bluuebunny/crossref_metadata_2025 huggingface dataset:
THU090 18F-FET PET-MRI; A Novel And Improved Technique For Detection Of Small Functional Pituitaryadenomas
Authors: Pruis Ilanah , Verbrug Erik , Smits Marion , Vernooij Meike , Feelders Richard Abraham , Blavers Rutger , Velthuijzen Sophie , Neggers Sebastian J CM M
Published: October 2023

Disclosure: I. Pruis: None. E. verbrug: None. M. smits: None. M. vernooij: None. R.A. Feelders: None. R. Blavers: None. S. velthuijzen: None. S.J. Neggers: None.

Background Small functional pituitary adenomas can cause severely disabling symptoms and early death, however, surgical planning is often complicated due to inconclusive diagnostic MRI in up to 40% of patients and therefore hamper cure rates. We here introduce a novel method for the detection of small functional pituitary adenoma by O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET-MRI. Methods Patients with Cushing’s disease (CD) or acromegaly with a suspected primary or recurrent small functional pituitary adenoma underwent [18F]FET PET-MRI. Focal uptake of [18F]FET was evaluated by a single nuclear radiologist and MRI was separately evaluated by a single neuroradiologist. Outcomes were compared with clinical follow-up and sensitivity and positive predictive values (PPV) were calculated. Findings Consecutive 28 patients, 68% female, mean age 50 years (range: 24–71), with CD (n=22; 79% or acromegaly (n=6; 21%) were scanned. 17 CD patients with a primary diagnosis had also undergone IPSS and 3 (50%) had a primary acromegaly diagnosis. 14/22 CD patients (64%) and 1/6 acromegaly underwent transsphenoidal surgery after [18F]FET PET, others are waiting or refused. Twenty-two CD patients (100%) had a positive [18F]FET PET, allowing to identify pituitary adenomas as small as 3 mm in size on accompanying MRI. 11/14 CD patients who underwent subsequent transsphenoidal surgery are biochemically in remission; rendering an estimated sensitivity of 100% and a PPV between 78–100% to detect CD. Four acromegaly patients (67%) had a positive [18F]FET PET. One acromegaly patient was biochemically in remission after transsphenoidal surgery. Conclusion [18F]FET PET-MRI shows high accuracy for localizing small functional pituitary adenoma in patients with CD and acromegaly. The diagnostic yield of this hybrid imaging technique exceeds that of MRI alone and IPSS and provides a welcome improvement for diagnosis, planning of surgery and follow-up.

Presentation: Thursday, June 15, 2023
THU120 Validation Of A Novel Automated System, Fluispotter®, For Serial Sampling Of Dried Blood Spots
Authors: Krogh Jesper , Plomgaard Peter Stendahl , Frikke-Schmidt Ruth , Velschow Sten , Johannesen Jesper , Hilsted Linda , Schrøder Malene , Feldt-Rasmussen Ulla
Published: October 2023

Disclosure: J. Krogh: None. P. Plomgaard: None. R. Frikke-Schmidt: None. S. Velschow: None. J. Johannesen: None. L. Hilsted: None. M. Schrøder: None. U. Feldt-Rasmussen: None.

Repeated blood sampling is required in certain clinical and research settings, which is currently performed by drawing blood from venous catheters requiring manual handling of each sample at time of collection. Collecting samples in a stressful environment, e.g. during the night or admission as inpatient to hospital potentially influences the hormone concentrations to be studied. The hypothesis of this study was that a novel body-worn device for repeated serial samples, Fluispotter®, with automated extraction, collection and storage of up to 20 venous dried blood spot samples over the course of 20 hours may overcome problems with current methods for serial sampling. The purpose of the study was to assess the performance and safety of Fluispotter for the first time in healthy subjects and perform cortisol measurements from the blood spots by mass spectrometry. Fluispotter consists of a cartridge with tubing, reservoir for flushing solution, pumps and filter-paper and a multi-lumen catheter placed in the brachial vein. We recruited healthy subjects for testing in an in-hospital setting. Fluispotter was attached to 22 healthy subjects of which 9/22 (40.9 %) participants had all 20 samples taken, which was lower than the expected 80% (p = 0.02). The main reason for sample failure was clogging of blood flow which was observed in 11/22 (50 %) of the participants. No serious adverse events occurred, and the participants rated the pain from insertion and removal of catheter as very low. A cortisol profile showed nadir values at midnight and highest values at 5 a.m. Although full sampling was not successful in all participants, the Fluispotter technology proved safe and highly acceptable to the participants producing the expected cortisol profile in an undisturbed environment without the requirement of staff during sample collection. The minor technical problems of blood clotting can be solved by increasing the flow of the rinsing fluid between samples. The Fluispotter may thus facilitate future circadian hormone assessments e.g. in patients on pituitary cortisol replacement with a perspective of improving management of patients with pituitary insufficiency.

