bluuebunny/crossref_metadata_2025 huggingface dataset:
8750 Characterization of 11βHSD1-Like Protein: A Novel Species-Restricted Member of the 11βHSD Enzyme Family
Authors: Valbe E , Ng J , Fuller P J , Cole T J
Published: October 2024

Disclosure: E. Valbe: None. J. Ng: None. P.J. Fuller: None. T.J. Cole: None.

The 11β-hydroxysteroid dehydrogenases (11bHSD) are a subfamily of short-chain dehydrogenase/reductase enzymes, which regulate cortisol metabolism and their physiological actions in vivo. Although much is known about the biology and function of 11bHSD1 and 11bHSD2, little is known of a recently discovered third member of the 11bHSD family, 11bHSD1L, which is expressed in primates, fish, plants, and other mammals, but is absent in most rodent species. Current expression profiling in human, sheep and marmoset tissues suggest that 11bHSD1L may be linked to the regulation of reproduction through the hypothalamic-pituitary-gonadal (HPG) axis and/or to an unknown regulatory role in the central nervous system. The definitive physiological substrate for 11bHSD1L is unknown. We have assessed the expression of 11bHSD1L in the non-human primate marmoset and show that 11bHSD1L mRNA and protein levels are highest in regions of the brain and reproductive organs, which parallels expression patterns in human tissues. Localization of 11bHSD1L protein in marmoset tissue sections by immunohistochemistry identified several cell populations previously unreported for 11bHSD1L, that included the Sertoli cells in the testis, prostate epithelial cells and theca cells in the ovary, further implicating 11bHSD1L as a potential novel regulator of the HPG Axis. Furthermore, we have measured expression of 11bHSD1L in sub-regions of the foetal sheep brain and other tissues, where mRNA levels were elevated in neural-derived tissues. There is some evidence that 11bHSD1L has a functional role in cortisol turnover, as a cortisol oxidase. Using a dual-luciferase based reporter system and a quantitative LC-MS/MS technique with HSD1L overexpressing cells, we show that cortisol is unlikely to be a substrate of 11bHSD1L. We have also demonstrated via CRISPR-CAS9 mediated gene knockout that 11bHSD1L may play a role in cell proliferation or survival in the human neuroblastoma cell line SH-SY5Y, which expresses very high levels of HSD1L. Upon knockout of both 11bHSD1L alleles, SH-SY5Y cells become unviable. This may further implicate 11bHSD1L as a relevant gene in cancer cell growth, particularly considering its increased expression in many tumour cell lines. Finally, we discuss our progress in purifying 11bHSD1L as a recombinant protein for in vitro substrate and structural studies.

Presentation: 6/3/2024
12612 Chiasmal Herniation - A Rare Complication Of Prolactinoma Treatment
Authors: Syeda A , Kantorovich V
Published: October 2024

Disclosure: A. Syeda: None. V. Kantorovich: None.

Introduction: Primary treatment of symptomatic prolactinomas is medical therapy with dopamine agonists (DA). Herniation of optic chiasm is a rare complication of tumor shrinkage induced by DA therapy which causes secondary deterioration in visual fields. Case:A 26-year-old man presented to our hospital after a syncopal episode. He had headaches and blurry vision in the left eye for the past 4 months. He was diagnosed with a 4 cm x 3.6 cm x 2.6 cm pituitary macroprolactinoma compressing the optic chiasm, his prolactin (PRL) was 4700 ng/mL (N: 4.0-15.2 ng/mL) and testosterone was suppressed to 10 ng/dL (N: 249-836 ng/dL). Other hormonal workup was unremarkable. Ophthalmologic evaluation was consistent with left optic nerve pallor and neural rim thinning suggestive of a guarded prognosis. Immediate neurosurgical intervention was deemed unnecessary. Cabergoline 0.25 mg twice a week was initiated. Subsequently, the PRL levels improved but remained elevated to 414.2 ng/mL and cabergoline dose was increased to 0.5 mg twice a week. MRI Brain after 10 months revealed significant tumor reduction to 2.1 cm x 2.1cm x 1.2 cm. He was inconsistent with his endocrinology follow up appointments and was also non-adherent to cabergoline intermittently. After 14 months of starting DA therapy, he presented with worsening blurriness in his left eye. A repeat brain MRI showed stable appearance of the large pituitary macroadenoma with inferior bowing of the optic chiasm. Significant distortion, tented appearance, and attenuation of the left prechiasmatic optic nerve was also noted. He was evaluated by neuro ophthalmology and a diagnosis of secondary visual deterioration due to optic chiasmal herniation was made. Cabergoline therapy was promptly discontinued. Two weeks post-cabergoline cessation, he underwent trans-sphenoidal resection reporting vision improvement pre-surgery. Post-operative MRI depicted changes with no residual tumor and improved optic chiasm position. Discussion:Various theories explain chiasmal herniation with dopamine agonist (DA) treatment for prolactinomas. Pre-existing chiasm-tumor tethering may exacerbate downward pull during tumor reduction caused by DA therapy. Some case series have suggested that not all patients with chiasmal herniation have visual field defects and that despite improvement in visual fields with decrease in DA dosage, there are no appreciable radiographic changes/reversal of chiasmal herniation. One of the explanations for this lack of correlation is that visual impairment is rather a consequence of vascular compression. This case underscores the need for regular perimetry in macroprolactinoma patients on medical treatment. Adjusting dopamine agonist dosage to allow controlled tumor regrowth, monitored closely with frequent visual field and prolactin assessments, is crucial for relieving optic chiasm tension.

