bluuebunny/crossref_metadata_2025 huggingface dataset:
THU219 Vascular Damage After Craniopharyngioma
Authors: Beckhaus Julia , Boekhoff Svenja , Bison Brigitte , Friedrich Carsten , Muller Hermann Lothar
Published: October 2023

Disclosure: J. Beckhaus: None. S. Boekhoff: None. B. Bison: None. C. Friedrich: None. H.L. Muller: None.

Craniopharyngiomas are rare, embryonic, malformational tumors of the (supra-)sellar region. Due to tumor and/or treatment-related hypothalamic lesions, patients develop morbid obesity. Obesity is a major vascular risk factor, leading to reduced 20-year overall survival and a 3- to 19-fold higher cardiovascular mortality after craniopharyngioma compared to the general population. An analysis within the Childhood Cancer Survivor Study (CCSS) revelaed a 10-fold higher relative risk for stroke in adult survivors of childhood/young adult cancers compared to their siblings. To study craniopharyngioma-specific risk factors for vascular damages we searched three databases (Pubmed, CINAHL and Web of Science) and included 49 articles after title and abstract screening. Eligible studies were case reports, cohort and cross-sectional studies. Neurovascular damages due to surgical interventions included cerebral infarcts, stroke, aneurysms, anterior/middle cerebral artery syndrome (ACA/MCA), cerebral venous sinus thrombosis, and seizures. Radiation-induced vascular disease described Moyamoya syndrome, radionecrosis and thrombosis. Tumor-induced inflammation is suspected to play a causal role in the etiology of vascular complications in proximity of the tumor. Therefore, early diagnostics such as echocradiography or cardial MRI and risk-adapted prevention and treatment options for vascular disease are needed to improve long-term prognosis after craniopharyngioma treatment. This review summarizes the available evidence for vascular disease after pediatric- and adult-onset craniopharyngioma to derive possible treatment pathways. Individualized, tertiary prevention programs are required for craniopharyngioma patients and survivors to overcome or reduce the risk of vascular complications and elevate their quality of survival.

Presentation: Thursday, June 15, 2023
THU618 Adrenal Cell Carcinoma Presenting With Post-menopausal Bleeding And IGF-2 Induced Hypoglycaemia
Authors: Lonergan Eibhlin Marie , Joyce Tan Lok Yi , Ali Elsheikh , Joyce Caroline Martha , Conlon Niamh , O'Sullivan Adrian , O'Halloran Domhnaill Jude
Published: October 2023

Disclosure: E.M. Lonergan: None. L.J. Tan: None. E. Ali: None. C.M. Joyce: None. N. Conlon: None. A. O'Sullivan: None. D.J. O'Halloran: None.

Background: Non-islet cell tumour hypoglycaemia (NICTH) as a result of IGF-2 secretion is rare with a few case reports associated with adrenal tumours. Clinical Case: We present the case of a 59-year-old female initially presenting to gynaecology services with post-menopausal bleeding due to endometrial hyperplasia. Serum testosterone, oestradiol and adrenal androgens were found to be elevated and LH and FSH suppressed. A subsequent CT adrenals demonstrated a 12.8 x 13.2 x 10.6cm left adrenal mass and she failed a 1mg overnight dexamethasone suppression test. In the interim, while undergoing evaluation, the patient presented to A+E Department with point-of-care confirmed hypoglycaemia with a capillary blood glucose of 1.6mmol/L and neuroglycopaenic symptoms. There was no history of diabetes mellitus, prolonged fasting, access to sulphonylureas or insulin. During a supervised fast, symptomatic hypoglycaemia occurred within 5 hours at 2.0mmol/L fulfilling Whipple’s triad. Results of samples taken during hypoglycaemia revealed an elevated IGF-2 : IGF-1 ratio of 60.7 (normal <10) with a low paired C-peptide, insulin and pro-insulin, consistent with a suspected IGF-2-secreting tumour. Hypoglycaemia was successfully managed with low glycaemic index foods and clinical nutrition input. Radical surgical excision was undertaken including left adrenalectomy, nephrectomy, partial pancreatectomy and splenectomy. Post-operative pathology revealed an adrenocortical carcinoma (ACC) measuring 16.4cm in maximum dimension; Ki67 12%; Weiss score 5; lymph nodes negative. Tissue has been stained for IGF-2-IR. Post-operative IGF-2 : IGF-1 ratio normalised to 3.4. The patient is under active follow up with 3-monthly surveillance CT-TAP and has declined Mitotane therapy at present. Conclusion: This is a rare case of ACC secreting multiple hormones, resulting in post-menopausal bleeding and IGF-2 mediated hypoglycaemia.

Presentation: Thursday, June 15, 2023
THU234 An Adolescent Patient With Asymptomatic Hypocalcemia And Extensive Cerebral Calcification Due To Pseudohypoparathyroidism Type 1B: A Care Report
Authors: Alemzadeh Ramin , Ross Jordan Douglas , Guillen-Mendoza Daniel
Published: October 2023

Disclosure: R. Alemzadeh: None. J.D. Ross: None. D. Guillen-Mendoza: None.

