While lymphocytic hypophysitis was initially thought to only affect the anterior pituitary, it is now known to affect the posterior pituitary and pituitary stalk as well, causing inflammation and lymphocyte, macrophage and plasma cell infiltration of the pituitary gland.[7] Lymphocytic hypophysitis can lead to deficiencies in one or more pituitary hormones, causing central diabetes insipidus if the posterior pituitary gland is affected as well as central adrenal insufficiency and central hypothyroidism if the anterior pituitary gland is affected.[5][7] 

Other conditions that can occur due to pituitary inflammation include hypogonadotropic hypogonadism and growth hormone deficiency.[2] Enlargement of the pituitary gland can also compress the optic apparatus/chiasm and cause neuro-ophthalmic manifestations such as a decrease in vision and color perception.[8][4] 

Often times, headache is the first symptom and occurs at the onset of the disease and is usually followed by visual field defects/ophthalmoplegia and, at times, diplopia when the cavernous sinus, cranial nerves three, four and six are affected.[7] Eventually, pituitary destruction can occur due to infiltration and inflammation, and hypopituitarism can result in affecting almost all pituitary hormones.[7] Common symptoms include nausea, vomiting, fatigue, loss of libido, amenorrhea, and dizziness.[2]

Lymphocytic hypophysitis continues to be a diagnosis of exclusion, and histopathology with tissue biopsy is needed for a definitive diagnosis.[3] However, clinical, laboratory data, and imaging can all help with the diagnosis.[8] First and foremost, patients present with symptoms of hypopituitarism and must undergo pituitary hormone function evaluation.[7]

The hormones that need to be measured include prolactin, adrenocorticotropic hormone, cortisol, IGF-1, growth hormone, thyroid-stimulating hormone, free thyroxine, testosterone, luteinizing hormone, and follicle-stimulating hormone. Diabetes insipidus should also be evaluated by obtaining electrolyte levels, anti-diuretic hormone, serum, and urine osmolality, and water deprivation testing if needed.

About 20% to 50% of those with lymphocytic hypophysitis have been shown to have other autoimmune conditions.[5] At times, antipituitary antibodies and antihypothalamus antibodies have also been found. However, it is not always practical to obtain these antibodies.[2] However, assessment for other autoimmune and inflammatory diseases should be performed by obtaining complete blood count, complete metabolic panel, c-reactive protein, erythrocyte sedimentation rate, antinuclear antibody, and lupus antibodies at the very least.

Gadolinium-enhanced MRI of the pituitary is the imagining of choice, and it is important to distinguish lymphocytic hypophysitis from a pituitary adenoma. With a pituitary adenoma, MRI shows asymmetrical pituitary enlargement, with the pituitary stalk being deviated as well. However, in lymphocytic hypophysitis, the pituitary gland and the pituitary stalk is symmetrically enlarged, but there is no stalk deviation. MRI also shows a homogeneously intense pituitary with dura enhancement, also referred to as a dural tail along with arachnoid enhancement in lymphocytic hypophysitis.[4][7] 

In those with a pituitary adenoma, there is no enhancement of the dura or arachnoid. Despite these findings, radiological imaging cannot always distinguish between an adenoma and lymphocytic hypophysitis so easily, and in fact, at one point, 40% of patients with lymphocytic hypophysitis were misdiagnosed as having pituitary macroadenomas.[3] Often times, many of these patients are noted to have undergone surgery because a pituitary adenoma is suspected to be the cause of their symptoms.[7] However, this is not a surgical disease, and surgery should be avoided if a diagnosis can be made without histopathology. Surgery, however, is recommended if pituitary inflammation and infiltration are affecting a patient’s vision.[9]

In response to the high number of misdiagnosis, a scoring system, known as the Gutenberg scoring, was developed to correctly identify lymphocytic hypophysitis. This scoring system looks at various MRI features in an attempt to diagnose this disease prior to any surgical procedure.[3]

The scoring system and scoring are as follows:

• Age less than or equal to 30 receives a score of -1
• Current pregnancy or being less than or equal to 6 months postpartum receives a score of -4
• An increased stalk size receives a score of -5
• Increased gadolinium enhancement receives a score of -1
• Loss of pituitary bright spot receives a score of -2
• Pituitary volume greater than 6cmreceives a score of +2
• Sphenoid mucosal thickening receives a score of +2
• Heterogeneous gadolinium enhancement receives a score of +1
• Asymmetrical sellar enlargement receives a score of +3

