Enlargement Of Pituitary Gland Research Articles

A case of hypophysitis after COVID-19 vaccination with a detection of anti-pituitary antibody, with review of literature.

COVID-19 vaccines have resulted in a remarkable reduction in both the morbidity and mortality associated with COVID-19. However, there are reports of endocrine rare clinical conditions linked to COVID-19 vaccination. In this report, we present a case of hypophysitis following COVID-19 vaccination and review the literature on this condition. This case involved a 72-year-old male with type 1 diabetes who experienced symptoms such as vomiting, appetite loss, and headaches following his fifth COVID-19 vaccine dose. He was diagnosed with secondary adrenal insufficiency; subsequent assessment revealed an enlarged pituitary gland. Unlike previous cases, our patient has partial recovery from pituitary insufficiency, and his pituitary function gradually improved over time. Anti-pituitary antibodies (APAs) against corticotrophs, thyrotrophs, gonadotrophs, and folliculo stellate cells (FSCs) were detected in serum samples taken 3 months after onset. Hypophysitis after COVID-19 vaccination is a rare clinical condition, with only eight cases reported by the end of 2023, most occurring after the initial or second vaccination. Symptoms of hypophysitis after COVID-19 vaccination are similar to those of classic pituitary dysfunction. Pituitary insufficiency is persistent, with five of the above eight patients presenting posterior pituitary dysfunction and three patients presenting only anterior pituitary dysfunction. Two of those eight patients had autoimmune diseases. Our case suggests a potential link between acquired immunity, APA production, and pituitary damage. To elucidate the etiology of hypophysitis associated with COVID-19 vaccination, detailed investigation of patients with nonspecific symptoms after vaccination against COVID-19 is necessary.

Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis.

Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.

THU385 Refractory Hyperglycemia As Main Presenting Symptom In A Patient With Acromegaly

Abstract Disclosure: T. Rave: None. J. Vidovic: None. Y. Gu: None. Acromegaly is a rare disorder caused by the overproduction of growth hormone (GH) from an anterior pituitary adenoma. GH regulates glucose control and about 10% of patients with acromegaly can have complications of hyperglycemia. GH stimulates hepatic release of insulin-like growth hormone-1 (IGF-1), which increases gluconeogenesis and lipolysis and decreases glucose uptake throughout the body. The increase in gluconeogenesis and decrease in glucose uptake results in hyperglycemia. The excess release of fatty acids increases insulin resistance. In this case report we present a case of hyperglycemia resistant to multiple modes of medical management with limited acromegaly features found to have acromegaly induced hyperglycemia. A 58-year-old male with a past medical history of type II diabetes mellitus, hypertension, and obesity presented to the endocrinology clinic with treatment resistant hyperglycemia. The patient also endorsed having progressive carpal tunnel symptoms. He had been using an insulin pump and requiring 3 or more boluses per day for the last 6 months. Trulicity was added in addition to current insulin pump therapy, however, sugars remained elevated with an unimproved A1c level of 9% and a fructosamine level of 538 µmol/L correlating to an A1c of 10.8%. An IGF-1 level was sent to rule out acromegaly in the setting of carpal tunnel symptoms. The IGF-1 resulted in 580 ng/mL with a z-score of +5.1. The patient underwent a GH suppression test with a glucose load which showed a significantly elevated nadir GH level of 26.3 ng/mL. Of note, the patient did not have other acromegaly symptoms such as frontal bossing, ring or shoe enlargement, coarse facial features, headaches or vision changes. An MRI pituitary was obtained which was notable for an enlarged pituitary gland with heterogeneous signal, measuring approximately 2.0cm CC x 1.5cm AP x 1.7cm TV, with the pituitary stalk deviated to the left. At this time the intervention for hyperglycemic therapy shifted. The patient was started on octreotide and referred to neurosurgery for transsphenoidal surgery. The pathophysiology of type II diabetes is complex and multifaceted. Additionally, secondary causes of hyperglycemia must be considered in refractory cases, such as in this patient. This case highlights the importance of considering acromegaly and other hormonal conditions in the treatment of patients with uncontrolled hyperglycemia, even in otherwise asymptomatic patients. Presentation: Thursday, June 15, 2023

