bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT169 Sugar Crash: A Case Of Recurrent Hypoglycemia
Authors: Malvar Cyerwin Monique T , Patel Pooja , Moran Heberth , Bleich David
Published: October 2023

Disclosure: C.T. Malvar: None. P. Patel: None. H. Moran: None. D. Bleich: None.

Introduction: Post-prandial hypoglycemia is a rare complication following Roux-en-Y gastric bypass surgery (RYGB). Some theories suggest that post-operative beta cell expansion and altered beta cell function may lead to increased secretion of insulin, thereby causing hypoglycemia. We report a 39-year-old female with multiple episodes of recurrent post-prandial hypoglycemia following RYGB. Case Report: A 39-year-old female with a past medical history of type 2 diabetes managed with insulin, hypertension, hyperlipidemia, and obesity underwent RYGB and developed multiple episodes of fatigue, diaphoresis, palpitations, and tremulousness a year later. The patient continued to have worsening symptoms, leading to multiple hospitalizations for hypoglycemia. During her initial presentation to the emergency department, she was found to be afebrile, tachycardic with stable blood pressure. Work up revealed a glucose of 34 mg/dl (70 - 109 mg/dl), insulin of 40.1 (2.6 - 24.9 uIU/mL), C-peptide of 3.8 (1.1 - 4.4 ng/mL), potassium of 3.2 (3.5 - 4.8 meq/l), negative sulfonylurea screen, normal renal function, and a mild leukocytosis of 12.6 (4.0 - 11.0 x 10*3/µL). CT abdomen/pelvis, chest x-ray, and urinalysis were normal and did not reveal any infection. The patient denied taking any hypoglycemic agents and reported consuming high glycemic index meals. During her hospitalization, she received a bolus of dextrose followed by a continuous dextrose drip; however, she continued to experience recurrent hypoglycemic events requiring glucagon and dextrose tablets. Subsequent morning labs showed elevated insulin levels at 34.6 (2.6 - 24.9 uIU/mL) and a normal IGF-1 level. Her 8AM cortisol level was 2.3 (6.0 - 18.4 ug/dl). Due to high suspicion of adrenal insufficiency, she was started on Hydrocortisone. Pituitary MRI was negative for any adenoma. Hydrocortisone was held and a cosyntropin stimulation test established appropriate adrenal response. Hydrocortisone and dextrose tablets were discontinued. She was educated on eating low glycemic index meals to prevent future hypoglycemic episodes. She was started on acarbose as it delays carbohydrate degradation, thereby preventing reactive hypoglycemia. Conclusion: This case highlights the importance of having a thorough differential diagnosis in patients with a history of bariatric surgery and hypoglycemic episodes including adrenal insufficiency, which in this case was ruled out. RYGB increases stimulation of islet β-cells by enteral signals and enhances GLP-1 sensitivity and insulin secretion, predisposing some individuals to hypoglycemic episodes. Patients may have remission of diabetes and no longer need medications post-operatively. Dietary modification is fundamental in the management of hypogylcemia after RYGB. Pharmacotherapy is an adjunctive treatment if symptoms persist.

Presentation: Saturday, June 17, 2023
OR06-03 Intergenerational Exposure To Endocrine-disrupting Chemicals (Edcs) Affects Dopamine-mediated Behaviors In A Sex-Specific Manner In Rats
Authors: Hilz Emily N , Schnurer Cameron , Bhamidipati Swati , Thompson Lindsay , Morales-Ledesma Ellyzabeth , Gore Andrea C
Published: October 2023

Disclosure: E.N. Hilz: None. C. Schnurer: None. S. Bhamidipati: None. L. Thompson: None. E. Morales-Ledesma: None. A.C. Gore: None.

Polychlorinated biphenyls (PCBs) are a weakly estrogenic class of ubiquitous environmental EDCs that affect a range of sex-specific neuroendocrine and reproductive outcomes. Furthermore, these effects can extend intergenerationally via epigenetic changes carried down the germline. In humans, PCBs are associated with sexually dimorphic and hormone sensitive neurobehavioral disorders including attention deficit hyperactivity disorder (ADHD) and mood disorders such as depression; however, little preclinical work has modeled these cognitive changes in rats and none has determined if they extend intergenerationally via endocrine-mediated changes to the brain dopamine system. In the current work, three generations of male and female Sprague-Dawley rats were exposed to the PCB mixture Aroclor 1221 (A1221) at different life stages: as adults; through perinatal exposure via mother's diet; or preconceptionally, as the germ cells within the exposed fetus. Adults of each generation underwent a battery of behavioral tasks to assess attentional phenotype, cognitive flexibility, and affect as measured by attentional set-shifting, conditioned orienting, and sucrose preference tests. These outcomes were correlated with both serum estradiol concentrations and dopamine cell quantity in the midbrain. Results revealed that A1221 treatment had sex- and generation-specific effects: in adult-exposed females, decreased conditioned orienting suggested a hyporesponsive attentional phenotype; in males, preconceptional exposure reduced cognitive flexibility via impaired attentional set-shifting. All rats showed a strong preference for sucrose solution; however, A1221 treatment decreased the total amount of sucrose solution consumed (indicating anhedonia) regardless of sex or timing of exposure. Dopamine cell numbers were inversely affected by A1221 between the sexes: decreased in females and increased in males, which correlates well with the cognitive changes observed. Relationships among estradiol concentration, cognitive changes, and dopamine cell quantity will be ascertained using a multilevel model that accounts for endocrine-mediated disruptions at the brain, body, and behavioral levels. These data show that the PCB mixture A1221 impairs different aspects of cognitive behavior between the sexes depending on timing of exposure, while having a broader effect of increased anhedonia, in a manner potentially mediated by hypo- or hyper-availability of midbrain dopamine and serum estradiol. Supported by RO1 ES029464.

