ACTH Deficiency Research Articles

Paraneoplastic isolated adrenocorticotropic hormone deficiency revealed after immune checkpoint inhibitors therapy: new insights into anti-corticotroph antibody.

A recently discovered facet of paraneoplastic adrenocorticotropic hormone (ACTH) deficiency exists in two forms: a paraneoplastic spontaneous isolated ACTH deficiency (IAD) and an immune checkpoint inhibitor (ICI)-related hypophysitis. Autoantibodies against corticotrophs, such as circulating anti-proopiomelanocortin (POMC) antibodies are considered disease markers. However, the number of identified cases was limited, implying that the characteristics of these autoantibodies are not fully understood. We investigate circulating autoimmune autoantibodies in detail through a novel case of IAD that developed as a paraneoplastic autoimmune ACTH deficiency. The patient developed IAD after 25 weeks of ICI therapy for metastasis of large-cell neuroendocrine carcinoma at 69 years of age. Ectopic ACTH expression and infiltration of CD3+, CD4+, CD8+, and CD20+ lymphocytes were observed in the tumor tissues and circulating anti-POMC antibodies were detected specifically in the patient's serum. Moreover, detailed analyses of immunofluorescence staining using patient serum revealed that the recognition site of the autoantibody was ACTH25-39, which had not been identified in previous cases of paraneoplastic autoimmune ACTH deficiency. This case involved a combination of paraneoplastic spontaneously acquired IAD and ICI-related hypophysitis occupying the middle ground. Moreover, our study reveals new aspects of anti-POMC antibodies in patients with paraneoplastic ACTH deficiency. This report expands our understanding of the immunological landscape and provides new insights for the identification of antibodies associated with paraneoplastic autoimmune ACTH deficiency.

Hypopituitarism after traumatic brain injury in adults: Clinical guidelines of the neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition (SEEN)

Traumatic brain injury (TBI) is associated with hypopituitarism with a variable incidence, depending on the time and methods used to diagnosis, and on factors related to the trauma, such as its severity, its anatomical location and the drugs used in the acute phase. The pituitary gland can be damaged directly by the impact or secondary to factors such as ischemia, inflammation, excitotoxicity or immunity. In acute phases ACTH deficiency is the most relevant, since failure to detect and treat it can compromise the patient's life. Clinical manifestations are typical of each hormone deficient axes, although the combination hypopituitarism-trauma has been associated with cognitive deterioration, worse metabolic profile and greater impairment of quality of life. One of the clinical challenges is to determine which patients benefit from a systematic hormonal evaluation, and therefore from hormone replacement, and what is the appropriate time to do so and the most suitable diagnostic methods.

Significance of the autoantibody assay in predicting the development of immune-related adverse events in patients receiving atezolizumab plus bevacizumab combination therapy for unresectable hepatocellular carcinoma.

Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy. Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline. Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n=10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p=0.047) and RF at baseline (HR 5.4, p=0.035) and to achieve complete response (HR 5.8, p=0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development. In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.

THU243 Fitting Together The Pieces Of The Puzzle Between Isolated ACTH Deficiency And Immunodeficiency: DAVID Syndrome

Abstract Disclosure: K.V. Buchanan: None. A.C. Hurst: None. A.P. Ashraf: None. Objectives: DAVID syndrome is a rare genetic disorder with common variable immunodeficiency (CVID) and anterior pituitary hormonal deficiencies due to a pathogenic variant in NFKB2. We aim to describe asymptomatic ACTH deficiency identified after the diagnosis of CVID in a patient with DAVID syndrome. Methods: A retrospective chart review of a patient with DAVID syndrome was performed. Results: The patient is a 15 year and 9-month-old female with weight in the 71st percentile and height in the 64th percentile, who was diagnosed with DAVID syndrome at 10 years through a Primary Immunodeficiency panel which identified a pathogenic variant in NFKB2 c.2557C>T,p.Arg853* and a variant of unknown significance in STAT2 c.1301C>T (p.Thr434Met). The panel was performed due to the patient’s history of recurrent sinus infections, hypogammaglobulinemia, and alopecia totalis. The patient did not have symptoms of ACTH deficiency including hypoglycemia and hypotension. After the genetic diagnosis was made, an anterior pituitary hormone evaluation was performed which showed an ACTH <5 pg/ml, AM cortisol <0.2 mcg/dL, TSH 3.48 uIU/ml, FT4 0.82 ng/dL, thyroid peroxidase antibody 29 IU/mL (normal <9), somatomedin-c 44 ng/mL (reference range 152-593), LH 5.36 mIU/mL, and FSH 14.25 mIU/mL. Adrenal insufficiency was diagnosed since the patient did not show incremental cortisol response (serum cortisol <0.2 mcg/dL at 30 and 60 minutes) post Cosyntropin stimulation test. The patient had normal electrolytes. Hydrocortisone replacement therapy was initiated. A growth hormone stimulation test was not performed since the patient had normal height and interval height velocity. The thyroid function remained stable, and the patient attained menarche at age 14. Conclusions: This patient is unique in having asymptomatic, acquired, isolated ACTH deficiency diagnosed in later childhood, despite having frequent sinopulmonary infections since infancy as part of DAVID syndrome. Further research needs to be done to elucidate how NFKB2 variants contribute to acquired, isolated, central ACTH deficiency or autoimmune pituitary disease. Presentation: Thursday, June 15, 2023