THU577 Acth Dependent Cushing Syndrome Identification And Management Challenges

Abstract Disclosure: B.C. Barreto: None. S. Patrick: None. H. Oktaei: None. H.O. Steinberg: None. Endogenous Cushing Syndrome(CS) is rare with an incidence of 0.2-5.0 per million people per year. 70 to 80% of CS is ACTH dependent and subclassified into Cushing Disease, Ectopic ACTH Syndrome and Ectopic CRH Syndrome. Ectopic ACTH secretion(EAS) has a variable clinical presentation. Atypical features like refractory hypokalemia in a patient with a tumoral lesion should raise suspicion. When imaging is inconclusive, differentiating between pituitary or ectopic disease includes invasive and noninvasive methods. We report a case of EAS. Case: A 57-year-old male with history of metastatic small-cell lung-cancer on palliative chemotherapy was admitted for acute coronary syndrome. Endocrinology evaluated the patient’s uncontrolled hypertension, hyperglycemia, and hypokalemia (1.5 mmol/L). He had no suppression with low dose dexamethasone (cortisol>75mcg/dL, ACTH 926pg/mL). Examination was pertinent for an elevated BMI 36.1kg/m2, hyperpigmented anterior thorax but no other stigmata of hypercortisolism. Laboratory analysis showed baseline cortisol 146.1mcg/dL(8.7-22), ACTH 590pg/ml(6-50), 24hr Urine Free Cortisol 736mcg/24h(5-50), which were not suppressed by high dose dexamethasone suppression test(HDDST). Aldosterone and PRA were undetectable. Brain MRI showed an enlarged pituitary gland, but no focal mass. CT abdomen pelvis showed bilateral adrenal hyperplasia, multiple hepatic masses, and bone lesions. Since the patient was a poor surgical candidate, medical therapy was initiated with ketoconazole 200mg TID, aldactone 50mg BID and potassium chloride 40mEq TID. After twelve days cortisol levels decrease to 65.2 mcg/dL, potassium 3.8 mmol/L and glucose 146 mg/dL. Hospitalization was complicated by a small bowel ileus. Medications were held due to poor gastrointestinal absorption and parenteral octreotide 200mcg TID was initiated. Once the ileus resolved, ketoconazole 200mg TID, eplerenone 50mg daily, and dexamethasone 0.5mg daily was started. Despite medical care, the patient eventually expired. Discussion: The HDDST can help distinguish pituitary from an ectopic ACTH overproduction. HDDST with >50% suppression, has been described with sensitivity-specificity of 60 to 100% for pituitary ACTH source. Symptomatic treatment of CS requires rapid normalization of hypercortisolism action. Surgery is the first line approach. When surgery is not an option, medical therapy should be considered. Adrenal steroidogenesis inhibitors, such as ketoconazole, are the first line due to rapid onset of action. Agents such as glucocorticoid receptor antagonists have limited availability in the inpatient setting. Somatostatin analogs and etomidate that inhibit 11-ßhydroxylase are potential options but require close monitoring. Severe hypercortisolism in the critically ill prompts the use of noninvasive evaluation tools and alternative medical approaches. Presentation Date: Thursday, June 15, 2023

FRI214 Adrenal Adenoma With Biochemical Findings Suggestive Of Cushing's Disease

Abstract Disclosure: A. Calimag: None. U. Tarabichi: None. M. Ahmad: None. M. Kazi: None. Introduction: We are presenting a case of a young female with prior history of multiple endocrinopathies presenting with a left adrenal adenoma with biochemical findings suggestive of Cushing's disease. Case Presentation: A 22-year-old female with a history of Type 1 Diabetes Mellitus was found to have a left adrenal adenoma 2.8 cm on CT. Absolute washout of 85 % and a relative washout of 63%, having 12 Hounsfield units (HU) on the non-contrast phase, findings suggestive of a benign adenoma. Further work up including 1 mg Dexamethasone suppression test (DST) showed unsuppressed plasma ACTH 17 pg/ml and total cortisol 9.4 mcg/dL. 8 mg DST showed ACTH 12 pg/ml, AM cortisol 8.8 mcg/dL, and Dexamethasone 991 ng/dl. Late night salivary cortisol 0.07 ug/dl, and 0.09 ug/dl, 24 hr urine cortisol 40.7. Other labs showed Aldosterone level was normal at 6.7, Renin level was also normal at 1.1. 24 hr urine catecholamines were Norepinephrine 35 mcg/24 hr, Epinephrine 3.9 mcg/24 hr, while urine Metanephrine level was <0.24, and normetanephrine level at 0.34. TSH 1.2mcU/ml. One day prior to surgery ACTH level was suppressed at 2.1 pg/ml drawn from a different lab. MRI of the Pituitary showed a slightly enlarged pituitary gland with uniform contrast enhancement and no definite lesion. The patient underwent a laparoscopic left adrenalectomy. Pathology showed an adrenal cortical neoplasm consistent with adrenal cortical adenoma, with no significant cytologic atypia, mitotic activity, or necrosis. Immunoperoxidase stain, the tumor is positive for inhibin and negative for PAX8. Post-op she developed adrenal insufficiency which was treated with hydrocortisone. The follow-up cortisol level was 11.3 mcg/dL when the patient was off hydrocortisone. Discussion: In this case, the biochemical exam showed elevated cortisol with ACTH not fully suppressed at both 1 mg and 8 mg DST which was done twice, and normal 24-hour urine cortisol. Determining whether this is adrenal vs pituitary mediated was one of the clinical dilemmas of this case. Initially, the patient’s ACTH was unsuppressed however the day before surgery ACTH was suppressed and the patient’s cortisol level normalized after the left adrenalectomy. Immunoassays for ACTH levels may occasionally be susceptible to analytical errors. (1-2) There are several case series and studies mentioning assay interference when using Immulite Assay versus Cobas ACTH assay. (1-2) Therefore, it is important to analyze clinical findings and biochemical testing and if lab tests are discordant, recheck using a different analytical platform in a different lab or an alternate ACTH assay to confirm ACTH levels. (1-2)

FRI339 Hypophysitis Secondary To Small Vessel Anca Vasculitistreated With Rituximab

