bluuebunny/crossref_metadata_2025 huggingface dataset:
THU018 Remarkable Response Of ACTH-secreting Pituitary Carcinoma To Immune Checkpoint Inhibitors: A Case Report
Authors: Park Ji Yong , Choi Wonsuk , Ram Hong A , Yoon Jee Hee , Kim Hee kyung , Kang Ho-Cheol
Published: October 2023

Disclosure: J. Park: None. W. Choi: None. A. Hong: None. J. Yoon: None. H. Kim: None. H. Kang: None.

Background: ACTH-secreting pituitary carcinoma transformed from Cushing’s disease is very rare and has aggressive characteristics with limited treatment options. We report a case of ACTH-secreting pituitary carcinoma patient who showed a excellent response to immune checkpoint inhibitors (ICIs). Clinical Case: A 70-year-old female presented with a rapidly growing pituitary carcinoma transformed from Cushing’s disease after bilateral adrenalectomy. Her tumor initially responded to 6 cycles of temozolomide and 7 cycles of temozolomide plus capecitabine. However, multiple brain and pulmonary metastases were newly seen on following imaging studies and the patient had worsening generalized pigmentation on her whole body with newly developed headache, diplopia, and ptosis of the left eye. After introduction of three cycles of ipilimumab plus nivolumab therapy, her plasma ACTH level decreased dramatically from 58,000 pg/ml to 198 pg/ml with improving skin pigmentation and headache episodes. We maintained nivolumab and observed that the plasma ACTH level be normalized to 44 pg/ml (normal range: 6 – 60 pg/ml). Her follow-up brain MRI and chest CT scan also showed marked response, some of the chest lesions even showed nearly complete response (figure 1). On the last follow-up visit, we confirmed that she was in good general condition and tolerable to nivolumab maintenance therapy with glucocorticoid replacement. Conclusion: Immune checkpoint inhibitors (ICIs) may be effective therapeutic options in aggressive pituitary carcinoma and can be considered in temozolomide resistant cases. Moreover, because of the excessively high cost, we emphasize the necessity of clinical trials of ICIs for rare diseases like pituitary carcinomas to expand insurance coverage and reduce the unmet needs of medical care.

References:(1) Reincke, M., et al., Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations. Eur J Endocrinol, 2021. 184(3): p. P1-P16.

(2) Raverot, G., et al., Temozolomide treatment in aggressive pituitary tumors and pituitary

carcinomas: a French multicenter experience. J Clin Endocrinol Metab, 2010. 95(10): p. 4592-9.

(3) Lin, A.L., et al., Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab. The Journal of Clinical Endocrinology & Metabolism, 2018. 103(10): p. 3925-3930.

(4) Raverot, G., et al., Aggressive pituitary tumours and pituitary carcinomas. Nat Rev Endocrinol, 2021. 17(11): p. 671-684.

Presentation: Thursday, June 15, 2023
THU026 Severe Insulin Resistance In Type 1 Diabetes Due To Growth Hormone Producing Pituitary Macroadenoma
Authors: Pansare Rahul , Khurram Daniyeh , Folsom Lisal
Published: October 2023

Disclosure: R. Pansare: None. D. Khurram: None. L. Folsom: None.

Background: Acromegaly is a rare disorder with an incidence ranging from 28 to 137 per million. Elevated IGF-1 in acromegaly is associated with severe insulin resistance and diabetes mellitus in the absence of visceral adiposity. We present a case of acromegaly identified in a lean individual with type 1 diabetes with progressive, severe insulin resistance requiring U-500 insulin via insulin pump. Clinical Case: A 28-year-old individual with type 1 diabetes mellitus diagnosed at age 17 years, hyperlipidemia, PCOS, rheumatoid arthritis, depression, and fibromyalgia presented with symptoms of brain fog, fatigue, functional decline, and nocturnal hyperhidrosis. Vital signs obtained in endocrinology clinic revealed blood pressure 100/70 mmHg and BMI 27 kg/m2. Glycemic control was suboptimal with HbA1c ranging from 7.5-9.5% over the past 2 years. The patient had developed progressive insulin resistance with subsequently increased insulin needs, ultimately requiring U-500 insulin administered via insulin pump. Brain MRI ordered due to additional symptoms revealed a sellar mass. Dedicated pituitary MRI confirmed a 2.1 cm anterior pituitary macroadenoma with compression of the optic chiasm, without cavernous sinus invasion. Biochemical evaluation at 9:57am revealed elevated IGF-1 801 ng/ml (93 - 297), Z-score +5.1. Additional testing revealed ACTH 17.9 pg/ml (7.2 - 63.3), cortisol 9.6 mcg/dl (3.7 - 19.4), TSH 0.741 mIU/L (0.27 - 4.2), free T4 1.32 ng/dl (0.93 - 1.7), prolactin 8.4 ng/ml (5.2 - 26.5), leptin 14.4 ng/ml (0.5 - 15.2), LDL 151 mg/dl (0 - 100), triglycerides 203 mg/dl (0 - 149). The patient subsequently underwent transsphenoidal resection of the pituitary macroadenoma. Discussion: Diabetes mellitus in acromegaly is associated with increased mortality. When elevated, IGF-1 level has been shown to be an independent predictor for risk of development of diabetes mellitus in acromegaly and correlates with insulin resistance. A unique challenge arises when the diagnosis of acromegaly is suspected in existing uncontrolled diabetes, as IGF-1 levels may be elevated, normal, or low. Post-surgical reduction in serum IGF-1 level is associated with early postoperative improvement in glucose tolerance. As such, once the diagnosis is confirmed, prompt surgical intervention is imperative to decrease this risk, as well as to improve hyperglycemia and decrease insulin requirements. Although de novo type 2 diabetes in acromegaly is common, our case is novel as it highlights the need to expand the differential diagnosis to include exogenous causes for progressively worsening insulin resistance in individuals with type 1 diabetes.

