bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRI284 The GnRH Pulse Generator Activity In Mouse Models Of Polycystic Ovary Syndrome
Authors: Zhou Ziyue , Pardo-Navarro Maria , Han Su Young , Herbison Allan Edward 
Published: October 2023

Abstract
Disclosure: Z. Zhou: None. M. Pardo-Navarro: None. S.Y. Han: None. A.E. Herbison: None.
Up to one in five women worldwide suffer from polycystic ovary syndrome (PCOS), a condition typified by problems with fertility, high androgen levels, and altered metabolism. Primarily due to the unknown aetiology of this disorder, limited strategies are available for PCOS treatment. The hypothalamic GnRH pulse generator is responsible for driving the pulsatile release of LH to control ovarian function. As PCOS patients show profound increase in LH pulse frequency, it is thought that over-activity of the GnRH pulse generator may have a major role in generating the sub-fertility of women with PCOS. Recent studies involving the real-time imaging of neural activity in genetic mouse models have revealed that a population of kisspeptin neurons located in the arcuate nucleus of the hypothalamus is the long-sought after “GnRH pulse generator”. These arcuate kisspeptin neurons exhibit synchronization events (SEs) that correlate perfectly with pulsatile LH secretion. With this technique, we aimed to characterize the activity pattern of the arcuate kisspeptin neurons in two most-widely used mouse models of PCOS: prenatal androgen (PNA) and peripubertal androgen models. In the first model, PNA female mice exhibited near-acyclic estrous cycles as previously reported, but surprisingly exhibited only a slightly (∼30%) increased frequency of arcuate kisspeptin neuron SEs over a 24-hour recording period compared to the controls. The profiles and dynamics of individual SEs were not different between PNA and control animals. Concurrent fiber photometry recording and serial blood sampling showed that each SE is tightly followed by an LH pulse in all animals. Three weeks following ovariectomy, the SE frequency and profile were not different between PNA and control mice. In the second peripubertal model, female mice implanted with dihydrotestosterone capsules at 3-weeks of age exhibited significant weight gain but decreased arcuate kisspeptin neuron activity over a 24-hour recording period also without changes in SE dynamics compared to the controls. In conclusion, it appears that neither of the two most-commonly used PCOS mouse models mirror the human condition in which many PCOS women exhibit robust increases in pulsatile LH secretion.
Presentation: Friday, June 16, 2023
FRI285 Evidence For ZIC1 As A Novel Gene For Isolated Hypogonadotropic Hypogonadism With Phenotypic Pleiotropic Intersection With Cerebellar Malformation
Authors: Cassin Jessica , Keefe David L , Sung Kaitlin E , Bojo Celine C , Santiago Gisselle , Plummer Lacey , Salnikov Kathryn B , Seminara Stephanie B , Balasubramania Ravikumar , Mellon Pamela L 
Published: October 2023

Abstract
Disclosure: J. Cassin: None. D.L. Keefe: None. K.E. Sung: None. C.C. Bojo: None. G. Santiago: None. L. Plummer: None. K.B. Salnikov: None. S.B. Seminara: None. R. Balasubramania: None. P.L. Mellon: None.