THU126 SARS-CoV-2 Infection And Vaccination In Patients With Pituitary Diseases: A Pilot Study

Abstract Disclosure: M.C. Silva: None. L.M. Del Corso: None. C.L. Boguszewski: None. Introduction: The COVID-19 pandemic caused by the SARS-CoV-2 virus brought several questions globally. Among patients with pituitary diseases, there are few data in the literature about prevalence of SARS-CoV-2 infection, vaccination and their possible consequences and adverse events. Aim: To evaluate the prevalence and characteristics of SARS-CoV-2 infection, and the prevalence, efficacy and safety of vaccination in adult patients with pituitary diseases. Methods: Observational, cross-sectional study of adult patients with pituitary diseases followed in a reference center. Clinical data were collected and a questionnaire about SARS-CoV-2 infection, vaccination and its possible adverse effects was applied. The severity definitions used for COVID-19 disease were based on the World Health Organization: Mild – symptoms of infection without pneumonia; Moderate – presence of pneumonia; Severe – severe pneumonia (respiratory rate greater than 30 breaths per minute, severe respiratory distress or oxygen saturation less than 90% on room air). Results: We have studied 116 consecutive patients, 59 women (50.9%), with a median age of 47.5 years (range 39-59). The cause of pituitary disease was tumoral in 82 cases (70.7%) and non-tumoral in 34 (29.3%), the most prevalent etiologies were prolactinoma (n=31; 26.7%), idiopathic hypopituitarism (n=30; 25.9%) and acromegaly (n=23; 19.8%). Among hypopituitary patients (n=65; 56%), thirty (46.2%) had ACTH deficiency and all were on glucocorticoid replacement. The median time of pituitary disease was 14 years (range 6-23) and the median age at diagnosis was 32 years (range 18.5-45). SARS-CoV-2 infection was confirmed in 33 patients [28.4%; 17 before vaccination; 21 women; prolactinoma (n=12), acromegaly (n=9), non-tumoral disease (n=8); ACTH deficiency (n=6)]. The median age of infected patients was 47.5 years (range 29.5-57). In 20 cases (60.6%) the infection was mild, in 8 (24.2%) was moderate and in 5 (15.2%) was severe. All severe cases required hospitalization, although one patient refused. All but one of the participants were vaccinated against COVID-19, mostly Oxford-AstraZeneca (41.7%) and Pfizer-BioNTech (35.8%). Among those vaccinated, 64 (55.7%) reported on some adverse events, the most common pain at the site of vaccine shot (28.3%), fever (19.5%) and headache (9.7%), with a median duration of 1.5 days (range 1-3). In 61 cases, the reversal of symptoms was spontaneous (95.3%), two patients required outpatient care, and in one permanent alopecia developed. Conclusions: The prevalence of SARS-CoV-2 infection in patients with pituitary diseases was 28.4%, with 5% of severe cases requiring hospitalization. The vaccination was almost universal among our patients, being safe and effective in preventing severe cases of SARS-CoV-2 infection. Presentation: Thursday, June 15, 2023

