bluuebunny/crossref_metadata_2025 huggingface dataset:
6579 Neuroendocrine Signatures of Social-Defeated Stress Expressed by Adrenal Hormones in Mice
Authors: Noh Jongsung , Choi Jeongyoon , Myung Seung-Woon , Kim Min Soo , Choi Man-Ho
Published: October 2024

Disclosure: J. Noh: None. J. Choi: None. S. Myung: None. M. Kim: None. M. Choi: None.

While psychological stress is one of the prevalent contributors to depression, the precise role of metabolic phenotypes in the development of depression remains elusive. Abnormality in hypothalamus-pituitary-adrenal (HPA) axis is a classical feature of depression. Here, an animal model of social defeat stress (SDS) was established with five-week-old C57BL/6J mice to repeated episodes of social defeat for a period of 10 days, facilitated by an aggressive CD-1 mouse. Liquid chromatography-mass spectrometry-based profiling of 29 adrenocortical steroids and 6 medullary amines was employed for serum samples collected at 3, 5, 7, and 10 days during the modeling from both control (n = 28) and SDS (n = 32) group. In response to initial stress, corticosterone (B) and its two precursors were significantly increased (p < 0.03 for all) during 3 days, while 18-hydroxyB was remarkably elevated (p < 0.003 for 3 days and p < 0.005) in SDS mice. In contrast, dopamine (p < 0.03) and metanephrine (p < 0.008) were significantly increased during 5 days in SDS mice, while remarkably higher levels of norepinephrine were also observed during 7 days (p < 0.01). The SDS mice showed the increased levels of normetanephrine for all days of repeated stress exposure (p < 0.002 for all, except 10 days of p < 0.02). In this study, the HPA regulated negative feedback in short period, whereas sympathetic nervous system was continuously stimulated during repeated stress exposure. The present study may provide insight into the neuroendocrine effects of social stress on allostatic overload.

Presentation: 6/2/2024
12583 Nutrient Intake And Physical Performance In Patients With Acromegaly
Authors: Hupalowski Natália N , Rocha Claudia P S , Fidalski Solena Z K , Boguszewski Cesar Luiz , Borba Victoria Z C
Published: October 2024

Disclosure: N.N. Hupalowski: None. C.P. Rocha: None. S.Z. Fidalski: None. C.L. Boguszewski: Consulting Fee; Self; Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Novo Nordisk. V.Z. Borba: None.

Acromegaly is a chronic disease characterized by increased levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). These patients exhibit increased skeletal muscle mass but poorer performance in functional physical assessments. Certain nutrients are important for both muscle mass and strength, as well as for maintaining an anti-inflammatory state in the body. Objective: To assess the correlation between nutrient intake and physical performance in patients with acromegaly. Patients and Methods: An observational, cross-sectional study of patients with acromegaly matched 1:1 by sex and age with a control group. Patients underwent analysis of dietary patterns using the validated Food Frequency Questionnaire (FFQ), and physical performance and strength were measured using Hand Grip Strength (HGS), 5 Times Seat to Stand Test (STST), Time Up and Go (TUG), and Short Physical Performance Battery (SPPB) tests. Results: It was evaluated 47 patients (54.1% women; mean age 56.3 ± 11.6 years), which were compared with 36 controls (53.9% women; mean age 56.7 ± 13.4). There was no difference between groups in HGS evaluation. The performance of patients with acromegaly were poorer in the STST, SPPB and TUG. Better performance was associated with selenium (p=0.045), vitamin E (p=0.034), flavonol (p=0.02) and vitamin A (0.024) intake. Conclusion: Physical performance is compromised in patients with acromegaly, especially in lower limbs, and it was associated with lower consumption of selenium, vitamin E, flavonol and vitamin A.

Presentation: 6/2/2024
7427 Cellular Senescence As A Pro-Tumorigenic Process And Therapeutic Target In Adrenocortical Carcinoma
Authors: Smith Lorenzo , Warde Kate , Haston Scott , Martinez-Barbera Juan Pedro , Basham Kaitlin
Published: October 2024

Disclosure: L. Smith: None. K. Warde: None. S. Haston: None. J. Martinez-Barbera: None. K. Basham: None.

Adrenocortical carcinoma (ACC) is a rare, yet highly aggressive malignancy that arises in the adrenal cortex. Advanced age is a major risk factor for ACC, with the peak age incidence between 50 and 60 years old. Older individuals above age 50 also have significantly worse survival outcomes. A better understanding of how aging contributes to the development and progression of ACC will uncover new treatment strategies. A major hallmark of aging is the systemic accumulation of senescent cells. While senescent cells have been implicated in various age-related diseases, including cancer, their role in ACC remains poorly understood. ACC tumors from older patients have an enrichment of senescence-associated gene signatures. Moreover, advanced ACC patients are treated with etoposide, doxorubicin, and cisplatin (EDP), which are chemotherapies that induce senescence. While EDP offers short-term benefit in some patients, more than half will progress within 6-months. We hypothesize that the accumulation of senescent cells that arise after EDP treatment are ultimately tumor-supportive long-term. As a result, we postulate that the use of senolytic compounds that clear away senescent cells after EDP treatment will lead to improved survival outcomes for ACC patients. We developed a new ACC mouse model that provides a window to study the role of senescence in ACC tumor progression and treatment. Our model is based on adrenal specific loss of ZNRF3, which is a Wnt inhibitor that is frequently inactivated in human ACC tumors. Despite early adrenal hyperplasia, we showed that Znrf3 conditional knockout (cKO) mice do not develop adrenal tumors until 18-months of age, which corresponds to the peak age incidence in humans. Additionally, the adrenals of Znrf3 cKO mice show a robust senescence activation phenotype that precedes adrenal tumorigenesis. We hypothesize that the accumulation of senescent cells is pro-tumorigenic long-term. To test our hypothesis, we combined Znrf3 cKO mice with a newly established mouse model that enables selective ablation of senescent cells (ZKO-FDR mice). Ongoing aging studies will determine whether the removal of early and late senescent cells in ZKO-FDR mice reduces adrenal tumorigenesis. Further, we established new primary tumor cell lines from aged ZKO-FDR mice. These cell lines will facilitate testing of the pro-tumor mechanisms of senescence. Additionally, they will permit the removal of senescent cells, both genetically and pharmacologically with senolytics, as a new treatment strategy in ACC. Overall, this project aims to investigate the pro-tumor biology of age- and therapy-induced senescence in ACC. Results from these studies will advance our understanding of senescence in cancer and aid in the development of new therapeutic strategies for ACC, including senolytics.