Presentation: 6/3/2024
6616 Copeptin Use To Reduce Hospital Stay In A Complicated DI Case
Authors: Kowsika Sree S , Moran Heberth , Yuksel Simge , Bleich David
Published: October 2024

Disclosure: S.S. Kowsika: None. H. Moran: None.

Introduction: While there is literature describing the use of copeptin for the diagnosis of polyuria-polydipsia syndrome, its utilization remains very limited in many hospitals. We present a case where the patient, initially misdiagnosed with central diabetes insipidus (DI), was appropriately diagnosed with partial nephrogenic DI through the use of copeptin. Case: A 48-year old female with a history of cardiac arrest, anoxic brain injury and diabetes insidious (DI) presented to the emergency department with hypernatremia (Na 154 mmol/L). The patient had been initiated on desmopresin (DDAVP) at an outside facility prior to her current admission. Despite receiving high doses of DDAVP, her sodium levels remained elevated, prompting further investigation. DDAVP administration was discontinued. A water deprivation test was subsequently performed, followed by IV administration of 2 mcg of DDAVP, which resulted in an increase in urine osmolality from 191 to 331 mosm/kg, which was less than the expected 50% increase observed in central DI. Additionally, a baseline copeptin level was obtained and noted to be 31 pmol/L, confirming the diagnosis of partial nephrogenic DI. The patient was started on Amiloride, leading to normalization of sodium levels. Discussion: Many patients with polyuria-polydipsia syndrome are frequently misdiagnosed and receive incorrect treatment, potentially worsening their clinical condition. Copeptin (Carboxy-Terminal-Pro-vasopressin) is the C-terminal peptide of pro-vasopressin, co-secreted with arginine vasopressin (AVP). It has been proposed as a direct test for diagnosing polyuria-polydipsia syndrome. Baseline Copeptin testing without stimulation can accurately diagnose nephrogenic DI if elevated (>21.4, pmol/L). To differentiate between central DI and chronic polyuria, prior thirsting with hypertonic saline or glucagon stimulation is necessary, with stimulated copeptin <4.9 pmol/L diagnosing central DI. Despite its diagnostic potential, Copeptin is underutilized in many settings. In this case, using Copeptin to accurately diagnose our patient led to appropriate treatment and the resolution of hypernatremia.

Presentation: 6/1/2024
6630 Crooke Cell Pituitary Adenoma Without a Cushingoid Appearance
Authors: Hodge Jordesha , Idriss Setana , Jamal Issra , Panta Raju
Published: October 2024

Disclosure: J. Hodge: None. S. Idriss: None. I. Jamal: None. R. Panta: None.

Background: Crooke cell pituitary adenomas are corticotroph adenomas with Crooke’s cell changes, which are cytoplasmic accumulation of cytokeratin filaments in response to glucocorticoid excess. They are aggressive, invasive tumors, typically macroadenomas, with a high rate of Cushing’s disease and post -treatment (surgery and/or radiotherapy) recurrence. We present a case of Crooke cell pituitary adenoma without a Cushingoid appearance. Clinical Case: A 66-year-old Hispanic male with a 16-year history type II diabetes mellitus with retinopathy, presented with a pituitary macroadenoma at age 60. This was found incidentally when he had a brain CT for evaluation of vertigo. Subsequent brain MRI demonstrated a large 2.4 x 2.0 x 1.7 cm pituitary macroadenoma with extension into the suprasellar cistern and the left cavernous sinus. He was asymptomatic, without Cushingoid features. Hormonal evaluation revealed central hypogonadism and hypothyroidism, mildly elevated prolactin of 39.3 (4-15.2 ng/mL) and morning cortisol level of 12.7 (6-18.4 ug/dL). A 24-hour urine cortisol was normal. He was started on testosterone and thyroid hormone replacement therapy. His diabetes mellitus became progressively difficult to control with a peak HbA1C of 10.1%, about 7 years prior the macroadenoma finding. His HbA1C remained persistently elevated in the 8.1-9.5% range despite being on 6 anti-hyperglycemic agents, including basal insulin. A morning ACTH level 4 years after the initial visit, was 115 (6-50 pg/mL) with a cortisol level of 13.7 (6-18.4 ug/dL). Repeat morning ACTH and cortisol levels 7 months later were very similar. 5 years after the macroadenoma finding, he was noted to have worsening glaucoma, which was believed to be due to optic nerve compression. Therefore, he underwent endoscopic transphenoidal resection for tumor debulking. Pathology supported the diagnosis of Crooke cell corticotroph pituitary adenoma. Repeat brain MRI 3-months post-surgery demonstrated residual tumor, but normal optic chiasm and optic tracts. He had an abnormal dexamethasone suppression test prior to surgery (cortisol 6.4 ug/dL) and continued to do so post-operatively (cortisol 3.7 ug/dL with persistently elevated ACTH). Just prior to his surgery, testosterone replacement therapy was held. Total testosterone level after surgery was normal 309.6 (280-800 ng/dL) and free testosterone 7 (5-21 ng/dL); he remained off replacement therapy. Conclusion: Crooke cell pituitary adenomas are rare with limited data on prognosis and guidance for clinical management. Some patients may have subtle features of hypercortisolism, such as difficult to control diabetes mellitus, without an overt Cushingoid appearance.