Presentation: Thursday, June 15, 2023
SAT438 Nivolumab Induced Endocrinopathies- Outcomes And Learning
Authors: Kethireddi Keerthi Madhurya , Jhetam Suhail , Parthasarathy Sathish Babu
Published: October 2023

Disclosure: K. Kethireddi: None. S. Jhetam: None. S.B. Parthasarathy: None.

Background: Nivolumab is an anti PD-1 mAB (Programmed Cell Death protein) used in the treatment of melanoma, renal, head & neck and other cancers. Use of Nivolumab either as a single therapy or in combination with other immune check point inhibitors (CPI) like Ipilimumab, Pembrolizumab often results in immune mediated endocrinopathies. Existing literature on Nivolumab indicates median time to the onset of hyperthyroidism, hypothyroidism, type 1 diabetes mellitus, and hypophysitis as 1.5 months, 2.9 months, 4.4 months and 4.9 months respectively. Our objective is to add to the existing body of knowledge, compare local data on presentation and other variables of these endocrinopathies with recommendations to improve diagnosis and access to treatment of these endocrinopathies. Design: It is a retrospective analysis of the patients who received Nivolumab (single or combination therapy) between 2019 and 2022 in our hospital. Methodology: A total of 83 patients were treated either with single therapy Nivolumab (n=44) or combination therapy (n=39) and were screened for immune endocrine toxicities. Data was collected mainly from hospital based clinical software for routine use. Data was also collected on prior endocrine tests such as Hba1c and Thyroid function, if done prior to commencement of immunotherapy. Major results: Nineteen patients (23%) developed immune related endocrinopathies which included Thyroiditis/hypothyroidism (n= 12) followed by adrenalitis (n= 6), Type 1 Diabetes (n=1) and hypophysitis (n=3). Onset of thyroid dysfunction occurred between 4 to 8 weeks, adrenalitis between 8 to 32 weeks, hypophysitis between 4 weeks to 12 weeks and 24 weeks for type 1 diabetes mellitus. All patients were appropriately counselled and were provided with Patient Information leaflet. Regular screening bloods (Hba1c, Glucose, Cortisol and Thyroid function tests) were requested in most patients. Emergency presentations of Diabetic ketoacidosis (n=1) and Adrenal insufficiency (n=2) were noted with no mortality. Conclusion: 23% of the patients on Nivolumab had immune mediated endocrinopathy with Thyroiditis/Hypothyroidism being the commonest and the earliest endocrine abnormality. A Standard Operating Procedure for acute endocrine emergencies post Immunotherapy based on Society for Endocrinology guidance, needs to be implemented with education to create greater awareness given the expected high prevalence of these endocrinopathies post Immune CPI therapies. We recommend oral steroid (prednisolone/hydrocortisone) rescue pack and patient education on SMBG (Self-monitoring of blood glucose) as a part of sick day rule management in these patients and we believe this to be lifesaving and resource saving measure given the critical nature of these endocrine emergencies post immune CPI therapies.

Presentation: Saturday, June 17, 2023
SAT441 Association Of PFOS Exposure And The Risk Of Coronary Artery Disease In Postmenopausal Women
Authors: Eve Alicia Arredondo , Tunc Elif , Mehta Dhruv , Erbak-Yilmaz Huriye , Emren Sadik Volkan , Akyildiz-Akcay Filiz , Erdogan Zeynep Madak
Published: October 2023

Disclosure: A. Arredondo Eve: None. E. Tunc: None. D. Mehta: None. H. Erbak-Yilmaz: None. S. Volkan Emren: None. F. Akyildiz-Akcay: None. Z. Madak Erdogan: None.

Cardiovascular diseases (CVD) are the number one cause of death globally. In addition to traditional risk factors such as unhealthy lifestyles (smoking, obesity, sedentary) and genetics, common environmental exposures, including persistent environmental contaminants, may also influence cardiovascular disease risk. Perfluoroalkyl substances (PFAS) are a class of highly fluorinated chemicals used in our daily household necessities and industrial products known to persist in our environment for years, causing health concerns that are now linked to endocrine disruptions and related outcomes in women, including interference of the cardiovascular and reproductive systems. In postmenopausal women, higher levels of PFAS are observed than in premenopausal women due to the cessation of menstruation, which is crucial for PFAS excretion. Because of these findings, we explored the association between Perfluorooctanoic acid (PFOA), Perfluorooctane sulfonate (PFOS), Perfluorobutanesulfonic acid (PFBS) in postmenopausal women from our previously established CVD cohort using liquid chromatography with tandem mass spectrometry (LC-MS-MS) analysis and supported by machine learning approaches. Here we show that PFOS levels were significantly higher in postmenopausal women with coronary cardiovascular disease (CAD) when compared to control and coronary microvascular disease (CMD) group. We also found that specific metabolite concentrations (alanine, isoleucine, proline, and tyrosine) were negatively associated with serum PFOS levels. A significant correlation with changes in the expression of proteins such as growth hormone (GH), tyrosine-protein kinase Mer (MERTK), metalloproteinase inhibitor 4 (TIMP4), transferrin receptor protein 1 (TFRC), thrombospondin-2 (THBS2) and PFOS was observed. Our findings may provide new insight into the potential mechanism underlying the increased risk of cardiovascular events in postmenopausal women and the emerging evidence on PFAS-induced risk of cardiovascular diseases in this vulnerable population.