Presentation: 6/2/2024
7068 Paraganglioma in Cyanotic Congenital Heart Disease
Authors: Lis Rita , Hamidi Vala
Published: October 2024

Disclosure: R. Lis: None. V. Hamidi: None.

Paragangliomas arise from the non-chromaffin cells of the parasympathetic nervous system, which are composed of glomus cells. These function as chemoreceptors in response to hypoxia. Carotid body paragangliomas have been linked to conditions with chronic hypoxia. This was first seen in residents of high altitude locations in a case report presented by Saldana et. al and regression of a paraganglioma with resolution of hypoxia was reported by Gruber et. al. There have been few additional case reports of Paraganglioma in other hypoxic states. We present a rare case of a functional Paraganglioma in a patient with Cyanotic Congenital Heart Disease (CCHD).This is a 19 year old female with a history of CCHD due to double inlet left ventricle and transposition of the great arteries. Soon after birth, she had a fontan procedure. She subsequently developed fontan associated liver disease as well as chronic kidney disease, hypertension, sinus node dysfunction, and complete heart block. Her baseline oxygen saturation was 78-85%. Her heart rate was 40-49 beats per minute with upcoming plans for pacemaker placement. Her blood pressure ranged 90/50 to 150/80 mmHg on Amlodipine 5 mg and Lisinopril 2.5 mg. She routinely received abdominal imaging to monitor her liver disease. A liver MRI incidentally revealed a retroperitoneal mass concerning for a paraganglioma. Serum Normetanephrines were found to be 26.60 nmol/L (reference range less than 0.89). 24 hr Urine Norepinephrine was 1,187 ug/d (reference range 14-20). Further imaging was negative for additional sites of disease. Given her complete heart block, she was started on alpha blockade only prior to pacemaker placement. After the pacemaker was placed, she was started on beta blockade and underwent surgical resection of her paraganglioma. The pathology confirmed paraganglioma and mutation testing was negative for germline mutations including SDH, VHL, RET, NF1 mutations. Paragangliomas in patients with CCHD have been scarcely described in the literature given the rarity of both of these conditions. However, there is a relatively increased incidence of paragangliomas in the CCHD population due to chronic hypoxia triggering the hypoxia pathway. EPAS1 mutated HIF2alpha is often found to be the culprit in these patients. In addition, case reports have often described these patients to either be asymptomatic or have potential symptoms masked by their cardiac disease. Therefore, CCHD patients are at increased risk for paragangliomas and warrant additional awareness and regular screening. Screening has been proposed to start after 10 years of hypoxia in a case review by Agarwal et. al. as paraganglioma incidence in CCHD populations has not been seen before age 11. Incidence of recurrence is not yet widely studied, but significant concern for recurrence is warranted if the etiology of hypoxia is not reversed.

Presentation: 6/3/2024
8452 Paraganglioma Masquerading as Neurological Symptoms: A Rare Case Presentation
Authors: Basnet Arjun , Sharma Sapna , Acharya Madhav , Basnet Sijan , Brenan-Rothschild Kelly , Sherpa Chheki
Published: October 2024

Disclosure: A. Basnet: None. S. Sharma: None. M. Acharya: None. S. Basnet: None. K. Brenan-Rothschild: None. C. Sherpa: None.

Introduction: Paragangliomas (PG) are rare tumors of neural crest origin. We report an unusual case of a PG wherein the patient presented to the hospital with complaints of bilateral numbness, tingling, and intermittent difficulty in grasping objects. Case presentation: A 51-year-old female with a prior history of Guillain-Barre Syndrome and hypertension presented to the hospital due to bilateral numbness, tingling, and intermittent difficulty grasping objects in her hands for four weeks. At presentation, her vitals were stable, and her physical examination was positive, only for diminished sensation in her upper extremities. Lab work, including TSH, B12/Folic Acid/ANA, was unremarkable at presentation. CT head and MRI brain were negative for acute intracranial pathology. MRI of the cervical spine showed multilevel degenerative changes (C5-6) and a 1.9 cm soft tissue mass just above the left carotid bifurcation. CTA of the neck revealed a 2.7 x 1.6 x 1.7 cm enhancing mass at the left carotid bifurcation and a contralateral 5 x 3 mm lesion at the right carotid bifurcation. EMG/NCS was performed, which did not meet the diagnostic criteria for Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP/GBS) or cervical radiculopathy. Biochemical workup with plasma metanephrine, 24-hour urine catecholamines/metanephrine/normetanephrine, and 24-hour vanillylmandelic acid was normal. She underwent resection of the left carotid body tumor. The histopathology was consistent with PG. Following the diagnosis, blood tests with PTH, calcium, and calcitonin were performed and were normal. The thyroid ultrasound did not show any thyroid nodules. The patient is scheduled to follow up with Endocrinology as an outpatient to complete genetic testing. Discussion: PG of the head and neck are rare. PG are benign in most cases, but 10% are reported to be malignant. PG may occur sporadically or as inherited familial tumors. Classic tumor syndromes associated with PG include MEN 2A and 2B, von Hippel-Lindau disease, Neurofibromatosis type 1 (NF-1), and Carney-Stratakis dyad. Most cases are non-functional, and symptoms result from mass effects. A preoperative diagnosis usually involves biochemical and radiographic (CT/MRI/PET/MIBG) testing. Biochemical evaluation with measurement of urinary and/or plasma fractionated metanephrines and catecholamines is indicated for all PG, even if clinically non-functional. The definitive diagnosis is histopathological. Treatment options include surgical resection, radiation, and stereotactic radiosurgery.