Abstract Disclosure: A. Rivadeneira: None. N. Kumar: None. S. Banerjee: None. M. Gubbiotti: None. D. Yoshor: None. J. Kharlip: None. C.A. White: None. Introduction: Granulomatosis with polyangiitis (GPA) is an autoimmune small-vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCAs) that rarely involves the pituitary. Conventional treatment of GPA includes high dose glucocorticoids with cyclophosphamide. Rituximab has been used in refractory cases with high rates of remission. We present a case of pituitary GPA treated with and excellent response to rituximab. Case: 51-year-old woman with hypothyroidism, post I-131 treatment for Graves’ disease. Patient presented with 1 year of worsening fatigue, myalgias, frontal headaches, sinus congestion and epistaxis. CT sinus showed pituitary enlargement and chronic mucosal disease. MRI pituitary showed diffusely enlarged pituitary with non-visualized posterior pituitary bright spot and thickened stalk. CT chest showed 18x11 mm nodular opacity and peribronchial fibrosis. Laboratory evaluation showed ACTH 26.7 pg/mL, cortisol 13.4 mcg/dL, TSH 1.1, T4 9.7, prolactin 53 ng/dL, estradiol <20, LH 4, FSH 23. Sodium 140 and urine osm 488. There was positive p-ANCA staining and elevated serum anti-proteinase 3 antibody (PR3), 74 units (0-20). Myeloperoxidase antibody was not elevated. ESR 73 mm/h (0 - 30) and CRP 7.9 (<7.4). Due to atypical ANCA pattern (p ANCA typically is associated with MPO not PR3), pituitary biopsy was performed and showed adenohypophysis with dense lymphoplasmacytic infiltration with nodularity of the inflammatory infiltrates, some arranged peri vascularly, compatible with involvement of the pituitary gland by GPA. She began rituximab 375 mg/m2 weekly for four weeks with plan to continue every 6 months. After treatment, the patient experienced resolution of daily frontal headaches, congestion, cough and epistaxis. CT chest showed improvement of prior lung findings, and ESR/CRP normalized. Repeat pituitary MRI is pending. Discussion: Pituitary involvement is uncommon in GPA, occurring in only 3.9% of cases. It may lead to partial or complete pituitary dysfunction, particularly central diabetes insipidus (87.5%) and hypogonadism (75%). Typical MRI abnormalities include diffusely enlarged pituitary gland, thickened pituitary stalk and absence of posterior bright spot. Treatment of GPA includes a combination of corticosteroids, Cyclophosphamide, Azathioprine and Rituximab. Remission is achieved in up to two thirds of patients. Treatment of lymphocytic hypophysitis, another common cause of diffuse pituitary enlargement, relies on high dose glucocorticoids, leading to many side effects and taper is limited by worsening symptoms. This case highlights the critical role in serologic evaluation and targeted pituitary biopsy to identify the specific etiology of pituitary infiltration to help guide alternate treatment options, and the emerging role of Rituximab as a steroid sparing agent for treatment of pituitary inflammation. Presentation: Friday, June 16, 2023

Challenges of transsphenoidal pituitary surgery in severe brachycephalic dogs.

Transsphenoidal hypophysectomy is the standard surgical technique for the excision of pituitary neoplasms. Anatomy may be more obscured in brachycephalic skull types due to the crowding of soft tissue and osseous structures. We describe the unique challenges to approach the sphenoid bone and localize the correct burr hole site in severe brachycephalic dogs. A single institution retrospective case series of brachycephalic dogs with pituitary-dependent hypercortisolism (PDH). Preoperative computed tomography enabled 3D-, and cross-sectional reconstruction to plan and dry-practice the position of the ideal burr hole in relation to the sella turcica, pterygoid hamular processes, and hard palate. Rostral burring of the caudal hard palate obscuring the direct sphenoid approach necessitated adaptations to the original transsphenoidal hypophysectomy procedure. Postoperative outcomes and complications with respect to those seen in mesocephalic dogs are described. Ten brachycephalic dogs including French Bulldogs (n = 9) and a single Dogue de Bordeaux were included. All dogs were diagnosed with PDH and had preoperative advanced imaging performed on the skull. All but one dog had an enlarged pituitary gland, with a median pituitary/brain value of 0.5 (range 0.21-0.9). A total of 11 transsphenoidal hypophysectomy procedures were performed in these 10 dogs. Rostral extension of the soft palate incision into the hard palate was performed to access the burr hole site on the sphenoid bone. Major complications included aspiration pneumonia (n = 1), severe gastroesophageal reflux (n = 1), and central nervous signs (=1). All dogs survived until discharge, with a median time to follow-up of 618 days (range 79-1,669 days). Seven dogs experienced long-term remission of PDH. Brachycephalic dogs undergoing transsphenoid al hypophysectomy benefit from meticulous presurgical planning and extension of the approach into the caudal hard palate. Advanced surgical skills can render a good outcome in a technically challenging environment.

Central diabetes insipidus following COVID-19 mRNA vaccination: a case report

The coronavirus disease 2019 (COVID-19) has been a major public health emergency worldwide. Vaccines were rapidly developed and approved to prevent the spread of viral infection. However, various side effects of the COVID-19 messenger RNA (mRNA) vaccines have been reported after their commercialization. A 24-year-old man visited our emergency department with polyuria and polydipsia that occurred after he received a COVID-19 mRNA vaccine 10 days beforehand. The initial laboratory findings showed very low urine osmolality with hyperosmolar hypernatremia. Based on these findings, diabetes insipidus was suspected, and sella magnetic resonance imaging showed an enlarged pituitary gland and the absence of posterior pituitary higher intensity. After 12 hours of using oral desmopressin acetate, urine volume decreased, and after 5 days of administration, serum electrolyte and serum osmolality improved. This case report of diabetes insipidus occurring after vaccination with the BNT162b2 mRNA COVID-19 vaccine is presented as a reminder that close monitoring is necessary for patients with polyuria and polydipsia after vaccination.

