bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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
7295 Giant Pituitary Adenoma with Rapid Symptomatic Progression and Postoperative Mortality
Authors: Kennedy R D , Nicholson M 
Published: October 2024

Abstract
Disclosure: R.D. Kennedy: None. M. Nicholson: None.
Introduction: Giant pituitary adenomas, defined as pituitary adenomas measuring greater than 4 cm, present a therapeutic challenge because of their size, clinical features, and increased potential for complications following surgical intervention. Early detection and intervention to prevent growth and progression is paramount. We present a case of a patient with a giant 6.3 cm pituitary adenoma who had significant neurologic compromise, requiring surgical intervention, with resultant postoperative complications and death. Case:Patient is a 41 year old male with known history of pituitary adenoma who presented on 11/1/2023, from outside hospital, to the Neuroendocrine clinic with complaints of excessive truncal obesity, impotence, fatigue, and apathy. Vital signs were within normal limits. Physical exam revealed clouding of consciousness, grossly intact cranial nerve function, truncal obesity, and diminished power, tone, and bulk of the extremities. Formal visual field testing revealed bitemporal hemianopsia. A head CT scan revealed a 6.3 cm sellar mass with expansion of the sella, invasion of soft tissue into the sphenoid sinus, and extension of soft tissue cranially to the level of the third ventricle eccentric to the left. There was no evidence of apoplexy. Lab results revealed Prolactin of 924 ng/mL. The patient had been taking Bromocriptine, 2.5 mg daily, for at least three weeks. Less than three weeks after his initial evaluation, he returned to the hospital with complaint of acute ataxia. Pituitary MRI revealed 6.3 cm sellar mass with evidence of acute and subacute blood products, stretching of the optic chiasm from mass effect, extension into the bilateral cavernous sinuses, superior left MCA displacement, posterior left PCA displacement, 5 mm midline shift, uncal herniation and descending transtentorial herniation. The patient underwent endoscopic transsphenoidal resection with subsequent craniotomy for debulking. Postoperatively, he developed new right sided hemiplegia with aphasia with subsequent MRI finding of watershed infarct at the left MCA/PCA lateral posterior border zone territories with increasing mass effect over a 30 day hospital stay. He developed progressive global edema with worsening uncal and tonsillar herniations. Brain death was pronounced on 11/30/23. Discussion:This case highlights the importance of early intervention in patients with giant pituitary adenomas. Our patient had been experiencing right sided weakness for at least one year prior to his admission to our facility. In this case, earlier treatment with a dopamine agonist may have decreased the size of the adenoma or prevented rapid growth. This may have precluded the need for surgical intervention on an adenoma of this size, which carries increased risk for postoperative complications.
Presentation: 6/2/2024
12218 Gnrh Pulse Frequency And Irregularity Play A Role In Depression
Authors: Choi J , Kim M 
Published: October 2024

Abstract
Disclosure: J. Choi: None. M. Kim: None.
Gonadotropin-releasing hormone (GnRH) has a role in hypothalamic control of depression, but the underlying patterns and relationship with downstream reproductive hormones are still unclear. Here we report that hypothalamic GnRH pulse frequency and irregularity increase before GnRH pulse amplitude slowly decreases during social defeated stress models (SDS). While mice castrated and testosterone inhibited induced depression by conducting SDS, these mice led to anti-depression effects and affected by GnRH signaling, indicating that high-frequency GnRH pulses. Regramming the endogenous GnRH pulses of depressed male mice via an optogenetic approach revealed that increasing GnRH pulses frequency causes depression acceleration, while lowering the frequency of and stabilizing GnRH pulses can slow down depression. In conclusion, GnRH pulses are important for depression in male mice.
Presentation: 6/1/2024
7541 Growth Hormone Secreting Pituitary Macroadenoma Presenting as Intractable Headache, Right Eye Epiphora and Ptosis
Authors: Niedzialkowska Ewelina Marta , Aljaloudy Mustafa , Banka Ajaz Ahamad 
Published: October 2024