Isolated Hypogonadotropic Hypogonadism (IHH) is a condition marked by absent pubertal development and low sex steroids in the setting of low/normal gonadotropins. Mutations in known IHH genes only explain &lt;50% of the genetic etiology suggesting significant missing heritability in IHH. To explore this missing IHH heritability, we examined whole exome sequencing data from approximately 1400 IHH probands for rare genetic variants in novel genes that are enriched in IHH patients. We identified four IHH probands with rare, novel heterozygous variants in ZIC1 (p.H134Rfs*21, p.Y287X, p.E299K, p.S413Y), a gene encoding C2H2-type zinc finger protein (rare variant enrichment p &lt;0.0001 for both truncating and missense alleles). Prior literature review show that heterozygous deletions affecting the ZIC1 gene have been linked to Dandy Walker malformation [DWM], a cerebellar malformation, while gain-of-function ZIC1 single nucleotide variants have been linked to coronal craniosynostosis (premature cranial suture fusion). Notably, two IHH subjects with novel ZIC1 variants in our cohort exhibited posterior fossa abnormalities (DWM [p.H134Rfs*21] and ventriculomegaly [E299K]) but none had any cranial suture defects. Given the above genetic enrichment, phenotypic overlap between DWM and IHH, and ZIC1’s known high expression in the hypothalamus, we explored whether ZIC1 regulates the expression of hypothalamic releasing factors. We determined that ZIC1 overexpression increases GNRH1 luciferase expression in the immortalized GnRH cell line, GT1-7. We next explored whether the rare ZIC1 variants identified in the four IHH probands would affect this phenotype. We discovered that three of the four ZIC1 variants significantly reduced GNRH1-luciferase expression. Of those, one truncating mutation, p.H134Rfs*21, resulted in lower ZIC1 protein content in the cell and failure to localize to the nucleus, suggesting a hypomorphic mechanism of action. These findings implicate ZIC1 variants as putatively causal for IHH. Further studies will define the precise ZIC1 transcriptional targets that relate to ZIC1’s pleotropic effects on GnRH transcription, neuronal function, cerebellar development, and cranial suture fusion.
Presentation: Friday, June 16, 2023
FRI286 Stimulation Of Egr1 Expression Is Mediated By A Gαq/11-signaling Pathway In A Pattern Distinct From That Of MEK/ERK At High And Low GnRH Pulse Frequencies
Authors: Stamatiades George Alexiades , Kim Han K , Carroll Rona Stephanie , Kaiser Ursula B 
Published: October 2023

Abstract
Disclosure: G.A. Stamatiades: None. H.K. Kim: None. R.S. Carroll: None. U.B. Kaiser: None.
Introduction: The pulsatile release of the hypothalamic decapeptide, GnRH, activates signal transduction cascades in pituitary gonadotropes to control the synthesis and secretion of LH and FSH, hormones critical for normal reproductive function and fertility. LH and FSH release are differentially regulated by varying GnRH pulse patterns, with LH secretion being preferentially stimulated at high (e.g., every 30 min) GnRH pulse frequencies, while FSH secretion is preferentially induced at low (e.g., every 2 hour) GnRH pulses. LH is a heterodimer comprised of a common α subunit and a distinct LHβ subunit, with Lhb gene (encoding LHβ) transcription being preferentially stimulated at the higher GnRH pulse frequencies. It is well established that Egr1 is a key inducer of Lhb expression upon pulsatile GnRH stimulation. In addition, it has been shown that MEKI/II inhibition abrogates the induction of Lhb mRNA levels at both high and low GnRH pulse frequencies. Hypothesis:Egr1 expression is mediated by a Gαq/11-signaling pathway that includes MEK/ERK at both high and low GnRH pulse frequencies. Methods: To determine whether a Gαq/11-mediated pathway regulates Egr1 expression upon GnRH stimulation, LβT2 cells transduced with lentiviruses encoding scrambled or Gnaq/11 shRNA were perifused and treated with pulsatile GnRH at either high (q30min) or low (q2h) pulse frequencies, or with medium only, for 20 hours. Following the same perifusion paradigm, ERK1/2 phosphorylation was also assessed. Results: LβT2 cells transduced with a scrambled control shRNA showed a GnRH pulse frequency-dependent pattern of induction of Egr1 expression, with significantly greater induction at high than at low GnRH pulse frequency, compared to cells perifused with media only. In addition, Gαq/11 depletion reduced Egr1 mRNA levels at both high and low GnRH pulse frequencies, but the frequency dependence was maintained. A GnRH pulse frequency-dependent pattern of induction of ERK1/2 phosphorylation was observed, with significantly greater induction at low than at high GnRH pulse frequency in control cells transduced with scrambled control shRNA, consistent with prior studies from our group. Following Gnaq/11 KD, the induction of ERK1/2 phosphorylation was reduced at both GnRH pulse frequencies, with loss of the pulse frequency dependence. Conclusion: Taken together, these findings suggest that a Gαq/11-signaling pathway involving Egr1 induces Lhb expression at both pulse frequencies. However, the link between MEK/ERK and Egr1 needs to be further investigated, given the differences in the GnRH pulse frequency dependent patterns of induction.