Presentation: 6/1/2024
6743 Decline in IGF-1 after surgery of the nonfunctioning pituitary neuroendocrine tumor
Authors: Sugata J , Fujio S , Makino R , Hanada T , Hanaya R
Published: October 2024

Disclosure: J. Sugata: None. S. Fujio: None. R. Makino: None. T. Hanada: None. R. Hanaya: None.

Background: Patients undergoing surgical treatment for nonfunctioning pituitary neuroendocrine tumors (PitNET) may experience impaired secretion of growth hormone (GH). The optimal timing for assessing GH secretory function postoperatively remains unclear. In our department, we typically conduct hormone-loading tests three months after surgery. However, even in some cases without a diagnosis of growth hormone deficiency (GHD) at that point, there might be a gradual decline in Insulin-like growth factor-1 (IGF-1). Methods: We studied patients who exhibited peak GH levels > 1.8ng/ml in an insulin tolerance test (ITT) three months after undergoing surgery for nonfunctioning PitNET. We evaluated the levels of IGF-1 during the last observation, excluding cases where reoperation or radiosurgery was performed. Results: We identified 67 cases (29 males, 38 females) meeting the study criteria, with a median age of 54 years. The median follow-up time spanned 6 years (range 1-13 years). The median standard deviation (SD) scores of IGF-1 three months after surgery were -0.96, with 14 cases (21%) below -2.0 SD. At the end of the follow-up period, the median SD scores of IGF-1 were -1.31. This was significantly lower than the three-month time point (p<0.01), and 21 cases (31%) recorded were below -2.0 SD. In 6 cases suspected of severe GHD due to subjective symptoms or decreased IGF-1, ITT, or GH-releasing peptide-2 were retested. Among these, 2 cases were diagnosed with severe GHD, while the remaining demonstrated normal secretion of GH despite the low concentration of IGF-1. The IGF-1 SD scores at the end of follow-up and the three-month time-point exhibited a significant correlation (R2=0.74, p<0.01). However, no correlation was found between IGF-1 scores and peak GH concentration, age, tumor size, pituitary apoplexy, or preoperative IGF-1 SD scores. Conclusions: IGF-1 exhibited a progressive decrease in the majority of cases without severe GHD, with some cases showing reductions greater than -2.0 SD. Our findings emphasize the importance of cases with long-term clinical follow-up low IGF-1 after PitNET surgery, even when GH secretion appears normal.

Presentation: 6/1/2024
7464 Delayed Diagnosis of Cushing’s Disease after Five Year History of Hirsutism
Authors: McBride Erin , Davis Adam N , Elshimy Ghada , Vender John
Published: October 2024

Disclosure: E. McBride: None. A.N. Davis: None. G. Elshimy: None. J. Vender: None.

Introduction: Women may experience hirsutism for years before seeing a physician or before undergoing diagnostic testing. This case demonstrates that delayed workup of hirsutism can lead to delayed diagnosis and treatment of aggressive Cushing’s disease. Case: A 40-year-old African American female presented for initial evaluation with a 5-year history of hirsutism, which had never been evaluated, and a high cortisol level in the setting of type 2 diabetes mellitus and hypertension. She had a 60lb weight gain over 5 years, progressive hirsutism, easy bruising, and purple striae. Labs were significant for cortisol 23.86mcg/dL, ACTH 67pg/mL, HbA1c 8.9%, DHEAS 347mcg/dL, 17-OH progesterone 102ng/dL. A 1mg dexamethasone suppression test resulted in a non-suppressed cortisol of 12.64mcg/dL. She had an elevated 24 hour urine free cortisol level of 78mcg and an elevated midnight salivary cortisol with values of 474ng/dL and 396ng/dL. An 8mg dexamethasone suppression test resulted in a cortisol of 5.55mcg/dL. MRI brain pituitary protocol revealed a 6x4mm microadenoma of the pituitary gland. This is consistent with an ACTH producing pituitary adenoma (Cushing’s disease). The microadenoma was surgically removed by transsphenoidal approach. The pathology of the tumor revealed an elevated Ki-67 of 5%. Patient required hydrocortisone replacement for a couple of months that was later discontinued. Moreover, she is no longer on any medications for her diabetes, and her hypertension significantly improved postoperatively. Discussion: Hirsutism and androgen excess in women are most commonly caused by polycystic ovarian syndrome (PCOS). However, non-PCOS diagnoses, such as Cushing’s disease, should be considered as they are commonly missed due to lack of a pragmatic screening approach. Pituitary microadenomas are often benign, but 30-40% of cases are invasive and considered aggressive. Aggressiveness can be evaluated by using the tumor marker Ki67, which is a nuclear marker that reflects cell proliferation. While controversial, one proposed cutoff for aggressive pituitary adenomas is Ki67 ≥3%. The pathology of the tumor in this patient was aggressive with Ki67 of 5% This case demonstrates the importance of identifying hirsutism early in order to exclude the more dangerous causes of hirsutism such as Cushing’s disease. By early diagnosis and surgery, we may limit the progression of associated comorbidities such as diabetes mellitus and limit the growth of a potentially aggressive adenoma.

Presentation: 6/1/2024
7594 Diagnostic utility of 11C-Methionine PET-CT imaging in persistent or recurrent Cushing’s disease after transsphenoidal surgery
Authors: Furnica R , Devuyst F , Mathey C , Constantinescu S , De Herdt C , Renaud L , Maiter D M
Published: October 2024

Disclosure: R. Furnica: None. F. Devuyst: None. C. Mathey: None. S. Constantinescu: None. C. De Herdt: None. L. Renaud: None. D.M. Maiter: None.

