen
eous and eous and
strong strong
enhance enhance
ment of ment of
pituitary pituitary
on on
postgadol postgadol
inium inium
MRI MRI
– Lymphoc
ytic
in"ltratio
n of
pituitary
gland or
stalk
IgG4 – Any of – Any of – Any of – More

hypophysiti the the the common
s* following: following: following: in older
● Signs ● Signs ● Signs men
or or or – Central
sympt sympt sympt diabetes

oms of oms of oms of insipidus
mass mass mass symptom
e#ect e#ect e#ect s may be
or or or masked if
hypopi hypopi hypopi patient
tuitaris tuitaris tuitaris has
m m m secondar
● Signs ● Signs ● Signs y adrenal
and and and insu$cie
sympt sympt sympt ncy
oms of oms of oms of – Serum
central central central IgG4
diabet diabet diabet levels are
es es es > 135
insipid insipid insipid mg/dL
us us us (measure
– PLUS all – PLUS all – PLUS all prior to
of the of the of the corticoste
following: following: following: roid
therapy,
● Di#use ● Di#use ● Di#use
which
enlarg enlarg enlarg
can
ement ement ement
decrease
of of of
IgG4
pituita pituita pituita
levels)
ry ry ry
– Increased
gland gland gland
serum
and/or and/or and/or
IgE levels
stalk stalk stalk
possible
● IgG4- ● IgG4- ● Elevate
– > 10
positiv positiv d
IgG4-
e e serum
positive
plasm plasm IgG4
plasma
a cell a cell levels
cells per
in"ltra in"ltra ● Either
high-
tion of tion of decrea
power
other other sed
"eld or >
involve involve levels 40% ratio

d d of ≥ 1 of IgG4 to
organs organs anterio IgG-
● Either ● Either r positive
decrea decrea hormo cells
sed sed ne and – Detection
levels levels those of
of ≥ 1 of ≥ 1 from retroperit
anterio anterio target oneal
r r organs "brosis,
hormo hormo AND interstitia
ne and ne and impair l
those those ed pneumon
from from anterio ia,
target target r autoimm
organs organs hormo une
AND AND ne pancreati
impair impair respon tis,
ed ed se in dacryoad
anterio anterio stimul enitis,
r r ation and
hormo hormo tests, sialadenit
ne ne OR is likely
respon respon laborat
se in se in ory
stimul stimul "nding
ation ation s
tests, tests, consist
OR OR ent
laborat laborat with
ory ory central
"nding "nding diabet
s s es
consist consist insipid
ent ent us
with with
central central
diabet diabet
es es
insipid insipid
us us
Abbreviations: Ig, immunoglobulin; MRI, magnetic resonance imaging; NA, not applicable.
* Information presented is for both isolated IgG4 hypophysitis (primary hypophysitis) and
IgG4 hypophysitis in the context of IgG4-related disease (secondary hypophysitis).
Reference - Endocr J 2020 Apr 28;67(4):373 full-text .
● proposed diagnostic criteria for some forms of secondary hypophysitis

⚬ immune checkpoint inhibitor-induced hypophysitis
– strict diagnostic criteria have not been established
– proposed diagnostic criteria includes
● ≥ 1 pituitary hormone de"ciency (adrenocorticotropic hormone [ACTH] or
thyroid-stimulating hormone [TSH] de"ciency is required) plus evidence of
magnetic resonance imaging abnormality
● ≥ 2 pituitary hormone de"ciencies (ACTH or TSH de"ciency is required) plus
headache and other symptoms of hypophysitis in the absence of MRI
evaluation or "ndings
● Reference - Endocr Relat Cancer 2021 Jun 2;28(7):419 full-text
⚬ antipituitary speci"c transcription factor 1 (anti-PIT-1) hypophysitis 2
– de"nitive diagnosis established if patient presents with both of
● acquired speci"c growth hormone, thyroid-stimulating hormone, and prolactin
de"ciencies with no pituitary axes impairment
● circulating anti-PIT-1 antibodies or PIT-1-reactive cytotoxic T lymphocytes
– consider probable diagnosis if patient presents with acquired speci"c growth
hormone, thyroid-stimulating hormone, and prolactin de"ciencies with no other
pituitary axes impairment
– presence of underlying thymoma or other malignant neoplasm that exhibits
ectopic expression of anti-PIT-1 antibodies may help diagnosis and clarify
pathogenesis, but may not be obvious at diagnosis based on endocrine
abnormalities
Di!erential Diagnosis
⚬ di#erential diagnosis of primary hypophysitis is based on exclusion of other pituitary

conditions 5
– sella and parasellar masses, including
● pituitary adenoma (including pituitary apoplexy)
● pituitary metastases (especially in those with suspected hypophysitis and
malignant tumors who are receiving immune checkpoint inhibitors)
● other sella and parasella tumors, such as
⚬ germinomas
⚬ craniopharyngiomas
⚬ gliomas
⚬ meningiomas
⚬ lymphomas
⚬ pituicytomas
⚬ chordomas
⚬ teratomas
⚬ dermoid
⚬ epidermoids
● Rathke cleft cyst
● pituitary abscess
– thyrotropic hyperplasia associated with untreated, severe primary
hypothyroidism
– physiological pituitary hypertrophy in children and adolescents (particularly
pubertal) and perimenopausal persons
– other medical conditions and medications associated with secondary
hypophysitis
⚬ di#erential diagnosis for histologic subtypes of primary hypophysitis
– for lymphocytic hypophysitis, di#erential diagnosis includes 5
● pituitary hyperplasia associated with pregnancy
● Sheehan syndrome
– for idiopathic granulomatous hypophysitis, di#erential diagnosis includes
hypophysitis secondary to granulomatous conditions (such as sarcoidosis and
tuberculosis) 1
– for xanthomatous hypophysitis, rule out secondary causes of xanthomatous and
xanthogranulomatous lesions (such as Erdheim-Chester disease) in patients
where multiple organs are involved and especially if somatic BRAF V600 variant is
present 1 , 2
– for immunoglobulin (Ig)G4-related hypophysitis, di#erential diagnosis includes
other pituitary diseases such as 4
● pituitary adenoma
● Rathke cleft cyst
● craniopharyngioma
● malignant lymphoma
● granulomatosis with polyangiitis (can accompany secondary in"ltration with
small numbers of IgG4-positive plasma cells)
– for necrotizing hypophysitis, di#erential diagnosis includes assessing for other
causes of pituitary necrosis including 1
● Sheehan syndrome
● macroadenomas
● pituitary metastases
● septic shock
● snake venom poisoning
● secondary hypophysitis
⚬ secondary hypophysitis has a broad di#erential diagnosis due to the many potential
conditions serving as risk factors 3
⚬ critical in the di#erential diagnosis of immune checkpoint inhibitor-induced
hypophysitis is distinguishing pituitary metastases 5
Table 9. Comparing Findings of Immune Checkpoint Inhibitor-induced Hy-

pophysitis and Pituitary Metastases
Diagnostic Immune Checkpoint Pituitary Metastases

Characteristics Inhibitor-induced
Hypophysitis
Clinical presentation – Anterior pituitary – Anterior pituitary

de"ciencies common de"ciencies reported
(mainly ACTH, in about 24% of
FSH/LH, and TSH)* patients
– Central diabetes – Central diabetes
insipidus rare insipidus common
– Headache a frequent – Headache and retro-

symptom orbital pain reported
in about 16% of
patients
– Cranial nerve de"cits
due to cavernous
sinus and chiasm
involvement
reported in about
22%-28% of patients
MRI – Mild-to-moderate – Sella or suprasellar

di#use pituitary mass
enlargement (up to – T1WI shows
60%-100% of isointense or
baseline size)** hypointense mass
– Heterogenous or – T2WI typically shows
homogenous high-intensity sign
postgadolinium – Homogenous
enhancement postgadolinium
– Suprasellar enhancement
extension with (hemorrhage,
compressed and necrosis, cystic
displaced chiasm degeneration
uncommon possible)
– Pituitary stalk might – Cavernous sinus,
be thickened but not chiasm, or
deviated hypothalamus
– Posterior pituitary invasion reported in
usually preserved about 14%
– Pituitary stalk
thickened and
enhancing
– Other brain
metastases reported
in about 15%
– Posterior pituitary
bright spot
reportedly lost in
about 13%
– Dumbbell-shaped
mass reported in
about 11%
– Sphenoid sinus
invasion reported in
about 9%
CT NA Bony destruction
possible
Abbreviations: ACTH, adrenocorticotropic hormone; CT, computed tomography; CTLA-4,

cytotoxic T lymphocyte-associated protein 4;FSH, follicle-stimulating hormone; LH,
luteinizing hormone; MRI, magnetic resonance imaging; NA, not applicable; PD-1,
programmed cell death protein-1; PD-L1, programmed death ligand-1; T1WI, T1-weighted
image; T2WI, T2-weighted image; TSH, thyroid-stimulating hormone.
* Immune checkpoint inhibitor-induced hypophysitis due to PD-1 inhibitors or PD-L1

inhibitors typically presents as isolated ACTH de"ciency, while immune checkpoint
inhibitor-induced hypophysitis due to CTLA-4 inhibitors often has numerous pituitary
de"ciencies.
** Radiologic abnormalities (including pituitary enlargement, altered contrast

enhancement, and stalk widening) are more common with immune checkpoint inhibitor-
induced hypophysitis due to CTLA-4 inhibitors compared to immune checkpoint inhibitor-
induced hypophysitis due to PD-1 or PD-L1 inhibitors.
● in pediatric population, congenital disorders with abnormal pituitary development due

to PIT1 or PROP1 mutations (typically present during infancy or early childhood) leading
to panhypopituitarism must be ruled out 1
Testing Overview
● if suspect hypophysitis
⚬ perform blood tests to assess for pituitary hormone abnormalities, including
pituitary hormonal de"ciencies and hyperprolactinemia
– diagnostic tests to con"rm pituitary hormonal de"ciencies include
● basal secretion of pituitary and peripheral hormones in the morning, after the
patient has fasted (can be used to diagnose most pituitary hormone
de"ciencies, except for growth hormone [GH] and adrenocorticotropin
hormone [ACTH] de"ciency)
● dynamic hormone stimulation tests if there is suspected GH or ACTH de"ciency
or if there are unclear results on basal hormone tests
– single measurement of serum prolactin above upper limit of normal con"rms
diagnosis of hyperprolactinemia (in absence of excessive venipuncture stress or
recent food intake/exercise) (Endocrine Society Strong recommendation, High-
quality evidence)
⚬ obtain gadolinium-enhanced pituitary magnetic resonance imaging to assess for
mass e#ect and to rule out other suprasellar or sellar mass lesions
● additional blood testing based on clinical suspicion includes assessing for
immunoglobulin (Ig) levels (particularly IgG4 levels) if suspect IgG4 hypophysitis
● consider additional imaging to help identify other sites of disease in patients suspected
of having secondary hypophysitis due to systemic pathology
● consider performing pituitary biopsy if diagnosis of primary hypophysitis is uncertain
Blood Tests
Blood Tests to Assess for Pituitary Hormone Abnormalities
● if suspect hypophysitis, evaluate for pituitary hormonal de"ciencies and assess for
hyperprolactinemia 1
⚬ overview of blood tests to assess for pituitary hormone de"ciencies
– most pituitary hormone de"ciencies can be diagnosed by measuring basal
secretion of pituitary and peripheral hormones in the morning, after the patient
has fasted
– dynamic hormone stimulation tests are necessary to diagnose suspected growth
hormone (GH) or adrenocorticotropin hormone (ACTH) de"ciency, and can also
be used if there are unclear results on basal hormone tests
– testing for suspected ACTH de"ciency
● central adrenal insu$ciency (AI) can be diagnosed using low-dose and
standard-dose ACTH stimulation tests (most common) or insulin tolerance test
● insulin tolerance test is the gold standard for diagnosis of ACTH de"ciency in
adults but contraindications may limit its use (contraindications include older
age, history of cardiovascular disease, or seizure)
● synthetic ACTH (ACTH 1-24, known as tetracosactide [Synacthen] in Europe and