Immune-related hypophysitis: An analysis of a heterogeneous entity.

e14704 Background: Immune-checkpoint inhibitors (ICIs) have led to revolutionary breakthroughs in the management of many malignancies. With the increasing use of ICIs, immune-related adverse events (irAE) have emerged and led to significant challenges and limitations. Immune-related hypophysitis, a potentially life-threatening irAE, has limited data on its diagnosis, clinical findings, and management. This was our incentive to characterize our single-institution experience with immune-related hypophysitis over the past 5 years. Methods: We retrospectively studied a cohort of adult patients who received ICIs at the Cleveland Clinic Foundation between 2017-2022. Our search was done by utilizing an outpatient oncology pharmacy database. Analyzed ICIs included atezolizumab, nivolumab, pembrolizumab, ipilimumab, avelumab, and durvalumab. The occurrence of immune-related hypophysitis was as determined by an endocrinologist or oncologist. Results: 6,615 patients received ICIs from 2017-2022, of which 27 patients were diagnosed with hypophysitis. Immune-related hypophysitis occurred with ICI monotherapy in 44.4% and combined therapy (ipilimumab and nivolumab) in 55.5%. The most commonly implicated agents were ipilimumab (74%), followed by nivolumab (59.3%), pembrolizumab (18.5%), and durvalumab (3.7%). In patients receiving ipilimumab-nivolumab, hypophysitis was detected after a median duration of 65 days (range: 29-163 days) from ICI initiation, compared to 58 days (38-112) with ipilimumab alone and 155 days (8-294) with pembrolizumab. Hypophysitis was grade 1 in 18.5%, grade 2 in 29.6%, grade 3 in 37%, and grade 4 in 14.8% of all patients. No hypophysitis-related deaths occurred. Signs and symptoms included constitutional symptoms (fever, anorexia, myalgia) in 88.89%, severe/intractable headaches in 40.7%, gastrointestinal complaints in 29.6%, dermatologic findings in 7.4%, visual symptoms in 7.4%, and syncope in 3.7% of all patients. Lab findings included abnormalities of TSH in 77.78%, ACTH in 70.60%, FSH and/or LH in 52.63%, and a positive ACTH stimulation test in 69.3%. Imaging findings were present in 62.5% of patients, and most commonly revealed pituitary gland enlargement, enhancement, or stalk thickening on brain/pituitary MRI. Treatment included glucocorticoid replacement in 92.6%, thyroid replacement in 40.7%, and testosterone in 7.4% of patients. All patients remained on glucocorticoid therapy indefinitely after hypophysitis was diagnosed. ICIs were momentarily held in 22.2% and discontinued in 51.86% of patients, while 25.9% of patients did not experience treatment interruptions. Conclusions: Immune-related hypophysitis is an uncommon irAE that presents with variable clinical and diagnostic findings. Nonetheless it is a cause of permanent glucocorticoid dependence. Healthcare professionals should be aware of this entity so treatment can be promptly started.

Increased pituitary volumes in patients with Sanfilippo syndrome (mucopolysaccharidosis type 3, MPS III).

To evaluate apparent pituitary gland enlargement in patients with Sanfilippo syndrome observed at our institution. Twelve patients with Sanfilippo syndrome with brain MRI were studied. Anterior, posterior, and whole pituitary volumes were estimated using the prolate ellipsoid volume calculation method (π/6 × L × W × H). Convexity along the upper pituitary margin (Elster's grade) was also measured. These values were compared to two age- and sex-matched groups (normal controls and patients with Hurler syndrome) using one-way ANOVA followed by Tukey's post hoc analysis for multiple comparisons. In the Sanfilippo cohort, the mean whole pituitary volume was 529.9 mm, the mean anterior pituitary volume was 333.4 mm, and the mean posterior pituitary volume was 59.1 mm with Elster's grade of 4.2. In the control cohort, the mean whole pituitary volume was 217.4 mm, the mean anterior pituitary volume was 154.8 mm, and the mean posterior pituitary volume was 28.4 mm with Elster's grade of 2.5. In the Hurler syndrome cohort, the mean whole pituitary volume was 310.0 mm, the mean anterior pituitary volume was 178.2 mm, and the mean posterior pituitary volume was 35.4 mm with Elster's grade of 3.5. In our cohort of patients with Sanfilippo syndrome, whole, anterior, and posterior pituitary volumes and degree of convexity along the upper pituitary border were all significantly greater than controls. The cause of these morphological changes is unclear, as is clinical correlation of the findings.