Abstract
Disclosure: E.M. Niedzialkowska: None. M. Aljaloudy: None. A.A. Banka: None.
Introduction: Headache is not an uncommon feature in patients with pituitary tumors. It is present in up to 70% of cases and is irrespective of tumor volume or cavernous sinus invasion. Intractable headache is common in patients with GH secreting tumors. Unilateral ptosis and epiphora (excessive tearing) is an extremely rare phenomenon in this patient population. Case:44 y.o. male with a history of chronic occipital headaches and pituitary mass (diagnosed 2 years prior) was referred to our hospital for worsening right eyelid ptosis with inability to open his eye, photophobia and worsening occipital headache. The patient was diagnosed with occipital neuralgia in the past and received nerve blocks without improvement of symptoms. On admission, physical examination was positive for right eyelid ptosis, brisk and symmetric pupils, negative for features of acromegaly. Imaging revealed normal CT orbits but was concerning for pituitary mass. Pituitary MRI confirmed a mass within the right aspect of the pituitary gland measuring 9x12x12 mm with mild impression into the right cavernous sinus and stalk deviation to the left, without optic nerve chiasm impression. Laboratory results showed IGF-1 514 ng/ml (N &lt;215), testosterone 232 ng/dl (N 240-890), LH 1.8 mIU/ml (N 0.6- 12.1), FSH 3.1 mIU/ml (1-12), normal alfa subunit, prolactin, ACTH, cortisol, TSH and ft4. The patient underwent endonasal transsphenoidal resection of pituitary mass with complete resolution of headaches, and photophobia as well as improvement of ptosis and lacrimation. Repeat IGF-1 postoperatively was mildly elevated at 239 ng/ml. 6 months after surgery IGF-1 remained elevated at 299 ng/ml, GH 5.1 ng/ml (N 0.1-3), repeat brain MRI was concerning for residual tumor tissue within the left superior aspect of the gland. The patient was started on lanreotide 60 mg monthly. The patient also reported recurrence of intractable occipital headaches and recurrence of right eye lacrimation at that time. Repeat lab studies showed IGF-1 464 ng/ml, LH 0.5 ng/ml, testosterone 155 ng/dl consistent with central hypogonadism and residual GH secreting tumor. The patient is currently awaiting Neurosurgery evaluation. Conclusion: Headache is present in up to 12.5% of patients with acromegaly. It is commonly persistent, severe, unrelieved by the surgery and irrespective of biochemical markers. Lacrimal gland volume is higher in patients in this population and shows positive correlation with IGF-1 and GH levels. GH and IGF-1 independently induce features of hypersomatotropism that may stimulate exocrine glands. Epiphora in the setting of acromegaly is exceptionally infrequent in patients with acromegaly and usually presents bilaterally. GH secreting pituitary tumor presenting with unilateral ptosis and unilateral epiphora is an extremely rare phenomenon.
Presentation: 6/3/2024
7251 Heterozygous Sox2 Knockout Mice have Delayed Puberty, Fertility Deficiencies, and a Decreased Number of GnRH Neurons
Authors: Cassin Jessica , Nguyen Ryan D , Tonsfeldt Karen J , Dunn Geneva A , Chen Vivian , Yeo Seung E , Mellon Pamela L 
Published: October 2024

Abstract
Disclosure: J. Cassin: None. R.D. Nguyen: None. K.J. Tonsfeldt: None. G.A. Dunn: None. V. Chen: None. S.E. Yeo: None. P.L. Mellon: None.
Mutations in the SOX2 gene have been previously linked to a syndromic form of Isolated Hypogonadotropic Hypogonadism (IHH), with additional ocular and neurodevelopmental phenotypes. Recently, we published research detailing novel variants in SOX2, which demonstrated a functional role for SOX2 in Kisspeptin-expressing hypothalamic neurons, establishing a mechanistic relationship between SOX2 heterozygous variants and IHH. To further test the role of SOX2 in the hypothalamus, we utilized Sox2tm[1].[1]Lan/J mice to generate whole body heterozygous knockout (Sox2het) mice. We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2het mice compared to wild type (WT) controls (male WT: 29.7±0.7 days, Sox2het: 32.3±0.5 days and female WT: 28.8±0.9 days, Sox2het: 33.8±1 days). This difference is explained in part by a weight phenotype with Sox2het mice being significantly smaller at weaning and into adulthood despite observing no difference in weight at birth. We next examined the effect of Sox2het on fertility in both sexes. Sox2het male mice had a significant decrease in sperm motility compared to WT controls (WT: 40.4%±1.5, Sox2het: 29.5%±1.3); however, this decrease was insufficient to affect time to first litter or to decrease the number of pups per litter. In females, we observed a significant delay in time to first litter of Sox2het dams compared to WT controls (WT: 20.6±0.4 days, Sox2het: 26.5±1.7 days), which may arise from disrupted estrous cyclicity. Although Sox2het females did not spend an extended period of time in any one stage, they did not progress linearly through the stages as did their WT controls and therefore completed fewer cycles during our study (WT: 3.6±0.3 cycles, Sox2het: 2.5±0.2 cycles in 21 days). Finally, we assessed the number of GnRH neurons in the adult mouse and found that Sox2het mice have significantly fewer GnRH neurons (WT: 570.6±42.8 neurons, Sox2het: 228.4±32.8 neurons). Together these data further substantiate a role for SOX2 in the HPG axis by addressing the effects of Sox2 heterozygous knockout on the hypothalamus. Future studies will further define the role of SOX2 directly in the Kisspeptin and GnRH neurons.
Presentation: 6/3/2024
9270 Human loss-of-function variants in the TRPC5 associated with Postpartum Depression
Authors: Li Yongxiang , Farooqi Ismaa Sadaf , Xu Yong 
Published: October 2024

