bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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&gt;T, c.3916C&gt;T, c.1246C&gt;T), and 2 splicing defects (c.4269+1 G&gt;A, c.1885G&gt;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

Abstract
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

Abstract
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&lt;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

Abstract
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
5152 The interplay of FOXO1 and NR3C1 in the development and function of pituitary somatotropes
Authors: Das Pratyusa , Jabal Dania Abou , Sunny Dale Ann , Ellsworth Buffy Sue 
Published: October 2024

Abstract
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
9384 Two Siblings With Hypogonadotropic Hypogonadism As First Presentation Of The Severe Neuroendocrine Disorder Caused By RNF216
Authors: Rochtus A M , Vermeer S , Antonio L 
Published: October 2024

Abstract
Disclosure: A.M. Rochtus: None. S. Vermeer: None. L. Antonio: None.
Background: Biallelic mutations in RNF216 cause a syndrome characterized by hypogonadotropic hypogonadism, cerebellar ataxia, chorea and cognitive impairment, a combination first described over a century ago named Gordon Holmes syndrome (MIM 212840). Hypogonadotropic hypogonadism can be the initial manifestation of this severe neuroendocrine disorder. Case reportWe report two siblings born to consanguineous parents who were referred due to absent or delayed puberty progression. The elder sibling, a 17-year old male adolescent, presented with absence of secondary sexual characteristics and a high-pitched voice. He had normal cognitive development and no anosmia. Clinical examination revealed Tanner stage 1 and bilateral gynecomastia. Blood tests showed low levels of gonadotropins (LH &lt; 0.3 IU/L [normal range: 1.7-8.6] and FSH &lt; 0.3 IU/L [normal range: 1.2-7.7]) and low morning testosterone 11.4 ng/dL [normal range: 300-1000]. Examination of other pituitary hormones was normal. His 15-year old sister was referred due to primary amenorrhea. She had spontaneous thelarche and presented with Tanner stage 3. Blood examination revealed LH 1.1 IU/L, FSH 4.6 IU/L, and estradiol 2.5 ng/L [normal range: 15-350 ng/L]. Pituitary MRI was performed in the brother due to suspicion of Kallmann syndrome, revealing a normal anterior pituitary, hypoplastic posterior pituitary, and an extensive supratentorial leuko-encephalopathy. Whole-exome sequencing revealed a homozygous variant in RNF216 (c.1705_1710del, p.(Leu569_Ile570del)) (OMIM #212840) in both affected siblings. Further segregation analysis revealed that both parents were heterozygous carriers. RNF216 mutations cause a disorder characterized by combined neurodegeneration and reproductive dysfunction, with the majority of variants leading to amino-acid changes or truncation of the RBR domain or C-terminal extension, as observed in our family. ConclusionThis case report describes two siblings with absent or delayed puberty progression due to a homozygous novel RNF216 mutation. Further research is essential to elucidate the phenotypic variability present in patients with RNF216 mutations.
Presentation: 6/1/2024
8698 Unique populations of pituitary macrophages regulate gonadotropin secretion
Authors: Del Mundo Z , Ha J , Zhang A , Wiggins K D , De Robles G , Garcia C , Ujagar N , Nicholas D 
Published: October 2024

Abstract
Disclosure: Z. Del Mundo: None. J. Ha: None. A. Zhang: None. K.D. Wiggins: None. G. De Robles: None. C. Garcia: None. N. Ujagar: None. D. Nicholas: None.
Chronic inflammation disrupts hormonal balance in the Hypothalamic-Pituitary-Gonadal (HPG) axis, contributing to reproductive disorders. Despite extensive studies on immune cells in the hypothalamus and ovaries, their impact on the pituitary is largely unexplored. Our research reveals that macrophages are the primary immune population in the pituitary during homeostasis. In response to in vivo chronic lipopolysaccharide exposure in mice, a transient macrophage population emerges, associated with reproductive changes, including elevated serum testosterone, prolonged estrous cycle stage, and reduced ovarian antral follicle count. This study aims to characterize pituitary macrophages and elucidate their impact on the HPG axis. We hypothesize that pituitary macrophages change inflammatory status as a response to stimuli and, as a result, modulate gonadotropin secretion. We pinpointed differentially expressed genes (DEGs) in pituitary macrophages using scRNAseq, distinguishing them from other tissue-resident macrophages, including microglia. These DEGs include markers for macrophage activation, phagocytosis, migration, hormone synthesis, and lipid metabolism. Immunohistochemistry validated the distinctive morphology of pituitary macrophages compared to microglia. In vitro depletion of macrophages from mouse pituitaries resulted in decreased pituitary hormone secretion and decreased secretion of G-CSF, IL-9, and CXCL5. These results highlight the role of pituitary macrophages in hormonal regulation, setting the stage for future immunotherapeutic strategies to restore hormonal balance in reproductive disorders.
Presentation: 6/3/2024
6977 Unraveling Secondary Adrenal Insufficiency and an Invasive Pituitary Macroadenoma in a COVID-19 Positive Patient
Authors: Sayed Farah El , Banka Ajaz Ahamad 
Published: October 2024