cosyntropin [Cortrosyn] in the United States) 250 mcg IV or intramuscular
injection is most widely used test for adrenal insu$ciency
⚬ normal adrenocortical reserve con"rmed if peak cortisol concentrations >
500-600 nmol/L (18.1-21.7 mcg/dL)
⚬ adrenal insu$ciency indicated if peak plasma cortisol level < 500 nmol/L (18
mcg/dL) (this di#ers from Addison disease [primary adrenal insu$ciency], in
which basal morning ACTH levels are inappropriately normal or low in
patients with central hypoadrenalism)
– testing for suspected TSH de"ciency
● TSH de"ciency can be diagnosed using thyroid function tests
● TSH de"ciency related to the pituitary gland can be distinguished from primary
hypothyroidism as it presents with a low basal serum free thyroxine (T4) level
with a low or inappropriately normal TSH
– testing for suspected gonadotropin hormone de"ciency
● gonadotropin hormone de"ciency can often be diagnosed with a basal
hormone test
⚬ in women, low serum estradiol coincident with low or inappropriately
normal FSH and LH levels reported to be diagnostic in presence of
oligomenorrhea or amenorrhea
⚬ in men, measurements of morning serum total testosterone < 10.4 nmol/L
(< 300 ng/dL) with low or inappropriately normal gonadotropin
concentrations on 2 occasions reported to be diagnostic of gonadotropin
de"ciency
● dynamic testing with gonadotropin-releasing hormone (GnRH) not
recommended (Endocrine Society Weak recommendation, Low-quality
evidence)
– testing for suspected growth hormone de"ciency
● consider biochemical testing for GH de"ciency only when there is high pretest
probability of de"ciency, which is indicated if ≥ 1 of the following prescreening
criteria are ful"lled
⚬ young adults with normal pituitary imaging requiring GH therapy for short
stature secondary to diagnosed GH de"ciency during childhood
⚬ possible cause of pituitary damage, which may include history of pituitary
surgery or radiation therapy for intrasellar lesion, pituitary hypoplasia,
hypothalamic mass or in"ltration, head trauma, contact-sports injury, or

stroke
● testing involves biochemical stimulation of GH
⚬ insulin tolerance test (ITT) is the gold standard for diagnosis of GH de"ciency
in adults but contraindications may limit its use
⚬ commonly used alternatives to ITT include glucagon stimulation test and
macimorelin test
– testing for suspected antidiuretic hormone de"ciency
● no diagnostic gold standard exists for diagnosis of antidiuretic hormone
de"ciency
⚬ water deprivation test is often used for initial diagnosis and can help identify
cases of partial inability to concentrate urine
⚬ an alternative to the water deprivation test may include the use of 3% saline
infusion with copeptin assay
● measure serum and urine osmolality simultaneously in patients with polyuria
(> 50 mL/kg of body weight in 24 hours or 3.5 L/day in a 70 kg [154 lbs] person)
(Endocrine Society Strong recommendation, Moderate-quality evidence)
⚬ normal results are characterized by serum osmolality > 295 mOsm/kg, urine
osmolarity about 600 mOsm/kg or higher (urine osmolality to plasma
osmolality ratio ≥ 2), and glucose negative urine dipstick
⚬ diabetes insipidus is con"rmed by plasma osmolality > 295 mOsm/kg with
inappropriately hypotonic urine (below 600 mOsm/kg; urine osmolality to
plasma osmolality ratio < 2)
– consider measuring serum prolactin, as severe hypoprolactinemia (serum
prolactin concentrations < 100 pmol/L) reported to be marker for severe
hypopituitarism
– see Hypopituitarism for details
⚬ single measurement of serum prolactin above upper limit of normal con"rms
diagnosis of hyperprolactinemia (in absence of excessive venipuncture stress or
recent food intake/exercise) (Endocrine Society Strong recommendation, High-
quality evidence)
– assay-speci"c normal values are higher in women than in men, typically prolactin
< 25 mcg/L
– if possible excessive venipuncture stress or recent food intake/exercise, sampling
can be repeated on di#erent day after an overnight fast at 15- to 20-minute
intervals to account for prolactin pulsatility

– Reference - J Clin Endocrinol Metab 2011 Feb;96(2):273
– see Hyperprolactinemia for additional information
Table 10. Reported Pituitary Hormone Abnormalities in Patients With Primary

Hypophysitis and Immune Checkpoint Inhibitor-induced Hypophysitis
Type of Hypophysitis Pituitary Hormone

Abnormalities
Primary hypophysitis – ACTH de"ciency in

60%
– FSH/LH de"ciency in
55%
– TSH de"ciency in
52%
– ADH de"ciency in
39%
– GH decreased in
38%
– Hyperprolactinemia
in 37%
Immune checkpoint inhibitor-induced hypophysitis – ACTH de"ciency in

91%*
– TSH de"ciency in
84%
– FSH/LH de"ciency in
83%
– GH decreased in
43%
– Hyperprolactinemia
in 9%
– ADH de"ciency in 1%
Abbreviations: ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CTLA-4,
cytotoxic T lymphocyte-associated protein 4; FSH, follicle-stimulating hormone; LH,

luteinizing hormone; GH, growth hormone; PD-1, programmed cell death protein-1; PD-L1,
programmed death ligand-1; TSH, thyroid-stimulating hormone.
* Immune checkpoint inhibitor-induced hypophysitis due to PD-1 inhibitors or PD-L1

inhibitors typically presents as isolated ACTH de"ciency, while immune checkpoint
inhibitor-induced hypophysitis due to CTLA-4 inhibitors often has numerous pituitary
de"ciencies.
● assess for sodium, since hyponatremia is common in patients with adrenal

insu$ciency (J Clin Endocrinol Metab 2016 Feb;101(2):364 full-text )
● recommendations for biochemical evaluation of immune checkpoint inhibitor-induced
hypophysitis
⚬ American Society of Clinical Oncology (ASCO) recommendations for biochemical
evaluation of immune checkpoint inhibitor-induced hypophysitis
– perform pituitary axis evaluation that includes (ASCO Moderate recommendation,
Expert consensus)
● morning ACTH
● morning cortisol
● TSH and FT4
● electrolytes
– in patients with fatigue, loss of libido, mood changes, or oligomenorrhea, consider
evaluating (ASCO Moderate recommendation, Expert consensus)
● LH and testosterone levels (in male patients)
● FSH and estrogen (in premenopausal patients)
– in patients on corticosteroids for other conditions, cannot perform workup using
simple morning cortisol level (ASCO Moderate recommendation, Expert
consensus)
– do not attempt laboratory con"rmation of adrenal insu$ciency until
corticosteroid treatment for other conditions can be discontinued (ASCO
Moderate recommendation, Expert consensus)
– hold hydrocortisone for 24 hours and other steroids for longer before
endogenous function is assessed (ASCO Moderate recommendation, Expert
consensus)
– Reference - ASCO guideline on the management of immune-related adverse
events in patients treated with immune checkpoint inhibitor therapy (J Clin Oncol
2021 Dec 20;39(36):4073 ), correction can be found in J Clin Oncol 2022 Jan
20;40(3):315
⚬ Guideline Summary • Updated 17 Mar 2023 European Society for Medical Oncology (ESMO)
recommendations for biochemical evaluation of immune checkpoint inhibitor-
induced hypophysitis includes
– ACTH
– 9 am cortisol (random level acceptable if unwell and treatment cannot be
delayed)
– TSH or FT4
– LH and FSH
– insulin-like growth factor-1 (IGF-1)
– prolactin
– estradiol in premenopausal patients
– testosterone in male patients
– Reference - ESMO guideline on the management of toxicities from
immunotherapy (Ann Oncol 2022 Dec;33(12):1217 )
Additional Blood Tests Based on Clinical Suspicion or Di!erential Diagnosis

● for primary hypophysitis
⚬ if lymphocytic hypophysitis is suspected, consider assessing for
– pituitary antibodies (may indicate lymphocytic hypophysitis), such as alpha-
enolase and pituitary gland speci"c factors 1 and 2, if any of the following
● patient with idiopathic hypopituitarism, particularly if patient has an
autoimmune disease
● patient with hyperprolactinemia without evidence of pituitary adenoma on
magnetic resonance imaging, without hypothyroidism, or associated to an
iatrogenic cause
● patient with hypoprolactinemia and lactation failure
● patient with empty sella
● Reference - Pituitary 2016 Dec;19(6):625 full-text
– thyroid peroxidase antibodies (can help exclude Hashimoto thyroiditis, since
patients with Hashimoto thyroiditis often present with pituitary antibodies) 3 , 5
– antinuclear antibodies (disease speci"c antibody that can help assess for
secondary hypophysitis) 3
– anti-RO, anti-La, anti-SSa, anti-Ds-DNA (if autoimmune features present) 3
⚬ if immunoglobulin (Ig)G4 hypophysitis is suspected, assess for Ig levels (particularly
IgG4 levels); IgG4 levels > 135-140 mg/dL are considered elevated 2 , 3 , 4
● for secondary hypophysitis
⚬ if granulomatous lesions are suspected, consider assessing for
– antineutrophil cytoplasmic antibodies (disease speci"c antibodies that can help
assess for conditions associated with secondary hypophysitis, including
sarcoidosis, tuberculosis, and vasculitis) 1 , 3
– serum angiotensin converting enzyme levels (if sarcoidosis suspected) 3
– interferon gamma assay (if history of travel and tuberculosis suspected) 3
⚬ if germinoma is suspected (if considered a di#erential to hypophysitis), consider
assessing serum alpha-fetoprotein and human chorionic gonadotropin 3
⚬ if other in"ltrative or infectious etiologies are suspected, consider assessing lactic
acid dehydrogenase 3
Imaging Studies
Magnetic Resonance Imaging (MRI)
MRI Assessment in Patients With Hypophysitis
● gadolinium-enhanced magnetic resonance imaging is the preferred imaging modality
to de"ne pituitary anatomy and pathology 1 , 2 , 3
● obtain gadolinium-enhanced pituitary MRI in patients with suspected hypophysitis to
assess for mass e#ect and to rule out other suprasellar or sellar mass lesions 1 , 2
● reported common MRI "ndings in patients with hypophysitis include 1
⚬ pituitary enlargement in 23%-93%
⚬ homogeneous pituitary contrast enhancement in 23%-92%
⚬ pituitary stalk thickening (> 4 mm antero-posterior diameter on sagittal section) in
34%-96%
⚬ loss of posterior pituitary bright spot (on T1-weighted imaging) in 18%-71%
Additional MRI Findings in Patients With Primary Hypophysitis