Presentation: Thursday, June 15, 2023
THU044 The Subcellular Localization Of β-Catenin Is Associated With Tumor Size And The Surgical Remission Rate In Growth Hormone-producing Pituitary Adenomas
Authors: Kuwabara Saki , Kameda Hiraku , Nomoto Hiroshi , Cho Kyu Yong , Nakamura Akinobu , Ishi Yukitomo , Motegi Hiroaki , Miki Fujimura , Miyoshi Hideaki , Atsumi Tatsuya
Published: October 2023

Disclosure: S. Kuwabara: None. H. Kameda: None. H. Nomoto: None. K. Cho: None. A. Nakamura: None. Y. Ishi: None. H. Motegi: None. F. Miki: None. H. Miyoshi: None. T. Atsumi: None.

The Wnt/β-catenin pathway is the best understood Wnt signaling pathway and controls cell proliferation. In the presence of Wnt, the translocation of β-catenin from the cytoplasm to the nucleus leads to pathway activation. It has been reported that the nuclear accumulation of β-catenin is associated with Ki-67 expression in pituitary adenomas and that the invasiveness of growth hormone (GH)-producing pituitary adenomas is associated with β-catenin expression. We aimed to clarify the effects of the Wnt/β-catenin pathway in GH-producing pituitary adenomas. We performed immunofluorescence staining using antibodies against GH and β-catenin in pathological samples of pituitary adenoma from 62 patients with acromegaly who underwent pituitary surgery at our hospital between January 2008 and December 2021. We also obtained clinical data for the patients, including the results of endocrine testing, and evaluated the relationships of key indices with the intracellular localization of β-catenin. Samples from 26 cases (42%) showed strong punctate expression of β-catenin in the nuclei (dot pattern (DP) group), and samples from 36 cases (58%) showed β-catenin expression in the cytoplasm or cell membrane (non-DP group). There were no differences in the sex, age, GH concentration, or insulin-like growth factor I (IGF-1) SD scores of the two groups, but the DP group had larger tumors (diameters 18±8 vs. 13±7 mm) and a higher prevalence of macroadenomas (77% vs. 53%). In the DP group, a paradoxical preoperative GH response (an increase of ≥30% of the basal concentration) to 75-g oral glucose tolerance testing was more frequent (46 vs. 22%, p<0.05) and postoperative remission was less frequent (23% vs. 50%, p<0.05). Accordingly, the Wnt/β-catenin pathway appears to be more active in the DP group. The larger tumors and lower postoperative remission rate of the DP group suggest that the Wnt/β-catenin pathway may influence tumor growth. Wnt/β-catenin pathway could play a major role in GH-producing pituitary tumor growth, therefore this pathway would be a potential therapeutic target in the affected patients.

Presentation: Thursday, June 15, 2023
THU067 Long-term Depot Specific Changes In Adipose Tissue After Treatment Of Acromegaly
Authors: Falch Camilla Maria , Godang Kristin , Lekva Tove , Heck Ansgar , Bollerslev Jens , Olarescu Nicoleta Cristina
Published: October 2023

Disclosure: C.M. Falch: Speaker; Self; Pfizer, Inc. K. Godang: None. T. Lekva: None. A. Heck: Speaker; Self; Ipsen, Recordati. J. Bollerslev: Advisory Board Member; Self; Pfizer, Inc. Speaker; Self; Ipsen, Pfizer, Inc. N.C. Olarescu: Speaker; Self; Pfizer, Inc., CORE2ED.

Objective: Patients with active acromegaly present a decreased adipose tissue (AT) mass, and short-term studies show that the AT increases following treatment. However, it remains unclear if the increase is persistent in the long-term perspective. Aim: To characterize the depot specific changes of AT after treatment of acromegaly and identify contributing factors. Methods: In a clinically well-defined cohort of patients with acromegaly (n = 62), visceral (VAT), subcutaneous (SAT), total (TAT) adipose tissue, and android to gynoid ratio (A/G ratio) were measured by Dual Energy X-ray Absorptiometry (DXA). Measurements were assessed at diagnosis, and at a short- and long-term visit (median follow-up time (IQR): 1.9 (1.5-2.3) and 5.5 (3.6-9.6) years, respectively). Growth hormone (GH), insulin-like growth factor I (IGF-I), glucose and HbA1c levels, gonadal status, and the presence of diabetes mellitus were recorded prospectively. Remission status was assessed at the long-term visit (IGF-I ≤ 1.3 x ULN). Comparison between time points was performed using paired t-test or Mann-Whitney U test depending on distribution, and chi-square test for categorical variables. Differences in the temporal course were evaluated by mixed model analyses, adjusted for age. Results: VAT and A/G ratio increased at both time points, whereas SAT and TAT mainly increased at short-term, plateauing afterwards (p < 0.05 for all). VAT and A/G ratio were higher in men (p = 0.035 and p < 0.001), and the A/G ratio increased more compared to women (p = 0.003). BMI remained stable. Glucose and HbA1c decreased at short-term (p < 0.05) and remained stable at long-term, with no obvious sex differences. The gonadal status had no effect on the increase in AT in women. The increase in VAT (p = 0.046), but not SAT, TAT or A/G ratio, was more pronounced in patients with diabetes mellitus. The increase in AT strongly correlated with the decrease in GH (SAT (R = -0.48), TAT (R = -0.51), p < 0.001 for both) and IGF-I (VAT (R = -0.28, p = 0.036), SAT (R = -0.27, p = 0.046), TAT (R = -0.26, p = 0.048) at long-term. The decrease in glucose correlated with the decrease in HbA1c (R = 0.38, p = 0.009) and IGF-I (R = 0.32, p = 0.014) at long-term. Remission status had no effect on changes in AT mass during follow-up. Conclusion: Treatment of acromegaly leads to an increase in AT mass in a depot and sex specific manner both at short-term and long-term follow-up. Glucose metabolism improves rapidly after disease control and persists, whereas patients with diabetes mellitus have a higher VAT increase that may worsen their long-term metabolic outcome.