Presentation: Saturday, June 17, 2023
OR01-05 Growth Hormone Action In Somatostatin Neurons Regulates Anxiety And Fear Memory
Authors: dos Santos Willian O , Juliano Vitor A L , Vieira Henrique R , Frazao Renata , Munhoz Carolina Demarchi , Donato Jose
Published: October 2023

Disclosure: W.O. dos Santos: None. V.A. Juliano: None. H.R. Vieira: None. R. Frazao: None. C.D. Munhoz: None. J. Donato: None.

Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and depression. Furthermore, GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of post-traumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence neuropsychiatric diseases. Here we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SSTΔGHR mice) led to increased anxiety in the light-dark box and elevated plus maze tests, whereas SSTΔGHR females showed no changes in anxiety, compared to control animals. Using auditory Pavlovian fear conditioning, both male and female SSTΔGHR mice exhibited a significant reduction in fear memory. In contrast, GHR ablation in SST neurons did not affect memory in the novel object recognition test. The gene expression was analyzed in a bilateral micropunch comprising the central nucleus of the amygdala and basolateral complex of male mice. Increased mRNA expression of Gabbr2 (GABAB2 receptor), Syp (synaptophysin), and Bdnf were observed in the amygdala of SSTΔGHR mice. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not in female mice. GHR ablation in SST neurons also decreases fear memory and affects the gene expression in the amygdala. Our findings identified for the first time a specific neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases.

Presentation: Thursday, June 15, 2023
OR01-06 Single Nucleus Multi-omics Analysis Identifies Cellular Trajectories And Dynamic Changes In Gene Expression And Chromatin Accessibility In The Pituitary During The Mouse Estrous Cycle
Authors: Ruf-Zamojski Frederique Murielle , Cheng Wan Sze , Zhang Zidong , Zamojski Michel , Smith Gregory R , Chen Xi , Mendelev Natalia , Strupinsky Galia , Alonso Carlos Agustín , Gambino Luisina Ongaro , Zhou Xiang , Brule Emilie , Amper Mary Anne S , Hanna Pincas , Nair Venugopalan D , Andoniadou Cynthia Lilian , Turgeon Judith L , Troyanskaya Olga , Zaslavsky Elena , Bernard Daniel J , Sealfon Stuart C
Published: October 2023

Disclosure: F.M. Ruf-Zamojski: None. W. Cheng: None. Z. Zhang: None. M. Zamojski: None. G.R. Smith: None. X. Chen: None. N. Mendelev: None. G. Strupinsky: None. C.A. Alonso: None. L. Ongaro Gambino: None. X. Zhou: None. E. Brule: None. M.S. Amper: None. P. Hanna: None. V.D. Nair: None. C.L. Andoniadou: None. J.L. Turgeon: None. O. Troyanskaya: None. E. Zaslavsky: None. D.J. Bernard: None. S.C. Sealfon: None.

Single cell multi-omics datasets provide an unparalleled power to resolve gene regulatory circuits underlying cellular function in complex tissues such as the pituitary gland [1, 2]. To better understand cellular plasticity and dynamics in the mouse pituitary during the estrous cycle in vivo, we performed same-cell single nucleus (sn) multi-omics for gene expression and chromatin accessibility on individual pituitaries collected from mice at 9am on each day of the cycle, as well as at 6pm and 11pm on proestrus and at 2am on estrus to capture surge events. Cycle stage was determined by vaginal cytology and post-mortem measurement of serum LH and FSH levels. In total, 102,069 cells passed rigorous quality control (QC, [2]), with over 5,000 cells analyzed per sample, ∼2,000 genes/cell, ∼15,000 ATAC median high-quality fragments, and Transcription Start Site (TSS) enrichment scores above 9 for all samples. We identified 13 well-separated clusters in the snRNAseq and 10 in the snATACseq datasets representing the pituitary cell types that were followed over time. We integrated the gene expression and chromatin accessibility datasets and analyzed changes in cell type proportions, gene expression, and chromatin accessibility through time. We detected major differential gene expression changes in the gonadotropes and lactotropes, which we further investigated using pseudotime trajectory analyses. Several upstream Fshb loci showed dynamic changes during the estrous cycle. Additionally, we uncovered regulatory components of major pituitary genes over time using linkage data analysis.To our knowledge, this is the first study to present detailed and comprehensive data on gene expression and chromatin structure changes at sn resolution in all pituitary cell types during a dynamic physiological process. Thus, it provides critical new resources to the field of endocrinology.

References:[1] Nat Comm, 2020, 12(2677), PMID:33976139.[2] Cell Reports, 2022, 38(10): 110467, PMID:35263594.

Presentation: Thursday, June 15, 2023
THU020 Bilateral Adrenal Hyperplasia (BAH): Undesirable Effect Of Glucocorticoid Receptor Competitive Antagonist (GRCAnt) In Cushing’s Disease
Authors: Canturk Ayse , Villabona Carmen , Kargi Atil
Published: October 2023

Disclosure: A. Canturk: None. C. Villabona: None. A. Kargi: None.