● MRI abnormalities reported in up to 98% of patients with primary hypophysitis 1
● MRI "ndings are helpful in di#erentiating between primary hypophysitis and pituitary
adenoma (most frequent di#erential diagnosis in adults) 5
Table 11. MRI Findings With Primary Hypophysitis and Pituitary Adenoma
MRI Primary Hypophysitis Pituitary Adenoma
Pregadolinium contrast ⚬ Acute/subacute ⚬ Microadenoma < 1

phase cm (unilateral,
– Homogeneous asymmetric
enlarged pituitary endosellar mass)
with symmetrical ⚬ Macroadenoma > 1
suprasellar cm (heterogeneously
expansion expanding pituitary
– Suprasellar mass with
extension with asymmetrical
compressed and suprasellar
displaced chiasm expansion)
– Stalk thickened but ⚬ Compressed and
not deviated* displaced chiasm with
– Loss of posterior macroadenoma
pituitary bright ⚬ Contralateral stalk
spot if posterior deviation
pituitary ⚬ Posterior pituitary
involved** bright spot usually
visible**
⚬ Chronic phase
– Pituitary atrophy
– Empty sella
Postgadolinium contrast ⚬ Intense and ⚬ Slight, delayed, and

homogeneous heterogeneous
enhancement enhancement
⚬ Cystic areas possible, ⚬ Cystic and necrotic
especially in areas common in
xanthomatous macroadenomas
subtype ⚬ Absent dural tail
⚬ Presence of dural tail common***
sign possible
(thickening of
enhanced dura
resembling tail
extending from
mass)***
* Pituitary enlargement also possible with other intracranial pathologies such as metastasis,
sarcoidosis, germinoma, craniopharyngioma, astrocytoma, pituitary adenoma, lymphoma,
Langerhans cell histiocytosis, Erdheim-Chester disease, tuberculosis.
** Posterior bright spot reported to be potentially absent in 20% of healthy persons,

particularly in older adults.
*** Dural tail (meningeal tail) sign is not speci"c to hypophysitis. Most frequently can be
observed in meningioma, but can also be present in other intracranial pathologies (metastasis,
lymphoma, chloroma, multiple myeloma, glioblastoma multiforme, schwannoma,
medulloblastoma, aspergillosis, chordoma, pleomorphic xanthoastrocytoma,
hemangiopericytoma, granulomatosis with polyangiitis, sarcoidosis, eosinophilic granuloma,
pituitary adenoma, pituitary apoplexy, and Erdheim-Chester disease.
Reference - Endotext 2018 .
● rare radiological "ndings reported in patients with primary hypophysitis include 1

⚬ parasellar extension
⚬ cystic changes
⚬ central necrosis/apoplexy
⚬ '"gure-of-8' appearance
⚬ presence of meningeal or dural tail (contrast-enhanced in!ammation along dura
mater)
⚬ empty sella (in late disease stage)
⚬ mixed signal intensity on T1/T2 imaging in xanthomatous and xanthogranulomatous
hypophysitis (due to cholesterol deposits)
Recommendations and Additional Findings for MRI in Patients With Immune

Checkpoint Inhibitor-induced Hypophysitis
● recommendations for performing MRI in patients with suspected immune checkpoint
inhibitor-induced hypophysitis
⚬ American Society of Clinical Oncology (ASCO) suggests MRI of brain with or without
contrast including pituitary/sellar cuts, particularly in patients with multiple
endocrine abnormalities with or without new severe headaches or vision changes
(ASCO Moderate recommendation, Expert consensus) (J Clin Oncol 2021 Dec
20;39(36):4073 ), correction can be found in J Clin Oncol 2022 Jan 20;40(3):315
⚬ Guideline Summary • Updated 17 Mar 2023 European Society for Medical Oncology (ESMO)
recommendations for performing MRI in patients with suspected immune

– for patients who are asymptomatic or have vague symptoms, such as mild fatigue
or anorexia, and in absence of headache, perform MRI according to pituitary
protocol
– for moderate symptoms (such as headache without visual disturbance) or fatigue
and mood alterations without hemodynamic or electrolyte instability, perform
MRI according to pituitary protocol (in addition to excluding brain metastases)
– for severe mass e#ect symptoms (such as severe headache or any visual
disturbances) or severe hypoadrenalism (such as hypotension or severe
electrolyte disturbances), perform MRI according to pituitary protocol (in addition
to excluding brain metastases)
⚬ see Toxicities of Immune Checkpoint Inhibitors for additional information
● MRI abnormalities in patients with immune checkpoint inhibitor-induced hypophysitis
⚬ 77% of patients with immune checkpoint inhibitor-induced hypophysitis reported to
have abnormal MRI "ndings; therefore, normal MRI does not exclude immune
checkpoint inhibitor-induced hypophysitis 1 , 5
⚬ MRI abnormalities reported to precede clinical symptoms in about 50% of patients
with immune checkpoint inhibitor-induced hypophysitis 5
⚬ radiologic abnormalities (including pituitary enlargement, altered contrast
enhancement, and stalk widening) are more common with immune checkpoint
inhibitor-induced hypophysitis due to cytotoxic T-lymphocyte associated protein 4
(CTLA-4) inhibitors compared to immune checkpoint inhibitor-induced hypophysitis
due to programmed cell death protein-1 (PD-1) or programmed death ligand-1 (PD-
L1) inhibitors (Expert Rev Endocrinol Metab 2019 Nov;14(6):381 )
Image 1 of 1
Hypophysitis
Sagittal (a) and coronal (b) unenhanced images of the

pituitary, revealing a slightly atrophic pituitary gland at
baseline. 2 months later, at presentation, sagittal (c)
and coronal (d) postcontrast images reveal enlarged
pituitary size with di#use enhancement of the pituitary
and infundibulum without focal lesion.
Majchel D, Korytkowski MT. Anticytotoxic T-lymphocyte antigen-

4 induced autoimmune hypophysitis: a case report and
literature review. Case Rep Endocrinol 2015;2015:570293.
Reproduced with permission from Hindawi.
● MRI "ndings are helpful in di#erentiating between immune checkpoint inhibitor-

induced hypophysitis and pituitary metastases (an important di#erential diagnosis) 5
Table 12. Comparing MRI Findings of Immune Checkpoint Inhibitor-induced Hy-

pophysitis and Pituitary Metastases
Diagnostic Immune Checkpoint Pituitary Metastases

Characteristics Inhibitor-induced
Hypophysitis*
MRI ⚬ Mild-to-moderate ⚬ Sella or suprasellar

di#use pituitary mass
enlargement (up to ⚬ T1WI shows
60%-100% of baseline isointense or
size) hypointense mass
⚬ Heterogenous or ⚬ T2WI typically shows
homogenous high-intensity sign
postgadolinium ⚬ Homogenous
enhancement postgadolinium
⚬ Suprasellar extension enhancement
with compressed and (hemorrhage,
displaced chiasm necrosis, cystic
uncommon degeneration
⚬ Pituitary stalk might possible)

be thickened but not ⚬ Cavernous sinus,
deviated chiasm, or
⚬ Posterior pituitary hypothalamus
usually preserved invasion reported in
about 14%
⚬ Pituitary stalk
thickened and
enhancing
⚬ Other brain
metastases reported
in about 15%
⚬ Posterior pituitary
bright spot reportedly
lost in about 13%
⚬ Dumbbell-shaped
mass reported in
about 11%
⚬ Sphenoid sinus
invasion reported in
about 9%
Abbreviations: CTLA-4, cytotoxic T lymphocyte-associated protein 4; MRI, magnetic resonance

imaging; PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-1;
T1WI, T1-weighted image; T2WI, T2-weighted image.
* Radiologic abnormalities (including pituitary enlargement, altered contrast enhancement,

and stalk widening) are more common with immune checkpoint inhibitor-induced
hypophysitis due to CTLA-4 inhibitors compared to immune checkpoint inhibitor-induced
hypophysitis due to PD-1 or PD-L1 inhibitors.
Additional Imaging Based on Clinical Suspicion or Di!erential Diagnosis

● in patients suspected of having secondary hypophysitis due to systemic pathology,
consider additional imaging to help identify other sites of disease 3
⚬ consider computed tomography of the chest, abdomen, and pelvis in patients
suspected of having tuberculosis, connective tissue disorders, sarcoidosis, or if
malignancy is a potential di#erential diagnosis
⚬ consider skeletal survey and whole bone scan if suspect Erdheim-Chester disease or
Langerhans cell histiocytosis
⚬ !uorodeoxyglucose-positron emission tomography (FDG-PET) may help con"rm
multisite disease in patients with immunoglobulin (IG)G4-related disease or
Langerhans cell histiocytosis
Cerebrospinal Fluid (CSF) Analysis

● consider performing CSF analysis if any of the following conditions are suspected 3
⚬ for granulomatous lesions, consider assessing
– glucose, protein, and angiotensin converting enzyme levels in CSF
– oligoclonal bands in CSF
⚬ for other in"ltrative or infectious etiologies, consider assessing CSF cytology and
oligoclonal bands in CSF
Biopsy and Pathology

Biopsy and Pathology in Patients With Primary Hypophysitis
● biopsy and histopathological evaluation is required for de"nitive diagnosis of primary
hypophysitis, but this invasive procedure is only performed if management outcome of
biopsy outweighs its risks (for example, consider performing pituitary biopsy if
diagnosis is uncertain) 2 , 5
● perform pituitary biopsy only in properly equipped facilities with experienced
neurosurgeon 1
● histopathological characteristics of subtypes of primary hypophysitis
Table 13. Histopathological Characteristics of Subtypes of Primary Hypophysitis
Subtype of Primary Hypophysitis Histopathology
Lymphocytic hypophysitis ⚬ Focal or di#use lymphocyte

in"ltration (primarily T cells) of the
pituitary gland
⚬ Lymphocytes can be arranged in
lymphoid follicles with germinal
centers
⚬ Occasionally plasma cells,

"broblasts, and eosinophils are
present
⚬ Pituitary "brosis and atrophy might
occur in later stages of disease
Idiopathic granulomatous hypophysitis ⚬ Numerous multinucleated giant

cells and histiocytes arranged in the
form of granulomas
⚬ Areas of "brosis possible
Xanthomatous hypophysitis ⚬ Foamy histiocytes (lipid-rich

macrophages)
⚬ Absence of granulomas, plasma
cells, or small, round mature
lymphocytes
⚬ Pituitary "brosis possible in later
stages of disease
IgG4 hypophysitis (both isolated and ⚬ Mononuclear in"ltration with

systemic) abundant lymphocytes and plasma
cells
⚬ ≥ 10 IgG4-positive cells per high-
power "eld
⚬ Storiform "brosis is observed
⚬ Pituitary "brosis and atrophy might
occur in later stages of disease
Necrotizing hypophysitis ⚬ Di#use nonhemorrhagic necrosis

surrounded by lymphocytes, plasma
cells, and eosinophils
⚬ Fibrosis (if chronic in!ammation)
Mixed-form hypophysitis ⚬ Lymphogranulomatous hypophysitis

can contain features of both
lymphocytic and granulomatous
forms
⚬ Xanthogranulomatous hypophysitis
presents with foamy xanthoma cells
and multinucleated giant cells;
cholesterol clefts, and hemosiderin
deposits may also be present
Abbreviation: Ig, immunoglobulin.
Neuroendocrinology 2020;110(9-10):822 .
Biopsy and Pathology in Patients With Secondary Hypophysitis

● biopsy may be required to determine the underlying disorder in a patient with
suspected secondary hypophysitis, particularly if the suspected underlying condition is
an in!ammatory or in"ltrative disorder 3
Table 14. Examples of Forms of Secondary Hypophysitis and Associated

Histopathological Characteristics
Form of Secondary Hypophysitis Histopathology
Hypophysitis secondary to sarcoidosis Noncaseating granulomas
Hypophysitis secondary to ⚬ Necrotizing granulomas

granulomatous polyangiitis ⚬ Vasculitis in small and medium-sized
blood vessels
Hypophysitis secondary to Langerhans Pituitary in"ltration with Langerhans

cell histiocytosis cells, neutrophils, eosinophils, small
lymphocytes, and histiocytes
Hypophysitis secondary to Erdheim- Histiocytes with non-Langerhans

Chester disease features
Anti-PIT-1 hypophysitis Pituitary in"ltration with CD8+ cells
Hypophysitis secondary to Rosai- ⚬ Plasma cell in"ltration, mixed with

Dorfman disease lymphocytes
⚬ Large histiocytes with foamy
cytoplasm
⚬ Touton giant cells
Hypophysitis secondary to Tolosa-Hunt Nonspeci"c granulomatous or

syndrome nongranulomatous in!ammation
Hypophysitis secondary to Cogan Granulomatous in"ltration

syndrome
Hypophysitis secondary to pituitary B-cell in"ltration

lymphoma
Abbreviations: anti-PIT-1, antipituitary speci"c transcription factor 1; Ig, immunoglobulin.
Reference - Neuroendocrinology 2020;110(9-10):822 , Endocr Rev 2020 Apr