Teaching Neuro Images : Intracranial hypotension in a patient with Marfan syndrome

An 18-year-old man with Marfan syndrome and migraine headaches presented with acute worsening of headaches with postural changes following spinal fusion surgery for scoliosis. Lumbar spine MRI done before surgery showed diffuse dural ectasia (figure 1). Brain MRI after surgery showed distended transverse and sagittal dural venous sinuses1 and an enlarged pituitary gland suggesting intracranial hypotension (figure 2). He was treated conservatively with rest, fluids, and caffeine. Patients with Marfan syndrome frequently have dural ectasia2 and are at risk of CSF leaks after spinal surgery leading to intracranial hypotension. Our case highlights subtle changes on brain MRI suggesting intracranial hypotension.

Hypophysitis and Secondary Adrenal Insufficiency From Immune Checkpoint Inhibitors: Diagnostic Challenges and Link With Survival.

Hypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diagnostic challenges, and evaluate an association with survival in a large cancer cohort. We performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a combination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology. A total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9/16; 56.2%) or renal cell carcinoma (4/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were younger compared with those who did not develop hypophysitis (median age, 57 vs 65 years; P=.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monotherapy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) (P<.0001). Pituitary gland enlargement on MRI occurred more frequently after CTLA-4 inhibitor monotherapy or combination therapy (5/7; 71.4%) compared with PD-1/PD-L1 inhibitor monotherapy (1/6; 16.7%). The survival benefit of hypophysitis was not apparent after addressing immortal time bias and adjusting for other variables affecting patient outcomes. Secondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1/PD-L1 inhibitor-induced hypophysitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysitis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation.

TEST ARTICLE: Hypophysitis and Secondary Adrenal Insufficiency From Immune Checkpoint Inhibitors: Diagnostic Challenges and Link With Survival.

Hypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diagnostic challenges, and evaluate an association with survival in a large cancer cohort. We performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a combination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology. A total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9/16; 56.2%) or renal cell carcinoma (4/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were younger compared with those who did not develop hypophysitis (median age, 57 vs 65 years; P=.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monotherapy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) (P<.0001). Pituitary gland enlargement on MRI occurred more frequently after CTLA-4 inhibitor monotherapy or combination therapy (5/7; 71.4%) compared with PD-1/PD-L1 inhibitor monotherapy (1/6; 16.7%). The survival benefit of hypophysitis was not apparent after addressing immortal time bias and adjusting for other variables affecting patient outcomes. Secondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1/PD-L1 inhibitor-induced hypophysitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysitis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation.

A detailed pituitary profile always matters

Abstract 29-year-old female with known hypothyroidism and positive thyroid auto antibodies, followed up throughout pregnancy for adjusted doses of thyroid replacement therapy, presented 2 months post-partum with gradually increasing fatigue, repeated pre-syncope experience, inability to cope with daily home and family needs and headache. Adequacy of thyroid replacement therapy was questioned, TSH has been performed: 0.18 mIU/ml. Checking the blood pressure in lying and standing position has showed Postural hypotension. An urgent measurement of Cortisol (am) showed a result of1.06 ug/dl. Preliminary Differential Diagnoses have been suggested; Pituitary apoplexy, Pituitary adenoma, Autoimmune adrenalitis (Autoimmune Polyglandular Syndrome) or Others. On further detailed history, the patient affirmed dizziness and fainting liability on standing from lying position, bitemporal headache more in the morning. However, she denied frequent urination throughout the day, neither repeated times at night. In addition, she confirmed efficient breast feeding. Continued Lab investigations: ACTH (am) (Low); FT4 (Low; on replacement therapy); IGF1 (Normal) Serum osmolality (Normal); Urine osmolality (Normal); E2 / LH / FSH (normal physiological levels) Prolactin (normal for breast feeding) MRI pituitary and sella: Diffuse isointense enlargement of anterior pituitary gland. Homogenous and strong diffuse pituitary enhancement with gadolinium contrast. History and investigations were not fully matching with any of the previously proposed differential diagnoses, especially in regards of selective corticotroph and thyrotroph affection, sparing other pituitary cell types. Moreover, the autoimmune predisposition, the nature of the clinical presentation and its timing during early postpartum period, together with the laboratory and imaging investigations were all matching with the diagnosis of Lymphocytic Hypophysitis. The Patient got pregnant again 14 months post-partum, reflecting spared gonadotroph function and highlighting the importance to identify this uncommon diagnosis and to notify the patient about normal gonadal function and the normal possibility of pregnancy. However, she remained on hydrocortisone and thyroxine replacement. Finally, it is important that this condition should not be misdiagnosed in the first place as postpartum thyroid disturbance and TSH results, especially during and after pregnancy, shall always be interpreted in the clinical context and with the overall thyroid profile.

ODP317 Hypophysitis or No? A Rare Case of Bipolaris Fungal Sinusitis Causing Severe Pituitary Inflammation.