Presentation: 6/2/2024
6797 Pituitary Apoplexy as initial Presentation of IgG4-Related hypophysitis
Authors: Alameri Majid , Alnuaimi Abdulla
Published: October 2024

Disclosure: M. Alameri: None. A. Alnuaimi: None.

Introduction: IgG4-related hypophysitis is a rare disease due to IgG4 lymphoplasmacytic infiltration of the pituitary gland. It can either be isolated or part of a multisystemic disease. We report a rare case of pituitary apoplexy as first manifestation of IgG4-RD. Case report: A 27-year-old previously healthy male presented to emergency department with severe headache, nausea, vomiting and visual impairment. CT brain showed a large sellar suprasellar mass of 3cm with thick rim enhancement. Blood test showed evidence of central adrenal insufficiency, central hypothyroidism and secondary hypogonadism. Patient was started on hormone replacement therapy for central adrenal insufficiency and central hypothyroidism. Pituitary magnetic resonance imaging (MRI) demonstrated a 3.1 x 2.4 x 2.4 cm well-defined large sellar suprasellar mass with thick rim enhancement with intrinsic heterogeneous T2 signal with hypointense T1 signal on fat-suppressed post contrast imaging consistent with necrotic haemorrhagic suggestive of pituitary apoplexy and background of hypophysitis. Upward displacement of optic chiasm was noted without involvement of cavernous sinus. The patient was initially treated with high-dose steroids aiming for reduction of the pituitary mass. However, eventually, he underwent transsphenoidal surgery due to alternated level of consciousness. Pituitary histopathology showed that vast majority of the tissue is necrotic. A small fragment of viable anterior pituitary tissue is present, which measures up to 5.5 mm in greatest dimension which exhibited marked chronic inflammation, predominantly comprised of small lymphocytes. Plasma cells were present and staining with IgG/IgG4 revealed two high-power fields with clusters of approximately 25 and 50 IgG4 positive plasma cells, respectively. Blood test showed elevated blood IgG4 levels of >2.60 g/L (normal reference range 0.03-2.01 g/L). Case was discussed at Endocrine MDT meeting which agreed that blood tests result along with histopathology findings were in keeping with IgG4-Related hypophysitis as per the Mayo Clinic, Leporati and Japan-Korea proposed criteria. Because blood IgG4 levels were elevated, a systemic evaluation was performed. No evidence of other systemic disease found. High dose steroid therapy was initiated, which reduced remnant inflammatory sellar changes. Discussion and conclusion: IgG4-related pituitary disease should be considered as differential diagnosis in unusual presentations of pituitary apoplexy in the context of sellar suprasellar hypophysitis.

Presentation: 6/2/2024
7498 Pituitary Apoplexy Associated With COVID 19 Infection in a 55 Year Old Filipino Male: A Case Report
Authors: Macrohon Calvin Lontoc , Mercado Joseph Aljen Y , Gan Robert Michael Go
Published: October 2024

Disclosure: C.L. Macrohon: None. J.Y. Mercado: None. R.G. Gan: None.

Introduction: Pituitary apoplexy is a rare fatal disorder resulting from acute ischemia or hemorrhage of the pituitary gland. Major predisposing factors include patients with anti-thrombotic drugs. However, there has been an increasing number of cases reported associating COVID- 19 and pituitary apoplexy. Case: This is a case of a 55-year-old Filipino male, who came in with right eye ptosis and blurring of vision associated with headache and dizziness. Significantly, 2 weeks prior the patient had developed cough and colds. On admission, he was noted to be febrile and presented with a visual acuity of light perception on the right eye and hand movements on the left. Plain MRI of the brain revealed a well-circumscribed hemorrhagic sellar-suprasellar mass with mass effect on adjacent structures worrisome for pituitary apoplexy. Incidentally, patient tested positive for COVID- 19. Hormonal work- up revealed hypopituitarism presenting with central hypothyroidism and hypogonadism. Patient was then started on Hydrocortisone 100mg intravenously as loading dose then 50mg intravenously every 6 hours to cover for adrenal insufficiency. At this point, thyroid hormone replacement was also started at 100mcg/day. Initially, patient was scheduled for endoscopic endonasal transsphenoidal surgery. However, due to euvolemic hyponatremia with a serum sodium of 119mmol/L secondary to SIADH, surgery was delayed and was performed on the fourth day of admission. Post- operatively, patient had improvement of vision and was eventually discharged stable without any complications. He was sent home on thyroid hormone replacement and steroids were discontinued since adrenal insufficiency was ruled out with a post operative serum Cortisol of 27.27ug/dL taken 24 hours after last dose of hydrocortisone. Discussion: COVID- 19 with associated hypophysitis or pituitary apoplexy has been reported in literature. The pituitary gland was proposed as possible targets of SAR- CoV-2 due to the presence of ACE- 2 receptors on the surface of their cells. Hazzi et al. discussed that infection by COVID-19 could play a role in the disruption of the equilibrium between the high energy demand and limited blood supply of underlying adenomas. They also discussed on possible routes of entry of COVID 19 particularly thru the nasopharyngeal epithelium via olfactory nerve or pass through blood brain barrier or thru the median eminence. Other possible contributing factors may be due to coagulopathy, endothelial dysfunction and hypercoagulative state seen in COVID- 19. Conclusion: With increasing reports of pituitary apoplexy in the setting of SARS-COV-2 infection there is a possibility that COVID 19 may be a risk factor for pituitary apoplexy. Hence, the prevalence of COVID- 19 may increase risk of patients with underlying pituitary tumors to develop pituitary apoplexy.