1;41(2):doi:10.1210/endrev/bnz003 .
Management
Management Overview
● management of hypophysitis includes reduction in in!ammatory pituitary enlargement
associated with mass e#ect consequences and/or replacement of any pituitary
hormone de"ciencies 3
● if signs and symptoms of mass e#ect are present
⚬ consider surgical decompression by transsphenoidal hypophysectomy (preferred) or
administering glucocorticoids as "rst-line treatment for patient with hypophysitis
who has severe signs and symptoms of mass e#ect
⚬ if patient with severe mass e#ect signs and/or symptoms is refractory to
glucocorticoid therapy, glucocorticoids are not tolerated or cause unacceptable
adverse e#ects, or patient has recurrent hypophysitis, consider either of
– other immunosuppressive agents or monoclonal antibodies
– stereotactic radiation therapy
● if hypopituitarism is present, provide hormone replacement therapy
⚬ speci"c treatment for hypopituitarism depends on speci"c endocrine de"ciency

⚬ for adrenal insu$ciency
– adrenocorticotropic hormone (ACTH) de"ciency can be treated with
glucocorticoid hormone replacement therapy using either hydrocortisone or
prednisone (no need for mineralocorticoid replacement in patients with central
hypoadrenalism)
– in patients who also require thyroid hormone replacement therapy,
due to increased rate of glucocorticoid metabolism caused by thyroid hormone
and subsequent risk of precipitating acute adrenal crisis
– treat patients with suspected adrenal crisis due to secondary adrenal insu$ciency
immediately with hydrocortisone 50-100 mg parenteral injection followed by
appropriate !uid resuscitation (Endocrine Society Strong recommendation,
Moderate-quality evidence)
⚬ for thyroid hormone de"ciency
– levothyroxine recommended in doses su$cient to achieve serum free thyroxine
(T4) levels in mid to upper half of reference range; appropriate doses usually up
to 1.6 mcg/kg/day, with dose adjustments based on clinical context, age, and free
T4 levels (Endocrine Society Strong recommendation, Moderate-quality evidence)
– evaluate patient for adrenal insu$ciency before starting levothyroxine therapy;
consider prescribing empiric glucocorticoid therapy in patients starting
levothyroxine therapy until de"nitive evaluation for adrenal insu$ciency
(Endocrine Society Weak recommendation, Low-quality evidence)
⚬ for gonadotropin de"ciency
– gonadal hormone replacement therapy (estrogen and progestin) recommended
in premenopausal patients with central hypogonadism, assuming no
contraindications present (Endocrine Society Strong recommendation, Moderate-
quality evidence)
– consider testosterone replacement for patients with central hypogonadism and
no contraindications in order to (Endocrine Society Weak recommendation, Low-
quality evidence)
● reduce fat mass
⚬ for growth hormone (GH) de"ciency
– o#er GH replacement to patients with proven GH de"ciency and no

contraindications; recommended starting dose (Endocrine Society Strong
recommendation, Moderate-quality evidence)
– GH replacement should be commenced only after replacing other pituitary
hormone de"ciencies
– titrate GH doses, maintain insulin growth factor-1 levels below upper limit of
normal, and reduce dose if side e#ects manifest (Endocrine Society Strong
recommendation, Very low-quality evidence)
⚬ for antidiuretic hormone de"ciency
– individualized therapeutic schedule suggested for desmopressin (DDAVP), a
synthetic analogue of arginine vasopressin (Endocrine Society Ungraded Good
Practice Statement)
– DDAVP should ideally be initiated at bedtime, but some patients may also require
morning (twice daily) and, rarely, midday (3 times daily) doses
– to reduce hyponatremia, educate all patients receiving DDAVP about risks of
overdosing (Endocrine Society Ungraded Good Practice Statement)
● if symptomatic hyperprolactinemia is present, treat with dopamine agonist (such as
cabergoline and bromocriptine) with dosage adjusted based on prolactin levels
● consider treating patients with primary hypophysitis who do not have severe
(observation with long-term clinical and radiological follow-up); exception is patients
with immunoglobulin (Ig)G4 hypophysitis who require prompt treatment to prevent
"brosis
Recommendations
Recommendations for Lymphocytic and Immunoglobulin (Ig) G4
Hypophysitis
● Japan Endocrine Society recommendations for the management of lymphocytic and
immunoglobulin (Ig)G4 hypophysitis 4
⚬ lymphocytic hypophysitis
– for patients with enlarged pituitary and signs and symptoms of mass e#ect (such
as visual defects and severe headache)
● give pharmacological dose of glucocorticoids (for example, prednisolone 0.5-1
mg/kg/day) after excluding infectious diseases such as tuberculosis and

considering need for pituitary biopsy
● adjust glucocorticoid dose according to age and severity of hypophysitis
● consider high-dose glucocorticoid therapy (as pulse or mini-pulse therapy) in
severe cases
● taper glucocorticoid dose if signs and symptoms of mass e#ects improve
● consider pituitary biopsy and decompression by partial resection if signs and
symptoms of mass e#ect are severe or progressive despite glucocorticoid
therapy
– if hypopituitarism present, administer hormone replacement therapy
– for asymptomatic cases or mild symptoms, follow-up with magnetic resonance
imaging of the pituitary
⚬ IgG4 hypophysitis
– for patients with signs and symptoms of mass e#ect associated with pituitary
enlargement, administer prednisolone 30-40 mg/kg/day as starting dose
– continue with low-dose prednisolone even with improvement of pituitary
enlargement
– if improvement in pituitary enlargement occurs for extended period, consider
stopping prednisolone (though discontinuing treatment can lead to relapse)
Recommendations for Immune Checkpoint Inhibitor-induced

Hypophysitis
● professional organizations vary regarding recommendations for immune checkpoint
inhibitor-induced hypophysitis in patients with mild to moderate symptoms in terms of
discontinuing immunotherapy, but agree to administer hormone replacement therapy
as needed, and that consultation with or referral to endocrinologist is needed in all
cases
⚬ American Society of Clinical Oncology (ASCO) recommendations for the
management of immune checkpoint inhibitor-induced hypophysitis
– general treatment considerations for hypophysitis
● when planning hormone replacement therapy for multiple de"ciencies, "rst
initiate glucocorticoid replacement to prevent adrenal crisis due to lack of
cortisol (ASCO Moderate recommendation, Expert consensus)
● educate all patients with adrenal insu$ciency on glucocorticoid stress dosing
and need for medical alert bracelet for adrenal su$ciency to trigger stress-
dose glucocorticoids by emergency medical services (ASCO Moderate
recommendation, Expert consensus)
● isolated central adrenal insu$ciency may occur due to glucocorticoid use

● consult endocrinologist for recovery and weaning protocols using
hydrocortisone (ASCO Moderate recommendation, Expert consensus)
– for grade 1 toxicity (asymptomatic or mild symptoms)
● consider holding immunotherapy until patient is stabilized on hormone
replacement therapy (ASCO Moderate recommendation, Expert consensus)
● consult endocrinologist (ASCO Moderate recommendation, Expert consensus)
● o#er hormonal supplementation as needed (such as hydrocortisone 10-20 mg
orally in morning, 5-10 mg in afternoon for adrenal insu$ciency, and/or
levothyroxine by weight for hypothyroidism) (ASCO Moderate
⚬ follow free thyroxine (FT4), not thyroid stimulating hormone (TSH), for
titration of thyroid hormone replacement for central hypothyroidism (ASCO
⚬ always start glucocorticoids several days before thyroid hormone to prevent
adrenal crisis due to lack of cortisol (ASCO Moderate recommendation,
Expert consensus)
● if no contraindications, o#er testosterone or estrogen therapy as needed for
central hypogonadism (ASCO Moderate recommendation, Expert consensus)
– for grade 2 toxicity (moderate symptoms, able to perform activities of daily living)
● consider holding immunotherapy until patient is stabilized on hormone
● o#er hormonal supplementation same as for grade 1 toxicity (ASCO Moderate
● consider oral pulse dose therapy (prednisone 1 mg/kg/d or equivalent) in
patients with MRI "ndings of swelling or threatened optic chiasm compression,
with taper over 1-2 weeks and transition to physiologic maintenance therapy
once down to 5 mg prednisone equivalent (ASCO Moderate recommendation,
Expert consensus)
– for grade 3-4 toxicity (signi"cant or life-threatening toxicity, severe symptoms,
unable to perform daily activities)
● temporarily discontinue immunotherapy until patient is stabilized on hormone
● hospitalize the patient or refer to emergency department for the following
⚬ normal saline (≥ 2 L) or monitored free water replacement if diabetes

insipidus (ASCO Moderate recommendation, Expert consensus)
⚬ IV stress dose steroids (hydrocortisone 50-100 mg IV every 6-8 hours
initially) with taper down to oral maintenance doses over 5-7 days (ASCO
⚬ initial pulse dose therapy with prednisone 1-2 mg/kg/day orally tapered over
> 1-2 weeks in patients with signi"cant swelling on MRI, optic chiasm
compression, severe headache, or visual changes (ASCO Moderate
● o#er maintenance hormonal supplementation same as for grade 1 toxicity
(ASCO Moderate recommendation, Expert consensus)
20;40(3):315
⚬ European Society for Medical Oncology (ESMO) recommendations for the
management of immune checkpoint inhibitor-induced hypophysitis
– for patients who are asymptomatic or have vague symptoms (mild fatigue or
anorexia in absence of headache)
● wait for pituitary axis results to con"rm diagnosis; however, counsel patient to
seek urgent review if unwell
● continue immunotherapy in addition to appropriate hormone replacement
therapy
● provide hormone replacement including cortisol and/or thyroxine
⚬ if 9 AM cortisol is low according to institutional reference range (for
example, < 250 nmol/L [9.06 mcg/dL])
– replace with hydrocortisone 20 mg in morning, 10 mg in afternoon, and
10 mg in evening
– if normal thyroid function tests, monitor every 1-2 weeks initially (always
replace cortisol for 1 week before starting thyroxine)
⚬ if decreasing thyroid-stimulating hormone with or without low FT4, consider
thyroxine replacement 0.5-1.5 mcg/kg based on symptoms with or without 9
am weekly cortisol
● refer to endocrinologist
– for patients with mild to moderate symptoms, including fatigue and mood
alterations without hemodynamic or electrolyte instability

● continue immunotherapy in addition to appropriate hormone replacement
therapy
● provide hormone replacement including cortisol and/or thyroxine (ESMO
Grade A, Level IV)
⚬ if 9 AM cortisol is low according to institutional reference range (for
example, < 250 nmol/L [9.06 mcg/dL])
– replace with hydrocortisone 20 mg in morning, 10 mg in afternoon, and
10 mg in evening
– if normal thyroid function tests, monitor every 1-2 weeks initially (always
replace cortisol for 1 week before starting thyroxine)
⚬ if decreasing thyroid-stimulating hormone with or without low FT4, consider
thyroxine replacement 0.5-1.5 mcg/kg based on symptoms with or without 9
am weekly cortisol
● refer to or consult with endocrinologist
● monitor thyroid function tests
– for patients with moderate symptoms, including headache without visual
disturbance
● discontinue immunotherapy
● provide glucocorticoids
⚬ provide oral prednisolone 0.5-1 mg/kg/day after pituitary axis assessment
⚬ if no improvement within 48 hours of starting glucocorticoids, treat as
severe toxicity with methylprednisolone
⚬ wean glucocorticoids to prednisolone 5 mg over 1-2 weeks based on
symptoms, but do not stop completely (ESMO Grade A, Level IV)
– for patients with severe mass e#ect symptoms (severe headache or any visual
disturbances) or severe hypoadrenalism (such as hypotension or severe
electrolyte disturbances)
● discontinue immunotherapy
● provide methylprednisolone 1 mg/kg IV after pituitary axis assessment
● attempt to wean glucocorticoids to prednisolone 5 mg over 2-4 weeks based
on symptoms, but do not stop completely (ESMO Grade A, Level IV)
● if headache present, provide analgesia as appropriate; consult with neurologist
if resistant to acetaminophen (paracetamol) or nonsteroidal anti-in!ammatory

drugs
Conservative Management
● consider treating patients with primary hypophysitis who do not have severe
(observation with long-term clinical and radiological follow-up); exception is patients
with immunoglobulin (Ig)G4 hypophysitis who require prompt treatment to prevent
"brosis 5
● 10%-40% of patients with primary hypophysitis treated with conservative management
reported to relapse 5
STUDY
● SUMMARY
conservative management with observation alone reported to be associated with
regression of space-occupying lesion in 46% of patients and improvement in
pituitary function in 27% of patients with lymphocytic or granulomatous
hypophysitis DynaMed Level 3
CASE SERIES: J Clin Endocrinol Metab 2015 Sep;100(9):3460