Introduction: Equivocal or negative pituitary magnetic resonance imaging (MRI) findings pose a significant challenge in the management of persistent or recurrent Cushing’s disease (CD), compromising the chances of success of a further transsphenoidal surgery (TSS). The aim of our study was to determine the diagnostic utility of [1][1]C-methionine (MET) positron emission tomography coupled with computerized tomography (PET-CT) in localizing the residual corticotroph adenoma. Methods: We retrospectively analyzed the results of all MET-PET-CT performed between May 2002 and November 2023 in patients with a CD persisting or relapsing after TSS, and equivocal (n=14) or negative pituitary MRI findings (n=8). In 15 cases, images obtained from MET-PET were also co-registered with a high-resolution 3D pituitary MRI. All patients had a pathologically confirmed corticotroph tumor, and/or biochemical evidence of early postoperative remission after the first TSS, and/or proven ACTH-dependent Cushing’s syndrome with positive bilateral inferior petrosal sinus sampling. Results: Twenty-two patients were included (18 females and 4 males), with a mean age of 35.5 years at diagnosis. Initial tumors were mostly microadenomas with a mean tumor volume of 15 mm3. Thirteen out of the 22 patients had a suspect anomaly on conventional MRI that could however not be clearly distinguished from postsurgical changes, while the remaining 9 had a negative MRI. A significant MET standardized uptake value (SUV) in the suspected area of the tumor residue was defined as a ratio ≥ 1.80 relative to cerebellum SUV and was found in 12/22 patients (55%; 4 patients with negative pituitary MRI and 8 with equivocal findings). On the basis of positive imaging, repeat TSS was performed in 10 patients and was successful in 6, while Gamma Knife radiosurgery (GKRS) was performed in 2 patients allowing remission in both (total remission rate: 8/12). Among the 4 patients not cured by TSS, the presence of corticotroph adenoma in the resected tissue was found in 3 cases. Exploratory TSS was performed in 4 of the 10 PET negative patients, with no remission. Two patients were treated with GKRS, with remission in 1 case. Among the 4 other patients, bilateral adrenalectomy was performed in one case and adrenal steroidogenesis inhibitors were used in the remaining patients. Conclusions: [1][1]C-Methionine PET-CT imaging can provide valuable diagnostic information to detect a residual active corticotroph adenoma in about half of patients with a persistent or recurrent CD and equivocal or negative MRI results, thereby allowing targeted TSS or radiosurgery with a global success rate of 67% in this selected subpopulation.

Presentation: 6/1/2024
12353 Differential Gene Expression And Pathway Analysis In Growth Hormone Secreting Pituitary Tumors According To Granulation Pattern
Authors: Shin Hyeju
Published: October 2024

Disclosure: H. Shin: None.

Differential gene expression and pathway analysis in growth hormone-secreting pituitary tumors according to granulation pattern. Hye Ju Shin [1], Kyung Won Kim[2], Chan Woo Kang[2], Eun Jig Lee[2], Cheol Ryong Ku[2]. [1]Department of Clinical Drug Discovery & Development, Yonsei University College of Medicine, Seoul, Republic of Korea, [2]Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Objective: The purpose of this research is to explain clinical variations in patients with acromegaly by exploring gene expression differences according to granulation patterns in growth hormone (GH)-secreting pituitary tumors. Materials & methods: Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). Results: The median age at diagnosis was 50 years, with a predominance of female patients (60%). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enriched the pathways involved in neuronal development (axon development, axonogenesis, axon guidance, synapse and presynapse organization, gliogenesis, glial cell differentiation, nerve development, synaptic membrane adhesion, semaphorin-plexin signaling pathway involved in neuron projection guidance) and acute inflammatory response. No pathways were significantly downregulated in SGST compared with those in DGST. Three signaling pathways (JAK-STAT, phosphatidylinositol 3-kinase, and MAP cascade) and three neuronal development processes (generation of neurons, nerve development, and neurogenesis) were significantly enriched in both GO and GSEA analysis. The PPI networks constructed with the up- and downregulated DEGs consisted of 128 and 132 PPI pairs, respectively. There were 10 hub proteins, top highly connected DEGs: ANLN, TLE3, TLE2, DMD, ADRA1A, RBFOX1, MMP2, LMO1, RUNX1T1, and NPPA. Conclusion: The results indicate that granulation-specific gene expression may underpin diverse clinical characteristics in acromegaly. Overall, this study emphasizes the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK-STAT signaling in SGST.

Presentation: 6/3/2024
7141 Disruption of Transient Receptor Potential Channel 5 Causes Obesity and Maladaptive Behavior
Authors: LI Y , Cacciottolo T , Farooqi I S , Xu Y
Published: October 2024

Disclosure: Y. Li: None. T. Cacciottolo: None. I.S. Farooqi: None. Y. Xu: None.

