bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &gt;4700ng/mL, adrenocorticotrophin hormone &lt;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

Abstract
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 &gt;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

Abstract
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

Abstract
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

Abstract
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

Abstract
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