Details
⚬ based on case series
⚬ 76 patients with primary hypophysitis (70% with lymphocytic hypophysitis and 30%
with granulomatous hypophysitis) were initially treated with conservative
management, glucocorticoid therapy, pituitary surgery, surgery plus glucocorticoids,
or immunosuppressive therapy
⚬ 30 patients had initial treatment with conservative management consisting of
observation with close follow-up schedule
– no patient in observation group had chiasmal syndrome
– of the 30 patients initially treated with conservative management, 4 patients
required additional treatment (second-line therapy included glucocorticoid
therapy for 2 patients and surgery for 2 patients)
⚬ after mean follow-up of 4.1 years in the 22 of 30 patients initially treated with
conservative management with outcome data for the observation period (outcome
data does not include treatment with subsequent therapies)
– space-occupying lesion assessed by magnetic resonance imaging (data available
for 22 patients)
● regressed in 10 patients (46%)
● unchanged in 6 patients (27%)
● progressed in 6 patients (27%)
– pituitary function (data available for 22 patients)
● improved in 6 patients (27%)
● stable in 12 patients (55%)
● deteriorated in 4 patients (18%); only reported in patients with progressive
lesions
– headache (out of 9 patients who reported headache before therapy initiation)
– ocular paresis improved in 1 patient with the condition at baseline
⚬ Reference - J Clin Endocrinol Metab 2015 Sep;100(9):3460
Fluid and Electrolytes

● Endocrine Society recommendations for !uid and electrolytes in adults with acute
adrenal crisis
⚬ appropriate !uid resuscitation should occur following hydrocortisone 50-100 mg
parenteral injection in patients with suspected acute adrenal crisis (Endocrine
Society Strong recommendation, Moderate-quality evidence)
⚬ initial appropriate !uid resuscitation includes either
– rapid infusion of isotonic saline 1,000 mL within the "rst hour, followed by 500 mL
in the second hour
– infusion of 5% glucose in isotonic saline within "rst hour
⚬ follow with continuous IV isotonic saline based on individual patient needs
⚬ Reference - Endocrine Society clinical practice guideline on diagnosis and treatment
of primary adrenal insu$ciency (J Clin Endocrinol Metab 2016 Feb;101(2):364 full-
text )
⚬ see Adrenal Insu$ciency in Adults for additional information
Medications
Hormone Replacement Therapy

● if hypopituitarism is present, provide hormone replacement therapy 5
● overview of hormonal replacement therapy for hypopituitarism
⚬ speci"c treatment for hypopituitarism depends on speci"c endocrine de"ciency
⚬ for adrenal insu$ciency
– adrenocorticotropic hormone (ACTH) de"ciency can be treated with
glucocorticoid hormone replacement therapy using either hydrocortisone or
prednisone (no need for mineralocorticoid replacement in patients with central
hypoadrenalism)
– in patients who also require thyroid hormone replacement therapy,
due to increased rate of glucocorticoid metabolism caused by thyroid hormone
and subsequent risk of precipitating acute adrenal crisis
– treat patients with suspected adrenal crisis due to secondary adrenal insu$ciency
immediately with hydrocortisone 50-100 mg parenteral injection followed by
appropriate !uid resuscitation (Endocrine Society Strong recommendation,
Moderate-quality evidence)
– in patients with suspected pituitary apoplexy, preemptive glucocorticoid therapy
recommended before laboratory diagnosis of acute pituitary insu$ciency
established, as untreated adrenal insu$ciency is major cause of mortality
(Endocrine Society Strong recommendation, Low-quality evidence)
– in patients with partial ACTH de"ciency (for example, blood cortisol levels > 10
mcg/dL in patient without speci"c symptoms of de"ciency), decision must be
made whether to provide lifelong therapy or to treat only during periods of high
stress
● treatment options include watchful waiting without medication or trial of either
hydrocortisone 10 mg or prednisone 2.5 mg
● if patient has little or no clinical response to drug administration, treatment can
be discontinued
● if improvement in clinical outcomes seen, options include proceeding with
same dose or increasing dose to hydrocortisone 12.5-15 mg or prednisone
3.75 mg
⚬ for thyroid hormone de"ciency
– levothyroxine recommended in doses su$cient to achieve serum free thyroxine
(T4) levels in mid to upper half of reference range; appropriate doses usually up
to 1.6 mcg/kg/day, with dose adjustments based on clinical context, age, and free
T4 levels (Endocrine Society Strong recommendation, Moderate-quality evidence)

– evaluate patient for adrenal insu$ciency before starting levothyroxine therapy;
consider prescribing empiric glucocorticoid therapy in patients starting
levothyroxine therapy until de"nitive evaluation for adrenal insu$ciency
(Endocrine Society Weak recommendation, Low-quality evidence)
⚬ for gonadotropin de"ciency
– gonadal hormone replacement therapy (estrogen and progestin) recommended
in premenopausal women with central hypogonadism, assuming no
contraindications present (Endocrine Society Strong recommendation, Moderate-
quality evidence)
– consider testosterone replacement for men with central hypogonadism and no
contraindications in order to (Endocrine Society Weak recommendation, Low-
quality evidence)
● reduce fat mass
– consider starting testosterone replacement therapy at normal age for puberty
onset (11.5-12.5 years) in adolescent boys with hypogonadism
– gonadotropin therapy or pulsatile gonadotropin-releasing hormone can be used
for treatment of infertility in women and men
⚬ for growth hormone (GH) de"ciency
– o#er GH replacement to patients with proven GH de"ciency and no
contraindications; recommended starting dose (Endocrine Society Strong
recommendation, Moderate-quality evidence)
– GH replacement should be commenced only after replacing other pituitary
hormone de"ciencies
– titrate GH doses, maintain insulin growth factor-1 levels below upper limit of
normal, and reduce dose if side e#ects manifest (Endocrine Society Strong
recommendation, Very low-quality evidence)
⚬ for antidiuretic hormone de"ciency
– individualized therapeutic schedule suggested for desmopressin (DDAVP), a
synthetic analogue of arginine vasopressin (Endocrine Society Ungraded Good
Practice Statement)
– DDAVP should ideally be initiated at bedtime, but some patients may also require
morning (twice daily) and, rarely, midday (3 times daily) doses
– to reduce hyponatremia, educate all patients receiving DDAVP about risks of
overdosing (Endocrine Society Ungraded Good Practice Statement)
⚬ see Hypopituitarism for details
Glucocorticoid Therapy
In Patients With Primary Hypophysitis
● indications and administration of glucocorticoid therapy in patients with primary
hypophysitis
⚬ consider administering glucocorticoids as "rst-line therapy in patient with primary
hypophysitis presenting with severe mass e#ect signs and/or symptoms (such as
severe headache, cranial nerve de"cits, or visual disturbances) due to pituitary
enlargement 1 , 3 , 5
– give high dose glucocorticoids (for example, prednisone 20-60 mg/day or
equivalent dose)
– if patient has a good response to glucocorticoids based on clinical and
radiological "ndings, then gradually taper down glucocorticoids and continue
physiological replacement if patient has adrenal insu$ciency
– if patient has a poor response to glucocorticoids based on clinical and radiological
"ndings or high-dose glucocorticoids are not tolerated, then consider other
treatment options
⚬ for patient with immunoglobulin (Ig)G4 hypophysitis, promptly give glucocorticoids
to revert symptoms and prevent "brosis 2
– initially give prednisone 30-40 mg/day to induce symptom remission (occurs
within a few weeks)
– gradually taper prednisone over 2-6 months (some patients may bene"t from
long-term use, such as those with multiorgan involvement)
● Japan Endocrine Society recommendations for glucocorticoid therapy in patients with
lymphocytic or IgG4 hypophysitis 4
⚬ if patient with lymphocytic hypophysitis has enlarged pituitary and signs and
symptoms of mass e#ect (such as visual defects and severe headache)
– give pharmacological dose of glucocorticoids (for example, prednisolone 0.5-1
mg/kg/day) after excluding infectious diseases such as tuberculosis and
considering need for pituitary biopsy

– adjust glucocorticoid dose according to age and severity of hypophysitis
– consider high-dose glucocorticoid therapy (as pulse or mini-pulse therapy) in
severe cases
– taper glucocorticoid dose if signs and symptoms of mass e#ects improve
⚬ if patient with IgG4 hypophysitis has signs and symptoms of mass e#ect associated
with pituitary enlargement
– administer prednisolone 30-40 mg/kg/day as starting dose
– continue with low-dose prednisolone even with improvement of pituitary
enlargement
– if improvement in pituitary enlargement occurs for extended period, consider
stopping prednisolone (though discontinuing treatment can lead to relapse)
● glucocorticoids reported to be less e#ective for granulomatous and xanthomatous
hypophysitis compared to lymphocytic hypophysitis 1 , 2
STUDY
● SUMMARY
oral glucocorticoid therapy reported to improve headache and vision impairment
and induce regression of sellar lesion in adults with lymphocytic hypophysitis
DynaMed Level 3
CASE SERIES: Clin Endocrinol (Oxf) 2017 Aug;87(2):177

Details
⚬ 50 adults (mean age 37 years) with lymphocytic hypophysitis were given hormone
replacement therapy and treated with glucocorticoids, surgery, or conservative
management (observation only)
⚬ adults were followed for ≥ 6 months
⚬ 26 adults were treated with pharmacological-dose oral glucocorticoid therapy
(prednisone 20-60 mg/day, or equivalent) for median treatment duration of 7
months (range 3-27 months)
⚬ among patients treated with glucocorticoids
– headache and vision impairment improved in 100% of adults with symptoms at
baseline at median interval of 7 days after glucocorticoid initiation
– sellar lesion
● shrinkage occurred in 100% of adults after median treatment duration of 14.5
days
● recurrence observed when treatment was tapered or withdrawn in 46% of
adults (median time to recurrence 5.7 months)

– anterior pituitary insu$ciency (in 22 adults)
● improved in 40.9%
● unchanged in 59.1%
– central diabetes insipidus (in 20 adults)
● improved in 10%
● unchanged in 90%
⚬ Reference - Clin Endocrinol (Oxf) 2017 Aug;87(2):177
STUDY
● SUMMARY
glucocorticoid pulse therapy reported to induce regression of space-occupying
lesion in 66% of patients with lymphocytic or granulomatous hypophysitis
DynaMed Level 3

Details
with granulomatous hypophysitis) were treated with conservative management,
glucocorticoid pulse therapy, pituitary surgery, surgery plus glucocorticoids,
immunosuppressive therapy, and/or radiation therapy
⚬ 32 patients were treated with glucocorticoid pulse therapy (surgery plus
glucocorticoid combination therapy was not included) with median dose of
prednisolone 65 mg/day (range 20-500 mg/day) or equivalent for median treatment
duration of 2 months (range 4 days to 1 year)
⚬ after mean follow-up of 2.3 years in the 29 of 32 patients treated with glucocorticoid
pulse therapy with outcome data
for 29 patients)
● regressed in 19 patients (66%)
● progressed in 1 patient (3%)
● recurred after 0.2-1.4 years of glucocorticoid pulse therapy in 11 patients (38%);
initial dose and duration of therapy were not signi"cantly correlated with
recurrence