The global surge in obesity over recent decades poses formidable challenges to public health and economic well-being. Transient Receptor Potential Channel 5 (TRPC5) emerges as a pivotal membrane-spanning cation channel implicated in energy homeostasis, pain modulation, and fear responses. Here, we identified microdeletions on chromosome Xq23 disrupting TRPC5 in boys with food-seeking, obesity, anxiety and autism. Significantly, these microdeletions were inherited from mothers grappling with a constellation of health issues, including obesity and anxiety, suggesting a potential intergenerational aspect to TRPC5-related conditions. We examined approximately 450,000 individuals with exome sequence data from the UK Biobank and found that the TRPC5 gene is the most strongly associated X-linked gene for human body mass index. Moreover, we identified 7 rare TRPC5 variants in patients with severe obesity underscores the potential role of TRPC5 in shaping the obesity phenotype. Functional experiments with HEK293 cells demonstrated that these variants led to a loss of Trpc5 function. Knock-in male mice harboring a human loss-of-function (LOF) TRPC5 variant developed obesity, anxiety, reduced social exploratory behavior and increased aggression; female mice homozygous for the same variant showed similar deficits with reduced severity. We found approximately 91% proopiomelanocortin (Pomc) neurons in arcuate nucleus of the hypothalamus (ARH) express Trpc5 in wild-type male mice. Utilizing the TRPC5 agonist benzothiadiazide derivative (BTD), we found that BTD (i.p., 10 mg/kg) reduced food intake and increased c-Fos expression in Pomc neurons in wild-type mice compared to the vehicle injection group. Importantly, the activation of Trpc5 using BTD did not induce toxicity or aversive effects. Importantly, chemogenetic inactivation using designer receptor exclusively activated by designer drugs (DREADD) of hM4Di-expressing Pomc neurons with clozapine N-oxide (CNO; i.p., 1 mg/kg) effectively blocked BTD-induced anorexia and c-Fos expression in Pomc neurons. Furthermore, we found that BTD-induced anorexia and c-Fos expression in Pomc neurons were blocked in mice with a LOF TRPC5 variant. This suggesting that the effects of BTD on food intake are mediated through Trpc5 in Pomc neurons. In conclusion, our study provides compelling evidence for the involvement of TRPC5 in the intricate regulation of human appetite, body weight, and maladaptive behaviors. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying TRPC5 variants. We suggest that TRPC5 should be included in diagnostic gene panels for severe childhood-onset obesity.

Presentation: 6/1/2024
7433 Distribution of Kisspeptin Neurons in the Adult Sheep Amygdala
Authors: Igler A , Amodei R , Roselli C E
Published: October 2024

Disclosure: A. Igler: None. R. Amodei: None. C.E. Roselli: None.

Kisspeptin (Kiss1) neurons are primarily recognized for their role in regulating reproductive function by stimulating the release of hormones that control puberty and fertility. While these neurons are more commonly associated with the hypothalamus, recent research has suggested their presence in other brain regions, including the amygdala. The amygdala, a complex brain structure integral to emotional processing and social behaviors, encompasses various nuclei, yet the specific distribution and potential functional implications of Kiss1 neurons within this region remain to be elucidated. Studies in rodent models have indicated the presence of Kiss1-expressing neurons in the posterodorsal medial nucleus of the amygdala and implicated them in the modulation of sexual partner preference and anxiety in male mice. Understanding the distribution of Kiss1 neurons in the sheep amygdala could provide valuable insights into the potential roles of Kiss1 in modulating not only reproductive functions but also emotional and social behaviors in a species more closely related to humans. In this study, RNAscope® was performed to survey the distribution pattern of Kiss1 neurons within various nuclei of the amygdala in the adult sheep brain. In addition, duplex RNAscope® was used to examine co-localization of Kiss1 with estrogen receptor-α (ESR1) mRNA. We found widespread distribution of Kiss1 neurons within the major nuclei of the amygdala in adult male and luteal-phase female sheep. The density of Kiss1 neurons was highest in the cortical nucleus and ventral portion of the basal nucleus. Intermediate densities were observed in the medial, basal and lateral nuclei, while the lowest density was found in the central nucleus. There was extensive co-expression of Kiss1 and ERα mRNA throughout the amygdala. In the medial nucleus where co-localization was quantified, approximately 80% of Kiss1 neurons co-expressed ESR1; whereas only about 60% of ESR1 neurons co-expressed Kiss1. Notably, immunofluorescence histochemistry using antibody #AC564 (from A. Caraty) revealed that kisspeptin fibers were concentrated in the medial nucleus and sparsely distributed throughout other nuclei. These results are the first to establish a map of Kiss1-expressing neurons in different subregions of the amygdala, which provides a useful foundation for investigations into their potential involvement in the neurobiological mechanisms underpinning emotional processing, social and sexual behaviors. Supported by NIH Grant OD11047 to CER.

Presentation: 6/3/2024
6939 Do an empty sella and a partial empty sella affect the modeling and displacement of the optic chiasm?
Authors: Kaluza Bernadetta , Furmanek Mariusz , Domanski Jan , Zuk-Lapan Aleksandra , Babula Emilia , Iga Poprawa , Landowska Malgorzata , Jarzabek Karolina , Popczynska Justyna , Filipowicz Paulina , Wielgolewska Malgorzata , Walecki Jerzy , Franek Edward M
Published: October 2024

Disclosure: B. Kaluza: None. M. Furmanek: None. J. Domanski: None. A. Zuk-Lapan: None. E. Babula: None. P. Iga: None. M. Landowska: None. K. Jarzabek: None. J. Popczynska: None. P. Filipowicz: None. M. Wielgolewska: None. J. Walecki: None. E.M. Franek: None.