SAT319 Megestrol-induced Adrenal Insufficiency

Abstract Disclosure: C. Alcorn: None. P. Subarajan: None. S. Ghaith: None. K. Jordan: None. Introduction: Megestrol, a progestin derivative, is a common drug used for anorexia or cachexia. Chronic use of megestrol can lead to suppression of the pituitary-adrenal axis, causing secondary adrenal insufficiency (SAI). Case: A 93-year-old female with a history of dementia presented with one-week history of confusion and weakness. She was found to have hyponatremia with a sodium of 134meq, consistent with her baseline. CT head and infectious workup were negative. She received 600cc of normal saline and repeat sodium decreased to 124meq/l. Nephrology was consulted due to concern for SIADH. She remained altered and was given a short course of hypertonic saline, 25cc for 4 hours. Repeat sodium after hypertonic saline was 118meq/l. TSH was normal but 8 am cortisol was 1.3 mcg/dL and ACTH level was <1.5 pg/ml. Endocrinology was consulted for evaluation of adrenal insufficiency. Cosyntropin stimulation test was performed with inadequate response, consistent with secondary adrenal insufficiency (SAI). The patient was subsequently given 50mg IV hydrocortisone with improvement in sodium to 125meq/l. The patient had been prescribed megestrol 200mg at home for cachexia. Upon discussion with her family, she was receiving multiple extra doses of megestrol per day for further appetite stimulation. She was only started on 200mg daily dose on admission. It was determined the patient had SAI secondary to megestrol use. This medication was discontinued, and she was initiated on hydrocortisone therapy with endocrinology follow-up. Conclusion: SAI is defined by deficiency of ACTH in setting of hypocortisolemia. SAI is often associated with prolonged glucocorticoid use but can also be seen in patients with pituitary tumors, pituitary surgery, or granulomatous disease. SAI can cause hyponatremia, hypoglycemia, and fatigue but is not typically associated with hypotension or hyperkalemia as the mineralocorticoid function of the adrenals remains intact. Though rare, there have been case reports of patients developing SAI while taking megestrol. Megestrol acts as a progestin and is used for appetite stimulation in patients with cachexia. Megestrol is believed to have cross-affinity for glucocorticoid receptors which leads to suppression of the pituitary-adrenal axis. This suppression leads to decreased ACTH production, inducing SAI. In this case, the patient was receiving higher than prescribed doses of megestrol at home. When her dose was reduced on admission it precipitated her adrenal insufficiency, accounting for the worsening of her hyponatremia. Identification of SAI in patients taking megestrol is imperative as early recognition and diagnosis can prevent severe complications such as adrenal crisis. These patients should have megestrol discontinued and be placed on appropriate hydrocortisone therapy. Close follow-up is required as it can take 2-3 months for pituitary-adrenal axis recovery. Presentation: Saturday, June 17, 2023

SAT320 Cyclic Cushing Syndrome Caused By An ACTH-Producing Pheochromocytoma

Abstract Disclosure: Y.B. Omotosho: None. M.E. Wierman: None. K. Bukhari: None. K. Pacak: None. R. McGlotten: None. L.K. Nieman: None. Background: Although pheochromocytomas (Pheo) predominantly produce catecholamines, they also rarely produce Adrenocorticotropin (ACTH) and present with Cushing syndrome (CS). Cyclic CS is an uncommon presentation of hypercortisolism. We here report a unique case of cyclic ectopic ACTH secretion from a Pheo. Clinical case: A 72-year-old female was referred to the NIH with a five-year history of intermittent episodes of unintentional weight gain, hair loss, skin thinning, striae, tremors, labile emotions, glucose intolerance, and a sense of impending doom, interspersed with anorexia, weight loss, normal glucose levels, headaches, and fatigue. The external evaluation documented ACTH-dependent CS with episodes of hypercortisolism, thought to be occult ectopic ACTH secretion. On admission, blood pressure ranged from 122/75 to 171/78 mmHg, and she had a Cushingoid habitus. The biochemical investigation showed basal ACTH 219 pg/ml (NL 5- 46 pg/ml); serum cortisol of 76.9 mcg/dl after 1mg dexamethasone (Dex) suppression test (NL <1.8 mcg/dl), with Dex level of 903; cortisol increased from 13.3 mcg/dl to 15.5 mcg/dl after 8mg Dex, Dex level 4680 ng/ml; plasma normetanephrine 1.8 nmol/L, (NL < 0.9 nmol/L); metanephrine 0.6 nmol/L (NL <0.5 nmol/L); norepinephrine 1493 pg/mL (NL 70-750 pg/mL); epinephrine 298 pg/mL (NL <111 pg/mL); chromogranin A 1314 ng/mL (NL <93 ng/mL). MRI pituitary was normal and bilateral inferior petrosal sinus sampling did not show a central: peripheral gradient before or after desmopressin administration. CT abdomen showed a right adrenal nodule measuring 2.3 cm x 1.8 cm, with pre-and post-contrast Hounsfield units of 30 and 106, and 54% washout. The adrenal mass showed intense activity on 68Ga-DOTATATE and 18F-DOPA PET/CT scans. The patient underwent a right adrenalectomy; the 2.7 x 2.3 x 1.5 cm mass was a Pheo with immunohistochemical staining for ACTH, chromogranin A, and synaptophysin. Post-operatively, blood pressure normalized, and medications were reduced from preoperative metoprolol, lisinopril, and doxazosin to low-dose metoprolol at discharge. Morning cortisol and ACTH levels were <1 mcg/dl and <5 pg/ml. Physiologic replacement of hydrocortisone (15 mg on awakening and 5 mg in the afternoon) was started and switched to prednisone 5mg daily for ACTH deficiency and convenience. The pituitary-adrenal axis remained suppressed at her 6-month follow-up visit. Conclusion: Cyclic CS poses a diagnostic challenge. Here, desmopressin helped to exclude Cushing's Disease. Although ACTH-producing Pheo is rare, it should be considered in the context of ACTH-dependent hypercortisolism if an adrenal mass is present. Presentation: Saturday, June 17, 2023