Presentation: Thursday, June 15, 2023
SAT667 Follicle-Stimulating Hormone Does Not Directly Regulate Adipogenesis Via The FSH Receptor In Mice
Authors: Loka Mary , Gambino Luisina Ongaro , Uliasz Tracy , Jaffe Laurinda A , Kazak Lawrence , Bernard Daniel J
Published: October 2023

Disclosure: M. Loka: None. L. Ongaro Gambino: None. T. Uliasz: None. L.A. Jaffe: None. L. Kazak: None. D.J. Bernard: None.

Rising rates of obesity are a serious public health challenge. Post-menopausal women are at higher risk of developing obesity and associated comorbidities than premenopausal women, with hormonal changes, such as reduced estrogens, likely to be contributing factors. Menopause is also characterized by increases in pituitary-derived follicle-stimulating hormone (FSH). Recent data suggest that FSH may directly stimulate adipogenesis and block thermogenesis in adipocytes. FSH reportedly decreased expression of thermogenic genes (Cox8b and Ucp1) in murine 3T3-L1 cells differentiated into adipocytes. FSH’s inhibitory effects were no longer apparent in the presence of an FSH-neutralizing antibody. The same FSH antibody reduced fat mass and increased lean mass in ovariectomized (OVX) female mice, a rodent model of menopause. In these studies, it was not established whether FSH acted directly through its canonical receptor (FSHR) in adipocytes to mediate its effects. To address this gap, we differentiated 3T3-L1 cells to adipocytes and treated with FSH. In contrast to the earlier report, FSH did not alter the expression of markers of lipogenesis (Cebpa and Pparg2) or thermogenesis (Cox8b and Ucp1) nor did it impact mitochondrial respiration or lipid accumulation. We also did not detect Fshr mRNA in these cells. We next differentiated the stromal vascular fraction from inguinal adipose tissue of adult male mice into white adipocytes. After 10 days of differentiation, FSH treatment did not alter expression of several markers of adipogenesis and did not affect lipid accumulation. To assess FSH actions in vivo, we generated adipocyte-specific Fshr knockout mice (Fshrfx/fx;Adipoq-Cre, hereafter cKO). Ten-week-old cKO and control female mice were OVX and maintained on standard chow. Eight to 10 weeks later, we performed glucose tolerance and insulin tolerance tests, and determined body composition by EchoMRI. Cre-mediated recombination of the floxed Fshr locus in adipocytes was successful, but did not alter body weight, fat or lean mass, or glucose metabolism in cKO relative to control OVX mice. Furthermore, using a newly developed FSHR-3xHA knockin mouse model, we detected FSHR protein expression in ovary, but not in inguinal and perigonadal white adipose depots or in intrascapular brown adipose tissue. We similarly failed to detect Fshr mRNA in various fat depots in control mice. Collectively, our results fail to show FSH effects on adipogenesis in vitro and challenge the hypothesis that FSH acts through the classical FSHR in adipocytes in vivo.

Presentation: Saturday, June 17, 2023
THU083 Disulfiram Mediated Anti-tumor Effect In Pituitary Neuroendocrine Tumors By Inducing Cuproptosis
Authors: Huang Ning , Zhang Yong , Liu Yan Ting , Feng Yao , Xue Li , Wu Zhe Bao
Published: October 2023

Disclosure: N. Huang: None. Y. Zhang: None. Y. Liu: None. Y. Feng: None. L. Xue: None. Z. Wu: None.

Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors. Dopamine agonists and somatostatin analogues are the first-line drugs for PRL and GH-secreting PitNETs clinically. However, there is no effective drug for other subtypes and drug-resistant PitNETs. Thus, it’s impending to discover new therapeutic targets and medicine. Cuproptosis is a copper-dependent form of cell death driven by lipoylated protein aggregation, loss of Fe-S cluster-containing proteins, and induction of HSP70. However, the role of cuproptosis in PitNETs is not clear. In this study, a total of 17 primary samples of PitNETs were collected to perform high-throughput drug screening, an anti-abuse drug disulfiram (DSF) was identified that can induce cell death effectively. We found that disulfiram also has a strong inhibitory effect on pituitary tumor cell lines MMQ, Att20 and GH3 (-87.1%, -62.5%, -92.7%, p<0.001), but the inhibitory effect was eliminated by copper chelator TTM/BCS. This indicated that DSF played the anti-tumor effect requiring the participation of copper ions. To explore the underlying mechanism that DSF induces the cell death of PitNETs, we detected the hallmark of cuproptosis and found that DSF leads to a decrease in the acylation level of proteins related to the tricarboxylic acid cycle, limiting the function of the protein. On the one hand, DSF leads to the downregulation of iron-sulfur cluster-associated proteins, and the oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), which is eventually accompanied by an increase in the protein level of heat shock protein 70 (HSP70) at protein and mRNA level, causing proteotoxic stress leading to cell death. Finally, DSF treatment inhibited the tumor growth in MMQ cell transplanted mouse model and destructed the morphology of the pituitary tumor 3D sphere similarly demonstrating the inhibition effect. In conclusion, we find that the anti-abuse drug disulfiram can induce coproptosis in pituitary tumor cells in a copper-dependent manner and is a potential drug for the treatment of PitNETs.

Presentation: Thursday, June 15, 2023
THU096 When TSH Alone Is Not Enough
Authors: Awasty Sanjana S , Ghalib Luma
Published: October 2023

Disclosure: S.S. Awasty: None. L. Ghalib: None.

Background: A Thyrotropinoma or TSHoma is the rarest of all pituitary adenomas approximately 1-2%. TSHomas are often only found due to symptoms from co-secreting tumors with TSHomas or routine laboratory testing. Misinterpretation of laboratory values can cause misdiagnosis and inappropriate treatment. Clinical Case: A 45-year-old female presented to her primary care physician for a routine appointment. The patient reported concerns regarding weight and a TSH was ordered, TSH 7.00 uIU/mL (0.49 - 4.67) with no other thyroid function values. The physician prescribed levothyroxine 50mcg treating for primary hypothyroidism and over the next 37 months the patient was prescribed increasing doses of levothyroxine based on TSH values. This patient was eventually referred to Endocrinology. At the initial Endocrinology visit TSH 7.59 uIU/mL (0.27 - 4.2 uIU/mL) and fT4 3.2 ng/dL (0.7 - 1.7) on levothyroxine 125mcg. Levothyroxine was discontinued and labs were repeated 6 weeks later TSH 5.9 uIU/mL (0.27 - 4.2), fT4 4.8 ng/dL (0.7 - 1.7), fT3 2.1 pg/mL (2 - 4.4), and alpha-subunit 1.5ng/mL (<=1.2 premenopausal female, <=1.8 postmenopausal female). A pituitary macroadenoma was discovered on MRI. The patient was referred to Pituitary Clinic and noted to have a prolactin of 53.8 ng/mL (non-pregnant females 2.8-29.2) and IGF-1 291.6 ng/mL (60.0 - 240.0). The patient underwent transsphenoidal pituitary surgery; pathology reported a plurihormonal subtype pituitary adenoma which stained positive for Prolactin, HGH, and TSH. One week after removal of the TSHoma, TSH 0.014 uIU/mL (0.550 - 4.780) fT4 0.65 ng/dL (0.89 - 1.76), and levothyroxine replacement was initiated with plans for continued outpatient monitoring to assess need for levothyroxine replacement. Conclusion: This case primarily demonstrates the importance of evaluating TSH levels in conjunction with free T4 levels to effectively interpret central versus primary causes of thyroid dysfunction. The high molar ratio of the alpha-subunit to the TSH level lends itself to a TSHoma differentiating it from a diagnosis of syndrome of resistance to thyroid hormone. While rare missing a TSHoma diagnosis could have devastating consequences. Checking other pituitary hormones pre-operatively even without symptoms also gave the indication that this was a co-secreting tumor. After adenoma removal rechecking pituitary hormones is of great importance as exemplified by pituitary-thyroid axis suppression noted post-operatively in this case.

Presentation: Thursday, June 15, 2023
THU102 A Case Of Papillary Craniopharyngioma WHO Grade 1 Turned Into Abscess
Authors: Shah Rutu Jatin , Patel Janki , Belany Paul A
Published: October 2023

Disclosure: R.J. Shah: None. J. Patel: None. P.A. Belany: None.