Presentation: Thursday, June 15, 2023
FRI273 Generation And In Vitro Characterization Of A Novel Immortalized Ovine Neuronal KNDy Cell Line
Authors: Toyoizumi Rebekka , Markgraf Christopher Y , Starman Alia , Rodriguez Emily , Lee Blake L , Bahn-Bales Roxanne , Stricklin Olivia , Estill Charles , Roselli Charles E , Chappell Patrick E
Published: October 2023

Disclosure: R. Toyoizumi: None. C.Y. Markgraf: None. A. Starman: None. E. Rodriguez: None. B.L. Lee: None. R. Bahn-Bales: None. O. Stricklin: None. C. Estill: None. C.E. Roselli: None. P.E. Chappell: None.

The multiphenotypic hypothalamic KNDy neurons play a critical role in the neuroendocrine regulation of reproduction, and via their stimulation of GnRH release, are requisite for fertility and pubertal progression. In vivo evidence has accumulated identifying this more caudal population of Kisspeptin neurons in mediating predominantly negative feedback effects of gonadal steroids, and their ability to synthesize and secrete kisspeptin (KP), neurokinin B (NKB/Tac3), and dynorphin (Dyn) implicates them as crucial regulators of GnRH pulse generation. We have previously generated murine immortalized arcuate KNDy neuronal cell lines to explore molecular mechanisms underlying the steroid hormone regulation of these cells, and in the current study, we characterize a novel immortalized ovine neuronal cell line model of KNDy (oKNDy) cells derived from fetal female sheep brain (∼133 days of fetal development). Clonal lines were derived from isolated mediobasal hypothalamic explants using lentiviral infection of neurons with plasmids encoding SV40 large T-antigen. These neurons express ovine kiss1, tac3, and pdyn, as well as steroid receptors esr1, esr2, and pgr. Similar to KNDy neurons in vivo, receptors for Tac3 (tacr3) and Dyn (oprk1) were also found to be expressed in our oKNDy cells. Further, low physiological concentrations (5-50pM) of 17β-estradiol (E2) were found to significantly repress kiss1 and tac3 expression, while having no effect on tacr3. Concentrations of E2 and progesterone (P4) approximating proestrous levels maximally repressed kiss1 and tac3 after 24h, with elevations in pdyn noted under the same conditions. While cells exposed to higher E2 levels exhibited greater kiss1/tac3 repression, P4 exposure alone revealed stimulation of expression with increasing P4. Since these neurons were derived from the short-day seasonally breeding sheep, they can also be used to explore how circannual timing cues derived from the pituitary pars tuberalis may exert gating signals on the reproductive axis as previously modeled in vivo. Consistent with this, we have found high levels of thyroid hormone receptor α (thra) expression in our oKNDy neurons, suggesting they can respond to locally-synthesized T3. We are continuing to characterize these oKNDy neuronal cells in culture in order to provide insight into GnRH pulse generation and construct molecular models of neuronal responsiveness to steroids and other regulatory inputs.

Presentation: Friday, June 16, 2023
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

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

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 <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 <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

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

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 < 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

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 <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

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 <10ug/dL) and LNSC 0.58 and 0.64 mcg/dl (n <0.09), 24-hr UFC 264 (n <50 mcg/dl), abnormal ACTH 150 (n <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 <0.03 and <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

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

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 (<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, < 12.6 mIU/L (110-564) (prolactin prepregnancy was 233 mIU/L); TSH, 6.7 (0.3-4.2); free T4, <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
FRI347 Lymphocytic Hypophysitis In The Setting Of Necrotizing Granulomatous Inflammation
Authors: Kelly Clare , Ghalib Luma
Published: October 2023

Disclosure: C. Kelly: None. L. Ghalib: None.