Hipopituitarismo tras traumatismo craneoencefálico en el adulto: guía clínica del área de neuroendocrinología de la Sociedad Española de Endocrinología y Nutrición (SEEN)

Traumatic brain injury (TBI) is associated with hypopituitarism with a variable incidence, depending on the time and methods used to diagnosis, and on factors related to the trauma, such as its severity, its anatomical location and the drugs used in the acute phase. The pituitary gland can be damaged directly by the impact or secondary to factors such as ischemia, inflammation, excitotoxicity or immunity. In acute phases ACTH deficiency is the most relevant, since failure to detect and treat it can compromise the patient's life. Clinical manifestations are typical of each hormone deficient axes, although the combination hypopituitarism-trauma has been associated with cognitive deterioration, worse metabolic profile and greater impairment of quality of life. One of the clinical challenges is to determine which patients benefit from a systematic hormonal evaluation, and therefore from hormone replacement, and what is the appropriate time to do so and the most suitable diagnostic methods.

Metachronous immune-related adverse events involving type 1 diabetes and isolated adrenocorticotropic hormone deficiency associated with pembrolizumab monotherapy for metastatic head and neck cancer: a case report

BackgroundImmune checkpoint inhibitors might cause immune-related adverse events that are still largely unknown.Case presentationAn 80-year-old Asian female was diagnosed with cervical lymph node metastasis from lip cancer (cT1N0M0) and underwent right cervical neck dissection. Subsequently, she developed right cervical lymph node relapse and lung metastasis. The patient was deemed eligible for pembrolizumab owing to unresectable neck recurrence and pulmonary metastasis. The Combined Positive Score of the submandibular lymph nodes was 100. Pembrolizumab monotherapy was initiated, and complete remission was achieved. She developed diabetic ketoacidosis in the eighth month and was diagnosed with fulminant type 1 diabetes mellitus. Insulin induction was performed. The patient developed adrenal insufficiency after 10 months. These were immune-related adverse events, caused by pembrolizumab. The patient has remained in complete remission, and pembrolizumab therapy was continued.ConclusionsThe study presents the first reported case of type 1 diabetes in a patient with head and neck squamous cell carcinoma treated with pembrolizumab monotherapy, in Japan. Efficient interdepartmental collaboration will promote the management of severe immune-related adverse events and improve the quality of life of patients.

Idiopathic Isolated Adrenocorticotropic Hormone Deficiency: A Single-Center Retrospective Study.

Idiopathic isolated adrenocorticotrophic hormone deficiency (IIAD) is rare, with high clinical omission and misdiagnosis rates. This study retrospectively collected information on clinical presentation, laboratory findings, and treatment response of 17 patients with IIAD at Jining No. 1 People's Hospital from January 2014 to December 2022. The clinical characteristics were summarized, and the pertinent data were analyzed. As a result, most of the patients with IIAD were male (94.12%), with age at onset ranging from 13 to 80 years. The primary manifestations were anorexia (88.24%), nausea (70.59%), vomiting (47.06%), fatigue (64.71%), and neurological or psychiatric symptoms (88.24%). The median time to diagnosis was 2 months and the longest was 10 years. Laboratory tests mostly showed hyponatremia (88.24%) and hypoglycemia (70.59%). The symptoms and laboratory indicators returned to normal after supplementing patients with glucocorticoids. IIAD has an insidious onset and atypical symptoms; it was often misdiagnosed as gastrointestinal, neurological, or psychiatric disease. The aim of this study was to improve clinicians' understanding of IIAD, patients with unexplained gastrointestinal symptoms, neurological and psychiatric symptoms, hyponatremia, or hypoglycemia should be evaluated for IIAD and ensure early diagnosis and treatment.

Pituitary function before and after surgery for nonfunctioning pituitary adenomas - Data from the Swedish Pituitary Register.

Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to five years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA). Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded. Preoperative ACTH, TSH, LH/FSH and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742) and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm3. Amongst patients with preoperative, one year and five years postoperative data on the HPA axis (n=428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, one year postoperatively 163 (38%) patients were ACTH-deficient (P <0.001 vs. preoperatively). No further increase was seen five years postoperatively (36%, P=0.096). At one year postoperatively recoveries in the TSH- and LH/FSH-axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively. ACTH deficiency increased significantly at one year postoperatively. Event though not significant, some patients recovered from or developed new deficiency between one and five years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurs in polyglandular endocrinopathies

BackgroundWith the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events.MethodsA retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month.Results28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18–39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up.ConclusionsIAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

Hypothyroidism With ACTH Deficiency During Pembrolizumab Therapy for Lung Cancer: Case Report and Literature Review.

Immune-checkpoint inhibitors have recently shown great promise in treating various cancers, but often cause immune-related adverse events (irAEs). Simultaneous drug-induced hypothyroidism and isolated adrenocorticotropic hormone (ACTH) deficiency are rare irAEs. This combination of irAEs is associated with paradoxical endocrine dysfunction characterized by large amounts of thyroid-stimulating hormone (TSH) and small amounts of ACTH in the anterior lobe of the pituitary. We herein report a case of hypothyroidism with isolated ACTH deficiency during pembrolizumab therapy for recurrent lung cancer. Our patient was a 66-year-old man with recurrence of squamous cell lung carcinoma. Four months after chemotherapy that included pembrolizumab, the patient presented with general fatigue and laboratory tests showed high concentrations of TSH with low concentrations of free-T4. He was diagnosed with hypothyroidism and levothyroxine was prescribed. His ACTH concentration was found to be low 1 week later when he developed an acute adrenal crisis with associated hyponatraemia. We then changed his diagnosis to concurrent hypothyroidism with isolated ACTH deficiency. His condition improved after 3 weeks of administration of cortisol. It is difficult to diagnose a concurrent paradoxical endocrine disorder, such as hypothyroidism with isolated ACTH deficiency, as in the present case. Physicians should pay attention to symptoms and laboratory data to identify various types of endocrine disorders as irAEs.

Diagnosis and management of pituitary apoplexy: a Tunisian data

BackgroundPituitary apoplexy (PA) is defined as the hemorrhage or the infraction of a pituitary adenoma. Aiming to determine the epidemiological, clinical, paraclinical characteristics as well as management and outcomes of PA in our population, we conducted this cross-sectional study.MethodsThis cross-sectional study was conducted at the Department of Endocrinology of Hedi chaker university hospital, Sfax. Data was collected from medical charts of patients with pituitary apoplexy admitted in our department between 2000 and 2017.ResultsWe included 44 patients with PA. Their mean age was 50 ± 12.6 years. Among them, 31.8% had a known pituitary adenoma, and it was in all cases a macroadenoma, predominantly a prolactin secreting tumor (42.8%). A triggering factor of PA was encountered in 31.8% of cases and it was mainly: head trauma, dopamine antagonists, and hypertension. The clinical presentation of PA encompassed headaches (84.1%), visual disturbances (75%), and neurological signs (40.9%). Gonadotropin deficiency was the most frequent form of hypopituitarism noted (59.1%), followed by corticotropin deficiency (52.3%), thyrotropin deficiency (47.7%), and somatotropin deficiency (2.3%). Hormonal assessment at PA onset, concluded that 23 had a secreting adenoma: 18 prolactinomas, 3 ACTH-secreting adenomas, and 2 GH-secreting adenomas. In the 21 remaining cases, the tumor was non-functioning (47.7%).Pituitary MRI was performed in 42 cases (95.5%), revealing infraction and or hemorrhage in the pituitary gland in 33 cases; a heterogenous signal or a fluid level within the adenoma, in nine cases.Urgent administration of intra venous hydrocortisone was required in 19 cases. Mannitol administration was mandatory in a patient who had severe intracranial hypertension. Surgical management of the PA was imperative in 24 patients (54.5%): 15 suffered from severe visual impairment, 4 had an intracranial hypertension, 2 cases demonstrated an impaired consciousness, 2 patients experienced a tumor enlargement and one case had a severe Cushing’s disease. Operative complications found were rhinorrhea attributable to cerebral spinal fluid leakage, insipidus diabetes associated with rhinorrhea, isolated insipidus diabetes, and hydrocephalus in one case each. Long-term follow-up concluded that headaches persisted in five cases, owing to the tenacity of a macroprolactinoma regardless of cabergoline treatment in one case, the recurrence of an adenoma in two cases and its persistence despite the medical and the surgical treatment in two patients. Concerning the visual acuity defects, only two patients had persistent diminished visual acuity at long-term follow-up.Among 25 patients, 13 were diagnosed with definitive thyrotropin deficiency. Similarly, 14 patients had persistent corticotropin deficiency (CD). Additionally, CD was de novo diagnosed in two patients. Otherwise, gonadotropin deficiency prevailed in all cases. Persistent prolactin deficiency was seen in two patients. Disappearance of the pituitary tumor was encountered in 11 out of 24 cases at long-term follow-up. Overall, surgery was associated with better outcome than conservative management.Pituitary apoplexy is a challenging condition due to its variable course, its diagnosis difficulty and management, as gaps remain to determine the best approach to treat this condition.ConclusionsTo conclude, pituitary apoplexy is a challenging condition due to its variable course, its diagnosis difficulty and management, as gaps remain to determine the best approach to treat this condition. Further studies are thus needed.