A total score greater than 1 is suggestive of a pituitary adenoma, while a score of zero or less is suggestive of lymphocytic hypophysitis with a specificity of 99%, a sensitivity of 92%, and a positive and negative predictive value of 97%.[3]

The main goal of the treatment of lymphocytic hypophysitis is to manage any pituitary hormone deficiencies and to manage any mass-like effect that may occur due to pituitary gland enlargement. This treatment can consist of conservative management and the use of anti-inflammatory agents. Surgery or radiotherapy is rarely used. However, first and foremost, the pituitary function needs to be assessed and any pituitary hormone deficiencies need to be managed.[10] They should also be assessed for diabetes insipidus and treated accordingly if necessary. While there can be spontaneous resolution or regression of lymphocytic hypophysitis, if there is a high suspicion of lymphocytic hypophysitis steroid therapy is the mainline treatment of this condition.[4] 

However, if vision is affected, or if there is compressive mass like signs affecting nearby vital structures or if histology is needed to confirm the diagnosis, surgery becomes the main line of treatment. At times, patients require long term hormone replacement therapy, however, corticosteroid therapy, which has an anti-inflammatory response and can decrease the size of the mass lesion, can help patients regain pituitary function and decrease the need to be on lifelong replacement hormone therapy if recurrence after treatment does not occur. There is no consensus on the appropriate dosage and duration of glucocorticoid therapy and both these vary. One study in Germany had 32 patients treated with 20 to 500 mg daily of prednisolone equivalent glucocorticoids for a duration range of 4 days to a year.[11] 

Steroids should be tapered off accordingly based on the response as the number of adverse side effects has been increasingly reported. These adverse effects include weight gain, Cushing’s syndrome, edema, glaucoma, psychiatric symptoms, and diabetes mellitus. While there has been an initial good response to steroid therapy, there has also been a high rate of recurrence of approximately 38%. For those that show no improvement with corticosteroids or have relapsed after treatment with corticosteroids, immunosuppressive medications such as methotrexate, azathioprine, and cyclosporine can be used as well.[9] There have also been some cases where dopamine agonists such as cabergoline/bromocriptine have also been successfully used in those with hyperprolactinemia due to pituitary inflammation.[4]

Once again, it is important to note that surgery is only an option for those suffering from visual problems/ophthalmoplegia, have a mass like an effect from compression of nearby structures, or for those that have equivocal imagining findings and require histology for diagnosis. It does have the advantage of providing histological confirmation to correctly diagnose and manage lymphocytic hypophysitis and to exclude the diagnosis of a pituitary tumor. Surgery, which involves transsphenoidal or transcranial partial resection of the pituitary lesion or decompression of the mass, has a rate of recurrence of the lesion and associated symptoms of 11% to 25%. It was also noted that there is no relationship between the extent of the resection and the rate of recurrence. Surgical complications that have been noted include postoperative meningitis and rhinorrhea. There have also been cases where glucocorticoid therapy and surgery were both used.[11] However, if both these approaches and immunosuppressive therapy fail, fractionated radiotherapy can be used.

A detailed history and physical examination are helpful in diagnosing lymphocytic hypophysitis. However, without a tissue biopsy and with evidence of pituitary mass along with symptoms of hypopituitarism, the differential diagnosis continues to be large.[8] This differential diagnosis most commonly includes pituitary adenoma, however other differentials can be craniopharyngioma, Rathke cleft cyst, germinomas, pituitary apoplexy, and pituitary metastasis.[3][12][13] 

The differential diagnosis can also include infectious and inflammatory conditions as well. These include IgG4 hypophysitis, granulomatous hypophysitis which can be idiopathic or due to tuberculosis, syphilis, or sarcoidosis, Wegner’s granulomatosis and Langerhans cell histiocytosis.[4][5][6] Complete lab work and imaging need to be performed for further investigation.