● deteriorated in 4 patients (15%)
– headache (out of 14 patients who reported headache before glucocorticoid pulse
therapy initiation)
– new headache reported in 1 patient (7%) after glucocorticoid pulse therapy
– chiasmal syndrome (out of 5 patients with chiasmal syndrome before
glucocorticoid pulse therapy)
● improved in 1 patient (20%)
– ocular paresis (out of 4 patients with ocular paresis before glucocorticoid pulse
therapy)
– adverse e#ects (out of 19 patients with data) included Cushing syndrome (3
patients), weight gain without Cushing syndrome (7 patients), psychiatric
symptoms (2 patients), diabetes mellitus (1 patient), and glaucoma (1 patient)
In Patients With Immune Checkpoint Inhibitor-induced Hypophysitis

● consider administering glucocorticoids as "rst-line therapy to reduce severe mass
e#ect signs and/or symptoms 3 , 5
● recommendations for use of glucocorticoid therapy in patients with immune
⚬ American Society for Clinical Oncology (ASCO) suggests the following for patients
with grade 3-4 toxicity de"ned as signi"cant or life-threatening toxicity, severe
symptoms, or unable to perform daily activities
– IV stress dose steroids (hydrocortisone 50-100 mg IV every 6-8 hours initial
dosing) with taper down to oral maintenance dose over 5-7 days (ASCO Moderate
– initial pulse dose therapy with prednisone 1-2 mg/kg/day orally tapered over > 1-2
weeks in patients with signi"cant swelling on MRI, optic chiasm compression,
severe headache, or visual changes (ASCO Moderate recommendation, Expert
consensus) (
20;40(3):315
⚬ European Society for Medical Oncology (ESMO) recommendations for use of
glucocorticoid therapy in patients with immune checkpoint inhibitor-induced
hypophysitis
– for moderate symptoms (headache without visual disturbance or fatigue and
mood alterations without hemodynamic or electrolyte instability), provide
glucocorticoids
● provide oral prednisolone 0.5-1 mg/kg/day after pituitary axis assessment
● if no improvement within 48 hours of starting glucocorticoids, treat as severe
toxicity with methylprednisolone
● wean glucocorticoids to prednisolone 5 mg over 1-2 weeks based on
symptoms, but do not stop completely (ESMO Grade A, Level IV)
– for severe mass e#ect symptoms (severe headache or any visual disturbances) or
severe hypoadrenalism (such as hypotension or severe electrolyte disturbances)
● provide methylprednisolone 1 mg/kg IV after pituitary axis assessment
● attempt to wean glucocorticoids to prednisolone 5 mg over 2-4 weeks based
on symptoms, but do not stop completely (ESMO Grade A, Level IV)
STUDY
● SUMMARY
high-dose glucocorticoid therapy may reduce overall survival compared to low-dose
glucocorticoid therapy in adults with melanoma who develop ipilimumab-induced
hypophysitis DynaMed Level 2
COHORT STUDY: Cancer 2018 Sep 15;124(18):3706 | Full Text

Details
⚬ based on retrospective cohort study
⚬ 98 adults (mean age 64 years) with melanoma were treated with high- or low-dose
glucocorticoid therapy for ipilimumab-induced hypophysitis
– high-dose glucocorticoids de"ned as prednisone > 7.5 mg maximum average daily
dose (or equivalent glucocorticoid exposure) during "rst 2 months after
hypophysitis diagnosis
– low-dose glucocorticoids de"ned as prednisone ≤ 7.5 mg maximum average daily
dose (or equivalent glucocorticoid exposure) during "rst 2 months after
hypophysitis diagnosis
⚬ median time to diagnosis of ipilimumab-induced hypophysitis was 9.8 weeks
⚬ compared to low-dose prednisone therapy, high-dose prednisone therapy
associated with
– reduced overall survival (adjusted hazard ratio [HR] 0.24, 95% CI 0.07-0.61)
– shorter time to treatment failure (adjusted HR 0.28, 95% CI 0.11-0.62)
– reduced progression-free survival (adjusted HR 0.36, 95% CI 0.14-0.77)
⚬ Reference - Cancer 2018 Sep 15;124(18):3706 full-text
Other Immunosuppressive Agents or Monoclonal Antibodies

● consider other alternative immunosuppressive agents (such as azathioprine or
mycophenolate mofetil) or rituximab (a monoclonal antibody) with or without
glucocorticoid therapy in patients with hypophysitis who have severe mass e#ect signs
and/or symptoms (such as severe headache, cranial nerve de"cits, or visual
disturbances) if any of the following 1 , 2 , 3 , 5
⚬ patient is refractory to glucocorticoid therapy
⚬ glucocorticoids are not tolerated or cause unacceptable adverse e#ects
⚬ patient with recurrent hypophysitis
● azathioprine
⚬ most commonly used immunosuppressive agent 3
⚬ azathioprine is used o#-label for treatment of hypophysitis (FDA DailyMed 2020 Dec
29 )
⚬ azathioprine 100-150 mg once daily reported to resolve clinical symptoms and
radiological signs of sellar mass by 1- to 2-year follow-up in 2 adults (1 adult with
relapsed primary hypophysitis and 1 adult with primary hypophysitis who had
unacceptable adverse e#ects with glucocorticoids) in case series (Pituitary 2011
Mar;14(1):16 )
mycophenolate mofetil
⚬
●
⚬ mycophenolate mofetil is used o#-label for treatment of hypophysitis (FDA DailyMed

2020 Apr 6 )
⚬ mycophenolate mofetil 1 g/day for 1 month followed by mycophenolate mofetil 2
g/day for 12 months plus prednisolone 40 mg/day gradually tapered to 8 mg/day
over a period of 13 months reported to restore visual acuity and reduce pituitary
stalk and suprasellar mass at 13-month follow-up in 58-year-old patient with
recurrent lymphocytic hypophysitis in case report (BMJ Case Rep 2018 Jan
6;2018:doi:10.1136/bcr-2017-222678 full-text )
● rituximab
⚬ rituximab is used o#-label for treatment of hypophysitis (FDA DailyMed 2020 Dec 21
)
⚬ may be particularly bene"cial in patients with IgG4 hypophysitis or in those with B-
lymphocyte predominant, biopsy-proven hypophysitis (rituximab is an anti-CD20
antibody that depletes B lymphocytes) 1 , 2
⚬ rituximab 1,000 mg IV infusion for 2 doses plus prednisone 60 mg/day tapered to
discontinuation over a period of 6 months reported to resolve central diabetes
insipidus at 1 year and reduce size of pituitary gland and infundibular stalk at about
1.5 years in 53-year-old male with IgG4 hypophysitis in case report (N Engl J Med
2016 Oct 13;375(15):1469 )
⚬ rituximab (two 1,000 mg IV infusions separated by 15 days every 6 months) reported
to resolve vision loss and reduce sellar mass at 2-year follow-up in 41-year-old
female with recurrent B-cell predominant lymphocytic hypophysitis in case report (J
Neurosurg 2012 Jun;116(6):1318 )
Dopamine Agonists
● treat symptomatic hyperprolactinemia with dopamine agonist (such as cabergoline and
bromocriptine), with dosage adjusted based on prolactin levels 1
● cabergoline dosing for adults
⚬ initial dose 0.25 mg orally twice weekly as starting dose
⚬ increase by 0.25 mg orally twice weekly (up to 1 mg orally twice weekly) at 4-week
intervals based on serum prolactin level
● bromocriptine dosing for adults
⚬ initial dose 1.25-2.5 mg orally once daily
⚬ increase by 2.5 mg every 2-7 days based on serum prolactin level
⚬ usual total daily dose 2.5-15 mg orally once daily
Surgery and Procedures

● consider surgical decompression by transsphenoidal hypophysectomy in patient with
hypophysitis who has severe signs and symptoms of mass e#ect (surgical
decompression is the preferred "rst-line treatment for patient with hypophysitis who
has severe signs and symptoms of mass e#ect, particularly if signs and symptoms are
rapidly progressive) 1 , 2 , 3
● surgery is reported to have better outcomes compared to glucocorticoid therapy for
patients with granulomatous hypophysitis, including 1
⚬ better symptom resolution
⚬ less need for hormone replacement
⚬ lower recurrence rate
STUDY
● SUMMARY
surgery reported to definitively remove space-occupying lesion in 75% of patients
with lymphocytic or granulomatous hypophysitis DynaMed Level 3

Details
with granulomatous hypophysitis) were treated with conservative management,
glucocorticoid pulse therapy, pituitary surgery, surgery plus glucocorticoids,
immunosuppressive therapy, and/or radiation therapy
⚬ 33 patients were treated with pituitary surgery (not including patients treated with
surgery plus glucocorticoids)
– surgical approach included transsphenoidal in 30 patients, transcranial in 2
patients, and not speci"ed in 1 patient
– types of surgery included gross total resection in 13 patients, partial resection in
12 patients, biopsy in 7 patients, and unspeci"ed in 1 patient
– indications for surgery included ≥ 1 of
● large space-occupying lesion
● unclear di#erential diagnosis
● refractory to glucocorticoids
● severe symptoms
● visual deterioration
● progressive course
● compressed optic chiasm
● patient preference
⚬ after mean follow-up of 3 years in 28 out of 33 patients treated with surgery with
outcome data

for 28 patients)
● had no recurrence in 21 patients (75%)
● recurred in 4 patients (14%)
● progressed early in 3 patients (11%); progression and recurrence rate was not
signi"cantly di#erent by type of surgery
● deteriorated in 6 patients (24%); new postoperative de"cits reported in 4
patients after gross total resection, in 1 patient after partial resection, and in 1
patient after biopsy
– headache (out of 14 patients who reported headache before surgery)
● deteriorated in 1 patient (7%)
– chiasmal syndrome (out of 3 of 6 patients with condition before surgery)
– new headache and new chiasmal syndrome each reported in 1 patient after
surgery
– ocular paresis (out of the 2 patients with the condition before surgery) improved
in 1 patient and remained unchanged in 1 patient
– complications (out of 20 patients with data) included postoperative meningitis in 1
patient and rhinorrhea requiring operative revision in 1 patient
Radiation Therapy
● consider stereotactic radiation therapy in patient with hypophysitis who has
progressive and severe signs and symptoms of mass e#ect (such as visual "eld defects
or deterioration of visual acuity) and is both of 1 , 3 , 5
⚬ refractory to surgery
⚬ refractory or intolerant to glucocorticoid therapy
● radiation-induced hypopituitarism is a potential treatment complication of stereotactic
radiation therapy (reported in 20%-30% of patients, typically within 5 years of receiving

treatment) 2
● stereotactic radiation therapy using Gamma Knife (15 Gy to the margin) reported to
resolve clinical and radiologic evidence of hypophysitis after 3 years of follow-up in 42-
year-old woman with aggressive lymphocytic hypophysitis refractory to combined
immunosuppressive therapy (prednisone plus azathioprine) and transsphenoidal
surgery in case report (J Neurol Surg A Cent Eur Neurosurg 2018 Jan;79(1):77 )
Consultation and Referral