Hypophysitis is rare; accounting for 0.24-0.39% of all pituitary diseases. Hypophysitis can be primary or secondary in nature. Granulomatous disease rarely causes pituitary enlargement, but Sarcoidosis and Granulomatosis with Polyangiitis have been documented to cause granulomatous infiltration of the pituitary. This case regards a man with granulomatous infiltration of the pituitary not consistent with either of the aforementioned disease processes. A 40 year old male presented to Urgent Care with headaches and blurry vision. Headaches were unresponsive to analgesics. The patient then presented to his PCP with the same complaints. MRI was then performed which showed a heterogeneously enhancing sellar and suprasellar mass. He was evaluated by Neurosurgery who recommended he undergo endoscopic resection of the pituitary lesion. Preoperative evaluation of pituitary axes were concerning for central hypothyroidism with a TSH of 1.046 uIU/mL (0.550-4.780) and free T4 of 0.76 ng/dL (0.89-1.76),as well as central hypogonadism with a FSH of 0.4 mIU/mL (<18.1), LH of 0.18 mIU/mL (1.5-9.3),and testosterone of 17 ng/dL (87-814). All other axes normal. Resection of the pituitary mass occurred approximately one week later at which time he was evaluated by Endocrinology for the first time. Prior to discharge, the patient was started on levothyroxine, but gonadal replacement was deferred to outpatient setting. Grossly the pituitary mass was concerning for lymphocytic hypophysitis (LH), and thus the patient was discharged on prednisone for empiric therapy. At the time of his endocrinology follow up, his headaches and visual changes had improved, but he was experiencing polydipsia, polyuria, and nocturia. Labs were consistent with Diabetes Insipidus (DI), and he was started on desmopressin. Surgical pathology had returned “acute and chronically inflamed granulation-like tissue associated with necrosis” confirming LH. CT chest was performed to evaluate for secondary causes of granulomatous disease which showed mediastinal lymphadenopathy without parenchymal lung disease. Serologic evaluation was positive for ANA, myeloperoxidase antibody, and SS-B antibody. While attempting to wean his prednisone the patient experienced recurrence of his headaches, which resolved when he returned to higher doses. The patient was evaluated by Pulmonology given the mediastinally mphadenopathy, who recommended bronchoscopy. When specimens from the mediastinal lymph nodes were evaluated by pathology, it was again significant for necrotizing granulomatous disease, but ACE and IL-2 were negative which argued against a diagnosis of sarcoidosis. He was evaluated by Rheumatology who recommended further infectious work upas well as consideration of initiation of a steroid-sparing agent for granulomatous disease. Workup of secondary etiologies for LH is ongoing given the systemic involvement.

Presentation: Friday, June 16, 2023
FRI370 Hyperthyroidism And Acromegaly In A Patient With A Mature Plurihormonal PIT1 Lineage PitNET/Adenoma
Authors: Slack Daniel , Levine Alice C
Published: October 2023

Disclosure: D. Slack: None. A.C. Levine: None.