Presentation: 6/2/2024
8188 Pituitary hyperplasia resulting from primary hypothyroidism: A case report
Authors: Aziz Mohammad , Manolas Melina Ileana , Tabatabaie Vafa , Rincon Laura
Published: October 2024

Disclosure: M. Aziz: None. M.I. Manolas: None. V. Tabatabaie: None. L. Rincon: None.

Pituitary hyperplasia resulting from primary hypothyroidism: A case report.Background: Primary hypothyroidism is a common endocrine condition seen in 4.6% of USpopulation (1). We describe an uncommon presentation of prolonged severe primaryhypothyroidism leading to significant hyperplasia of the pituitary gland resembling a pituitarymacroadenoma. Clinical Case: A 34-year male with schizophrenia and Hashimoto’s hypothyroidism diagnosedat the age of 17 presented with hallucinations, chest pain, fatigue, and dyspnea. The patient hada 15-year history of uncontrolled hypothyroidism with persistently elevated TSH with values ashigh as 2,299 (n 0.30-4.20 uU/mL) due to poor adherence to levothyroxine. Initial laboratorystudies revealed hyponatremia (Na 130, n135-145 mEq/L), elevated TSH (>100, n0.30-4.20 uU/mL), undetectable FT4 (<0.4, n0.6-1.5 ng/dL) and elevated CK (5671, n<200 U/L).Levothyroxine was restarted at dose of 150 mcg daily. Head CT performed for evaluation ofaltered mental status and hallucinations revealed hyperdensity within the pituitary gland,concerning for underlying hemorrhage and apoplexy. Neurosurgical consultation was requested,and a pituitary MRI was obtained in preparation for potential surgical intervention. MRI showeda prominent anterior pituitary gland measuring up to 14 mm with homogeneous enhancementwithout evidence of hemorrhage. In the absence of any hemorrhage or definitive mass, thepituitary enlargement was considered secondary to the long-standing history of uncontrolledprimary hypothyroidism leading to pituitary hyperplasia, and surgical intervention was deemedunnecessary. Repeat labs 1 week later showed TSH >100uU/mL, FT4 0.6 ng/dL, CK 2799 andrepeat MRI showed slight decrease in size of the pituitary gland, confirming hyperplasiasecondary to severe, prolonged hypothyroidism. Conclusion: Prolonged primary hypothyroidism can lead to pituitary hyperplasia which can bemistaken as pituitary macroadenoma, leading to unnecessary surgical intervention. Carefulreview of history and TSH trends can help elucidate this diagnosis. References: (1) Wyne KL, Nair L, Schneiderman CP, et al. Hypothyroidism Prevalence in theUnited States: A Retrospective Study Combining National Health and Nutrition ExaminationSurvey and Claims Data, 2009-2019. J Endocr Soc. 2022;7(1):bvac172. Published 2022 Nov10. doi:10.1210/jendso/bvac172

Presentation: 6/3/2024
9183 Pituitary Metastasis Of Lung Adenocarcinoma Presenting As Anterior Pituitary Dysfunction
Authors: Faour Omar , Kinaan Mustafa , Suryanarayanan Sowmya K
Published: October 2024

Disclosure: O. faour: None. M. Kinaan: None. S.K. Suryanarayanan: None.

Introduction: The pituitary should not be overlooked as a site for metastasis and can be the first presentation of neoplastic disease in some patients. Most common presenting symptoms: headache, ophthalmoplegia, visual field defect and Arginine Vasopressin Deficiency (AVP-D). We present a case of pituitary metastasis of lung adenocarcinoma presenting as anterior Pituitary dysfunction that also showed partial AVP-D unmasked after starting steroids. Case Description: A 63-year-old male with history of tobacco use, COPD, and hypertension presented with syncope. He reported a 30lbs weight loss within prior 2 months, low energy, increased thirst, and polyuria. Physical exam was significant for cachexia, normal visual field on confrontation, and vital signs of BP 100/61, HR 83, and Weighing 180 lbs. Since he had syncope, Cortisol checked was undetectable and Free T4 was low, He was started on hydrocortisone and levothyroxine. CTA chest revealed a right hilar mass measuring 2.7 x 3 cm. Endobronchial biopsy was consistent with lung adenocarcinoma. MRI of pituitary gland revealed solid hypointense lesion with glandular thickening and diffuse heterogeneity involving most of the pituitary gland measuring up to 16 mm. No cavernous sinus invasion. Pituitary infundibulum showed diffuse thickening and enhancement of the pituitary stalk throughout with Intact posterior pituitary bright spot. Labs showed low LH, cortisol, ACTH, GH, TSH, and ADH. Initially, the patient was able to maintain a euvolemic status through increased water intake; however, he was later found to have partial central AVP-D when steroids were introduced. He responded to the use of Desmopressin, developed hyponatremia after 3 doses. He was started on a combination of carboplatin/pemetrexed/pembrolizumab but had no response and was transferred to palliative care/hospice and passed away within 7months after diagnosis.Discussion:Pituitary metastasis is rare and most commonly occurs in lung and breast cancers. Unfortunately, they are associated with poor prognosis. MRI findings of loss of posterior pituitary bright spot, thickening of the stalk, and dumbbell shape can be helpful in distinguishing between primary pituitary tumors and metastases. PET-FDG scan has limited value. Pituitary metastasis commonly presents with posterior pituitary dysfunction due to direct blood supply. Unmasking or worsening of AVP-D can happen with steroid replacement in patients requiring initiation or intensification of Desmopressin therapy. Treatment involves combination of surgery, radiation therapy, and systemic treatment for the primary cancer which can improve symptoms only but does not improve mortality.