Abstract Clinical case: A 28 year old male with uncontrolled diabetes mellitus presented to the hospital with severe, worsening holo-cephalic headache associated with fevers, light sensitivity which was unresponsive to pain medications. Initial CT of the brain showed severe paranasal sinus disease. Lumbar puncture was significant for elevated protein and cell count with neutrophilic predominance and negative CSF culture. Patient was empirically treated for meningitis. Due to no improvement in his symptoms, MRI brain with contrast was done that showed complete opacification of the left sphenoid sinus with partial opacification of the ethmoid sinus. Of note, heterogeneous enlargement and enhancement of pituitary gland including portion of distal infundibulum was seen with mild compression of optic chiasm. High dose dexamethasone was initiated. Pituitary workup revealed preservation of all axes including AM cortisol 36.5 mcg/dL (6.6mcg/dl- 33 mcg/dl), prolactin 2.9 ng/ml (2.1ng/ml-17.7ng/ml), TSH 1.4 uIU/mL (0.34-5.6 uIU/mL), FT4 0.99 uIU/mL (0.80-1.80 uIU/mL) with normal serum chemistry and hemodynamics. Repeat MRI brain showed sphenoid pyomucocele with infection extending to the sella, cavernous sinuses and anterior/middle cranial fossas. ENT surgery was emergently performed with surgical debridement of the sphenoid and ethmoid sinuses revealing green cement like debris causing posterior septal perforation from the pressure. Interestingly, ethmoid sinus fluid culture grew Bipolaris fungal species. Patient's condition gradually improved and he was discharged on oral itraconazole with steroid taper. The patient did not develop signs or symptoms of hypophysitis during his hospital course. Presentation: No date and time listed

PSAT328 Primary Hypothyroidism Presenting with Galactorrhea and Pituitary Hyperplasia

Abstract Introduction Pituitary Hyperplasia (PH) refers to diffuse enlargement of pituitary gland and is most commonly physiological as in pregnancy and lactation. PH can also be associated with end organ hormone deficiencies like primary hypothyroidism, Addison's disease and some neuroendocrine tumors. Primary hypothyroidism is a known cause of prolactin elevation however hyperprolactinemia in the presence of pituitary enlargement can often be mistaken for pituitary adenoma. We report a case of PH caused by primary hypothyroidism presenting with galactorrhea and hyperprolactinemia and successfully treated with thyroid hormone replacement. Case presentation 21-year-old female presented to the Primary Care Provider's office with galactorrhea from bilateral breasts for 2 months. Pregnancy was ruled out and prolactin levels were checked and noted to be elevated at 51.3 ng/mL. Subsequently MRI of Pituitary was done which showed diffusely enlarged, homogenously enhancing anterior pituitary gland with convex superior margin, measuring 12 mm in superior to inferior dimension, contacting and slightly elevating optic chiasm. Further testing showed TSH &amp;gt;100µIU/mL, and undetectable Free T4. She was started on Levothyroxine and then referred to Endocrinology for evaluation of Pituitary mass. Upon further questioning she reported headaches for few weeks associated with intermittent dizziness, fatigue, weight gain of 30-40 pounds, irregular menstrual periods, cold intolerance, and low libido for several months. Physical exam was remarkable for bradycardia, dry skin. Thyroid was normal on exam. Pituitary hyperplasia was thought to be secondary to primary hypothyroidism and patient was continued on Levothyroxine. At 3 month follow up visit, patient reported improvement in her symptoms of fatigue, menstrual periods and lost few pounds of weight. Her galactorrhea resolved completely. Repeat labs showed normal prolactin levels and her thyroid levels normalized after few dose adjustments. Follow up MRI done 1 year from initial presentation showed decrease in the anterior pituitary enlargement, now measuring 8 mm, and the superior margin was no longer contacting the optic chiasm. Conclusion Primary hypothyroidism is common, but often under recognized cause of Pituitary hyperplasia. The underlying pathophysiology is lack of negative feedback of Thyroid hormones on Hypothalamus resulting in elevated levels of Thyrotropin releasing hormone (TRH). Excess TRH leads to thyrotroph cell hyperplasia in anterior pituitary and elevated TSH levels, TRH also leads to lactotroph hyperplasia and can result in hyperprolactinemia. Neurological symptoms related to PH and symptoms related to hyperprolactinemia, can sometimes be the initial presenting symptoms of primary hypothyroidism. It is important to recognize primary hypothyroidism as the cause for pituitary hyperplasia and hyperprolactinemia (especially those with TSH &amp;gt; 50-100 microIU/mL) as the primary treatment is thyroid hormone replacement and not surgery. These patients should be followed closely with repeat MRI to document the resolution of pituitary hyperplasia. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PMON322 Gigantism in 13-Year-Old Male With Pituitary Tumor