Background: TSH- and GH-secreting pituitary neuroendocrine tumors (PitNETs) are both rare entities, with an incidence of 1 per million people and 1-4 per million people, respectively. Thyrotroph, somatotroph, and lactotroph cells have the same progenitor, regulated by the PIT1 transcription factor. Thus, it is not unusual for PIT1 positive tumors to exhibit immunhistochemical expression of TSH, GH, and prolactin. It is vanishingly rare, however, for these tumors to secrete multiple biologically active hormones with apparent clinical sequelae. We herein report on a case of a patient with a plurihormonal PIT1 lineage PitNET secreting prolactin with secondary amenorrhea, TSH causing central hyperthyroidism and GH resulting in acromegaly. Clinical Case: A 42-year-old woman with a 1-year history of amenorrhea presented with 3 months of progressive weight loss, fatigue, palpitations, and tremulousness. She was found to have central hyperthyroidism, with an elevated free T4 (>7.77 ng/dL, nl 0.82 – 1.77) and inappropriately normal TSH (3.25 uIU/mL, nl 0.45 – 4.5). Full endocrine workup confirmed central hyperthyroidism with elevated free T4 (5.02 ng/dL) and TSH (4.68 uIU/mL) and also demonstrated hyperprolactinemia (122 ng/mL, nl 4.8 – 23.3 ng/mL), elevated IGF-1 (795 ng/mL, nl 91 – 308 ng/mL), GH (19 ng/mL, nl 0 – 10) and free alpha subunit (28 ng/mL, nl <1.02). Over the ensuing 4 months, she noted enlargement of her lips, nose, feet, and hands. MRI demonstrated a pituitary macroadenoma measuring 2.2 cm x 2.7 cm x 2 cm with asymmetric extension into the left cavernous sinus and mild elevation of the adjacent optic chiasm. She underwent an uncomplicated transsphenoidal resection of the tumor with no residual tumor noted on post-op MRI. Discharge medications were hydrocortisone 10 mg AM and, 5 mg early afternoon and levothyroxine 50 mcg daily. One month postoperatively, labs were notable for a low TSH (0.16 mIU/L), normal free T4 (1.62 ng/dL), down-trending IGF-1 (339 ng/mL), and normal prolactin (15.1 ng/mL). Additionally, AM cortisol and ACTH levels remained normal after holding her morning dose of hydrocortisone. She reported resolution of all presenting symptoms of thyrotoxicosis as well as decreasing size of her hands, feet, and nose. Pathology revealed a mature plurihormonal PIT1-lineage PitNET, with immunoreactivity for PIT1, GH, TSH, and prolactin and MIB-1 index of 3%. Conclusion: This case demonstrates the potential for PitNETs to secrete multiple biologically active pituitary hormones, including prolactin, TSH and GH, highlighting the importance of maintaining an index of suspicion for pituitary causes in the evaluation of thyrotoxicosis and of considering the plurihormonal potential of PitNETs in patients presenting with multiple endocrinopathies.

Presentation: Friday, June 16, 2023
OR17-02 Combining Transcriptomics And Proteomics To Unveil Possible PROP1 Interactors During Embryonic Pituitary Development
Authors: Garcia Lucia Iglesias , Mercogliano María Florencia , Schuster Claudio , Cheung Leonard , Camper Sally Ann , Marti Marcelo , Perez-Millan Maria Ines
Published: October 2023

Disclosure: L. Iglesias Garcia: None. M.F. Mercogliano: None. C. Schuster: None. L. Cheung: None. S.A. Camper: None. M. Marti: None. M.I. Perez-Millan: None.

Congenital hypopituitarism (CH) is a deficiency of one or more hormones produced by the anterior pituitary. The most frequently mutated gene in CH is PROP1, which has a very dynamic expression pattern. In Prop1 mutant mice, the pituitary is dysmorphic, with increased apoptosis and abnormal vascularization. These mutant mice are dwarfs and develop hypopituitarism. In previous work we have shown that PROP1 has a key role in stimulating progenitors to undergo an EMT-like transition before differentiation. The general objective of this work was to elucidate the PROP1 protein complexes in order to understand its role during pituitary development and to evaluate them as candidate genes that can cause congenital hypopituitarism. A GHFT-1 murine cell line expressing biotinylated Prop1 was used and co-immunoprecipitation (Co-IP) assays were performed, followed by Rapid Immunoprecipitation Mass spectrometry of Endogenous (RIME). We obtained an initial set of 786 proteins that co precipitate with PROP1. Ontology enrichment analysis shows that PROP1 immunoprecipitated with several nuclear proteins related to transcriptional regulation and splicing and also with many non nuclear proteins related to cell adhesion and migration. We used LISA and TRANSFAC to predict transcriptional regulators using as input the genes that intersected from Prop1-ChIP-Seq and RNA-seq experiments and obtained 536 genes. We compared this result with the potential PROP1 interaction proteins derived from the RIME to obtain a final list of 37 transcription factors. One possible candidate from this list is the Nuclear Factor I/B or NFIB. Mutations in this gene are related to macrocephaly with impaired intellectual development. We performed a scRNA-Seq at P4 and it showed that NFIB expresses in the same cell clusters as Prop1. Also, we have preliminary results indicating that the pituitary in NFIB KO mice at E13.5 is dysmorphic.