Abstract
Disclosure: F. El Sayed: None. A.A. Banka: None.
Invasive pituitary macroadenomas extend into the extrasellar region and invade surrounding dural, periosteal, or mucosal tissues, often exceeding 1 centimeter and potentially compressing adjacent structures. Nonfunctioning pituitary adenomas (NFPAs), as they enlarge, can cause visual field impairment and ophthalmoplegia, with the decision for surgical intervention influenced by the degree of optic chiasm compression. NFPAs are sometimes associated with impaired endocrine function, particularly secondary adrenal insufficiency (sAI), which, warrants specific clinical attention. Management involves a combination of surgical interventions, such as transsphenoidal surgery, and medical approaches, including tailored hormone therapy or radiation therapy based on the tumor's characteristics. Clinical case: A 51-year-old female with a history of Sjogren's disease presented with a one-week duration of nausea, vomiting, diarrhea, and fatigue. Upon admission, she tested positive for COVID-19. Her vital signs indicated hypotension with a blood pressure in the 80s/40s range, a heart rate in the 90s, and she was afebrile on room air. Laboratory findings revealed significant hyponatremia (Na+ 118), K+ 4.3, HCO3- 19, and glucose 80. Workup for hyponatremia included a cortisol stimulation test, revealing secondary adrenal insufficiency with baseline cortisol of 3.5 ug/dl, 10.7ug/dl after 30 minutes, and 12.7ug/dl after 60 minutes. The patient denied exogenous steroid use, hypothyroid symptoms, polyuria, or polydipsia, and reported no headaches or visual symptoms. Endocrine evaluation showed hypogonadism despite post-menopausal status, with low estrone, estradiol, LH, and FSH levels. She was initiated on Cortef (hydrocortisone) with symptomatic improvement. Further investigation through an MRI revealed a large lobulated sellar mass measuring 3.2 x 2.8 x 3.5 cm compressing the optic chiasm and partially encasing the right internal carotid artery, leading to peripheral visual defects confirmed on perimetry. Following endoscopic endonasal pituitary macroadenoma resection, there was no evidence of interval growth on a one-year follow-up MRI scan. Discussion: The presented case highlights the importance of considering invasive pituitary macroadenomas in the differential diagnosis of patients with hyponatremia, particularly when accompanied by suggestive symptoms and an atypical cortisol response. The coexistence of COVID-19 adds a layer of complexity to the clinical scenario, necessitating a comprehensive approach to both infectious and endocrine management. Timely recognition, appropriate endocrine assessment, and targeted interventions, such as hydrocortisone replacement and surgical resection, are crucial for optimizing outcomes in patients with this intricate interplay of pituitary pathology and infectious states
Presentation: 6/1/2024
12391 When Pressure Drops, Consequences Rise: A Case Of Pituitary Apoplexy And Watershed Infarcts
Authors: Watashi Diego Moreno , Alkaissi Hussam R , Sharma Meeta B 
Published: October 2024

Abstract
Disclosure: D. Moreno Watashi: None. H.R. Alkaissi: None. M.B. Sharma: None.
Introduction: Pituitary apoplexy (PA) results from sudden hemorrhaging and infarction of the pituitary gland, typically within a pituitary adenoma. The primary symptom is a sudden, severe headache, often followed by acute endocrine dysfunction, ophthalmoplegia and visual or neurological disturbances. Case Description: A 68-year-old male with a past medical history of hypertension presented to the emergency department with acute chest and upper back pain, beginning one day prior. No history of smoking, alcohol intake or drug use. Blood pressure (BP) on arrival was 180/95 mmHg. Initial labs revealed mild electrolyte abnormalities. Troponins were normal, but ECG showed diffuse T wave inversion and ST depression. CT angiography revealed a type B aortic dissection. He was managed in the critical care unit with continuous esmolol intravenous (IV) infusion and planned for endovascular repair. During his stay, he became disoriented and hypotensive. MRI from the brain incidentally discovered a pituitary macroadenoma measuring 2.9x2.2x3cm and recent infarcts, with a distribution concerning for hypoperfusion. Fundoscopy concerning for optic chiasm compression. Labs indicated secondary hypothyroidism and hypogonadism (TSH 0.3 uUI/ml, free T4 0.88 ng/dL, total testosterone 56.3 ng/dL). Neurosurgical intervention was deferred until after aortic repair. Endovascular aortic repair was performed with episodes of hypotension. Post-procedure, the patient developed fever (39.5°C) and worsening mental status. Head CT revealed an increased suprasellar extension of the pituitary macroadenoma and vasogenic edema, consistent with hemorrhage of the lesion. He was started on stress doses of hydrocortisone, levothyroxine 125mcg and managed conservatively due to a high surgical risk. Discussion: PA's extrinsic risk factors include angiographic procedures, endocrinological dynamic tests, anticoagulation therapy, exogenous estrogen administration, orthopedic and cardiac surgeries (due to BP fluctuations). The intrinsic risk factors are non-functioning adenomas, macroadenomas and suprasellar extension. Treatment is focused on immediate correction of endocrine derangements and relieving local compression. Stress dosage of corticosteroids should be administered IV as soon as the diagnosis is confirmed to prevent life-threatening corticotropic deficiency. Neurosurgical decompression via a transsphenoidal approach is the definitive therapy to relieve local compression with severe visual loss, obtundation or rapidly progressive course. The potential outcomes are based on the extent of hemorrhage, necrosis, and edema. PA should be treated as a medical emergency in the setting of hemodynamic changes from acute corticotropic deficiency and irreversible neurological damage from acute intracranial compression. The risk factors for PA should be known to assist in early diagnosis.
Presentation: 6/1/2024