Abstract Background Pituitary gigantism is caused by excess growth hormone [GH] secretion from the pituitary gland when the growth plates are open leading to excessive linear growth and tall stature in the pediatric population. It is extremely rare with a reported incidence of 8 cases per million person-years. Clinical Case The patient is a 13-year-old male who presented with concerns of accelerated growth rate and tall stature. His father noticed the patient's tall stature when he passed his own height the last year. The patient was seen by his PCP who referred the family to pediatric endocrinology. His symptoms included snoring and bi-weekly headaches, but no vision changes. Review of his growth charts showed linear growth tracking at greater than the 95th percentile since the age of 9 years. His clinical features included large hands, large feet, prominent jaw, testicular volume &amp;gt;25 ml, tall stature [Ht &amp;gt; 99%, Z= +4.59 SD]. The patient's mid-parental height is 69.1 inches [175.5 cm] and the patient measured 76.6 inches [194.5 cm]. His predicted height was 7 feet 1.5 inches [217.2 cm] based on his bone age. His clinical features were strongly concerning for Gigantism. Initial labs showed IGF-1 of 924 ng/mL [168–576], prolactin of 20.1 ng/mL [2.8–11.0], and IGF-BP3 8.7 mg/L [3.1–9.5]. Cortisol, ACTH, TSH, FT4, LH, FSH, Testosterone were within normal limits. Bone age was concordant with chronological age. MRI showed enlarged pituitary gland measuring 1.3 cm in height, suspicious for macroadenoma. Cardiac evaluation including echocardiogram came back normal. GH suppression test resulted in a 2-hour GH level of 27.3 ng/mL [&amp;lt;1] and he was diagnosed with Gigantism due to GH-secreting pituitary tumor. The parents decided to consult neurosurgery team at a different facility, where transsphenoidal resection of the pituitary tumor was performed. He did not develop any postoperative complications, including Diabetes insipidus or any pituitary hormone deficiencies, and was discharged home shortly after. Follow-up MRI of the pituitary showed no evidence of residual tumor. Pathology of the macroadenoma expressed GH and prolactin on immunohistochemical stains and was negative for TSH, LH/FSH, and ACTH. Genetic studies obtained were negative, lowering the likelihood of inherited predisposition to endocrine neoplasms. The patient has remained well post-operatively and has been able to continue school and play basketball without issues. Conclusion Pituitary gigantism occurs in the pediatric population prior to skeletal epiphyseal closure and is caused by GH excess. Initial screening tests should evaluate for pituitary function including IGF-1 and prolactin levels. The gold standard for diagnosing GH excess is the GH suppression test. Even though rare, it is important for clinicians to keep a high level of suspicion for quick recognition and management of overgrowth syndromes. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

OR08-5 Associations Between Signal Transducer and Activator of Transcription (STAT) Mutations and Galactorrhea

Abstract Background Prolactin (PRL) is responsible for the development of mammary glands and milk production. STAT1 and STAT3 are genes that express transcription factors that mediate PRL's intracellular signaling, but an association between their function and galactorrhea has not yet been identified. Here we describe three patients with somatic STAT mutations and galactorrhea. A 27-year-old woman with hyper-IgE syndrome (Job's Syndrome) due to a STAT3 deletion mutation (p.Val463del) associated with recurrent infections reported thin, white, bilateral discharge with breast manipulation beginning in adolescence. She did not have spontaneous leakage or pain. At presentation, PRL was slightly elevated to 27.9 (ref. 2.0-25.0 mcg/L) with otherwise normal levels of anterior pituitary hormones. She was not on any drugs known to cause hyperprolactinemia. MRI showed a 5×4 mm microadenoma without any mass effect. A 32-year-old woman also with Job's syndrome due to a heterozygous loss-of-function STAT3 mutation (p.R382Q) associated with recurrent infections and papillary thyroid cancer described unilateral, chronic, thin, white nipple discharge with light touch of her right breast for "as long as she could remember." She had a history of breast abscesses, but at presentation there was no evidence of abscess or infection. PRL was 15.1 mcg/L, and other anterior pituitary hormones were normal. MRI showed a structurally normal pituitary. A 22-year-old woman with a STAT1 activating mutation (p.E235A) associated with recurrent infections, autoimmune hypothyroidism, T1DM, and hypogonadotropic hypogonadism requiring pubertal induction at age 12y reported bilateral galactorrhea starting at age 18y. A white, milky discharge could be expressed with light manipulation, but no discharge was produced spontaneously. PRL was 16.2 mcg/L with serial dilution and has consistently been in the reference range. Anterior pituitary evaluation was normal except for elevated TSH of 12.5 (ref. 0.27-4.2) consistent with autoimmune hypothyroidism. MRI revealed a diffusely enlarged pituitary gland (12mm in the cranio-caudal dimension) without focal hypo-enhancement. Conclusions It is known that PRL signaling involves the JAK/STAT pathway, and an analysis of human milk cells showed upregulated STAT3 and downregulated STAT1 during lactation (PMID 26909879). These three cases provide clinical evidence for a mechanistic connection between STAT signaling and galactorrhea and suggest that STAT3 and STAT1 function in opposite directions to regulate lactation. In our cases, increased STAT1 or decreased STAT3 activity are associated with normal-PRL, inducible galactorrhea. Beyond understanding the specific intracellular signaling pathways leading to galactorrhea, these observations may be utilized for developing therapies for those with impaired lactation. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

ODP292 A Xanthomatous Hypophysitis: Always Think Twice Before Pituitary Resection.