Presentation: 6/1/2024
8652 Real World Impact of Cushing’s Syndrome: A Shared Global Story
Authors: Edwin Leslie , Jordan Gretchen
Published: October 2024

Disclosure: L. Edwin: None. G. Jordan: None.

Introduction: Cushing's Syndrome creates short- and long-term challenges to physical and mental health. Clinical and surgical outcome statistics have improved over time, but patients continue to report diagnosis delays, confusion about treatments, and the feeling of being “dropped” once cortisol is normalized. White matter is damaged by persistent high cortisol, and a return to eucortisol often unmasks new or worsened autoimmune, neuropsychological, physical, and other conditions. Hypothesis: Patients have been sharing best practices and supporting each other through patient networks for decades on topics that are misunderstood, dismissed, and under-treated in the clinical setting. Improvements to care will come faster if this kind of patient-created data is made widely available, and advocacy groups must establish an acceptable method to accomplish this. Methodology: A committee of patients reviewed the design and content of two large Quality of Life surveys conducted in recent years, then built a new survey for a larger international patient cohort. SurveyMonkey was used for layout and response collection. Spanish and French translations were done with DeepL then cleaned up by native speakers. The survey was then promoted within global patient advocacy organizations and on social media. The survey comprised over 150 questions and received 438 responses from 38 countries. Results: Respondents answered questions about their daily lives including physical, emotional, mental and social well-being. Examples: •75% of respondents are still trying to determine their “new normal”.•Over 80% report memory problems that did not exist before.•Almost 90% took much longer than six weeks to return to work in any capacity.•A third of male patients and a fifth of female patients report that their marriage or long-term relationship ended because of Cushing’s.•Almost half of respondents felt that their medical team was unable to support them beyond cortisol issues.•More than 50% who answered this survey have experienced suicidal thoughts due to the overwhelming nature of Cushing’s. Conclusion: Dr. Harvey Cushing, namesake of the disease, identified the most underrated element of the patient experience when he made his famous statement: “A physician is obligated to consider more than a diseased organ, more than even the whole man—he must view the man in his world.”The man in his world. The results of our study paint a picture of the ongoing burden of hypercortisolism that often starts seven or more years before an official diagnosis is made and continues indefinitely. Patients can help fast-track the identification of areas where more work needs to be done. It is therefore incumbent on a group of well-organized advocates to develop a structure that translates the patient voice into datasets that are useable by all doctors, researchers, and stakeholders in the Cushing’s community.

Presentation: 6/3/2024
6534 Schwannoma-Induced Hyperprolactinemia: A Rare Presentation Unveiled
Authors: Naronowicz Gabriela , Foo Francine Fane , Cheng Jennifer , Ong Raquel Kristin , Holland Soemiwati Weidris , Chalasani Krishna
Published: October 2024

Disclosure: G. Naronowicz: None. F.F. Foo: None. J. Cheng: None. R. Ong: None. S.W. Holland: None. K. Chalasani: None.

Background: This case describes a rare presentation of a schwannoma manifesting with hyperprolactinemia. Case Description: A 37 year-old female with a past medical history including prolactinoma presented to our endocrine office to establish care. Prior to presentation, this patient had been diagnosed with a prolactinoma in 2015 via MRI. She was started on Cabergoline 0.5mg twice a week for treatment and continued this medication without any bothersome side effects. However, she began experiencing progressive dizziness, tinnitus, bilateral galactorrhea, and vision changes, prompting her to seek further intervention. The patient presented to our endocrine office in October 2017 for her initial visit. Due to ongoing symptoms, an MRI was done which revealed an adenoma vs hyperplasia of the pituitary gland. During this time her prolactin level was within normal limits, thus she continued her Cabergoline regimen. Soon thereafter, the patient was seen again in April 2018 with evidence of stable prolactin levels on Cabergoline treatment, although a repeat MRI showed a concern for a 1.2 cm mass in the left cerebellopontine angle extending to the right auditory canal. The patient underwent a follow-up consultation with a neurosurgeon; However given the unavailability of surgery at that time owing to insurance-related matters, a subsequent MRI was performed in August 2019 which revealed a vestibular schwannoma with no pituitary mass, and she ultimately underwent resection of this mass in February 2020. Throughout this period, the patient presented with a rise in prolactin levels (23.7 to 41.9 ng/mL). However, due to an asymptomatic state and the absence of concerning pituitary mass, the decision to be observed off Cabergoline therapy appeared to be the appropriate clinical course of action. Following the surgery, she was seen again in June 2020 with normalization of her prolactin levels without ongoing cabergoline treatment. We continue to follow this patient to present day for annual appointments and she continues to have normal prolactin levels. Conclusion: This report underlines the importance of a thorough and multidisciplinary approach in the assessment of elevated prolactin levels in light of a schwannoma. This also highlights the significance of continued surveillance and the value of repeat imaging. Exploring alternative diagnoses, such as Schwannoma, broadens the scope of etiologies, thus allowing a comprehensive approach for accurate diagnosis.