Pituitary function at presentation and following therapy in patients with non-functional pituitary macroadenomas: a single centre retrospective cohort study

BackgroundNon-functioning pituitary macroadenomas (NFPMs) may present with hypopituitarism. Pituitary surgery and radiotherapy pose an additional risk to pituitary function.ObjectivesTo assess the incidence of hypopituitarism at presentation, the impact of treatment, and the likelihood of endocrine recovery during follow-up.MethodsAll patients treated surgically with and without radiotherapy for NFPMs between 1987 and 2018 who had longer than six months follow-up were identified. Demographics, presentation, investigation, treatment, and outcomes were collected.ResultsIn total, 383 patients were identified. The median age was 57 years, with a median follow-up of 8 years. Preoperatively, 227 patients (227/375; 61%) had evidence of at least one pituitary deficiency. Anterior panhypopituitarism was more common in men (p = 0.001) and older patients (p = 0.005). Multiple hormone deficiencies were associated with large tumours (p = 0.03). Patients treated with surgery and radiotherapy had a higher incidence of all individual pituitary hormone deficiency, anterior panhypopituitarism, and significantly lower GH, ACTH, and TSH deficiencies free survival probability than those treated with surgery alone. Recovery of central hypogonadism, hypothyroidism, and anterior panhypopituitarism was also less likely to be reported in those treated with surgery and radiotherapy. Those with preoperative hypopituitarism had a higher risk of pituitary impairment at latest review than those presented with normal pituitary function (p = 0.001).ConclusionNFPMs are associated with a significant degree of hypopituitarism at time of diagnosis and post-therapy. The combination of surgery and radiotherapy is associated with a higher risk of pituitary dysfunction. Recovery of pituitary hormone deficit may occur after treatment. Patients should have regular ongoing endocrine evaluation post-treatment to assess changes in pituitary function and the need for long-term replacement therapy.

Central Endocrine Complications Among Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review

Children who receive cranial radiation therapy (RT) as a component of treatment for malignancy are often at risk of long-term central endocrine toxicity secondary to radiation to the hypothalamic-pituitary axis (HPA). A comprehensive analysis was performed of central endocrine late effects in survivors of childhood cancer treated with RT as part of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium. A systematic review of the risk of RT-related central endocrine effects was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 4629 publications were identified, of which 16 met criteria for inclusion in dose modeling analysis, with a total of 570 patients in 19 cohorts. Eighteen cohorts reported outcomes for growth hormone deficiency (GHD), 7 reported outcomes for central hypothyroidism (HT), and 6 reported outcomes for adrenocorticotropic hormone (ACTH) deficiency. Normal tissue complication probability modeling for GHD (18 cohorts, 545 patients) yielded D50 = 24.9 Gy (95% CI, 20.9-28.0) and γ50 = 0.5 (95% CI, 0.27-0.78). The normal tissue complication probability model fit for whole brain irradiation in children with a median age of >5 years indicated a 20% risk of GHD for patients who receive a mean dose of 21 Gy in 2-Gy fractions to the HPA. For HT, among 7 cohorts (250 patients), D50 = 39 Gy (95% CI, 34.1-53.2) and γ50 = 0.81 (95% CI, 0.46-1.35), with a 20% risk of HT in children who receive a mean dose of 22 Gy in 2-Gy fractions to the HPA. For ACTH deficiency (6 cohorts, 230 patients), D50 = 61 Gy (95% CI, 44.7-119.4) and γ50 = 0.76 (95% CI, 0.5-1.19); there is a 20% risk of ACTH deficiency in children who receive a mean dose of 34 Gy in 2-Gy fractions to the HPA. RT dose to the HPA increases the risk of central endocrine toxicity, including GHD, HT, and ACTH deficiency. In some clinical situations, these toxicities may be difficult to avoid, and counseling of patients and families with respect to anticipated outcomes is important.