Craniopharyngioma is a rare primary brain tumor located in the suprasellar region. Papillary craniopharyngiomas (PC) occur mostly in adults, between age 40-50. Despite surgery being the primary treatment, PCs have a high tendency for relapse. We present a case of PC WHO grade 1, positive for BRAF V600E mutation concerning for regrowth 10 months following surgical resection. A 45-year-old male presented to the emergency department with complaint of right orbital headaches, vision change and severe fatigue. CT head was normal and was discharged home. Headaches, fatigue, and vision change progressively worsened over the next week with new symptoms of erectile dysfunction, low libido, weight loss, polyuria, polydipsia and proximal muscle weakness developing. Morning labs showed FT4 0.5ng/dl, TSH 2.32uIU, cortisol 1.5ug/dl, ACTH 14 pg/mL, FSH 1.5mIU/mL, LH 0.2mIU/mL, total testosterone 6ng/dl, prolactin 17.5ng/mL, IGF-1 134 ng/mL and GH 0.2ng/dl concerning for panhypopituitarism. Chemistry panel was unremarkable. MRI pituitary confirmed sellar mass measuring 2.1x1.3x2.1cm compressing the optic chiasm. Evaluated by endocrinology, patient was started on hydrocortisone, levothyroxine and desmopressin and referred to neurosurgery. Following endoscopic endonasal approach (EEA), pathology showed PC WHO Grade 1 and molecular testing positive for BRAF V600E mutation. Two-month post-surgical MRI showed residual 8mm lesion. Active surveillance showed regrowth of sellar lesion to 1.8 cm with optic chiasm compression ten months following EEA. Repeat EEA was done with concern for relapse. Surprisingly, intraoperative purulent fluid draining from the sella was found and positive for Acinetobacter. Sellar abscess was drained and he received six weeks of intravenous antibiotics. Repeat MRI showed resolution of the entire sellar lesion, his vision normalized and continued to be on hormone replacement for panhypopituitarism. PCs are locally aggressive suprasellar lesions that can reach a large size prior to clinical symptoms developing. Around 90% of PC are positive for BRAF V600 mutation. Surgical resection and radiotherapy are the primary treatment, but newer studies have demonstrated tumor regression using BRAF targeted agents following relapse. Our case demonstrates a pituitary abscess (PA) found intraoperatively that was originally suspicious for tumor recurrence. PA is a rare and serious intrasellar infection associated with high mortality. It is difficult to diagnose preoperatively and can be misdiagnosed as recurrence or residual tissue. PA can be primary or secondary depending on etiology. PA associated with residual craniopharyngioma tissue is extremely rare and the exact pathophysiology is not well understood. If no evidence of sepsis or meningitis, treatment with transsphenoidal decompression and intravenous antibiotics has good clinical outcomes.

Presentation: Thursday, June 15, 2023
THU106 Malignant Epithelioid Neoplasm As The Cause Of A Rapidly Growing Pituitary Mass
Authors: Riahi Shayan , Chaidarun Sushela S
Published: October 2023

Disclosure: S. Riahi: None. S.S. Chaidarun: None.

Background: Malignant epithelioid neoplasm is a rare cause of a pituitary mass, and should be kept on the differential whenever evaluating patients with evidence of rapid pituitary enlargement. Clinical Case: A 43 year-old man presents with 3-month history of worsening severe headaches, decreased libido, erectile dysfunction, polydipsia, polyuria (6L/day) with nocturia every hour, and fatigue. He also noted some blurry vision without loss of his peripheral vision. MRI of the brain showed a 1.5cm mass in the sellar and suprasellar region abutting the optic chiasm. Of note, he had a brain MRI performed 18 months prior for vertigo which did not demonstrate any mass in the pituitary. He presented to the endocrinology office for evaluation. His laboratory tests demonstrated mildly elevated prolactin 31.2 ng/mL (n 4.0-15.2), and findings consistent with panhypopituitarism and central diabetes insipidus, including low FT4 of 0.46 ng/dL (n 0.93-1.70), FSH 0.7 mIU/mL (n 1.5-12.4), an undetectable LH (n 1.7-8.6mIU/mL), random cortisol of 1mcg/dL (n 4.8-19.5) ACTH 6.2 pg/mL (n 7.2-63), IGF-1 of 139 ng/mL (n 44-275), total testosterone undetectable (n 240-950 ng/dL), sodium 144mmol/L (n 135-145) with low urine specific gravity 1.008 and urine osmolality of 143mOsm/Kg (n 60-1200). HCG was undetectable (n 0-2mIU/mL) but LDH was elevated at 313 unit/L (n 110-220). He was started on corticosteroids, levothyroxine, DDAVP, and referred to neurosurgery. Specimens from his transphenoidal biopsy demonstrated findings consistent with a malignant epithelioid neoplasm. Further analysis and genetic testing is still pending. He has been referred to oncology service for further management and care. Conclusion: A rapidly growing symptomatic pituitary mass with central diabetes insipidus should raise suspicion for malignant etiology beyond the more prevalent pituitary adenoma. Malignant epithelioid neoplasm are uncommon tumors of the brain, however they are known to be aggressive tumors with high mortality. Treatment commonly includes some combination of surgery, radiotherapy, and chemotherapy1.

Reference: (1) Jog AP, Ronderos DM, Ali A, Niazi M, Diaz-Fuentes G. Malignant Epithelioid Neoplasm of the Brain. Cureus. 2020 Aug 27;12(8):e10079. doi: 10.7759/cureus.10079. PMID: 33005505; PMCID: PMC7523542.

Presentation: Thursday, June 15, 2023
THU107 A Case Of Primary Histiocytic Sarcoma Of Pituitary Gland Presenting With Central Diabetes Insipidus
Authors: Ahn Seong Hee , Kim Youngjoon , Cho Yongin , Seo Da Hea , Kim So Hun , Cho Jinhyun , Choi Suk Jin , Kim Kyung Min , Kim Eun-Young , Hong Seongbin
Published: October 2023

Disclosure: S. Ahn: None. Y. Kim: None. Y. Cho: None. D. Seo: None. S. Kim: None. J. Cho: None. S. Choi: None. K. Kim: None. E. Kim: None. S. Hong: None.