Further experimental work is needed to validate Prop1 interaction partners and to have a better understanding of Prop1 mechanism during pituitary development.

Presentation: Saturday, June 17, 2023
SAT587 Methylation-based Machine Learning Classifiers Discriminate Sellar Tumors By Lobe Origin Using Liquid Biopsy Or Surgical Specimens
Authors: Herrgott Grayson A , Asmaro Karam P , Wells Michael , Nelson Kevin , Thomas Bartow , Hasselbach Laura A , Transou Andrea , Cazacu Simona , Tundo Kelly M , Nadimidla Sudha , Scarpace Lisa , Barnholtz-Sloan Jill , Sloan Andrew E , Selman Warren R , deCarvalho Ana C , Mukherjee Abir , Robin Adam M , Lee Ian Y , Craig John , Kalkanis Steven , Snyder James , Walbert Tobias , Rock Jack , Noushmehr Houtan , Barros Castro Ana Valeria
Published: October 2023

Disclosure: G.A. Herrgott: None. K.P. Asmaro: None. M. Wells: None. K. Nelson: None. B. Thomas: None. L.A. Hasselbach: None. A. Transou: None. S. Cazacu: None. K.M. Tundo: None. S. Nadimidla: None. L. Scarpace: None. J. Barnholtz-Sloan: None. A.E. Sloan: None. W.R. Selman: None. A.C. deCarvalho: None. A. Mukherjee: None. A.M. Robin: None. I.Y. Lee: None. J. Craig: None. S. Kalkanis: None. J. Snyder: None. T. Walbert: None. J. Rock: None. H. Noushmehr: None. A.B. Castro: None.

Background: The differential diagnosis of challenging sellar tumor cases can be inconclusive through imaging features and could benefit from noninvasive diagnostic approaches, such as liquid biopsy (LB). Similar to tissue, LB specimens carry tumor-specific DNA methylation signatures amenable to the construction of accurate machine learning models able to discriminate CNS tumors. We aimed to develop methylation-based classifiers which classify sellar tumors by lobe of origin, using either LB or tumor tissue specimens. Methodology: We analyzed the DNA methylome (EPIC array) of tumor tissue (T) and LB specimens from adult patients with tumors representing each of the three pituitary lobes (Anterior: T=177; LB=37; Intermediate: T= 7; LB: 10 and Posterior: T=44, LB=2 cases). Using the most variably methylated CpG probes derived from the unsupervised variance-based analyses across tumors from different lobes, we applied multi-class linear discriminant analysis to construct machine learning models to classify sellar tumor tissue and/or LB specimens. Results: We generated classifiers based on lobe-specific methylation signatures that were able to discriminate across sellar tumors either using tissue and/or LB specimens (500 and 600 CpGs, respectively) with observed accuracies of ∼99% across independent validation. DISCUSSION/CONCLUSION: Our findings suggest that methylation-based classifiers constitute an accurate diagnostic approach to discriminate sellar tumors according to the lobe origin, either pre-surgically through a blood draw or through surgical tumor specimens. These classifiers are objective approaches that could complement imaging and pathology reports for an accurate diagnosis of inconclusive cases, ultimately leading to optimal management of the patients with these diseases.

Presentation: Saturday, June 17, 2023
SAT590 Complex Migraine Manifesting As CDI - A Rare Occurrence
Authors: Shahid Maham , Sari Esra , Timirau Wendy , Hamza Ameer , Guzman Nilmarie , Sultan Senan
Published: October 2023

Disclosure: M. Shahid: None. E. Sari: None. W. Timirau: None. A. Hamza: None. N. Guzman: None. S. Sultan: None.