We present a case of a complicated ACTH (adrenocorticotropic hormone)-dependent tumor and hypercortisolism, we discuss the potential side effects of mifepristone, a GRCAnt potentially causing bilateral adrenal hyperplasia and we discuss potential pathophysiologic mechanisms. This is a 73 years old male who presents to the clinic for a follow-up of Cushing’s Disease (CD). He has a pmh of osteoporosis, hypopituitarism, and secondary DM in the setting of an aggressive and medication-resistant Corticotroph Pituitary Neuroendocrine Tumor (cPNET). He has undergone a total of four transsphenoidal surgeries since 2013 and two treatments with external beam radiations. He still has residual tissue invading his cavernous sinus, thus another surgery was not an option, so Gamma Knife (GK) therapy was given. In the past, he has received a trial of ketoconazole for a period of 2-3 years, temozolomide, and octreotide, and is currently on mifepristone for the past four years. He underwent Bilateral Adrenalectomy in 2016 and had a small adrenal residual. It is demonstrated in a PET scan from 2018 that he had BAH and confirmed in a recent CT abdomen on 12/2022. While on mifepristone his ACTH was 1173pg/mL (nl:10 and 60 pg/mL), and cortisol 92.7 mcg/dL (nl:5 to 25 mcg/dL). Cortisol  urine was 1627.2 mcg/24hr (nl:4 to 40 mcg/24hr). For treatment of his cPNET, we discontinued mifepristone and started on ketoconazole, and referred him to surgery for a second adrenalectomy. We reordered IHC on pathology specimens obtained in 2019 for SSTRs 1-5 and might consider starting synthetic somatostatin analog. We illustrate the potential negative effect of the long-term use of mifepristone. This is a GRCAnt that increases ACTH levels (8-10 fold in some cases) and will potentially cause BAH. This is an aggressive cPNET with hypercortisolism, who has been on long-standing medical therapy with mifepristone. He has developed BAH which has been potentially caused or exacerbated by GRCAnt. Reviewing the literature, there is limited data on this topic. This effect appears not to occur in all patients with Cushing’s disease. We propose potential pathophysiologic mechanisms of the indirect or direct effect of mifepristone causing BAH and potential factors explaining why this phenomenon might only occur in selected patients, we also propose management of patients on long therapy with GRCAnts.

Presentation: Thursday, June 15, 2023
THU042 FOXO1 Stimulates Hsp90b1 Expression To Promote Efficient Glucocorticoid Signaling And Facilitate Maturation Of Somatotropes
Authors: Das Pratyusa , Abou-Jabal Dania M , Ellsworth Buffy Sue
Published: October 2023

Disclosure: P. Das: None. D.M. Abou-Jabal: None. B.S. Ellsworth: None.

Glucocorticoids promote differentiation and maturation of many tissues. There is significant evidence that glucocorticoids are also important for maturation of pituitary somatotropes. We find that treating pregnant mice with the synthetic glucocorticoid, dexamethasone, leads to premature appearance of GH-positive cells, suggesting premature somatotrope maturation. Expression of Gh1 and Foxo1 are significantly increased in mice treated with dexamethasone compared to control mice. We have previously shown that deletion of the forkhead transcription factor, FOXO1, causes a delay in somatotrope maturation. Thus, both FOXO1 and glucocorticoid signaling affect the timing of somatotrope maturation. Interestingly, we find that the ability of glucocorticoids to promote somatotrope maturation is impaired in mice lacking FOXO1. Similar to what we find in vivo, deletion of Foxo1 from the somatotrope-derived MtT/S cells (MtT/SΔFoxo1) impairs glucocorticoid-induced expression of Gh1 suggesting FOXO1 may be required for glucocorticoid-induced somatotrope maturation. Glucocorticoid signaling depends on a number of chaperone proteins. Heat-shock protein 90 (HSP90) is essential for protecting the glucocorticoid receptor (NR3C1) from degradation and preparing it for ligand binding. Hsp90aa1, Hsp90ab1, and Hsp90b1 are all expressed in MtT/S cells. Chromatin immunoprecipitation sequencing (ChIPseq) for FOXO1 reveals FOXO1 binding at the promoter of Hsp90b1. Consistent with this, we find a reduction in Hsp90b1 expression in MtT/SΔFoxo1 cells. Thus, Hsp90b1 may be a direct transcriptional target of FOXO1. Expression of Hsp90ab1 is also reduced in the absence of FOXO1, however FOXO1 binding is not detected at its promoter suggesting Hsp90ab1 may be an indirect target of FOXO1. Together these data suggest that FOXO1 promotes somatotrope maturation by fostering efficient glucocorticoid signaling.

Presentation: Thursday, June 15, 2023
SAT665 Effects Of Weight Cycling On Hepatic Protein Carbonylation And Lipid Peroxidation
Authors: Djalali-Gomez Maya Aliyeh , Bogart Jolie A , Ortiz Silvana Duran , Berryman Darlene E , Kopchick John Joseph , List Edward Owen
Published: October 2023

Disclosure: M.A. Djalali-Gomez: None. J.A. Bogart: None. S. Duran Ortiz: None. D.E. Berryman: None. J.J. Kopchick: None. E.O. List: None.