Abstract Background A xanthomatous hypophysitis is a rare form of primary hypophysitis common in females. Clinical case: A 47-year-old male was referred for pituitary adenoma resection. The patient presented with low libido and facial and body hair loss for 3 years. He reported increased thirst and nocturia for 2 years. 24-hr fluid intake showed 4,800 ml intake and 6,700 ml output. Physical examination revealed tanner 5 pubic hair with testicle size 12 ml bilaterally. He had a normal visual field. Laboratory testing revealed low morning total testosterone level of 108 ng/dL (241-872), low LH 0.39 mIU/mL (1.14-8.75) and low FSH 1.28 mIU/mL (1.37-13.58). Other pituitary hormones showed normal TSH 0.634 uIU/ml (0.35-4.9) with low free T4 0.64 (0.7-1.48), IGF-1 107 ng/mL (74-196), prolactin 10.92 mcg/mL (3.46-19.4), morning cortisol 8.9 mcg/dL (3.7-19.4). A 1 mcg ACTH stimulation test showed an inappropriate increase in cortisol level of 16.1 mcg/dL with baseline ACTH 28 pg/mL (0-46). Regarding polyuria, biochemical testing showed serum Na 148 mmol/L (136-145), Uosm 307 mOsm/Kg (50-1300), and Sosm 307 mOsm/kg (275-290). After the therapeutic trial with oral DDAVP, urine output significantly decreased. Subsequent tests showed serum Na 144 mmol/L, Uosm of 295 mOsm/kg, and Sosm of 278 mOsm/kg. The final diagnosis was hypopituitarism and central diabetes insipidus. MRI showed an enlarged pituitary gland with 2 decreased enhancing nodules in the post-contrast study of the anterior lobe measuring 4.2 and 6.7 mm in diameter. No stalk thickening was detected. There was no compression on adjacent organs. Since the pituitary lesions could not explain the hypopituitarism and DI. The surgery was postponed, and he underwent an endoscopic transsphenoidal biopsy. The procedure yielded a milky fluid content, and a circumferential dissection of a soft-yellow capsule was done. Pathology examination revealed a chronic hypophysitis with clusters of foamy macrophages. Immunohistochemistry showed positive for CD3, CD20, and CD138. A CD68 was positive in multiple clusters of foamy macrophages, while an IgG4 was negative. The final diagnosis is xanthomatous hypophysitis. The patient was treated with hormonal replacement therapy of levothyroxine, prednisolone, testosterone, and DDAVP. Until now, there are 36 cases in the literature reporting xanthomatous hypophysitis. The prevalences of hormonal deficits are 36.1% adrenal insufficiency, 42.4% central hypothyroidism, 54.6% central DI, 36.4% hypogonadism, 63.6% GH deficiency, and 54.6% hyperprolactinemia. The common MRI characteristic is a cystic mass with a ring or peripheral enhancement. Pituitary stalk thickening is shown in 50% of cases. Conclusion This clinical case demonstrated the rare entity of xanthomatous hypophysitis presenting with secondary AI, hypogonadotropic hypogonadism, central hypothyroidism, and DI. The discrepancy between clinical history and the MRI findings was a clue for pituitary biopsy leading to the final diagnosis and avoidance of unnecessary surgery. Presentation: No date and time listed

PMON80 Case of Cushing's Disease That Presented as Diabetic Ketoacidosis and Successfully Treated With Stereotactic Radiosurgery During the COVID-19 Pandemic

Abstract Background Although Cushing's disease is known to impair glucose metabolism, diabetic ketoacidosis (DKA) as its initial presentation has been reported in only a few case reports. The first-line treatment for Cushing's disease is transsphenoidal surgery, but safety concerns during the COVID-19 pandemic has led to the utilization of other treatment options. We present a case of Cushing's disease that presented initially as DKA and was successfully treated with stereotactic radiosurgery. Case Presentation Our patient was a 36-year-old female known to have diabetes mellitus and hypertriglyceridemia for one year. She presented with one-week history of generalized weakness, blurring of vision, and elevated blood pressure. Her blood glucose level was high at 523 mg/dL, associated with ketosis and metabolic acidosis. She was diagnosed with diabetic ketoacidosis which resolved after hydration and intravenous insulin administration. Further history revealed that she has been experiencing progressive weight gain and infertility for the past five years. She had cushingoid features including obesity, scalp hair thinning, moon facies, acne, hirsutism, and buffalo hump. Midnight salivary cortisol was high at 9.34 ng/mL (0.20-4. 00 ng/mL). Low dose dexamethasone suppression test showed an unsuppressed serum cortisol level at 31.2 mcg/dL (&amp;lt;1.8 mcg/dL). Adrenocorticotropic hormone (ACTH) level was high at 88.5 pg/mL (&amp;lt;46 pg/mL) and pituitary magnetic resonance imaging (MRI) showed an enlarged pituitary gland measuring 13.4 mm in the craniocaudal dimension with leftward displacement of the pituitary stalk. She was diagnosed with Cushing's disease and was initially advised transsphenoidal surgery. Due to concerns of COVID-19 transmission, the team and the patient decided to do stereotactic radiosurgery (SRS). The procedure was performed without complication. At 2 months follow-up, there was noted improvement of blurring of vision, normalization of cortisol level to 20.72 mcg/dL (4.30-22.40 mcg/dL), and a decreased ACTH level at 62.19 pg/mL. There was a 4 mm decrease in the craniocaudal dimension of the pituitary gland on repeat pituitary MRI. Thyroid stimulating hormone (TSH) level normalized from 0.209 to 0.647 uIU/mL (0.55-4.78 uIU/mL), and the glycohemoglobin decreased from 11.5% to 6.3%. Hypertension was controlled on one medication. Conclusion Stereotactic radiosurgery is usually reserved as a secondary option to transsphenoidal surgery. On average, normalization of cortisol levels after SRS takes 14 months. In our patient, the serum cortisol decreased to within normal levels at only 2 months after SRS. While a longer follow-up is desirable in order to assess the durability of control of hypercortisolemia, our case demonstrates that stereotactic radiosurgery is a safe and effective treatment option for Cushing's disease during the COVID-19 pandemic, when safety protocols and decreased hospital and patient resources might hinder the performance of transsphenoidal surgery. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.