Abstract
Disclosure: Y. Li: None. I.S. Farooqi: None. Y. Xu: None.
Postpartum depression is a serious psychiatric disorder that is understudied and underdiagnosed. Postpartum depression, the most common complication of childbirth negatively impacts the mother, with suicide accounting for approximately 20% of postpartum deaths. Further, postpartum depression also has adverse effects on infant behavioral, emotional, and cognitive development. However, the neurobiological mechanisms underlying postpartum depression remain to be comprehensively elucidated. Transient receptor potential channel 5 (TRPC5/Trpc5), an ion channel that conducts calcium inward currents, as a critical regulator of many behaviors. Here, we found that microdeletions on chromosome Xq23 disrupting TRPC5 gene in humans and identified seven rare TRPC5 variants in mothers who exhibited postpartum depression and reduced bonding with their infants. Heterozygous females with TRPC5 deletions had postpartum depression and anxiety after delivery. We then generated a knock-in mouse model of a human severe loss-of-function mutation, K34del (Trpc5K34del). Our study showed that Trpc5K34del/+ heterozygous dams abandoned their pups after delivery. The Trpc5K34del/+ dams also showed inefficient retrieval and increased the time to retrieve pups, which is associated with abnormal pup care. Importantly, Trpc5K34del/+ dams exhibited severe depression-like and anxiety-like behaviors during the postpartum period. Oxytocin (OXT), a polypeptide comprised of 9 amino acids, is primarily synthesized by neurons in the paraventricular nucleus of the hypothalamus (PVH) and the supraoptic nucleus (SON). We found that endogenous Trpc5 protein is abundantly expressed by OXT neurons in PVH but not by SON. Further, the Trpc5K34del/+ dams reduced OXT expression in the PVH but does not affect OXT expression in the SON. Deletion of Trpc5 in OXTPVH neurons recapitulated phenotypes in Trpc5K34del/+ dams, including inefficient retrieval, abnormal pup care, depression-like and anxiety-like behaviors during the postpartum period. We then bilaterally injected AAV-DIO-Trpc5 into the PVH of virgin female Trpc5K34del/+/OXT-Cre mice to result in restoration of Trpc5 only in OXTPVH neurons in these mutant mice. Restoration of Trpc5 in OXTPVH neurons in Trpc5K34del/+/OXT-Cre mutant mice significantly improved pup retrieval behavior and indices of maternal care. After weaning, Trpc5K34del/+/OXT-Cre dams with Trpc5 restoration in OXTPVH neurons showed reduced depression-like and anxiety-like behaviors. Our study indicates that the postpartum depression and impaired maternal behavior of Trpc5 deficient female mice are mediated by impaired function of OXTPVH neurons. This revelation not only offers crucial insights into the pathogenesis of postpartum depression but also provides a foundation for potential therapeutic interventions.
Presentation: 6/2/2024
7926 Hypophysitis and Hypopituitarism Caused by Neurosyphilis in a Patient with Chronic HIV Infection
Authors: Malapur Bina , Jakoby Michael G 
Published: October 2024

Abstract
Disclosure: B. Malapur: None. M.G. Jakoby: None.
Introduction: Neurosyphilis is now mostly limited to individuals with HIV infections. We present a case of neurosyphilis complicated by hypophysitis and hypopituitarism in an HIV patient. Case: A 44-year-old male with chronic HIV and noncompliance with antiretroviral therapy presented for evaluation of a rash and photophobia. A copper-colored maculopapular rash was observed on the face, trunk, palms, and lower extremities. Neurosyphilis was diagnosed based on positive RPR (titer 1:64) and treponemal antibodies in cerebrospinal fluid. Mild hyponatremia, systolic blood pressure &lt; 100 mm Hg, and plasma glucose 68 mg/dL raised concern for secondary adrenal insufficiency, and 8 AM cortisol was 2.7 mcg/dL. ACTH level was inappropriately low (16 mcg/dL), and the patient was also found to have secondary hypothyroidism (free T4 0.4 ng/dL [0.5-1.3], TSH 1.25 mIU/L [0.45-1.33]) and hypogonadism (testosterone &lt; 10 ng/dL [270-1070]), LH 1.0 mIU/mL [1.2-8.6]). MRI revealed a non-enhancing, hypointense 12 x 4 x 4 mm mass in the anterior pituitary. The patient was started on treatment for T. pallidum, antiretroviral therapy, and hormone replacement with hydrocortisone and levothyroxine. On evaluation six months later, hypogonadism had resolved (testosterone 387 ng/dL, LH 6.3), and repeat MRI demonstrated resolution of the pituitary mass. Unfortunately, the patient was subsequently lost to follow up. Discussion: Hypophysitis complicating neurosyphilis in adults is rare and appears to be documented entirely in the case report literature. The first two cases were published in the 1950’s, prior to awareness of HIV, and hypopituitarism resolving after treatment with penicillin was documented for one patient. The first case in an HIV patient was published in 2013, and a case in a patient confirmed to be free of HIV was published in 2015. This patient’s presentation and course is similar to other cases published to date, with headache and/or photophobia, diffuse pituitary enlargement or focal pituitary mass, hypopituitarism, and resolution of hormonal and anatomic abnormalities after treatment for neurosyphilis. Though hypophysitis and hypopituitarism appear to occur rarely, they should be considered in patients with suspected or confirmed neurosyphilis presenting with headache or photophobia and clinical or laboratory findings that may be due to anterior pituitary deficits.
Presentation: 6/1/2024
12219 Hypothalamic Regucalcin Modulates Body Temperature Through Thyrotropin-releasing Hormone (trh)in Aging
Authors: Kim Min Soo , Jang Min Jun , Choi Jeongyoon 
Published: October 2024