Over two-thirds of the U.S. population is overweight or obese which has been shown to increase oxidative stress. Oxidative stress damages biological molecules such as lipids, proteins, and DNA, ultimately contributing to the development of numerous diseases including cancer and diabetes. Increasing awareness of the health issues caused by obesity leads many to attempt weight loss. Unfortunately, successful weight loss is usually temporary as an estimated 80% of individuals who lose weight will gain it back within a year. Repeated cycles of weight gain and weight loss are known as weight cycling. While the prevalence of obesity and weight cycling has increased in recent years, research on the long-term health consequences of weight cycling is limited. In the current study, we evaluated how diet stability (i.e., weight-cycled diets vs stable diets) and immediate diet (i.e., diet at the time of tissue collection; high fat vs low fat) affect oxidative stress by measuring hepatic lipid peroxidation and protein carbonylation from mice exposed to long term weight cycling or a stable diet regimen with high or low-fat diets. Our results indicate that the immediate diet significantly impacted hepatic oxidative stress, as mice on a high-fat diet prior to sacrifice had significantly greater levels of hepatic protein carbonylation (p=.020) as well as hepatic lipid peroxidation (p=.010) compared to mice on a low-fat diet. Importantly, our results also indicate that diet stability significantly impacted hepatic oxidative stress as weight cycled mice had significantly greater levels of hepatic protein carbonylation (p=.030) and hepatic lipid peroxidation (p=.008) compared to mice fed stable diets. Overall, our results indicate that weight cycling, independent of immediate diet, increases oxidative damage in the livers of mice compared with mice fed stable (non-cycled) diet regimens.

Presentation: Saturday, June 17, 2023
THU053 Partial Third Nerve Palsy As A Presentation Of Prolactinoma, A Case Report
Authors: Ahmad Mobeen , Iqbal Iqra , Khan Malik , Estepa Adrian , Siddiqui Usman
Published: October 2023

Disclosure: M. Ahmad: None. I. Iqbal: None. M. Khan: None. A. Estepa: None. U. Siddiqui: None.

Introduction: Prolactinomas in men are often found when they are quite advanced, large and cause compression of surrounding structures. This compression causes patients to present with symptoms of hypogonadism, headaches, and vision changes. Uncommonly, pituitary adenomas have been shown to cause vision changes associated with third nerve palsy. We describe the case of a 21-year-old male presenting with vision changes and headaches who was found to have a large prolactinoma causing partial third nerve palsy. Case description: A 21-year-old male with no significant past medical history presented to the emergency department (ED)after being sent from his primary care provider’s office for headaches. The patient had been suffering from left sided headaches and blurry vision for the past two months. On physical examination the patient was normotensive (128/61 mmHg), afebrile (37.3 degrees Celsius) with a normal respiratory rate and heart rate (18 breaths per minute and 73 beats per minute respectively). He was noted to have left eyelidptosis with his left pupil being slightly more dilated than his right pupil at 5 mm and was slowly reactive. The patient’s blood work was significant for the following: sodium 141 mmol/L, potassium 4.4 mmol/L,bicarbonate 24 mmol/L, hemoglobin 13.4 g/dL, TSH 2.21 uIU/mL, free T4 0.9 ng/dL, prolactin >4700ng/mL, adrenocorticotrophin hormone <9 pg/ml, cortisol 0.9 mcg/dL, follicle-stimulating hormone 2.5uIU/ml, luteinizing hormone 4.7 uIU/ml, free testosterone 3.4 pg/ml, and total testosterone 19 ng/dL. The patient underwent brain imaging with his CT angiogram demonstrating a large sellar mass extending superiorly, causing displacement of the internal carotid artery. An MRI of the brain described the mass to be 3.4 x 2.7 cm in dimensions. The patient was first started on dexamethasone 4 mg intravenously every 6hours, tapered over a week, along with once weekly cabergoline which was eventually titrated up to 1 mg weekly. The patient had rapid clinical improvement with his symptoms resolving in four days, and was eventually discharged. He now follows with endocrinology as an outpatient. Discussion: Prolactinomas can present with a wide range of symptoms in men including headache, infertility, decreased libido and vision changes. Rarely, prolactinomas have been associated with third nerve palsy with proposed mechanisms including compression of the nerve in the cavernous sinus or compression of the nerve’s vascular supply. Through this case we hope to highlight this uncommon presentation of prolactinoma and propose it be considered in the workup for third nerve palsy.

Presentation: Thursday, June 15, 2023
THU087 Natural History Of Nonfunctioning Pituitary Macroadenomas Followed Without Intervention
Authors: Ayalon-Dangur Irit , Robenshtok Eyal , Duskin-Bitan Hadar , Tsvetov Gloria , Gorshtein Alex , Akirov Amit , Shimon Ilan
Published: October 2023

Disclosure: I. Ayalon-Dangur: None. E. Robenshtok: None. H. Duskin-Bitan: None. G. Tsvetov: None. A. Gorshtein: None. A. Akirov: None. I. Shimon: None.

Objective: The treatment strategy for non-functioning pituitary adenomas (NFPA) includes surgery, radiotherapy, medication, or follow-up. Data on non-operated patients with macroadenomas are sparse. This study sought to investigate the natural history of NFPAs followed without treatment. Design and patients: The database of a tertiary medical center was retrospectively searched (1995-2020) for adult patients with NFPA ≥10 mm who were naïve to surgery or medical treatment and were followed for ≥12 months after diagnosis. Patients with chiasmal threat were excluded. Follow-up was terminated if the patient underwent surgery, received cabergoline, or was lost to follow-up. Measurements: Data on tumor characteristics and size on imaging by MRI, symptoms including visual disturbances, and pituitary hormone levels were collected from the medical files. Tumor growth was defined as a maximal increase of >2 mm in diameter. Results: The cohort included 49 patients, 30 male and 19 female, of mean age 68.0±12.0 years. Median tumor size at diagnosis was 16 mm (range, 10-35), and median duration of follow-up was 3 years (range, 1-23(. Tumor’s size increased in 16 patients (33%), by a mean of 5.1±4.4 mm, and decreased in 10 patients (20%), by a mean of 3.5±1.3 mm; in 23 patients, the tumor remained stable. Overall, 33 patients (67%) were observed without intervention, 3 underwent surgery, and 13 received cabergoline. None of the parameters evaluated, including age, gender, baseline tumor size, tumor invasiveness, visual disturbances, or hypopituitarism at diagnosis, predicted tumor growth. Conclusions: Observation of NFPAs without surgery or medication is a reasonable approach in selected patients. In our study, there was no association of patient- or tumor-related parameters with tumor growth.