Lymphocytic hypophysitis often has symptoms and features similar to that of a pituitary adenoma.[7] Previously, the diagnosis was made on autopsy, however, due to advancement in imaging, the number of cases that have been reported in the past three decades has increased. Because of lymphocytic infiltration of the pituitary gland and subsequent gland inflammation, hypopituitarism involving all pituitary hormones can occur. Treatment options vary based on symptoms and can include expectant observation to monitor for spontaneous remission, glucocorticoid therapy, immunosuppressive agents, partial resection of the pituitary lesion, and surgical decompression if nearby vital structures are at risk due to mass effect.[7] 

Diagnosis without definite histopathology can be difficult because some patients can present with no symptoms, however majority of them do present with headaches, visual problems, or other endocrine-related symptoms.[13] 

Diagnosis often lags behind the onset of symptoms.[14] Often, recurrence still occurs even after medical therapy and surgical therapy and this is why lifelong hormone replacement therapy is needed.[9] It is important to timely diagnose and appropriately treat hormone deficiency problems, especially adrenal insufficiency which has a high rate of morbidity and mortality associated with itself.[10] Despite the complications and difficulty diagnosing lymphocytic hypophysitis, once it has been diagnosed, it can be managed accordingly with steroids, surgery, immunosuppressive agents, continuous monitoring and the overall prognosis can remain good.[14]

It is essential to diagnose and appropriately manage lymphocytic hypophysitis as soon as possible due to the complications that follow.[14] Many patients have anterior pituitary hormone deficiencies and diabetes insipidus resulting in panhypopituitarism. Prolactin levels can also be decreased, normal or increased. It is very important to check cortisol and adrenocorticotropic hormone in order to diagnose and treat adrenal insufficiency as well which occurs as a result of lymphocytic hypophysitis.[10] 

Due to rapid development of secondary adrenal insufficiency, a cosyntropin stimulation test may be normal because there is not enough time for adrenal glands to atrophy. An insulin induced hypoglycemia test may be required to assess adrenal insufficiency early on. Other hormone deficiencies can occur and prolactin, IGF-1, growth hormone, thyroid stimulating hormone, free thyroxine, testosterone, luteinizing hormone, follicle stimulating hormone, electrolyte levels, anti-diuretic hormone and serum and urine osmolality should be measures as well.[4] 

Pituitary gland enlargement can also cause neurological symptoms such as visual field defects due to mass effect and can lead to compression of the optic nerve, optic chiasm and cavernous sinus cranial nerves III, IV and VI. Visual field defects can include poor color vision perception, ophthalmoplegia and diplopia.[4][7][8]

Lymphocytic hypophysitis is a rare autoimmune condition where there is lymphocytic infiltration of the pituitary gland which causes inflammation of the pituitary gland.[2] It affects women more than men with the average age of diagnosis for men being approximately 45 years and for women 34 years.[7] 

Common symptoms include headaches, vision problems, nausea, vomiting, dizziness, fatigue, loss of libido and amenorrhea. It is important to make your physician aware of these problems so they can treat them accordingly. In most cases, blood work and MRI of the brain is obtained and treatment varies on a case by case basis.[4] Management can consist of supportive care, steroid use, immunosuppressive medications and at times surgery. Experiencing vision problems may be an instance where surgery may be required.[9] 

It is also very essential that close follow up appointments are made and kept with all your physicians for long term surveillance, especially to monitor hormone deficiencies and replacement therapy if needed.[1] If diagnosed and managed appropriately, the overall prognosis of lymphocytic prognosis is good.[14]

Often times, it is difficult to diagnose lymphocytic hypophysitis as patients can present with no symptoms or with vague symptoms such as headaches, fatigue, nausea. It is important to know that usually, the first symptom is headache followed by other endocrine-related symptoms due to anterior and posterior pituitary hormone deficiencies and visual field defects.[13] While biopsy does provide a definite diagnosis, it is impractical and not without risk.[4] 

Gadolinium-enhanced MRI of the pituitary is the imagining of choice and there are very fine differences in imaging that help radiologists discern between pituitary adenoma and lymphocytic hypophysitis.[4] For all these reasons, diagnosis often lags behind the onset of symptoms.[14] However as more cases are being recognized, there has been increased awareness of this condition as a possible diagnosis. There also has been an increased awareness of the treatment options available, which can include medical therapy, surgery, or radiotherapy.[4] 

An interprofessional team approach is required for the correct management of lymphocytic hypophysitis and often involves teamwork with primary care physicians, neurosurgeons, radiologists, ophthalmologists, endocrinologists, pharmacists, and nurses.[13]