The impact of transsphenoidal surgery on pituitary function in patients with non-functioning macroadenomas

PurposeTranssphenoidal surgery for non-functioning pituitary adenomas (NFPAs) can alter pituitary function. We assessed the rates of improvement and deterioration of pituitary function by axis and searched for predictive factors of these outcomes.MethodsWe reviewed consecutive medical files from patients having had transsphenoidal surgery for NFPA between 2004 and 2018. Pituitary functions and MRI imaging were analyzed prior and after surgery. The occurrence of recovery and new deficit were documented per axis. Prognostic factors of hormonal recovery and new deficits were searched.ResultsAmong 137 patients analyzed, median tumor size of the NFPA was 24.8 mm and 58.4% of patients presented visual impairment. Before surgery, 91 patients (67%) had at least one abnormal pituitary axis (hypogonadism: 62.4%; hypothyroidism: 41%, adrenal insufficiency: 30.8%, growth hormone deficiency: 29.9%; increased prolactin: 50.8%). Following surgery, the recovery rate of pituitary deficiency of one axis or more was 46% and the rate of new pituitary deficiency was 10%. Rates of LH-FSH, TSH, ACTH and GH deficiency recovery were 35.7%, 30.4%, 15.4%, and 45.5% respectively. Rates of new LH-FSH, TSH, ACTH and GH deficiencies were 8.3%, 1.6%, 9.2% and 5.1% respectively. Altogether, 24.6% of patients had a global pituitary function improvement and only 7% had pituitary function worsening after surgery. Male patients and patients with hyperprolactinemia upon diagnosis were more likely to experience pituitary function recovery. No prognostic factors for the risk of new deficiencies were identified.ConclusionIn a real-life cohort of patients with NFPAs, recovery of hypopituitarism after surgery is more frequent than the occurrence of new deficiencies. Hence, hypopituitarism could be considered a relative indication for surgery in patients with NFPAs.

Pituitary and growth disorders of pediatric survivors of head and neck tumors: a single center study

Objective The aim was to explore the prevalence and risk factors for pituitary and growth disorders in pediatric brain and neck tumor survivors. Methods 203 children with brain or neck tumors that survived 2 years after tumors treatment were included. Demographic data, anthropometric assessments, characteristics of the tumors, tumor treatment modalities, and hormonal profile evaluation were reported. Results After a mean follow-up of 4.77 years, 62 (30.54%) survivors were diagnosed with at least one pituitary disorder. Growth hormone deficiency (GHD) was detected in 17.28% of survivors, moreover, thyroid-stimulating hormone deficiency (TSHD), luteinizing hormone and follicle-stimulating hormone deficiency (LH/FSHD), adrenocorticotropic hormone deficiency (ACTHD)/cortisol deficiency and central precocious puberty were detected in 10.4, 9.09, 8.06, and 1.69% of survivors, respectively. The prevalence of short stature and obesity was 9.1% and 17.05%, respectively among survivors who attended follow-up clinics during data collection. The risk of developing pituitary disorders was associated with craniopharyngioma histology (OR, 6.207; 95% CI, 1.025–37.581) and a history of hydrocephalus at cancer diagnosis (OR, 3.075; 95% CI, 1.402–6.746). Older age at the time of radiotherapy was associated with a lower risk of developing pituitary disorders (OR, 0.928; 95% CI, 0.864–0.997). Conclusion This study observed a high prevalence of pituitary disorders among survivors of pediatric brain and neck tumors. So proper screening of pituitary disorders in survivors of brain and neck tumors is warranted.

Abstract #1413579: Rathke Cleft Cyst Unveiling Incidental Prolactin Producing Adenoma