An empty sella and a partial empty sella are a result of the bulging of the subarachnoid space into the sella turcica. Primary empty sella has no tangible cause, while secondary empty sella is due to a pathology in the central nervous system, which may be manifested as visual disorders occurring via optic chiasm modeling or displacement. The aim of the study was to determine whether an empty sella and a partial empty sella, both primary and secondary, were the risk factors for modeling the optic chiasm. In order to conduct the study, the hospital database was analyzed and 891 patients who had undergone pituitary and CNS MRI were selected. An empty sella and a partial empty sella were confirmed in 212 patients, of which 157 patients had a primary and 55 had a secondary form. Compression and modeling of the optic chiasm were found in 29 patients. Univariate logistic regression showed that the predictors of compression and modeling of the optic chiasm included: the presence of a pituitary adenoma (OR 2.275, 95% Cl 1.083-4.779, p=0.03) - especially macroadenoma (OR 29.472, [10.751-80.789], p=0.0001) and a status post CNS surgery (OR 10.226, [1.031-101.418], p=0.047). Conversely, an empty and partial empty sella (OR 1.02, [0.429-2.422], p=0.965) - both primary (0.741, [0.254-2.161], p= 0.584) and secondary (1.193, [0.353-4.034], p=0.776), as well as Rathke cleft cyst (OR 0.517,[0.121-2.206], p=0.373) and a pituitary cyst (OR 0.789, [0.184-3.383], p=0.749) were not found to play such a role. An empty and partial empty sella do not affect the modeling and displacement of the optic chiasm, so they may not contribute to visual symptoms such as the narrowing the visual field and diplopia.

Presentation: 6/3/2024
12408 Efnb2 Controls Pituitary Gland Development By Regulating Proliferation Of Pituitary Stem Cells
Authors: Gualtieri A , Gomez-Corral L , Nicholson J , Tan R , Guasti L , Gaston-Massuet C
Published: October 2024

Disclosure: A. Gualtieri: None. L. Gomez-Corral: None. J. Nicholson: None. R. Tan: None. L. Guasti: None. C. Gaston-Massuet: None.

Efnb2 encodes for the ligand Ephrinb2 that binds to its cognate Eph receptor, which plays an integral role in angiogenesis, stem cell regulation and tumorigenesis. Using a pituitary-specific Cre-driver (Hesx1Cre), we conditionally deleted Efnb2 from the early pituitary stem/progenitor cells (PSCs) of the developing pituitary gland. We found that Efnb2 is expressed in PSCs both during embryogenesis and adulthood, suggesting its involvement in PSCs maintenance. Here we show that genetic ablation of Efnb2 (Efnb2fl/fl;Hesx1Cre/+) results in severe pituitary hyperplasia, abnormal gland morphogenesis and delay in the terminal differentiation of hormone-producing cells. In order to understand the underlying molecular mechanisms by which Efnb2 deletion leads to pituitary abnormalities during embryogenesis, we performed transcriptomic analyses using mRNA-Seq at early stages of pituitary development on Efnb2+/+ and Efnb2−/− cell populations. Interestingly, unsupervised gene set enrichment analyses of the transcriptomic results identified Efnb2 as a key negative regulator of PSCs proliferation, whilst involved in the regulation of epithelial integrity and epithelial to mesenchymal transition (EMT). Functional assays performed to validate transcriptomic analyses revealed that Efnb2-null PSCs hyper-proliferate both in vitro and in vivo and downregulate the expression of genes involved in EMT, indicating a role of Efnb2 in these two developmental pathways. Indeed, whilst Efnb2-null PSCs within the marginal zone hyper-proliferate, they downregulate genes of epithelial integrity, resulting in an abnormal EMT transcriptomic profile. Additionally, these events lead to a significant delay of the pituitary cell lineage commitment program, leading to severe reduction in the expression of Pit1, Pomc1 and Gsu commitment markers. Taken together, our results reveal a novel role for Efnb2 (Ephrinb2) as key regulator of pituitary gland development. Efnb2 negatively regulates the proliferation of pituitary stem/progenitor cells controlling pituitary organ size while controlling the epithelial integrity of the stem cell niche.

Presentation: 6/2/2024
8719 Epidermal Inclusion Cyst Masquerading as Obstructive Craniopharyngioma
Authors: Murugesh M , Thelmo F , Watari J
Published: October 2024

Disclosure: M. Murugesh: None. F. Thelmo: None. J. Watari: None.

The most common cause of a sellar mass is notably pituitary adenoma (84.6%), followed by craniopharyngioma (3.2%), cystic nonneoplastic lesion (2.8%), inflammatory lesion (1.1%), meningioma (0.94%). Epidermoid cysts are benign congenital inclusion cysts that can occur anywhere in the body, with about 7% percent occurring in the head and neck region. Very rarely, they can present intracranially, accounting for about 0.3-1.8% of primary tumors. We present a rare case of epidermoid cyst growing as a suprasellar mass causing hypopituitarism.A 58-year-old female presented to the emergency department with dizziness in the setting of an ear infection. CT head showed 2.8 cm complex suprasellar mass, with adjacent 1 cm nodule at the cerebellopontine angle. MRI showed 2.7 x 2.4 x 2.7 cm suprasellar mass along with “a lobular component along the left posterior aspect extending to the cerebellopontine angle which measures about 1.3 cm, causing mass effect on the midbrain, pons, and optic chiasm”. The differential included craniopharyngioma, macroadenoma and meningioma. Notably, she denied any vision changes. She was evaluated by neurosurgery and after extensive multidisciplinary discussion with ENT and ophthalmology, the patient proceeded with endoscopic surgery for mass resection. Intra-operatively, the mass was noted to be densely adherent to the basilar artery, and sub-total resection was performed. Surprisingly on pathology the mass was identified as an epidermoid cyst, as evidenced by debris with cholesterol clefts and no lesional cells. The patient was started empirically on hydrocortisone 50mg three times a day post-resection. Endocrinology was consulted postoperatively with initial concerns of diabetes insipidus in the setting of hypernatremia, however, the patient’s sodium levels normalized. Pituitary panel at this time was concerning for central hypothyroidism (TSH 0.53 and FT4 0.8) and central adrenal insufficiency (ACTH <9 and AM cortisol 0.9). She was ultimately discharged on prednisone 5mg and levothyroxine 75 mcg with outpatient follow-up. While epidermoid cysts are present in the head and neck region about 7% of the time, they rarely occur in intracranial regions, with about 1.5% of intracerebral epidermoid cysts occurring intracranially. They tend to be slow growing and are often found only when they grow large enough to become symptomatic, as seen in our presented case. Our case highlights the importance of recognizing epidermoid cysts as a rare cause of sellar masses.