Introduction: Histiocytic sarcoma is a rare and aggressive hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. Here, we reported the first case of primary histiocytic sarcoma involving pituitary gland. Methods: Medical records were reviewed. Results: A 53 years old Korean men presented with general weakness, polydipsia, polyuria, and abnormal thyroid function test suspicious for secondary hypothyroidism. Laboratory examinations showed growth hormone deficiency, hypogonadotropic hypogonadism, and central diabetes insipidus. The magnetic resonance imaging showed a well-enhanced mass involving entire posterior pituitary gland with stalk thickening. The biopsy of pituitary mass was identified as a malignant tumor consistent with histiocytic sarcoma. This malignant tumor inoperably increased within a short duration and hormone deficiency such as secondary hypothyroidism and adrenal insufficiency additionally developed. Therefore, the patient started radiation therapy with desmopressin, levothyroxine, and hydrocortisone replacement. Conclusion: The biopsy is not regarded as the mandatory procedure for diagnosing patients with central diabetes insipidus with posterior pituitary lesion since in many cases, this is the result of hypophysitis. However, since there is still the possibility of primary malignancy and metastasis involving pituitary gland, an appropriate decision for performing biopsy should be made according to the patient’s clinical situations.

Presentation: Thursday, June 15, 2023
THU113 Psychopathological Characteristics In Patients With Arginine Vasopressin Deficiency (Central Diabetes Insipidus) And Primary Polydipsia
Authors: Beck Julia , Atila Cihan , Refardt Julie , Erlic Zoran , Drummond Juliana Beaudette , Soares Beatriz Santana , Beuschlein Felix , Winzeler Bettina Felicitas , Christ-Crain Mirjam
Published: October 2023

Disclosure: J. Beck: None. C. Atila: None. J. Refardt: None. Z. Erlic: None. J.B. Drummond: None. B.S. Soares: None. F. Beuschlein: None. B.F. Winzeler: None. M. Christ-Crain: None.

Introduction The differential diagnosis between arginine vasopressin deficiency (AVP-D), formally known as central diabetes insipidus, and primary polydipsia (PP) is challenging. In clinical routine, psychopathologic findings are often used as a hallmark for diagnosing PP; thus, it is often referred to as psychogenic polydipsia. Yet, psychopathologic characteristics are barely assessed in patients with AVP-D, and to date, no data exist comparing AVP-D and PP with regard to these features. Therefore, in this study, we aimed to compare levels of anxiety, depression, alexithymia, and overall mental health in patients with AVP-D and PP. Methods This study combined data from two diagnostic studies conducted at three tertiary medical centers. In total, 82 participants (n=39 with AVP-D, n=28 with PP, and n=15 healthy controls [HC]) underwent a psychological evaluation with standardized questionnaires at study inclusion. Anxiety levels were assessed using the State-Trait Anxiety Inventory, mood using the Beck’s Depression Inventory, alexithymia using the Toronto Alexithymia Scale, and overall physical and mental health using the Short Form 36 Health Survey (SF-36). Higher STAI, BDI, and TAS scores indicate higher anxiety, depression, and alexithymia levels. Higher SF-36 scores indicate better health and less disability. Results Compared with HC, patients with AVP-D and PP showed increased levels of anxiety (HC 28 points [24, 31] vs. AVP-D 36 points [31, 45], p<0.01; vs. PP 38 points [33, 46], p<0.01), depression (HC one point [0, 2] vs. AVP-D 7 points [4, 14], p<0.01; vs. PP 7 points [3, 13], p<0.01), and alexithymia (HC 30 points [29, 37] vs. AVP-D 43 points [35, 54], p<0.01; vs. PP 46 points [37, 55], p<0.01). Levels of anxiety, depression, and alexithymia showed no difference between patients with AVP-D and PP (p=0.58, p=0.90, p=0.50). Compared with HC, patients with AVP-D and PP reported comparable reduced self-reported mental health scores (HC 84 [68, 88] vs. AVP-D 60 [52, 80], p=0.05; vs PP 60 [47, 74], p<0.01). Conclusion This is the first study demonstrating comparable increased levels of anxiety, depression, alexithymia, and overall reduced mental health in patients with AVP-D and PP. Based on these data, psychopathological findings should not be used as a hallmark to differentiate between both conditions.

Presentation: Thursday, June 15, 2023
THU118 Prefrontal-Medullary Circuit Is Necessary For Chronic Stress-Induced Neuroendocrine And Behavioral Outcomes
Authors: Pace Sebastian A , Lukinic Ema , Barrette Paige , Wallace Tyler , Myers Brent
Published: October 2023

Disclosure: S.A. Pace: None. E. Lukinic: None. P. Barrette: None. T. Wallace: None. B. Myers: None.

Chronic stress exposure is a major risk factor for psychiatric and cardiometabolic diseases. Although the pathologies associated with chronic stress are well-documented, the biological mechanisms underlying these physiological changes remain unknown. Human imaging studies indicate the prefrontal cortex is a key site for processing stress-related information. Within the rat prefrontal cortex, the infralimbic area (IL) is critical for regulating physiological stress reactivity in a sex-specific fashion. Here we examined the necessity of an IL downstream circuit for neurogenic regulation of neuroendocrine susceptibility after chronic stress. We focused on an IL to rostral ventrolateral medulla (RVLM) circuit due to the ability of the RVLM to initiate the sympatho-adrenomedullary stress responses and influence HPA axis activity. Critically, the IL-RVLM circuit is structurally positioned to underlie a crucial link between stress appraisal and sympathetic reactivity. To determine the role of the IL-RVLM circuit during chronic stress, an intersectional viral strategy was used to express a light-chain variant of Tetanus Toxin (TeLC) in RVLM-projecting IL neurons, thereby disrupting IL-RVLM signaling. TeLC-expressing IL neurons had less synaptobrevin-2 protein located on terminals and fewer synaptic appositions in the RVLM. This chronic circuit disruption approach was evaluated in the context of a 2-week chronic variable stress (CVS) paradigm in male and female rats. In males, CVS-exposed TeLC rats displayed decreased corticosterone levels in response to a novel stressor compared to control rats. CVS-naïve males showed no significant changes. In females, we similarly observed no differences in unstressed rats. However, CVS TeLC female rats had increased glycemic and corticosterone stress responses compared to CVS control animals. Additionally, female CVS TeLC rats had increased behavioral avoidance indicated by less time spent in the center of an open field arena compared to CVS control rats. This behavioral effect was not present in males. These results suggest that the IL-RVLM circuit is essential for preventing chronic stress outcomes in female rats, but not males. Further, this circuit regulation is necessary only after chronic stress exposure. Future studies will be aimed at determining sex differences in chronic stress effects on IL-RVLM signaling.