● refer to an endocrinologist if patient presents with any of the following
⚬ menstrual irregularities
⚬ sexual disturbance or infertility
⚬ asthenia
⚬ headache
⚬ syncope
⚬ hyponatremia
⚬ polyuria and/or polydipsia
● refer to a rheumatologist if patient presents in the context of an autoimmune condition
● refer to an ophthalmologist or neurologist if patient presents with any of the following
⚬ visual "eld defects (including decline in visual acuity)
⚬ ocular motor (third, fourth, and sixth cranial nerves) neuropathy (including diplopia)
● Reference - Trends Endocrinol Metab 2019 Sep;30(9):590
Follow-up
● assess treatment response during "rst 3 months of follow-up with pituitary magnetic
resonance imaging; thereafter, conduct serial imaging until stability achieved 2 , 3
● for patient treated with hormone replacement therapy, monitor for hormonal
overreplacement (Endocrine Society Weak recommendation, Low-quality evidence)
⚬ assess glucocorticoid replacement and overreplacement to reduce risk of
osteoporosis
⚬ in men with hypopituitarism who are over replaced with glucocorticoids and are at
risk for fractures, consider vertebral fracture assessment using baseline plain spinal
x-rays or dual-energy x-ray absorptiometry to identify patients with unsuspected
vertebral fractures
⚬ monitor levothyroxine replacement to avoid overreplacement and reduce risk of
fractures
● in men receiving androgen therapy for gonadotropin de"ciency
⚬ check hematocrit in initial stages of treatment and after any dose adjustment
⚬ monitor prostate health by evaluating serum prostate-speci"c antigen and prostate
exam
⚬ measure lumbar spine and/or femoral neck bone mineral density
⚬ in prepubertal boys, monitor growth and pubertal progression and bone age to
avoid premature epiphyseal closure
⚬ Reference - Endocrinol Metab (Seoul) 2015 Dec;30(4):443 full-text
⚬ see Testosterone Therapy in Men for additional information
● for patient treated with dopamine agonist therapy, measure serum prolactin after 1
month on treatment and periodically thereafter to guide dose titration (J Clin
Endocrinol Metab 2011 Feb;96(2):273 )
● for patient treated with conservative management, perform long-term clinical and
radiological follow-up 3 , 1 , 4
Complications
● mass e#ect complications due to pituitary enlargement may include
⚬ headaches with or without nausea (most likely due to compression of the dura
mater and optic chiasm or cavernous sinus) 1
– typically generalized and severe (more severe in patients with primary
hypophysitis, but occur more consistently in patients with immune checkpoint
inhibitor-induced hypophysitis)
– reported in
● 47%-68% of patients with primary hypophysitis
● 57%-83% of patients with acute autoimmune hypophysitis
● 60%-61% of patients with immune checkpoint inhibitor-induced hypophysitis
⚬ ophthalmologic complications, such as
– bitemporal quadrantopsia or hemianopsia due to compression of the optic
chiasm 1 , 3
– reduction in visual acuity and color perception due to compression of the optic
apparatus 3
– pupillary defects due to compression of the ocular motor (third, fourth, and sixth
cranial) nerves 1
⚬ hyperprolactinemia due to compression of the pituitary stalk or immune-mediated
destruction of prolactin-secreting cells 1 , 5
⚬ panhypopituitarism due to pituitary damage 1
⚬ rare complications, such as
– facial paresthesia or orbital pain due to compression of the trigeminal ("fth
cranial) nerve 1
– ophthalmoplegia due to compression of the ocular motor (third, fourth, and sixth
cranial) nerves, which may present as diplopia 1 , 3
– internal carotid artery occlusion 1
● complications of hypopituitarism vary by hormone(s) a#ected
⚬ complications of corticotropin de"ciency include
– hypotension
– hyponatremia
– hypoglycemia
– anemia
– lymphocytosis
– eosinophilia
– delayed puberty in children
⚬ complications of thyroid-stimulating hormone de"ciency include
– weight gain
– bradycardia
– hypotension
– growth retardation in children
⚬ complications of gonadotropin de"ciency include
– osteoporosis
– infertility
– decreased muscle mass
– anemia
– delayed puberty in children
⚬ complications of growth hormone de"ciency include
– dyslipidemia
– premature atherosclerosis
– growth retardation in children
⚬ complications of antidiuretic hormone de"ciency include

– decreased urine osmolality
– hypernatremia
– polyuria
⚬ Reference - Lancet 2007 Apr 28;369(9571):1461
⚬ see Hypopituitarism for additional information
● long-term in!ammation due to primary hypophysitis can cause "brosis and pituitary
shrinkage, which can lead to empty sella syndrome 1 , 5
Prognosis
● prognosis of primary hypophysitis
⚬ mortality reported in 7% of patients with primary hypophysitis, probably due to
unrecognized acute adrenal insu$ciency 5
⚬ primary hypophysitis can be self-limiting 5
⚬ some patients may have complete remission of primary hypophysitis, while others
continue to have persistent hypopituitarism 5
– conservative management and medical or surgical treatment reported to improve
pituitary function in patients with primary hypophysitis, although relapse is also
possible with both management options
– 72% of patients with primary hypophysitis treated with either medical or surgical
treatment reported to require long-term hormone replacement
⚬ while there is a strong association between lymphocytic hypophysitis and
pregnancy, the former does not generally appear to negatively impact pregnancy or
fetal outcomes 1
● prognosis of immune checkpoint inhibitor-induced hypophysitis
⚬ enlarged pituitary is rare and reported to resolve in 83%-100% of patients with
immune checkpoint inhibitor-induced hypophysitis, but may then result in
diminished pituitary or empty sella (Endocrinol Metab Clin North Am 2020
Sep;49(3):387 )
⚬ adrenocorticotropic hormone de"ciency is permanent in most patients with immune
checkpoint inhibitor-induced hypophysitis, although recovery has been reported
(Endocrinol Metab Clin North Am 2020 Sep;49(3):387 )
⚬ thyroid-stimulating hormone (TSH) and gonadotropin de"ciencies may be reversible
in patients with immune checkpoint inhibitor-induced hypophysitis due to cytotoxic
T lymphocyte-associated protein 4 (CTLA-4) inhibitors (at last follow-up, 45% of
patients report TSH de"ciency and 37% of patients report gonadotropin de"ciency)
(Eur J Endocrinol 2019 Sep 1;181(3):R107 )
STUDY
⚬ SUMMARY
ipilimumab-induced hypophysitis might be associated with longer survival in
adults with metastatic melanoma
COHORT STUDY: J Clin Endocrinol Metab 2014 Nov;99(11):4078

Details
– based on retrospective cohort study with borderline statistical signi"cance
– 154 adults with metastatic melanoma treated with ipilimumab were evaluated
– 11% of patients (15 male and 2 female) were diagnosed with ipilimumab-induced
hypophysitis
● diagnosis was based on presence of new hypopituitarism and pituitary
enlargement after initiation of ipilimumab
● median follow-up in this group was 11.5 months after initiation of ipilimumab
– comparing patients with ipilimumab-induced hypophysitis vs. those without
hypophysitis
● median survival after ipilimumab 19.4 months vs. 8.8 months (p = 0.05)
● mean age 68.2 years vs. 59.9 years (p = 0.005)
– among 17 patients with ipilimumab-induced hypophysitis
● 15 were treated with high-dose corticosteroids after diagnosis of ipilimumab-
induced hypophysitis
● 13 had persistent hypopituitarism at follow-up
● 15 had radiographic resolution of pituitary enlargement at follow-up (2 patients
did not have repeat radiographic imaging yet at last follow-up)
– Reference - J Clin Endocrinol Metab 2014 Nov;99(11):4078
● insu$cient evidence on prognosis of anti-pituitary speci"c transcription factor-1 (anti-

PIT1) hypophysitis and isolated adrenocorticotropic hormone (ACTH) de"ciency due to
rarity of these forms 1
Prevention and Screening
Prevention
● not applicable
Screening
● screening for immune checkpoint inhibitor-induced hypophysitis
⚬ assess for signs and symptoms of hypophysitis (such as headache, nausea, visual
disturbances, and fatigue) prior to each infusion of immune checkpoint inhibitors 5
⚬ perform biochemical evaluation prior to "rst immune checkpoint inhibitor infusion;
blood tests include 5
– morning serum cortisol
– thyroid-stimulating hormone (TSH) and free thyroxine (FT4)
– prolactin
– insulin-like growth factor-1 (IGF-1)
– luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone in
male patients
– LH, FSH, and estradiol in premenopausal patients
⚬ suggested screening intervals for performing follow-up biochemical evaluation vary;
suggested options include performing follow-up biochemical evaluation
– prior to each immune checkpoint inhibitor infusion during the "rst 12-16 weeks 5
– at each immune checkpoint inhibitor infusion for the "rst 6 months, then at every
other infusion treatment for the following 6 months (Endocrinol Metab Clin North
Am 2020 Sep;49(3):387 )
– in patients receiving ipilimumab, at 8 weeks and again at week 16 if no signs or
symptoms of hypophysitis 5
⚬ continue screening after cessation of immune checkpoint inhibitor therapy, as late
onset adrenocorticotropic hormone (ACTH) de"ciency has been reported 6 months
after cessation of immune checkpoint inhibitor therapy (Endocrinol Metab Clin
North Am 2020 Sep;49(3):387 )
Guidelines and Resources
Guidelines
International Guidelines
● Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune
checkpoint inhibitor-related adverse events can be found in J Immunother Cancer 2021
Jun;9(6):doi:10.1136/jitc-2021-002435 full-text
United States Guidelines
● American Society of Clinical Oncology (ASCO) clinical practice guideline on management

of immune-related adverse events in patients treated with immune checkpoint
inhibitors can be found in J Clin Oncol 2021 Dec 20;39(36):4073 , correction can be
found in J Clin Oncol 2022 Jan 20;40(3):315
● Endocrine Society clinical practice guidelines on
⚬ hormonal replacement in hypopituitarism in adults can be found in J Clin Endocrinol
Metab 2016 Nov;101(11):3888
⚬ diagnosis and treatment of primary adrenal insu$ciency can be found in J Clin
Endocrinol Metab 2016 Feb;101(2):364 full-text
⚬ diagnosis and treatment of hyperprolactinemia can be found in J Clin Endocrinol
Metab 2011 Feb;96(2):273 , commentary can be found in Nat Rev Endocrinol 2011
May;7(5):247
● American College of Radiology (ACR) Appropriateness Criteria on neuroendocrine
imaging can be found at ACR 2018 PDF
United Kingdom Guidelines

● Society for Endocrinology guidance on acute management of endocrine complications
of checkpoint inhibitor therapy can be found in Endocr Connect 2018 Jul;7(7):G1 full-
text
European Guidelines
● European Society for Medical Oncology (ESMO) guideline on management of
immunotherapy toxicities can be found in Ann Oncol 2022 Dec;33(12):1217
● French Endocrine Society guidance on endocrine related side e#ects of
immunotherapy can be found in Endocr Relat Cancer 2019 Feb;26(2):G1 full-text
Asian Guidelines
● Japan Endocrine Society clinical guideline on diagnosis and treatment of autoimmune
and IgG4-related hypophysitis can be found in Endocr J 2020 Apr 28;67(4):373 full-
text
Review Articles
● reviews of hypophysitis
⚬ review can be found in Neuroendocrinology 2020;110(9-10):822
⚬ review can be found in Best Pract Res Clin Endocrinol Metab 2019 Dec;33(6):101371
full-text
⚬ review can be found in Endocrinol Metab Clin North Am 2015 Mar;44(1):143
● review of evaluation and management of hypophysitis can be found in Clin Diabetes

Endocrinol 2016;2:15 full-text
● review of diagnosis and management of hypophysitis can be found in Eur J Endocrinol
2018 Sep;179(3):R151
● review of pathophysiological and clinical aspects of autoimmune hypophysitis can be
found in Pituitary 2016 Dec;19(6):625 full-text
● reviews of immune checkpoint inhibitor-induced hypophysitis
⚬ review can be found in Endocrinol Metab Clin North Am 2020 Sep;49(3):387
⚬ review can be found in Eur J Endocrinol 2019 Sep 1;181(3):R107
● reviews of endocrine toxicities associated with immune checkpoint inhibitors can be
found in
⚬ Endocr Pract 2022 Jul;28(7):719
⚬ Endocr Rev 2019 Feb 1;40(1):17 full-text
⚬ J Emerg Med 2018 Oct;55(4):489
⚬ JNCI Cancer Spectr 2018 Jul;2(3):pky021 full-text
● reviews of immunoglobulin (Ig)G4-related disease can be found in
⚬ Mod Rheumatol 2012 Feb;22(1):1 full-text
⚬ N Engl J Med 2012 Feb 9;366(6):539
● review of pituitary imaging in endocrine disorders can be found in Handb Clin Neurol
2016;136:873
● review of endocrine manifestations in Langerhans cell histiocytosis can be found in
Trends Endocrinol Metab 2007 Aug;18(6):252
MEDLINE Search
● to search MEDLINE for (Hypophysitis) with targeted search (Clinical Queries), click
therapy , diagnosis , or prognosis
Patient Information
● handout on lymphocytic hypophysitis from National Organization for Rare Disorders
References
General References Used
The references listed below are used in this DynaMed topic primarily to support background
information and for guidance where evidence summaries are not felt to be necessary. Most
references are incorporated within the text along with the evidence summaries.
1. Gubbi S, Hannah-Shmouni F, Verbalis JG, Koch CA. Hypophysitis: An update on the

novel forms, diagnosis and management of disorders of pituitary in!ammation. Best
Pract Res Clin Endocrinol Metab. 2019 Dec;33(6):101371 full-text
2. Angelousi A, Alexandraki K, Tsoli M, Kaltsas G, Kassi E. Hypophysitis (Including IgG4 and