Presentation: Friday, June 16, 2023
FRI289 It Takes A Village: Musashi And Its Associated Proteins In The Adenohypophysis
Authors: Bronson Katherine L , Hardy Linda , Lagasse Alexandra , MacNicol Angus M 
Published: October 2023

Abstract
Disclosure: K.L. Bronson: None. L. Hardy: None. A. Lagasse: None. A.M. MacNicol: None.
Musashi is an RNA-binding protein that regulates stem and progenitor cell fates. Interestingly, we have reported expression of Musashi pituitary stem cells as expected but also in the differentiated anterior pituitary hormone-producing cell lineages as well as. The adult anterior pituitary relies on the functional cellular plasticity of its hormone-producing cell populations to maintain endocrine homeostasis when physiological demands change. Both Musashi isoforms (Musashi1 and Musashi2) are highly conserved across species and have two N-terminal RNA-recognition motifs (RRMs) and a disordered C-terminus containing two regulatory phosphorylation sites. Musashi can selectively activate or repress the translation of mRNAs depending on the transcript and cellular context. While Musashi phosphorylation is required for translational activation, Musashi does not possess inherent enzymatic activity; therefore, co-associated proteins must mediate Musashi-directed translational control. Musashi immunoprecipitation studies initially identified 50 co-associated proteins in Xenopus oocytes, but only a subset of these were directly implicated in Musashi-dependent translational activation (e.g. Elavl1 and Pabp4). The identity of Musashi-associated proteins in the anterior pituitary and their requirement for Musashi function are not known. To this end, we have immunoprecipitated Musashi from whole male mouse pituitaries for mass spectrometry analysis. 206 proteins significantly (adj p-value &lt; 0.05) associated with Musashi1 and Musashi2, and seven of these overlapped with the Xenopus dataset: Elavl1, Pabp4, Hnrnpc, Mov10, Pura, Rps27, and Upf1. Three proteins from the mouse mass spectrometry dataset were selected for further analyses. Sam68 is a multi-functional protein that sensitizes ovaries to FSH and LH, as well as mediates the activation of leptin and insulin signaling in a variety of tissues. Ago2 is a component of the RNA-induced silencing complex that is necessary for miRNA-directed translational control and is known to associate with Musashi1. The AU-rich element binding protein Elavl1 (HuR) contributes to Musashi-dependent activation of target mRNAs in Xenopus and also stabilizes Gnrhr mRNA in LβT2 cells and sensitizes them to GnRH signaling. We will present our ongoing studies on the requirement for these protein interactions for Musashi-directed mRNA translational regulation.
Presentation: Friday, June 16, 2023
FRI312 Diplopia And Headache After Treatment With GnRH Agonist
Authors: Zakkar Adam A , Al Mushref Mazen , Fadanelli Margaret 
Published: October 2023

Abstract
Disclosure: A.A. Zakkar: None. M. Al Mushref: None. M. Fadanelli: None.