Presentation: Thursday, June 15, 2023
THU095 Multilineage Plurihormonal (FSH LH TSH PRL ACTH) Pituitary Neuroendocrine Tumour: A Case Report
Authors: Mahfuza Ummul K , Preda Veronica Angela , Di Ieva Antonio , Rodiguez Michael
Published: October 2023

Disclosure: U.K. Mahfuza: None. V.A. Preda: None. A. Di Ieva: None. M. Rodiguez: None.

Plurihormonal pituitary neuroendocrine tumors (PitNETs) are adenomas that produce more than one hormone. This is an uncommon entity. The 2022 WHO classification has differentiated these pitNETs along histological subtyping based on the tumour cell lineage, cell type, and related characteristics1.We present a case of a 48-year-old gentleman, who initially sought attention for visual symptoms with findings of raised intraocular pressure. His ophthalmologist assessment showed temporal disc pallor. Subsequently, the MRI revealed a 30mm pituitary macroadenoma compressing the optic apparatus. He was referred to our Endocrinology service. He had a low testosterone level. He underwent an endoscopic trans-sphenoidal resection. Post-operatively he remained on testosterone replacement, the rest of the pituitary axes were intact. Pre- and post-operative visual assessment showed retinal ganglion cell loss which has negative prognostic implications. Overall, his eye pressure and visual fields improved following surgery. The histopathology diagnosis was a PitNET/adenoma with predominantly gonadotroph SF1, FSH and LH staining. In addition, there were single cells and nests of strongly TSH and PRL-positive cells scattered through the tumour, but no GH staining. There was specific ACTH staining; also in monophenotypic nests. Pit1 positive nuclei present. The TPit was negative within the tumour. There were some residual adenohypophysis cells which is a rare finding deep within a solid tumour. The tumour extended to the inferior surface of the dura. These unique features lead to uncertainty regarding the potential recurrence rate over time. Conclusion: Multilineage PitNETs are uncommon2. The literature reports that the surgical outcome depends on the histopathology characteristics of the immunohistochemistry and transcription factors. However, PitNETs positive for SF1, FSH, LH, PRL,rl and ACTH staining are not widely reported. With the updated WHO classification and consideration of cell lineage and cell type the knowledge of these tumours will eventually improve. Follow-up and tailored management in this patient’s cohort are needed. References: 1 Asa SL, Mete O, Perry A, Osamura RY. Overview of the 2022 WHO Classification of Pituitary Tumors. Endocr Pathol. 2022 Mar;33(1):6-26.2 Seckin Aydin, Nil Comunoglu, Merdin Lyutviev Ahmedov, Ozge Polat Korkmaz, Buge Oz, Pinar Kadioglu, Nurperi Gazioglu, Necmettin Tanriover, Clinicopathologic Characteristics and Surgical Treatment of Plurihormonal Pituitary Adenomas, World Neurosurgery, Volume 130,2019.

Presentation: Thursday, June 15, 2023
THU097 Primary Overproduction Of TSH Presenting As Intermittent Atrial Fibrillation Responding To Methimazole
Authors: Maher Thomas D
Published: October 2023

Disclosure: T.D. Maher: None.

Background: Intermittent Atrial Fibrillation (IAF) is commonly associated with Hyperthyroidism. TRH from the hypothalamus stimulates TSH production in the pituitary; a negative feedback loop of thyroxine to the hypothalamus is the primary regulator of TSH production. The Pituitary is adjacent to the sphenoid sinus; nasal and sinus inflammation and other factors may affect TSH production. With currently available thyroid tests it is a clinical challenge to be certain the thyroid is not contributing to IAF. Clinical Case: A 72-year-old male presented at age 57 (2007) with new onset IAF. The patient had Allergic Rhinitis since age 20. For IAF he was treated with Metoprolol, Flecanide and Dofenilide but IAF continued. On 3/2/11, TSH was 5.12 ((0.270-4.2 uU/Ml). At age 64 (2014), Catheter Ablation was performed. Before the Ablation, 08/16/2013, the FT4 was 1.2 (0.90-1.70) ng/ml and TSH 3.99 (0.270-4.200) uU/ml. Two years post Ablation, on 1/19/2016, TFTs were: FT4 1.10 (0.90-1.70) ng/ml; TSH 5.42 (0.270-4.200) uU/ml and repeat TFTs on 3/15/16 were: FT4 1.24 (0.90-1.70) ng/dl; TSH 4.10 (0.270-4.2 uU/dl. The diagnosis of Borderline Hypothyroid was entertained. He was trialed on Thyroxine 25 mcg daily with gradual increase to 75 mcg. The patient complained of being light headed, weak and having diffculty concentrating and the TSH was still elevated. Thyroxine was discontinued. In 2017, IAF returned. In October 2019 the thyroid was 35-40 Gm., firm, and with small nodules on palpation and ultrasound. The TFTs on 10/01/2019 were: FT4 0.81 (0.75-1.54) ng/ml and TSH 5.15 (0.3-4.2) uIU/ml. To test whether overproduction of TSH was causing excess Thyroxine release and IAF, low dose Methimazole was started at 5 mg, four days a week. There have been no episodes of AF for the past three years while on Methimazole. TFTs on 10/19/2022 were: FT4 0.94 (0.75-1.54) ng/ml and TSH 7.11 (0.099-4.2) uiU/m). Conclusion: In the clinical setting of IAF, elevated TSH and normal FT4, overproduction of TSH by extrinsic stimuli should be considered. Thyroid partial blockade with Methimazole is safe, economical, and reversible and may give valuable information about whether the thyroid is causing episodic Atrial Fibrillation.