Presentation: Thursday, June 15, 2023
THU119 Screening Publicly Available Data To Identify Candidate Genes For Congenital Hypopituitarism
Authors: Brinkmeier Michelle L , Martínez Mayer Julián Jorge , Ellsworth Buffy Sue , Raetzman Lori Therese , Cheung Leonard , Perez-Millan Maria Ines , Camper Sally Ann , Davis Shannon William
Published: October 2023

Disclosure: M.L. Brinkmeier: None. J.J. Martínez Mayer: None. B.S. Ellsworth: None. L.T. Raetzman: None. L. Cheung: None. M.I. Perez-Millan: None. S.A. Camper: None. S.W. Davis: None.

Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia and holoprosencephaly, are midline defects that cause significant morbidity for affected people. Variants in 44 genes are associated with CH, but most cases of CH are caused by unknown variants. Whole exome (WES) and whole genome sequencing (WGS) of CH patient DNA identifies variants in genes known to cause CH and variants of uncertain significance (VUS) in genes that are not currently associated with CH. The functional significance of VUS in CH candidate genes can be established using mouse models. Many of the human CH genes were first discovered in mice, and in most cases the mouse phenotype was an excellent predictor of the human phenotype. The International Mouse Phenotyping Consortium (IMPC) is an invaluable resource of phenotyping data generated by the international effort to determine function of all protein coding genes in the mouse genome through targeted disruption. Using the mouse phenotyping data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to characterize targeted alleles that cause embryonic lethality or subviability, we have identified 51 genes that cause embryonic pituitary malformations. The malformations range in severity and include absent adenohypophysis, absent neurohypophysis, hypoplasia, and hyperplasia. Using the GenePaint RNA in situ hybridization data for mouse embryos and single cell RNA sequencing (scRNAseq) data from e14.5 dissected pituitary glands, we confirmed expression for all candidate genes in the tissues that contribute to the developing pituitary gland. Using gene ontology (GO) terms associated with these 51 genes, we identified molecular pathways not previously associated with pituitary gland organogenesis, including cilia formation, amino acid metabolism, and epigenetic regulation. We present here the candidate gene list, scRNAseq expression data, GO term analysis, select images from GenePaint, and select images of the observed malformations. These genes associated with mouse pituitary malformations significantly expand the list of candidate genes for screening in WES and WGS in human cases of CH.

Presentation: Thursday, June 15, 2023
SAT672 Dulaglutide Might Reduce Visceral Fat In Patients With Metabolic Syndrome
Authors: Kim Yu Na
Published: October 2023

Disclosure: Y. Kim: None.

Liraglutide was shown to reduce visceral fat irrespective of T2DM status. However, due to cost and insurance coverage, dulaglutide has been prescribed more often than liraglutide in the clinical setting. This retrospective study aimed to evaluate the effect of dulaglutide on visceral fat among patients with metabolic syndrome. We reviewed medical records of patients aged ≥ 50 with metabolic syndrome and seen at a frailty clinic, where we measured body and visceral fat and BMI by bioelectrical impedance analysis and assessed frailty. One hundred ninety-six patients (average age 69.9, men 100, women 96) were seen from 12/1/2021 to 11/30/2022, and 53 patients were excluded due to missing data. Among 143 patients, five were taking dulaglutide when seen at the frailty clinic. We constructed a control group using matching sampling, but one patient was excluded because the matching pair was unavailable. We compared data between patients taking dulaglutide(study group) and the matched control group using a paired sample t-test. The % visceral fat of the dulaglutide group was lower than the control group (dulaglutide mean 10.75, control mean 11, P= 0.39). Three patients in the study group had the same % visceral fat as their paired control, and 2 out of 4 patients gained weight after starting dulaglutide. In this study, our study group was found to have lower % visceral fat on average than their paired control, although two patients gained weight. Given the small sample size, further studies with larger cohorts are needed to investigate this further.

Presentation: Saturday, June 17, 2023
THU126 SARS-CoV-2 Infection And Vaccination In Patients With Pituitary Diseases: A Pilot Study
Authors: da Silva Marcela Cunha , Del Corso Leticia Marinho , Boguszewski Cesar Luiz
Published: October 2023

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
FRI282 Sexually Dimorphic Responses Of Kisspeptin Expression To Neonatal Exposure To Estrogen In Rats
Authors: Marzbanabbasabadi Behrokh , Lin PoChing , Park ChanJin , Ko Chemyong
Published: October 2023

Disclosure: B. Marzbanabbasabadi: None. P. Lin: None. C. Park: None. C. Ko: None.