Case Report: The Patient is a 46-year-old male with past medical history of hypertension and prostate cancer, currently undergoing treatment with leuprolide acetate injections, who presented to the emergency department with a complaint of worsening headache. He received his second injection 3 days prior to admission and within hours he developed a headache in the frontal area that was continuous and worsening over time, increasing with positional changes of his head. One day after the treatment he developed persistent double vision. The patient reported that he has had worsening vision over the last year and was to see an ophthalmologist but was diagnosed with prostate cancer at the same time so he became more focused on the oncologic care. He also reported poor balance, excessive thirst and increased urination of large volumes of urine every hour with nocturia several times. On exam the vital signs were normal, he was A&Ox4 and in no distress. He had left abducens and oculomotor nerve palsy but an otherwise benign exam. MRI of the brain revealed a sellar mass measuring 2.2 x 1.7 x 2.3 cm consistent with pituitary macroadenoma extending into the suprasellar cistern, compressing the pituitary stalk and the optic chiasm. Patient was evaluated by ophthalmology who noted +2 optic nerve edema of the left eye. Laboratory evaluation revealed low ACTH of 6 pg/mL at 5:30AM along with corresponding cortisol level of only 1.6 mcg/dL. FSH was low and LH undetectable as expected with GnRH agonist therapy. Growth hormone level, IGF-1, l and prolactin levels were all normal. The TSH was 0.50 microunits/mL with a freeT4 of 1.0. Urinalysis revealed dilute urine with specific gravity &lt;1.006. Serum sodium on admission was 137 mmol/L and after overnight fasting was 140 mmol/L. The patient was started on desmopressin 0.1 mg po at bedtime and on intravenous dexamethasone 4 mg q6hrs. He was evaluated by neurosurgery and ENT who recommended trans-sphenoidal resection of the mass. Pathology report of the specimen was consistent with a pituitary adenoma with infarction without hemorrhage. The patient reported an improvement in his left eye vision and lateral rectus palsy. He was transitioned to oral hydrocortisone 20 mg daily and 10 mg every afternoon prior to discharge. On follow up with endocrinology several months later he was found to have persistent adrenal insufficiency and developed central hypothyroidism that required treatment. Conclusion: Patients with an undiagnosed pituitary adenoma are at risk of tumor expansion and mass effect as well as pituitary apoplexy during treatment with GnRH agonists. In our case clinical presentation was consistent with pituitary apoplexy without evidence of pituitary hemorrhage soon after GnRH agonist. A full ophthalmologic exam may be an appropriate screening prior to initiation of such therapy.
Presentation: Friday, June 16, 2023
FRI324 Pituitary Macroadenoma With Carcinomatous Transformation And Multiple Cranial Masses And Spinal Leptomeningeal Carcinomatosis: A Case Report
Authors: Cristancho Cagney , Szabo Gabriela 
Published: October 2023

Abstract
Disclosure: C. Cristancho: None. G. Szabo: None.
Background: Aggressive pituitary tumors are invasive tumors not responding to standard therapies and presenting with multiple local recurrences; if metastases occur, the tumors are defined as pituitary carcinoma (PC) Clinical Case: 51- year-old Hispanic woman with history of pituitary macroadenoma diagnosed at the age of 41, when presented with weight gain and decrease in visual acuity. Per records initial Brain MRI reported hyperintense sellar lesion of 2.1x2.3x2.6 cm with supra-sella extension and shift of optic chiasm. Patient had 4 pituitary surgeries between 2014-2018 due to growth and had radiation and Temozolomide between 2018-2020. Pathology was diffusely positive for ACTH, PRL, and Ki-67 was 10-20%, P 55 positive staining was 25-30%. As a result from pituitary surgeries patient developed central hypothyroidism, and central AI. Subsequent mornings cortisol were nl between 16-18. No UFC or LNSC were available. MEN1 negative. Brain MRIs done between 2019 and 2020 showed stable 13x8 mm residual pituitary mass with postoperative changes. Patient denied history of diabetes, fragility fractures, HTN, DVTs. She had regular menstrual periods until age of 42. Had left adrenal mass resection in 2019 with benign pathology results. During her initial endocrinology visit her ROS was positive for lower back pain and mild proximal muscle weakness. Patient denied visual