Presentation: 6/1/2024
7917 Bilateral Adrenal Hemorrhages As The Initial Presentation Of Poorly Differentiated Bronchogenic Carcinoma
Authors: Malapur Bina , Jakoby Michael G , Williams Vanessa
Published: October 2024

Disclosure: B. Malapur: None. M.G. Jakoby: None. V. Williams: None.

Introduction: Bilateral adrenal hemorrhage is rare, and most cases occur in the setting of bacterial sepsis, coagulopathies such as antiphospholipid antibody syndrome, treatment with anticoagulants, surgery, or trauma. We present a patient with asynchronous bilateral adrenal hemorrhages that resulted in an eventual diagnosis of poorly differentiated bronchogenic carcinoma. Case: A 65-year-old female smoker was found to have a large right adrenal hematoma on computed tomography (CT) obtained for evaluation of acute onset right flank pain. No hemorrhage or anatomic abnormalities of the left adrenal gland were apparent, and the patient was discharged home after her pain was controlled. Approximately one month later, she returned to hospital with bilateral flank pain, and bilateral adrenal hemorrhages were diagnosed on repeat CT imaging. An 8 cm left upper lobe lung mass was revealed on a chest CT scan, and cytology from a bronchoscopic biopsy confirmed poorly differentiated bronchogenic carcinoma. The patient had no recent surgeries, abdominal trauma, or treatment with anticoagulants, serologic evaluation for coagulopathies and disseminated intravascular coagulation was unremarkable, blood cultures failed to grow bacterial pathogens, and acid-fast staining of lung tissue was negative. The patient was discharged from her second hospital admission on hydrocortisone and fludrocortisone. Discussion: Adrenal hemorrhage in the setting of malignancy is usually a complication of adrenal metastases. The prevalence of adrenal metastases in advanced stage cancer is approximately 3%, with lung and breast cancers and melanoma showing the highest predilection for adrenal metastases. This case is unusual because the patient had no focal masses or disruption of left adrenal contour on CT to indicate adrenal metastases at the time of right adrenal hemorrhage, and she did not have other established risk factors for pathologic bleeding in the setting of malignancy such as thrombocytopenia or treatment with chemotherapy agents, anticoagulants, or nonsteroidal anti-inflammatory drugs. Adrenal hemorrhage is also a rare inciting event resulting in the diagnosis of lung cancer; to date, there are only 29 published cases of spontaneous adrenal hemorrhage as the initial presentation of lung cancer. This case illustrates the importance of careful evaluation for malignancy in patients with spontaneous adrenal hemorrhage and no clear etiology for adrenal bleeding.

Presentation: 6/1/2024
12525 Feline Hypersomatotropism In The USA And Canada: Demographics Of 4620 Cats With Presumed Acromegaly
Authors: Egbert Rebecca J , Fowkes Robert C , Niessen Stijn J M , Petroff Brian K
Published: October 2024

Disclosure: R.J. Egbert: None. R.C. Fowkes: None. S.J. Niessen: None. B.K. Petroff: None.

Spontaneous models of endocrinopathies are powerful tools to understand disease etiology. Endocrine diseases in companion animals are particularly useful to study, as they share their environment with humans and typically present with clinical disease that phenocopies human symptoms. One such disease in domestic cats, hypersomatotropism (HST, feline acromegaly), is a disorder of excessive growth hormone and increased IGF-1 (Insulin like Growth Factor 1), usually caused by hyperplasia or neuroendocrine tumors of the pars distalis of the pituitary gland. This retrospective study used serum IGF-1 results to investigate population characteristics for domestic cats with HST in the United States and Canada. Laboratory records from 1Jan06 to 31Dec22 were reviewed and animals with a circulating IGF-1 hormone concentration of 190 nmol/L (1,450 ng/mL) or greater were presumed to have acromegaly. This review identified 4,620 such cats with a mean age (n=4,351) of 11.2 years (median: 11.2, range: .5-20.3yr) and mean weight (n=2,086) of 6.03 Kg (median: 5.91, range: 2.27-15.0 Kg). Males outnumbered females in the database, which included 3,048 males and 1,181 females. Domestic Short/Medium/Longhair cats were the most prevalent breed (n=3,563; 77%), followed by Maine Coon cats (n=120; 2.6%) and Siamese cats (n=111, 2.4%). Just under half of the animals (n=2,037, 44%) had a history of diabetes mellitus on the submission form. Most submissions were from the US (n=4,347, 94%) with the most hypersomatotropic cats from California (n=841, 18.2%), New York (n=604, 13.1%), Massachusetts (n=402, 8.7%), Colorado (225, 4.9%), and Texas (200, 4.3%). The mean serum IGF-1 concentration of these animals was 358 nmol/mL (median: 345, range 190-761 nmol/mL). For comparison, an age and sex matched control group of 95 animals with residual samples previously submitted for unrelated testing was selected. The mean IGF-1 concentration for the control group was 97 nmol/mL (median: 85, range 0-311 nmol/mL). In summary, HST is diagnosed most frequently in older male cats in urbanized North America, and potentially displays some breed disposition, suggesting both a genetic and environmental component to the disease etiology.