Presentation: Thursday, June 15, 2023
THU125 Altered Pro-opiomelanocortin (POMC) Neuron Function Characterizes Energy Expenditure Dysfunction And Increased Body Weight Linked To Fragile X Gene Mutation
Authors: Ruggiero-Ruff Rebecca Elizabeth , Villa Pedro , Hijleh Sarah Abu , Avalos Bryant , DiPatrizio Nicholas , Coss Djurdjica
Published: October 2023

Disclosure: R.E. Ruggiero-Ruff: None. P. Villa: None. S. Abu Hijleh: None. B. Avalos: None. N. DiPatrizio: None. D. Coss: None.

Obesity is a world-wide epidemic that has become a major public health concern. Obesity increases the risk of cardiovascular disease, type 2 diabetes, stroke, and dementia. Children and adolescents with Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, have higher rates of obesity compared to peers. FXS is caused by a mutation of the Fragile X messenger ribonucleoprotein gene (FMR1), which leads to the loss of FMRP, a ubiquitously expressed mRNA binding protein. Food intake and energy expenditure are regulated by orexigenic neuropeptide Y (NPY)/agouti-related protein (AgRP) and anorexigenic pro-opiomelanocortin (POMC) neurons from the hypothalamus. While our understanding of mechanisms of intellectual disability in FXS patients is beginning to emerge, the role of FMR1 gene in the hypothalamus is unknown. In this study, we used a knock-out (KO) mouse model to analyze if obesity in FXS patients stems from dysregulation of the hypothalamic circuitry regulating food intake and energy expenditure. Consistent with what is seen in the human population, KO males weigh more than their WT littermates. There were no differences in growth hormone or basal or fasting glucose levels. There was no difference in food intake, however KO males exhibited lower locomotor activity in the dark cycle, during their active phase. Since POMC neurons regulate energy expenditure in addition to food intake, we analyzed POMC neuron number, using immunohistochemistry. We determined fewer POMC neurons in KO male mice compared to WT. AgRP/NPY neurons modulate POMC neurons through GABAergic neuronal transmission. We determined that KO males have increased obligatory GABAa receptor subunit on POMC neurons. We also analyzed GABAa receptor and vesicular GABA transporter (VGAT) apposition on POMC neurons to identify synaptic receptors and indeed, KO males had significantly higher levels of GABAa-VGAT appositions, indicating increased synaptic input. In summary, our results suggest a role for FMR1 in the regulation of POMC neuronal activity in the regulation of locomotor activity and point to a role in modulating motor activity and energy expenditure in obese Fragile X patients.

Presentation: Thursday, June 15, 2023
OR0304 Novel Dual Antagonists Of The Growth Hormone Receptor And The Prolactin Receptor
Authors: Basu Reetobrata , Kopchick John Joseph
Published: October 2023

Disclosure: R. Basu: None. J.J. Kopchick: None.

An excess of the human growth hormone (hGH) is associated with multiple pathophysiology including acromegaly, diabetes, cancer, renal dysfunction and age-associated cognitive impairment. On the other hand, a congenital lack of GH action in humans and mice render a protective effect from the above co-morbidities. Consequently, there exists significant pharmaceutical interest in developing antagonists of GH action - rendered via binding and activating the GHR, as well as the prolactin receptor (PRLR), which is particularly relevant for PRLR-rich cancers of the breast and prostate. Our laboratory has pioneered the discovery of the first and only FDA approved GHR antagonist - Somavert (pegvisomant for injection, Pfizer Inc., USA) - currently prescribed for the treatment of acromegaly. Here we present two new and unique designs of antagonists which block the complete spectrum of GH action at both GHR and PRLR binding. The first GHR antagonist design is a full-length G120K-hGH peptide at the core, incorporating targeted cysteine (single or double) substitutions at carefully selected solvent-accessible residues distal to the binding sites. To these substituted cysteines, maleimide activated discrete PEGs (MAL-dPEG; neutral or anionic, branched, different sizes) were specifically conjugated to build a library of multiple putative GHR antagonists. Binding studies and biochemical activities reveal multiple promising GHRA candidates with high binding affinities to both GHR and PRLR, while the biological assays show robust inhibition of GH driven intracellular signaling and oncogenic processes in cultured human cancer cell lines. Intraperitoneal administration of a selected candidate (compound-G) in mice significantly reduced serum IGF1 and IGFBP3 as well, confirming in vivo efficacy. The second candidate antagonist termed ‘S1H’ is a 16-amino-acid peptide designed as a direct sequence mimetic of a unique fragment of the site-1 binding helix of the hGH molecule. To this end we have characterized S1H with mass spectrometry, circular dichroism spectropolarimetry, and in vitro biological assays using human cell lines expressing GHR. S1H inhibited GH as well as PRL induced STAT5 phosphorylation in a dose-dependent manner in multiple cell lines. Moreover, using alanine scanning mutagenesis studies, we identified a strong correlation between the helical propensity and biological activity of S1H - allowing extensive structure activity relationship studies. Thus, we present two distinct designs, preparation and characterization of dual antagonists of the GH action at the level of GHR and PRLR, with prospective applications in pathologies associated with a GH excess and also as valuable compounds to study the nature of human GH-GHR interactions. We currently continue to develop both compounds for pre-clinical validations.