Immunotherapy). Neuroendocrinology. 2020;110(9-10):822-835
3. Joshi MN, Whitelaw BC, Carroll PV. Mechanisms in endocrinology: Hypophysitis:

diagnosis and treatment. Eur J Endocrinol. 2018 Sep;179(3):R151-R163
4. Takagi H, Iwama S, Sugimura Y, et al. Diagnosis and treatment of autoimmune and

IgG4-related hypophysitis: clinical guidelines of the Japan Endocrine Society. Endocr J.
2020 Apr 28;67(4):373-378 full-text
5. Prete A, Salvatori R. Hypophysitis . In: Feingold KR, Anawalt B, Boyce A, et al., eds.
Endotext [Internet]. South Dartmouth, MA: MDText.com, Inc; 2018
Recommendation Grading Systems Used

● American Society of Clinical Oncology (ASCO) guide to recommendations
⚬ strength of recommendations
– Strong - high con"dence that recommendation is best practice; strong evidence
that bene"ts exceed harms, consistent results with no or minor exceptions, no or
minor concerns about quality of studies
– Moderate - moderate con"dence that recommendation is best practice; good
evidence that bene"ts exceed harms, consistent results with few or minor
exceptions, few and/or minor concerns about quality of studies
– Weak - some con"dence that recommendation is best current guidance for
practice; limited evidence that bene"ts exceed harms, consistent results with
important exceptions, concerns about study quality
⚬ quality of evidence
– High - high con"dence that evidence re!ects true balance of bene"ts vs. harms,
further research is very unlikely to change magnitude or direction of net e#ect
– Intermediate - moderate con"dence that evidence re!ects true balance of
bene"ts vs. harms, further research is unlikely to change direction but may
change magnitude of net e#ect
– Low - low con"dence that evidence re!ects true balance of bene"ts vs. harms,
further research may change magnitude and/or direction of net e#ect

– Insu$cient - insu$cient evidence to discern true balance of bene"ts vs. harms,
further research may better inform the topic, consensus of experts
⚬ type of recommendation
– Evidence based - su$cient evidence from published studies to inform a
recommendation to guide clinical practice
– Expert consensus - available evidence deemed insu$cient to inform
recommendation to guide clinical practice; formal consensus process to reach
recommendation
– Informal consensus - available evidence deemed insu$cient to inform
recommendation to guide clinical practice; considered best current guidance for
practice based on informal consensus; formal consensus process not necessary
– No recommendation - insu$cient evidence, con"dence, or agreement to provide
a recommendation to guide clinical practice at this time; unlikely formal
consensus process would achieve level of agreement needed for
recommendation
⚬ Reference - ASCO guideline on the management of immune-related adverse events
in patients treated with immune checkpoint inhibitor therapy (J Clin Oncol 2021 Dec
20;39(36):4073 ), correction can be found in J Clin Oncol 2022 Jan 20;40(3):315
● European Society for Medical Oncology (ESMO) grades of recommendation
⚬ grades of recommendation
– Grade A - strong evidence for e$cacy with substantial clinical bene"t, strongly
recommended
– Grade B - strong or moderate evidence for e$cacy but with limited clinical
bene"t, generally recommended
– Grade C - insu$cient evidence for e$cacy or bene"t does not outweigh risk or
disadvantages (adverse events, costs, etc.), optional
– Grade D - moderate evidence against e$cacy or for adverse outcomes, generally
not recommended
– Grade E - strong evidence against e$cacy or for adverse outcome, never
recommended
⚬ levels of evidence
– Level I - evidence from ≥ 1 large, randomized, controlled trial of good
methodological quality (low potential for bias) or meta-analyses of well-conducted
randomized trials without heterogeneity
– Level II - small randomized trials or large randomized trials with suspicion of bias
(lower methodological quality) or meta-analyses of such trials or of trials with

demonstrated heterogeneity
– Level III - prospective cohort studies
– Level IV - retrospective cohort studies or case-control studies
– Level V - studies without control group, case reports, expert opinions
⚬ Reference - ESMO guideline on the management of toxicities from immunotherapy
(Ann Oncol 2022 Dec;33(12):1217 )
● Endocrine Society 2016 recommendations use Grading of Recommendations,
Assessment, Development, and Evaluation (GRADE) system
⚬ strength of recommendation
– Strong recommendation - task force has con"dence that persons who receive
care according to recommendation will derive, on average, more good than harm
– Weak recommendation - requires more careful consideration of person's
circumstances, values, and preferences to determine best course of action
– Ungraded Good Practice Statement - direct evidence either unavailable or not
systematically appraised and considered out of scope of guideline
– High-quality evidence - consistent evidence from well-performed randomized
controlled trials, or exceptionally strong evidence from unbiased observational
studies
– Moderate-quality evidence - randomized controlled trials with important
limitations (inconsistent results, methodological !aws, indirect or imprecise
evidence), or unusually strong evidence from unbiased observational studies
– Low-quality evidence - ≥ 1 critical outcome from observational studies,
randomized controlled trials with serious !aws, or indirect evidence
– Very low-quality evidence - ≥ 1 of the critical outcomes from unsystematic clinical
observations or very indirect evidence
● Endocrine Society uses GRADE system
⚬ strength of recommendation
– Strong recommendation - guideline panel members have high con"dence that
desirable e#ects of recommendation outweigh undesirable e#ects (or vice versa)
– Weak recommendation - guideline panel members conclude with less con"dence
that desirable e#ects of recommendation probably outweigh undesirable e#ects,
or bene"ts and harms are "nely balanced, or appreciable uncertainty

– High-quality evidence - consistent evidence from well-performed randomized
controlled trials, or exceptionally strong evidence from unbiased observational
studies
– Moderate-quality evidence - randomized controlled trials with important
limitations (inconsistent results, methodological !aws, indirect or imprecise
evidence), or unusually strong evidence from unbiased observational studies
– Low-quality evidence - ≥ 1 critical outcome from observational studies,
randomized controlled trials with serious !aws, or indirect evidence
– Very low-quality evidence - ≥ 1 of the critical outcomes from unsystematic clinical
observations or very indirect evidence
⚬ References
– Endocrine Society clinical practice guideline on diagnosis and treatment of
hyperprolactinemia (J Clin Endocrinol Metab 2011 Feb;96(2):273 ), commentary
can be found in Nat Rev Endocrinol 2011 May;7(5):247
– Endocrine Society clinical practice guideline on diagnosis and treatment of
primary adrenal insu$ciency (J Clin Endocrinol Metab 2016 Feb;101(2):364 full-
text )
Synthesized Recommendation Grading System for DynaMed

Content
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synthesis of the most valid relevant evidence to support clinical decision-making (see 7-
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● Guideline recommendations summarized in the body of a DynaMed topic are provided
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users to quickly see where guidelines agree and where guidelines di#er from each
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⚬ Strong recommendations are used when, based on the available evidence,
clinicians (without con!icts of interest) consistently have a high degree of con"dence

that the desirable consequences (health bene"ts, decreased costs and burdens)
outweigh the undesirable consequences (harms, costs, burdens).
⚬ Weak recommendations are used when, based on the available evidence, clinicians
believe that desirable and undesirable consequences are "nely balanced, or
appreciable uncertainty exists about the magnitude of expected consequences
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Overview and Recommendations

patient has fasted (can be used to diagnose most pituitary hormone

either hydrocortisone or prednisone. Mineralocorticoid replacement is not

⚬ Management of antidiuretic hormone de"ciency:

● secondary hypophysitis - forms of hypophysitis that develop secondary to

Table 1. Histologic Subtypes of Primary Hypophysitis and Reported Patient

Subtype of Histopatho Female to Mean Age Association

Lymphocyti – Focal or about 3:1 – 40-50 Yes (about

Idiopathic – Numerou 2.6:1 44 years No

Xanthomato – Foamy 3:1 40-50 years No

IgG4 – Mononuc 1:3 – 56.4 No

Necrotizing – Di#use 1:3 NA No

Abbreviations: Ig, immunoglobulin; NA, not available.

– histology-based classi"cation is not possible for all patients as it requires

– classi"cation by pattern of pituitary involvement does not relate to a particular

Table 2. Examples of Forms of Secondary Hypophysitis and Associated

Form of Secondary Hypophysitis Histopathology

Immune checkpoint inhibitor-induced ⚬ T-cell in"ltration

Hypophysitis secondary to sarcoidosis Noncaseating granulomas

Hypophysitis secondary to ⚬ Necrotizing granulomas

Hypophysitis secondary to Langerhans Pituitary in"ltration with Langerhans

Hypophysitis secondary to Erdheim- Histiocytes with non-Langerhans

Anti-PIT-1 hypophysitis Pituitary in"ltration with CD8+ cells

Hypophysitis secondary to Rosai- ⚬ Plasma cell in"ltration, mixed with

Hypophysitis secondary to Tolosa-Hunt Nonspeci"c granulomatous or

Hypophysitis secondary to Cogan Granulomatous in"ltration

Hypophysitis secondary to pituitary B-cell in"ltration

Abbreviations: anti-PIT-1, antipituitary speci"c transcription factor 1; Ig, immunoglobulin.

Reference - Neuroendocrinology 2020;110(9-10):822 , Endocr Rev 2020 Apr

Who Is Most A!ected

⚬ more awareness in medical community of condition

Table 3. Reported Prevalence of Subtypes of Primary Hypophysitis

Subtype of Primary Hypophysitis Prevalence of Subtype*

Lymphocytic hypophysitis 68%

Idiopathic granulomatous hypophysitis 20%

IgG4 hypophysitis (both isolated and in 4%

Necrotizing hypophysitis 0.6%

Abbreviation: Ig, immunoglobulin.

* Prevalence of subtype given as percentage of total cases of primary hypophysitis.

● reported prevalence of immune checkpoint inhibitor-induced hypophysitis 1

Immune checkpoint inhibitors (particularly CTLA-4 inhibitors) may be associated with

SYSTEMATIC REVIEW: JAMA Oncol 2018 Feb 1;4(2):173 | Full Text

– based on systematic review without assessment of study quality

CASE-CONTROL STUDY: J Clin Endocrinol Metab 2015 Nov;100(11):4092 | Full Text

Table 4. Percentage of HLA Class II Markers

Patient Group HLA-DQ8 HLA-DR53

Sporadic lymphocytic 87% 80%

Immune checkpoint 0% 25%

Controls 20% 48%

Abbreviation: HLA, human leukocyte antigen.

Etiology and Pathogenesis

Pathogenesis of Immune Checkpoint Inhibitor-induced Hypophysitis

– type 4 reaction is driven by cytotoxic T-lymphocyte activation that results in

Pathogenesis of Antipituitary Specific Transcription Factor 1 (Anti-PIT-1)

History and Physical

Table 5. Anterior Pituitary Deficiencies From Most to Least Frequent in Patients

De!ciency Signs and Symptoms

ACTH – Fatigue and low stamina

TSH – Fatigue and low stamina

FSH/LH (gonadotropins) – Fatigue and low stamina

Prolactin Lactation failure in postpartum