Introduction: There are many references in the literature to unexplained neurological symptoms occurring with complex migraines, however, complex migraine manifesting as central diabetes insipidus (CDI) is rare. Clinical Case: A 48-year-old female with past medical history of psoriatic arthritis, generalized anxiety disorder, and migraine presented with the worst headache of her life for 2 days, typical for her migraine but with increased severity, and minimally responsive to NSAIDs. Her headache was accompanied by nausea, photophobia, floaters, polydipsia and polyuria. She denied any neck pain/rigidity, focal deficits, or head trauma. She reported a similar episode with lesser severity 10 days ago which resolved in 3 days. She related her headache episodes with polyuria. Her medications included topiramate, escitalopram, apremilast, loratadine, and NSAIDs. She denied any new medications. Physical examination was unremarkable. Initial labs showed high-normal sodium 145 mMol/L, normal serum osmolality 292 mOsm/kg, low urine specific gravity 1.003, and low urine osmolality 117 mOsm/kg and urine sodium 32.4 mMol/L. HbA1c, B-hCG and urinalysis were normal. CT brain, CTA head and neck, MRI brain with/without IV contrast, and CSF analysis were unremarkable. The patient was started on abortive treatment for migraine. She had a negative fluid balance of 1500ml during first 24 hours. Polyuria did not resolve with water restriction but resolved with improvement of migraine; which favored the diagnosis of complex migraine manifesting with polyuria secondary to CDI. Patient was discharged on migraine prophylaxis and neurology follow-up. Conclusion: Link between migraine and endocrinological disorders has been well identified. Even though most cases are idiopathic, any disorder that acts at the hypothalamic-pituitary axis involved in ADH secretion can cause CDI, however migraines as an etiology remains rare. Early recognition of symptoms, treatment of migraine and introduction of migraine prophylaxis was crucial in our case to prevent further episodes of CDI.

Presentation: Saturday, June 17, 2023
SAT591 Abnormal Levels Of Thyroid Hormones During Development Alters The Migration And Activity Of GnRH Reproductive Neurons
Authors: Quignon Clarisse , Backer Annika , Wray Susan
Published: October 2023

Disclosure: C. Quignon: None. A. Backer: None. S. Wray: None.

Clinical studies have shown that thyroid hormones disorders and alteration of thyroid hormone production by environmental endocrine disruptors, have deleterious effects on reproduction. By acting in the brain on the hypothalamic component of the reproductive axis, abnormal levels of thyroid hormones can disturb sex hormones production, oestrus cycles or puberty onset, possibly leading to subfertility. Moreover, in animal models, endocrine disruptors and thyroid hormones have been shown to have long-lasting transgenerational effects with the maternal hormones influencing the development of foetal reproductive functions. Despite clear evidence of an interaction between the thyroid and reproductive systems, the effect of T3, the active form of thyroid hormones, on the GnRH neurons controlling reproduction, have been poorly studied. In this work we investigated how T3 functionally interacts with GnRH neurons and how abnormal concentration of T3 alters the migration of these neurons during development. Calcium imaging was used to study the direct effect of T3 on GnRH neuronal activity in an ex vivo nasal explants model. Acute administration of T3 (30nM) was found to stimulate the activity of GnRH cells. Dual labelling of GnRH and thyroid hormone receptors (TR) showed that the GnRH neurons express both nuclear and membrane receptors. However, the use of an antagonist that specifically blocks the TR nuclear receptors (1-850), didn’t inhibit the T3 stimulatory effect. In contrast, blockage of integrin αV/β3 membrane receptors (with cilengitide), which have been shown to be activated by T3, prevented the T3-induced increase in GnRH neuronal activity. During development GnRH neurons migrate from the nasal placodes into the brain. Acute administration of T3 for 1hr significatively decreased the migration rate of the GnRH neurons in our ex vivo model. To assess the effect of thyroid disruption during pregnancy on the development of reproductive axis in utero, pregnant females mice have been treated with methimazole to induce hypothyroidism from gestational day 6 to 13. E13 embryos have been collected from treated and control dams and the distribution of migrating GnRH neurons will be compared between both groups. Together these studies are the first to report a direct effect of thyroid hormones on GnRH neuronal activity, through the integrin αV/β3 membrane receptors and show that T3 can modulate the migration of GnRH neurons during development. These results will bring new insights on how thyroid disruption by endocrine disruptor chemicals or thyroid diseases, especially during foetal development, can lead to long term reproductive defects.

Presentation: Saturday, June 17, 2023