Rathke cleft cysts (RCCs) are benign sellar and or/suprasellar lesions that arise from remnants of Rathke's pouch. Pituitary hormonal dysfunction associated with RCCs most often present as hormonal deficiencies due to compression. However pituitary hyper-secretion may coexist with RCC challenging diagnosis and management. A 37-year-old female presented with worsening headache, bilateral blurry vision and pressure-like eye pain for two weeks. She denied any galactorrhea or irregular periods. Her medications included as-needed butalbital-acetaminophen-caffeine and alprazolam. CT Head without IV contrast revealed a pituitary lesion measuring 1.9 cm extending near the inferior margin of the optic chiasm. Subsequent MRI Pituitary with and without IV contrast revealed an enhancing sellar/suprasellar solid lesion measuring 1.6 x 2.7 x 1.9 cm with small hypoenhancing components associated with expansion of the sella, rightward infundibulum deviation, mass effect on the optic chiasm and left cavernous sinus invasion. Pituitary secretion workup revealed an elevated serum prolactin level of 50.4 ng/mL (range 4.8 - 23.3 ng/mL). Repeat prolactin level was 75.7 mg/ml. Dilution studies 1:10 and 1:100 revealed prolactin levels of 78.3 ng/mL and 75.9 ng/mL respectively; absence of hook effect. Her elevated prolactin was attributed to stalk effect given the large size of her sellar mass and relatively minimally elevated prolactin level. Serum Alpha Subunit, ILGF-1, TSH, FT4, LF, FSH, AM cortisol and ACTH level were all normal. She underwent endoscopic transsphenoidal pituitary mass resection with pathology results revealing prolactin producing adenoma and RCC. Immunostains were strongly positive for chromogranin A and prolactin while negative for FSH, ACTH, TSH, beta hCG, GH. Prolactin levels 11 days post-resection remained elevated at 50.7 ng/mL. She continued to have regular periods without galactorrhea. Additionally, she expressed desire to attain pregnancy. This case illustrates the presence of a secreting pituitary prolactinoma in the setting of an RCC. Whether these two entities share a common pathophysiology or simply co-exist is unknown. In one study of 33 surgically treated RCC at presentation, 60% had gonadotroph deficiency, 36% had ACTH deficiency, 36% had TSH deficiency, 18% had ADH deficiency and 31% had hyperprolactinemia (1). It is possible that the majority of this patient 's sellar mass was comprised of RCC as a much higher prolactin level would have been expect for the size of her mass. Interesting, her sellar mass exhibited enhancement which is uncharacteristic for RCC, classical described as cystic lesions without calcification or enhancement. Given that her post-resection prolactin level remained elevated and she desires pregnancy, she may require dopamine agonist therapy.

Abstract #1402123: A Rare Case of Hypophysitis with Isolated ACTH Deficiency and Thyroiditis Complicating Treatment with Pembrolizumab

Immune checkpoint inhibitors (CPIs) have been shown to be beneficial in the treatment of cancers by enhancing antitumor immunity. CPIs block intrinsic down regulators of immunity, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand programmed cell death ligand 1 (PD-L1). While useful for targeting malignant tissue, CPIs can have destructive effects on normal tissues, including endocrine organs. Hypophysitis is more common in those receiving anti-CTLA-4 therapy (up to 10% of patients) than those receiving anti-PD1-therapy (<1% of patients) whereas the opposite stands true for thyroiditis. We present a rare case of a woman with breast cancer treated with the anti-PD-1 therapy pembrolizumab who developed isolated ACTH deficiency from hypophysitis along with thyroiditis. A 39-year-old female with breast cancer treated with pembrolizumab presented with several weeks of fatigue and confusion. On exam, she was well-appearing and normotensive. Cortisol and TSH were found to be low at <0.1ug/dL and <0.01uIU/mol, respectively, raising concern for central adrenal insufficiency and hypothyroidism. Free T4 and free T3 were high indicating the low TSH was from primary thyroid rather than pituitary dysfunction. Cosyntropin stimulation test showed an insufficient rise in cortisol to 1.7ug/dL, which, along with an inappropriately normal ACTH of 9.9pg/mL, confirmed the diagnosis of central adrenal insufficiency. Sellar MRI revealed no abnormalities. Adrenal insufficiency was treated with hydrocortisone. Hyperthyroidism quickly transitioned to hypothyroidism, supporting a diagnosis of thyroiditis, which was treated with levothyroxine. Pembrolizumab was stopped and later resumed once clinical symptoms were stabilized while on the hormonal therapy. CPIs have been associated with a variety of immune mediated adverse endocrine events, including hypophysitis, primary thyroid dysfunction, autoimmune diabetes, and adrenalitis. Although thyroiditis is the most commonly reported adverse endocrine event associated with anti-PD-1 therapy, other adverse events can occur, including hypophysitis rarely. While the diagnosis of hypophysitis can be supported by sellar changes on MRI, it is important for clinicians to be aware that hypophysitis in those on anti-PD1 therapy may lack classic MRI changes. As the endocrine dysfunction can be life-threatening and symptoms often overlap with those of malignancy and related treatments, a high index of suspicion is necessary to ensure prompt diagnosis and treatment. In addition, screening for endocrine dysfunction is recommended in all patients receiving CPIs.