changes, headaches, skin changes, polydipsia or polyuria. Physical exam was remarkable for small buffalo hump, and 5-/5 proximal muscle weakness. Negative for moon face, purple striae, acanthosis nigricans, hirsutism, acne. Initial tests were consistent with ACTH-dependent CS: elevated cortisol PM: 18.2 (n &lt;10ug/dL) and LNSC 0.58 and 0.64 mcg/dl (n &lt;0.09), 24-hr UFC 264 (n &lt;50 mcg/dl), abnormal ACTH 150 (n &lt;50 pg/ml).Brain MRI revealing extra-axial mass of 1.6 x1.1 cm overlying posterior aspect of right cerebellar hemisphere and focal lesion in left prepontine cistern of 0.8 cm. Leptomeningeal Enhancement. No sellar mass. Spine MRI showed scattered nodules lining the cord throughout the cervical and upper thoracic spine concerning for metastatic disease. Right cerebellar mass biopsy positive for metastatic pituitary neuroendocrine tumor corticotroph cell subtype, ACTH, chromogranin A, synaptophysin positive; PRL, TSH, GnRH, alpha subunit staining was negative; Ki-67 of 2%. Temozolomide, Capecitabin, and Ketoconazole 200 mg TID were started. Subsequent LNSC &lt;0.03 and &lt;0.03 mcg/dl, UFC at 3 different times were 12.8, 11.2 and 8.1 mcg/dl showing rapid decrease of cortisol levels in a 4-week period. A block-replace approach was decided with Dexamethasone 1 mg daily and a lower dose of Ketoconazole 200 mg BID. Patient reports no side effects.
Presentation: Friday, June 16, 2023
FRI335 Late Surgical Management For Symptom Control In A Patient With History Of Pituitary Apoplexy
Authors: Zahra Sundas , Manas F N U , Yavuz Sahzene 
Published: October 2023

Abstract
Disclosure: S. Zahra: None. F. Manas: None. S. Yavuz: None.
Introduction: Pituitary Apoplexy is a rare life-threatening condition which presents with sudden onset headache, and neuro-ophthalmic symptoms. The diagnosis is challenging and requires a high index of clinical suspicion, especially in patients with pre-existing pituitary macroadenomas. MRI is the imaging modality of choice to confirm the diagnosis. The management is tailored according to the severity of clinical presentation. A conservative approach is recommended in stable patients with no or mild visual changes. Surgical management is usually reserved for patients with severely reduced visual acuity, and worsening mentation. Here we present a case of a patient with pituitary apoplexy who underwent late surgical resection due to persistent intractable headache. Case Presentation: 24 years old female with no significant past medical history presented to the emergency with worsening headache and blurry vision since last 2 weeks. The patient also complained of weight gain, fatigue, amenorrhea, and intermittent galactorrhea for the last 8 months. Physical examination was unremarkable, no visual deficit or neurological deficit was present. Blood work was remarkable for mildly elevated prolactin of 46.1 ng/ml (normal: 3.0-18.6 ng/ml) and low morning cortisol of 4.0ug/dl (normal:4.5-22.7 ug/dl). MRI of the brain revealed 13mm x 7.5mm focus of signal abnormality within the posterior aspect of the Sella, suggestive of a hemorrhagic adenoma. She was diagnosed with pituitary apoplexy with secondary adrenal insufficiency and was started on IV hydrocortisone. Neurosurgery was consulted, however no surgical interventions were recommended since the patient had no evidence of mass effect on optic chiasm or vision loss or changes in mentation. She was discharged on oral steroids. Her prolactin level, which was initially elevated likely due to compression of infundibulum from hemorrhage, normalized a few weeks after hospitalization. She was followed with MRI which showed a stable pituitary lesion. The patient continued to have intermittent episodes of headache which were initially managed conservatively but later the patient opted for elective surgery due to the persistence of intractable headaches. She underwent endoscopic transsphenoidal resection of pituitary tumor without any complications. At follow up visits, the patient’s symptoms had resolved, and her hypothalamic-pituitary axis evaluation and MRI was normal. Conclusion: The management of pituitary apoplexy is controversial due to its rarity and variation in the severity of symptoms at the time of presentation. In the recent past, conservative approaches have become more common in patients who are stable with little or no visual defects. The neurosurgical approach is usually reserved for patients with deteriorating mentation or worsening visual changes, but it can be used in patients with persistent severe symptoms.