Presentation: Thursday, June 15, 2023
FRI272 Sex-Specific Role Of ProkR2 Neurons Of The Posterior Amygdala In The Integration Of Odors And Neuroendocrine Responses
Authors: Cisneros-Larios Brenda , Elias Carol F
Published: October 2023

Disclosure: B. Cisneros-Larios: None. C.F. Elias: None.

Kallmann Syndrome (KS) is characterized by abnormal development of the reproductive axis and olfactory bulb dysgenesis. Genetic studies have revealed that Kallmann Syndrome is caused by loss-of-function mutations in several genes including the prokineticin receptor 2 (PROKR2) gene. Prokr2 null mice exhibit the same phenotype of KS patients. While the role of PROKR2 during development has been linked with GnRH neuron migration, limited data exists on PROKR2 neurons in adult reproduction. PROKR2 mRNA are highly expressed in reproductive control sites. Furthermore, our lab previously found sexually dimorphic expression of PROKR2 mRNA and Prokr2-Cre GFP+ cells in several reproductive control sites. The posterior amygdala had higher PROKR2 expression in males compared to female mice. More recently, we identified expression of sex steroid receptors in PROKR2 expressing cells of the PA. The amygdala is an important site of socio-sexual inputs and reproductive neuroendocrine responses in rodents and primates, including humans. We hypothesize Prokr2-Cre neurons in the PA have a role in male reproductive function. Using genetic tracing techniques, we mapped PA Prokr2-Cre neuronal projections in male mice and found dense innervation to reproductive control sites such as the medial preoptic area and the ventral premammillary nucleus. We found activation of these neurons, via fos expression, after opposite sex soiled bedding exposure (olfactory cues). Lastly, selective activation, using chemogenetic technology DREADDs, of PA Prokr2-Cre cells in males can induce a rise in circulating luteinizing hormone. These data suggest PA Prokr2-Cre cells have a role in pathways integrating olfactory cues and reproductive endocrine responses (e.g., aggression, mating behavior). We expect our studies will contribute to the understanding of the role of PROKR2 neurons in adult reproduction and reproductive deficits associated with PROKR2 mutations.

Presentation: Friday, June 16, 2023
FRI291 Musashi1 And Musashi2 Mark Distinct Pituitary Stem Cell Populations
Authors: Rahmatallah Yasir , Banik Jewel , Bronson Katherine , MacNicol Melanie C
Published: October 2023

Disclosure: Y. Rahmatallah: None. J. Banik: None. K. Bronson: None. M.C. MacNicol: None.

The cell plastic state of the pituitary is required to meet the changing demands upon pituitary function and may also result in these cells being more vulnerable to malignant transformation. The mechanisms that control pituitary cell plasticity are unknown. The RNA binding protein Musashi (MSI) is expressed in embryonic stem cells, and in cancer stem cells, where MSI functions to promote stem cell plasticity and to oppose premature cell maturation. MSI is also expressed at high levels in adult gonad and adult pituitary. The function of MSI in adult tissues is not fully understood, and the mechanisms that control the pro-proliferative and pro-malignant aspects of MSI function in adult tissues are not known. The two evolutionarily conserved MSI proteins, Musashi1 (MSI1) and Musashi2 (MSI2), are predicted to function redundantly, however, regulatory distinctions have been reported for MSI1 and MSI2. Towards a characterization of MSI1 and MSI2 in pituitary, we analyzed transcriptomics data from public datasets of single-nucleus and single-cell and bulk-tissue gene expression data from physiological and pathophysiological human pituitary tissue. We performed bioinformatics analysis utilizing the single-cell genomics analysis tool, Seurat in R and the pseudotime trajectory analysis tool Monocle and additional genomics and statistics analyses tools in R. We identify the MSI1-expressing pituitary cell population as immature stem cells and the distinct MSI2-expressing pituitary cell population as more mature, committed progenitor cells. Pituitary from human fetal tissue contains multiple distinct MSI1-expressing cell populations while, in contrast, pituitary from human adult tissue contains multiple distinct MSI2-expressing cell populations. Pituitary from human pediatric tissue demonstrates an intermediate state with both distinct MSI1-expressing and distinct MSI2-expressing cell populations. We identify increased MSI1 expression but not increased MSI2 expression in adult pituitary adenoma, and a high level of variation in the MSI1 to MSI2 expression ratio between distinct pituitary adenomas. Based upon this re-analysis of reposited datasets from other pituitary investigators, we hypothesize that the increase that we observe, in MSI1 to MSI2 expression ratio in adult pituitary tumors is consistent with a reversion of mature cells to an earlier immature state. Adult pituitary may contain the mechanisms that regulate MSI2 function but may not be equipped to properly control high levels of re-expressed MSI1. An understanding of the physiological functions and mechanisms of regulation of the distinct MSI proteins in pituitary may provide insight into potential mechanisms that could be recruited to increase physiological pituitary cell growth and differentiation in regenerative therapy and to oppose pathological cell growth in pituitary tumor.

Presentation: Friday, June 16, 2023