Kisspeptin neurons (Kiss1 neurons) are located mainly in anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) of hypothalamus and play a key role as regulators of GnRH secretion in all mammalian species. In both females and males, ARC contains more Kiss1 neurons than AVPV. Importantly, unlike ARC, AVPV displays sexual dimorphism; female AVPV contains significantly more Kiss1 neurons than males’. Recent studies showed that neonatal exposure to estrogen decreased Kiss1 expression in the hypothalamus, impacting fertility, in both sexes. However, whether such impact was driven by decreased number of Kiss1 neurons or expression of Kiss1 gene is not known. In this study, we tested our hypothesis that neonatal estrogen exposure decreases both the number of Kiss1 neurons and the Kiss1 gene expression in AVPV, in a gender-dependent manner. This hypothesis was tested in rats by treating them with estradiol benzoate (EB, a prodrug that is converted to estradiol) and measuring the effect by counting the number of Kiss1 neurons (Kiss1 mRNA expressing cells) and comparing Kiss1 mRNA expression levels between EB-exposed and control hypothalami. Male and female rat pups were injected, on postnatal day 1, subcutaneously with 0.3 mg EB via microsphere that was designed to release EB for 2 weeks; unexposed age matching pups were used as controls (n=6-7/group). Male rats were euthanized at 2.5 months of age and their entire brains were collected. Female brains were also sampled at 2.5 months of age, but after synchronizing their estrous cycle by injecting them with PMSG and hCG following an established superovulation protocol. The brains were serially sectioned and the sections from AVPV and caudal region of ARC where Kiss1 neurons most highly populated were identified and used for localizing Kiss1 neurons and quantitating Kiss1 mRNA expression level, using RNAscope. Results showed that in the AVPV, EB-exposed rats had less Kiss1 neurons both in males (8.7±1.9 vs. 42.2±7.9 Kiss1 neurons/section in control, p=0.02) and females (26.0±5.65 vs. 141.6±15.8 Kiss1 neurons/section in control, p=0.03) and showed lower Kiss1 mRNA expression in males (0.33 folds, p=0.03) and in females (0.44 folds, p=0.04) as well. In the ARC, EB-exposed rats had less Kiss1 neurons in females (27.5±4.3 vs. 56.0±2.4/section in control, p=0.00), but had same number in males (31.7±2.3 vs. 42.8±7.6 kiss1 neurons/section in control, p=0.22). EB exposure increased Kiss1 mRNA expression in both males (2.39 folds, p=0.00) and females (1.55 folds, p=0.05). In conclusion, this study showed that neonatal exposure to estrogen alters the number of Kiss1 neurons and Kiss1 mRNA expression in AVPV in a gender-dependent manner. In addition, neonatal estrogen exposure also alters Kiss1 neuron numbers and Kiss1 gene expression in the ARC as well.

Presentation: Friday, June 16, 2023
FRI283 Fragile X Gene Mutations Alter GnRH Neuron And Ovarian Innervation With Consequences On Reproductive Function
Authors: Villa Pedro A , Lainez Nancy , Jonak Carrie R , Berlin Sarah , Ethell Iryna , Coss Djurdjica
Published: October 2023

Disclosure: P.A. Villa: None. N. Lainez: None. C.R. Jonak: None. S. Berlin: None. I. Ethell: None. D. Coss: None.

Mutations in the Fragile X messenger ribonucleoprotein 1 gene (FMR1) cause Fragile X syndrome, the most common cause of inherited mental disability, attributed to the loss of the Fragile X messenger ribonucleoprotein (FMRP). FMR1 mutations also comprise a majority of the genetic causes of premature ovarian failure (POF) in women, mechanisms of which are unknown. We utilized the Fmr1KO mouse model to determine the role of the FMR1 gene in the reproductive system in females. Similarly to what occurs in women harboring the mutation, our data demonstrate that Fmr1KO female mice experienced premature reproductive senescence, where reproductive function stopped at p163; in contrast, wild type controls stopped reproducing at p263. Since POF in women can occur due to either an insufficient pool of primordial follicles or early depletion of follicles, we quantified primordial follicles in 3 week old females and determined there was no difference between KO and controls. We then determined that Fmr1KO females had a higher number of corpora lutea at 8 weeks of age and gave birth to larger litters, suggesting that KO females recruit more follicles in each estrus cycle. Given that follicle stimulating hormone (FSH) and luteinizing hormone (LH) are essential in ovarian function, we analyzed gonadotropin levels in Fmr1KO females and determined they have higher serum LH and FSH. Inhibin b, progesterone, and testosterone levels were also higher, suggesting that high gonadotropins do not result from the lack of feedback. Ovariectomy determined that the hypothalamus drives high LH in KO females, while increased FSH is dependent on the ovaries. Increased vasculature in the corpora lutea and higher sympathetic innervation of developing follicles may increase steroid hormone production and drive increased serum FSH levels. To investigate the hypothalamic role in increased LH, we determined that a majority of gonadotropin-releasing hormone (GnRH) neurons express FMRP, which also have a higher number of GABAergic synapses in Fmr1KO females. Given that GABA is excitatory to GnRH neurons, alterations in afferent synaptic input can affect GnRH and LH secretion. LH pulsatile analysis determined higher LH pulse frequency in both unmodified and ovariectomized females, indicating an increase in GnRH neuron activity. In summary, our results reveal hypothalamic and ovarian contributions to the reproductive phenotype of Fragile X mutation carriers that may lead to early menopause.

Presentation: Friday, June 16, 2023