Presentation: 6/1/2024
8663 Sex differences in delayed fear incubation in mice
Authors: Littlepage-Saunders Mydirah , Rusnak Milan , Tsuda Mumeko , John Wu T
Published: October 2024

Disclosure: M. Littlepage-Saunders: None. M. Rusnak: None. M. Tsuda: None. T. Wu: None.

Post-traumatic stress disorder (PTSD) has a lifetime prevalence of 1 in 13 people. It is not fully understood why some are more vulnerable to developing PTSD whereas others are more resilient. Among those who develop PTSD, about a quarter have delayed-onset PTSD where onset of symptoms occur at 6 months or later after experiencing a traumatic event. While there is recognition of this type of PTSD, the underlying mechanism is poorly understood. The development of PTSD is more prevalent in women than men. However, previous preclinical and clinical studies have focused mainly on males. Thus, there lacks an understanding of this sex difference. To enhance our understanding of the causal mechanisms, we designed a study with mice to compare the effect of sex on delayed fear incubation. We expected the female mice to show increased fear responses that would suggest more chronic delayed fear incubation than the male mice. To test this, we evaluated distance travelled, freezing, and latency until the first freezing episode in adult male and female C57Bl/6J mice (7-8 weeks of age; n=8/group) using a delayed fear incubation behavioral assay. Animals were placed in a fear conditioning chamber for a 198 s acclimation period and then administered a single 2 s scrambled footshock of 1.5 mA via the metal grid floor. After an additional 60 s, animals were returned to their home cage. At specific time after shock application, animals underwent a fear recall test where the animals were placed back in the shock chamber for a total of 180 s without any additional footshocks and then returned to their home cage. The study was based on a 2X2 factorial design comprising of sex (male vs female) and recall time (1 day and 14 days post shock). The data showed an increasing freezing trend (p=0.08) at d 14 compared to their recall d 1 counterparts. There was no effect of time or sex on distance travelled or latency until the first freezing episode. Interestingly, female mice showed less freezing when compared to the male mice. Ongoing experiments will look more into circuitry-level changes by comparing neuronal activation through cFos expression in different brain regions that are a part of the limbic system and/or have been associated with fear: the amygdala, hippocampus, prefrontal cortex, and paraventricular nucleus.

Presentation: 6/2/2024
8603 Sex Steroids Have Opposing Impacts on Female Gonadotrope Metabolism and LH Secretion via GLUT1
Authors: Garcia Christopher , Nguyen Christy , Wang Sizhe , Trinh Davina , Le Uyen-Vy , Kapadia Rubina , De La Torre Jamie-Jean , De La Cruz Chantal K , Nicholas Dequina
Published: October 2024

Disclosure: C. Garcia: None. C. Nguyen: None. S. Wang: None. D. Trinh: None. U. Le: None. R. Kapadia: None. J. De La Torre: None. C.K. De La Cruz: None. D. Nicholas: None.

Gonadotropes of the anterior pituitary regulate reproductive hormone synthesis and secretion not only through GnRH signaling from the hypothalamus, but by also determining if glucose availability, via GLUT1, meets the current requirements to support reproduction. GLUT1 facilitates glucose uptake and in gonadotropes its expression increases during the LH surge which indicates its necessity in the maximal secretion of LH through glycolysis. However, the mechanisms underlying the feedback from sex steroids that also mediate female reproduction have not been completely elucidated. By manipulating GLUT1 expression and sex steroid levels using cell lines and a conditional knockout of GLUT1 in mouse gonadotrope we show that sex steroids alter GLUT1 expression and translocation effecting gonadotrope glycolysis and subsequent gonadotropin secretion. Tamoxifen treated iGricCre +/+ GLUT1 fl/fl mice display disrupted estrous cycles and changes in serum gonadotropins. Dihydrotestosterone (DHT) or estradiol (E2) replacement in gonadectomized male and female, respectively, surprisingly result in increased (by DHT) or reduced (by E2) pituitary GLUT1 protein as measured by western blot despite both inhibiting serum LH. Using extracellular flux analysis and imaging flow cytometry, we show that LβT2 cells treated with DHT increase while E2 decreases glycolysis and translocation of GLUT1 to the cellular surface. We conclude that sex steroids regulate gonadotropin secretion and reproduction through direct impacts on gonadotrope metabolism through GLUT1.

Presentation: 6/1/2024
9363 Spontaneous Cushing Disease Remission Induced By Pituitary Apoplexy
Authors: Vargas Jose Edmond Esquivel , Salazar Francis Ruiz , Santos Rojo Ana B
Published: October 2024

Disclosure: J.E. Esquivel Vargas: None. F. Ruiz Salazar: None. A.B. Santos Rojo: None.