Presentation: Friday, June 16, 2023
FRI343 A Case Of Postpartum Adrenal Crisis Secondary To Empty Sella
Authors: Alzenaidi Ahlam 
Published: October 2023

Abstract
Disclosure: A. Alzenaidi: None.
Empty sella occurs when the pituitary gland appears shrunken or invisible and CSF fills the sella turcica space. It is commonly defined in the radiology literature as an incidental finding of no clinical significance, but an association with sequalae of lymphocytic hypophysitis (LH) was observed in a mouse model of the disease. However, patient data on the development of empty sella are scant and present later in life.To our knowledge, this is the second case of postpartum empty sella with clinically suspected LH and early presentation within 2 yr postpartum. A 31-year-old woman presented to our endocrine clinic for pituitary evaluation. She was 16 months post-spontaneous vaginal delivery with no history of excessive bleeding or blood transfusion. Her pregnancy was uneventful except for headache without visual changes after the thirty-fifth week, which improved with nasal steroid spray. Four to six weeks postpartum, she presented to her primary care physician with palpitations, fatigue and weight loss. Labs showed TSH, 0.001 mIU/mL (0.3-4.2); free T4, 30.98 pmol/L (9-19); free T3, 23.04 pmol/L (2.6-5.7); and thyroid peroxidase antibodies, 512.6 IU/mL (&lt;5.6). Thyroid function tests improved after a short course of carbimazole, although without significant improvement of her symptoms. At 10 months postpartum, she presented to the ED with worsening fatigue, weight loss, vomiting and dizziness. Further history revealed oligomenorrhea and an inability to lactate since delivery. On exam, her heart rate was 100 b/m, respiratory rate was 20 b/m, BP was 90/50 mmHg, and temperature was 38.8 C. Labs showed WBC, 4.26 x 103/µL (4-11); Hb, 9.9 g/dL (11.8-14.8); PLT, 181 x 103/µL (150-450); Na, 136 mEq/L (135-145); K, 3.6 mEq/L (3.5-5.1); HCO3, 20 mmol/L (22-29); creatinine, 62 µmol/L (49-90); lactate, 0.82 mmol/L (0.5-2.2); FSH, 6.16 IU/L; prolactin, &lt; 12.6 mIU/L (110-564) (prolactin prepregnancy was 233 mIU/L); TSH, 6.7 (0.3-4.2); free T4, &lt;5.15 pmol/L (9-19); ACTH, 0.22 pmol/L (1.03-10.73); cortisol, 50.3 nmol/L (1.82 µg/dl); and peak cortisol after 250 mcg ACTH stimulation test, 223.5 nmol/L (8.1 µg/dl). She was treated with intravenous fluids and hydrocortisone. Pituitary MRI showed marked compression of the pituitary tissue with concave superior margins due to partially empty sella. She was maintained only on hydrocortisone replacement. During follow-up, her menstrual cycle resumed regularly, and fatigue and thyroid function improved (TSH, 2.65 µIU/ml; free T4, 12.13 pmol/L). Our patient had autoimmune thyroiditis with positive TPO antibodies, and it is possible that she had coexistent LH. LH typically presents as a pituitary mass; however, our patient had empty sella.In conclusion, the development of empty sella in this case suggests that postpartum atrophy of the pituitary gland can be life threatening if associated with hypopituitarism. Early recognition could prevent serious consequences.
Presentation: Friday, June 16, 2023