Abstract
Disclosure: M. Kim: None. M. Jang: None. J. Choi: None.
Hypothalamic Regucalcin modulates body temperature through Thyrotropin-Releasing Hormone (TRH) in aging: Min Jun Jang[1],[2], Jeongyoon Choi[1] and Min Soo Kim[1],[3],[4]* [1] Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea, [2]Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, [3]Division of Bio-Medical Science & Technology, KIST School, Korea National University of Science and Technology (UST), Seoul 02792, Republic of Korea, [4]KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
Regucalcin (RGN), recognized as a calcium-binding protein and aging marker, plays a pivotal role in maintaining cellular homeostasis and function by contributing synthesis ascorbic acid in liver. However, the role of RGN in hypothalamus utilizing peripheral homeostasis is not unclear even the expression levels of mRNA increased in aged brain. Interestingly, the levels of RGN were decreased in other organ, including liver and kidney in aging progression. We found that RGN expression was highly increased in Medio-basal Hypothalamus (MBH) in aged mice. When we down-regulated RGN expression by using AAV-shRNA in MBH of aged mice, thermogenic activities in cold chamber were decreased compared to scramble virus injected mice (control). In addition, we found that over-expression of RGN in MHB of young mice showed increase of body temperature levels. Investigation into genes associated with TRH neuron activation, known to be stimulated under low-temperature exposure, confirmed our hypothesis, demonstrating reduced expression in TRH-related genes in mice with decreased RGN. The results suggest a vital role for hypothalamus-specific RGNs in the regulation of temperature homeostasis through the modulation of TRH neurons. Keywords: Regucalcin, RGN, Body Temperature, Thermoregulation, Cold stress, Thyroid hormone, TRH
Presentation: 6/2/2024
6509 IGF-1 receptor and insulin receptor in LepRb neurons coordinates body growth, reproduction, and metabolism
Authors: Wang Mengjie , Hill Jennifer Wootton 
Published: October 2024

Abstract
Disclosure: M. Wang: None. J.W. Hill: None.
Growth and reproduction are tightly linked. Growth hormone (GH) deficiency results in a profound suppression of postnatal growth accompanied by severely delayed puberty and reproductive senescence, while GH excess is correlated with the reverse. The specific mechanism underlying this delay is undefined. Although leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, the role of insulin-like growth factor 1 receptor (IGF1R) signaling in LepRb neuron function is unknown. Previous studies have shown that IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and mice simultaneously lacking IGF1R and IR in LepRb neurons (IGF1R/IRLepRb mice) to test if IGF1R and insulin receptor (IR) cooperatively regulate metabolic and reproductive functions. IGF1RLepRb and IGF1R/IRLepRb mice displayed delayed onset of puberty and impaired fertility in both sexes, which suggested that both IGF1R and IR in LepRb neurons are required for normal reproduction. Additionally, we found transient growth retardation in IGF1RLepRb and IGF1R/IRLepRb mice. Loss of IGF1R in LepRb neurons led to lower serum IGF-1 and GH levels in male mice and impaired trabecular and cortical bone development in mice of both sexes. Only transient and mild changes were noticed in the body weight. However, we found IGF1R and IR in LepRb neurons jointly regulate body mass composition, energy homeostasis and glucose homeostasis, as shown by elevated fat mass composition, low energy expenditure and low physical activity in IGF1R/IRLepRb mice. Taken together, these studies identify the unique and cooperative role of LepRb IGF1R and IRs in the regulation of body growth, reproduction, and metabolism.
Presentation: 6/3/2024