Background: Spontaneous remission of Cushing disease is rare, and it is mainly due to apoplexy of a pituitary tumor. Clinical case: 14-year-old female presented with clinical features of Cushing syndrome. Initial tests were consistent with Cushing disease (CD): elevated 24h urinary cortisol (235µg/24h, n<90µg/24h), abnormal 1 mg dexamethasone overnight test (cortisol after 1 mg dex 3.4µg/dL, n<1.8µg/dL), and elevated ACTH-concentrations (83.5 pg/mL, n 10-60pg/mL). Pituitary adenoma was suspected, and the patient was referred for a transsphenoidal resection of the adenoma. While waiting for surgery the patient presented to the Emergency department with a headache and clinical signs of meningism. Computed axial tomography of the central nervous system was performed, and no structural alterations were found. The symptoms subsided with analgesia. One month later she presented again to the Emergency department with clinical findings of acute adrenal insufficiency (cortisol level of 4.06 µg/dL), and she was noted to have spontaneous biochemical remission associated with resolution of her symptoms of hypercortisolism. Nuclear magnetic resonance imaging was performed describing a 2.6 x 1.8mm hypointense pituitary lesion, suggestive of cerebrospinal fluid, which could be a remnant of a pituitary microadenoma. For that reason, spontaneous CD remission induced by pituitary apoplexy (PA) was diagnosed. The patient has been managed conservatively since the diagnosis and remains in clinical and biochemical remission until the present time after 10 months of follow up. Conclusion: There are 3 unique aspects of our case: the early age of onset of symptoms, the spontaneous remission of CD due to PA which has been rarely reported in the medical literature, and the patient presented a microadenoma because there are less than 10 clinical case reports of PA associated with microadenoma.

Presentation: 6/1/2024
7694 Characterizing NF1 Germline Pathogenic Variants In A Cohort Of Patients With Pheochromocytomas And Neurofibromatosis Type 1
Authors: Hristova Tzvetena , Parisien-La Salle Stéphanie , Lapointe Sarah , Tremblay Danny , De Haan Emma , Dumas Nadine , Labidi Moujahed , El Haffaf Zaki , Bourdeau Isabelle
Published: October 2024

Disclosure: T. Hristova: None. S. Parisien-La Salle: None. S. Lapointe: None. D. Tremblay: None. N. Dumas: None. M. Labidi: None. Z. El Haffaf: None. I. Bourdeau: None.

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are the tumors with the highest heritability in adult patients, with identification of a germline mutation in more than 30% of cases. Up to 20 susceptibility genes for PPGLs are known, including NF1. Neurofibromatosis type 1 (NF1) is an inherited disease affecting approximately 1 in 3000 people that predisposes to the development of tumors, such as pheochromocytomas (PHEO). Up to recently, the diagnosis of NF1 was mainly based on clinical manifestations and NF1 genetic characterization was not systematically performed. Objectives: To characterize germline pathogenic variants in the NF1 gene in patients with NF1 developing and PHEO. Methods: We reviewed the charts of patients with a pathology-proven diagnosis of PHEOs that were investigated at Centre hospitalier de l’Université de Montréal (CHUM) between 2000 and May 2023. Genetic analysis included gene sequencing by Sanger method or multigene sequencing by NGS with a panel (Invitae, CA) Results: In our cohort of 220 PHEOs, 15 patients (6.8%) (Males: 6, Females: 9) had a diagnosis of NF1. Mean age at diagnosis of PHEO in NF1 patients was 48 ± 13.6 years, contrasting to the mean age of 38,7 ± 15.2 years in patients carrying germline mutations in non-NF1 genes, most likely reflecting lack of systematic biochemically screening of PHEO in NF1. Urinary metanephrines were elevated in 9/15 patients. 2/15 (15.4%) NF1 patients had bilateral PHEO and 1/15 (7,7%) metastatic disease. Mean tumour diameter was 4.64cm (min-max 1.5 – 12.5 cm). Eight out of 15 NF1 patients underwent NF1 genetic analysis. Heterozygous NF1 germline pathogenic variants were found in all of them: 3 deletions (c.7379delG, c.5844_5845delAA and one encompassing the entire gene), 3 premature stop codons leading to truncated proteins or loss of function (c.7549C>T, c.3916C>T, c.1246C>T), and 2 splicing defects (c.4269+1 G>A, c.1885G>A). Conclusions: We report a large cohort of patients with NF1 and PHEO. The older age at diagnosis of PHEO in NF1 is expected based on lack of systematic biochemical screening for PHEO in NF1 clinical guidelines. We report 8 germline NF1 mutations associated with PHEOs. Further studies are required to fully understand the impact of genetic pathogenic variants in this population and to unravel a possible genotype-phenotype correlation.

Presentation: 6/2/2024
7934 Tac1-expressing cells in the central premammillary nucleus are essential for induction of the pre-ovulatory LH surge
Authors: Leon Silvia , Navarro Marta , Perdices-Lopez Cecilia , Aguayo Inmaculada Velasco , Jimenez Encarnacion Torres , Garcia-Galiano David , Navarro Victor Manuel , Tena-Sempere Manuel
Published: October 2024

Disclosure: S. Leon: None. M. Navarro: None. C. Perdices-Lopez: None. I. Velasco Aguayo: None. E. Torres Jimenez: None. D. Garcia-Galiano: None. V.M. Navarro: None. M. Tena-Sempere: None.