Presentation: 6/2/2024
8168 From Salt to the Sella- Discovering Empty Sella Syndrome as a Rare Cause of Severe Hyponatremia
Authors: Vemparala Pranathi , Challagulla Sabita
Published: October 2024

Disclosure: P. Vemparala: None. S. Challagulla: None.

Introduction: Hyponatremia is a common electrolyte disorder with potentially life-threatening consequences. Careful evaluation of hyponatremia can uncover significant underlying conditions. We present an interesting case of a patient who presented with symptoms of severe hyponatremia and a workup led us to the discovery of empty sella syndrome as the etiology. Case Presentation: A 54-year-old male with hypertension presented with 2 days of left-sided headache, blurred vision, generalized weakness, and vomiting. Pertinent medication history revealed the use of thiazide diuretic, bupropion and varenicline. Physical examination was unremarkable. Laboratory data showed severe hyponatremia with a serum sodium of 118 meq/L. Initial improvement with fluids was followed by a decline (106-112 meq/L). CT head without contrast showed a prominent empty sella turcica. Workup revealed urine osmolality and elevated urine sodium. A low AM cortisol level of 1.0 mcg/dl (reference range- AM- 7.0 - 25.0 mcg/dl), and decreased adrenocorticotropic hormone (ACTH) level of 5.2 pg/ml (reference range- 7.2 - 63.3 pg/ml) suggested secondary adrenal insufficiency. All other anterior pituitary hormones were normal. Brain magnetic resonance imaging (MRI) confirmed the diagnosis of partial empty sella. Treatment with hypertonic saline, fluid restriction, and steroids led to symptom resolution. Conclusion: Empty sella syndrome is a rare pituitary condition that can be primary- characterized by herniation of the subarachnoid space within the sella, or secondary- which occurs when the sella is empty due to damage to the pituitary gland by tumor, radiation, etc. It can cause potential hypopituitarism, be asymptomatic, or present with symptoms of raised intracranial pressure. In patients with hypopituitarism, deficiencies of ACTH and TSH are rarer and appear to be more common with a complete empty sella. This case emphasizes the need for a comprehensive hyponatremia workup, awareness of secondary adrenal insufficiency, and recognition of the life-threatening potential of even partial empty sella syndrome when untreated.

Presentation: 6/1/2024
7704 Generating pituitary cells from iPSCs of patients with child onset congenital hypopituitarism harboring PROP1 pathogenic allelic variants
Authors: Marques Juliana M , Fattahi Faranak , Carvalho Luciani Renata Silveira
Published: October 2024

Disclosure: J.M. Marques: None. F. Fattahi: None. L.R. Carvalho: None.

Introduction: Reduced or absent levels of pituitary hormones due to genetic or organic causes is known as combined pituitary hormone deficiency (CPHD) and PROP1 is the most frequent cause of CPHD, but more than 85% of the cases are without molecular diagnosis. Novel Techniques such as induced pluripotent stem cells (iPSC), can be used to generate patient’s specific pituitary cells for disease modeling. Aim: To generate iPSC from CO-CH patients’ peripheral blood mononuclear cells (PBMC) and differentiate them into pituitary cells. Methods: Peripheral blood was collected from 2 siblings (HC1 and HC2) harboring compound heterozygous PROP1 allelic variants and their parents (HC3 and HC4). PBMCs were isolated and expanded with MNC medium prior to nucleoporation and transfection with plasmids containing pluripotency genes (OCT4 and SOX2; cMYC and KLF). After 48h, transfected cells were transferred to Geltrex coated plates and fed with E8, NaB and βFGF until pluripotent colonies were formed. iPSCs were differentiated into cranial placode cells using pituitary placode conditioned medium (PPCM) until day 15. For pituitary cell maturation, pituitary conditioned medium (PPCM without SB431542) was used until day 30. qPCR and flow cytometry using the Kit BD Stemflow - Human Pluripotent Stem Cell Transcription Factor Analysis (BD Biosciences) for stem cells and the eBioscience™ Foxp3 / Transcription Factor Fixation/Permeabilization (Thermo Fisher Scientific) for the placode and pituitary markers were used. Pituitary hormonal levels from cell supernatant were measured at the Laboratory of Hormones and Molecular Genetics - HCFMUSP. Results: we generated iPSCs from patient and control blood cells. iPSCs were more than 90% positive for the pluripotency markers SOX2, NANOG, OCT3/4. Pituitary cells were generated with positivity for the placode marker SIX1 (58%) and pituitary markers, as LHX3 (56%) and PROP1 (59%), at day 15. Control cell lineages expressed higher levels of pituitary hormones at days 15 and 30 at RNA and protein levels while patient cells failed to induce hormone-producing cells properly. Pituitary hormonal release was impaired in patients pituitary cells. Conclusion: CO-CH patients’ PBMC were dedifferentiated to a pluripotent state, being able to generate pituitary hormone producing cells. Patient cells were able to mimic human phenotype. These cells can be used, in the future, to study CO-CH basis in patients specific background, to develop pituitary disease modeling as well as test possible new treatments.

Presentation: 6/3/2024