Infertility/subfertility is a growing challenge in reproductive medicine. The most common cause of subfertility in females is ovulatory dysfunction. Conditions linked with oligo-/anovulation include polycystic ovary syndrome, hypothalamic amenorrhea and premature ovarian insufficiency. However, the central neuro-endocrine defects affecting the pre-ovulatory LH surge that drives ovulation remain ill defined. While hypothalamic GnRH neurons are the major output pathway for the brain control of ovulation, upstream Kiss1 neurons, particularly in the anteroventral periventricular area (AVPV) of the hypothalamus in rodents, are thought to be crucial for the timed activation of GnRH neurons and generation of the preovulatory surge of gonadotropins. Yet, the major upstream regulators of this Kiss1/GnRH pathway are largely unknown. Substance P (SP, encoded by Tac1), a member of the tachykinin (TAC) family that acts via the receptor, NK1R (encoded by Tacr1), has been shown to centrally regulate gonadotropin release, and, according to our initial data, might modulate the pre-ovulatory surge in mice through its direct action on AVPV Kiss1 neurons. We report herein that Tac1-expressing cells in the ventral premammillary nucleus (PMV) become activated during the preovulatory surge, as denoted by co-expression of c-Fos. Moreover, we document here that these neurons project to key reproductive areas, including the rostral preoptic area (rPOA), AVPV, arcuate nucleus (ARC), and the medial posterodorsal amygdala (MePD). Furthermore, the chemogenetic inhibition of Tac1-expressing neurons in the PMV dramatically decreases the magnitude of the pre-ovulatory LH surge, but has no influence on tonic LH pulsatility. Overall, our findings strongly support a relevant stimulatory role of SP originating from Tac1 neurons at the PMV in the generation of the pre-ovulatory surge of gonadotropins, responsible for ovulation.

Presentation: 6/1/2024
6455 The Effect of Gene Silencing on Inhibiting Stress Hormones in Wild Birds Raised Under Stressful Conditions
Authors: Abdulateef Salwan M , Mohammed Thafer , Al-Jugif Waleed , Khudair Marwa Yass , Abed Mohammed Qais
Published: October 2024

Disclosure: S.M. Abdulateef: None. T. Mohammed: None. W. Al-Jugif: None. M.Q. Abed: None.

Wild birds are notable for their ease of rearing, tolerance to extreme environmental conditions such as heat and cold, and their resistance to diseases. They are also recognized for their ability to withstand stress. However, their primary challenge is low egg production, stemming from their aggressive nature. This aggression elevates the secretion of stress and fear hormones, significantly impacting reproductive hormones. This study aims to explore the effects of gene silencing on the physiological traits of wild birds, particularly its influence on physiological responses and the reduction of stress hormone levels. Three treatments were employed: T1 (control), T2 (welfare treatment, wherein birds were raised with enhanced well-being), and T3 (using siRNA technology to silence the gene responsible for stress hormone corticosterone production). The silencing of CYP11B1 and CYP11B2 involved obtaining the cDNA of each gene from the NCBI, associated with corticosterone production. The coding sequence from the 5' end at the cap direction was reversed to complement mRNA. Two siRNAs were procured from Macrogene Company (South Korea) in lyophilized form at high concentration, with sequences: CYP11B2 5'-acacctctgcctttgccctgagtgccat-3' and CYP11B1 5'-ctaaagtcaaactcagccccacattcat-3'. These were dissolved in molecular-grade distilled water for a final concentration of 500 pmol/µl. Each hen was injected in the wing in the jugular artery with 125 µl of the siRNA solution at 14 and 18 weeks of age, before the commencement of the egg-laying cycle. Corticosterone levels were measured using the Sunlong Biotech CO., LTD kit. The results showed a significant decrease (p<0.01) in stress hormone levels in the third treatment group (gene silencing treatment), leading to notable physiological responses in the birds compared to the other treatments. This study highlights the impact of gene silencing on the physiological traits of wild birds and its effects on their physiological responses. The findings of this study are significant in the context of avian physiology and poultry farming. By elucidating the impact of stress hormones on egg production and demonstrating the efficacy of gene silencing as a method to enhance reproductive efficiency, this research opens new avenues for improving the productivity and well-being of wild birds in controlled environments. It also underscores the potential of genetic interventions in addressing physiological challenges in wildlife.

Presentation: 6/1/2024
9264 The interplay of FOXO1 and NR3C1 in the development and function of pituitary somatotropes
Authors: Das Pratyusa , Jabal Dania Abou , Sunny Dale Ann , Kittu Prisha S , Rizzoti Karine , Ellsworth Buffy Sue
Published: October 2024

Disclosure: P. Das: None. D.A. Jabal: None. D.A. Sunny: None. B.S. Ellsworth: None.

Our research focuses on the role of glucocorticoid (GC) in regulating the maturation of pituitary somatotropes. We previously demonstrated that deletion of the forkhead transcription factor, FOXO1, affects the development of somatotropes both in vivo and in vitro. Our studies reveal that treating pregnant mice with the synthetic glucocorticoid, dexamethasone leads to premature somatotrope maturation. Interestingly, we have observed that the ability of GC to promote Gh1 expression is compromised in the absence of FOXO1 in a somatotrope-like cell line. This finding leads to further investigation into the GC receptor, NR3C1, and its developmental role in the pituitary gland. In mouse embryos, we detect NR3C1-positive cells localized primarily in the nucleus, initially in small numbers at embryonic day (e)12.5 and becoming more abundant by e14.5. At e14.5 there is a subset of cells where NR3C1 co-localizes with POU1F1, a marker of pre-somatotropes, suggesting the importance of NR3C1 in the formation of the somatotrope lineage. In dexamethasone-treated animals, we observe an increase in NR3C1-positive cells. However, no significant change was noted in POU1F1 expression. Significantly, the premature somatotropes identified are NR3C1 and POU1F1-positive, suggesting the pituitary cells expressing both POU1F1 and NR3C1 at e14.5 are likely differentiating into somatotropes when exposed to GC. Normally, by e16.5, GH-positive cells begin to appear in mice. Double immunostaining reveals that some of these cells also express NR3C1. Further supporting this finding, the deletion of Nr3c1 results in a decreased number of GH-positive cells at e16.5. Altogether these findings demonstrate that NR3C1 and FOXO1 are key factors regulating somatotrope maturation.

Presentation: 6/2/2024