Background: Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders due to renal resistance to parathyroid hormone (PTH) resulting in biochemical hypoparathyroidism but with skeletal sensitivity to PTH. Case Presentation: A 15-year-old African American male was incidentally found to have biochemical evidence of severe hypocalcemia during routine evaluation of his bilateral slipped capital-femoral epiphyses. The patient was at age-appropriate stage of puberty with normal height and without any features of hereditary osteodystrophy. However, he had history of mild developmental delay requiring school accommodations. On physical exam, there was some mild dyscoordination with finger and toe-tapping and a Myerson’s sign, negative tetany signs. The biochemical screening revealed markedly low serum calcium (4.9 mg/dL) with elevated phosphorus (7.8 mg/dL) and PTH (1314 pg/mL) levels. His hypocalcemia was accentuated by the presence of severe 25 hydroxy-vitamin D deficiency (7.5 ng/mL) with mild hypomagnesemia (1.4 mg/dL). He had normal renal and thyroid function tests with normal growth factors. There were minimal plasma cyclic AMP responses to a single dose of intravenous teriparatide (Ellsworth-Howard test) consistent with diagnosis of pseudohypoparathyroidism. The skeletal survey showed bowing and under-tubulation of the radius, ulna, tibia, and fibula as well as slipped capital femoral epiphysis bilaterally. His brain CT scan showed symmetrical severe dense calcifications in the basal ganglia, bilateral frontal, parietal and temporal subcortical white matter, pons and right dentate nucleus. Genetic testing did not reveal any GNAS mutations. The patient was initially treated with parenteral calcium followed by high-dose oral calcium supplements and calcitriol. His coexisting hypovitaminosis D and hypomagnesemia were corrected with oral high-dose cholecalciferol and magnesium sulfate, respectively. Conclusions: An incidental finding of severe asymptomatic hypocalcemia and elevated PTH without hereditary osteodystrophy phenotype raised the clinical suspicion of pseudohypoparathyroidism type 1B. This was associated with cerebral calcifications with increasing risk of worsening learning disabilities and minimal neurological findings.

Presentation: Thursday, June 15, 2023
THU237 A Case Of Primary Hypothyroidism, Dysglycemia And Epilepsy With PAX8 And SETD1A Mutation
Authors: Singh Santosh Kumar
Published: October 2023

Disclosure: S.K. Singh: None.

KEYWORDS: PAX8, SETD1A, DYSGLYCEMIA

INTRODUCTION: Hypothyroidism is associated with dysglycemia linked with insulin resistance and shared common genetic determinants.PAX 8 gene regulates the development of thyroid gland as well as the expression of TG,TPO and NIS genes.It impacts glucose homeostasis by favoring beta-cell survival and through thyroid hormones.Epilepsy in hypothyroid patients can be idiopathic or due to Hashimoto’s Encephalopathy (HE). Thyroid hormones can impact epileptogenesis through mitochondrial dysfunction, oxidative-stress and GABAergic transmission. THE INDEX PATIENT: A 13 year old female(weight and height age 1.5 years below her chronological age by Indian growth chart and a further lag of 18 months and 6 months, respectively by CDC chart)was diagnosed as a case of thyroprivic hypothyroidism with TSH - 100 mIU/L and positive anti-TPO antibody. She was euthyroid on 112 ug/d L-T4.She is on anticonvulsant since 12 years of age for tonic-clonic epilepsy. The MRI of brain showed focal gliosis with few small encephalomalacic streaks in right occipital lobe. On evaluation at 12.5 years of age, her fasting plasma glucose was 80 mg/dl and her HbA1c was 4.8% but 2-h post glucose was 233 mg/dl with another value of 270 mg/dl. Her father has T2DM and Hypothyroidism. Her mother is Hypothyroid. Her genetic study showed SETDIA and PAX8(-) mutations. DISCUSSION: PAX8 regulates development of thyroid gland and biosynthesis of thyroid hormones. It can impact glucose homeostasis by enhancing beta-cell survival by inhibiting apoptosis, immunomodulation, maintaining local anti-inflammatory milieu in pancreas, ensuring systemic levels of thyroid hormone to stimulate insulin secretion and protect beta-cells from environmental stressors.PAX8 mutation in a family has been shown to be associated with a spectrum of disorders encompassing Gestational Thyroid Dysfunction(GTD),Gestational Diabetes Mellitus(GDM) and T2DM.[1] Although mutation analysis was done only in the index patient, Hypothyroidism and Dysglycemia (post- glucose>200 mg/dl)in the patient and family history of Hypothyroidism and T2DM could be linked with PAX8 mutation.SETD1A mutation has been linked with early-onset epilepsy with or without developmental delay. The mutation study can aid in deciding appropriate therapy including steroids for HE. CONCLUSION: This case highlights the significance of evaluation for PAX8 mutation in hypothyroid patients, even if anti-TPO positive, particularly when there is family history of thyroid dysfunction, GDM, T2DM. It also underlies the importance of SETD1A mutation analysis in hypothyroid patients with epilepsy.

Presentation: Thursday, June 15, 2023
THU243 Fitting Together The Pieces Of The Puzzle Between Isolated ACTH Deficiency And Immunodeficiency: DAVID Syndrome
Authors: Buchanan Katherine Virginia , Hurst Anna C E , Ashraf Ambika P
Published: October 2023

Disclosure: K.V. Buchanan: None. A.C. Hurst: None. A.P. Ashraf: None.

Objectives: DAVID syndrome is a rare genetic disorder with common variable immunodeficiency (CVID) and anterior pituitary hormonal deficiencies due to a pathogenic variant in NFKB2. We aim to describe asymptomatic ACTH deficiency identified after the diagnosis of CVID in a patient with DAVID syndrome. Methods: A retrospective chart review of a patient with DAVID syndrome was performed. Results: The patient is a 15 year and 9-month-old female with weight in the 71st percentile and height in the 64th percentile, who was diagnosed with DAVID syndrome at 10 years through a Primary Immunodeficiency panel which identified a pathogenic variant in NFKB2 c.2557C>T,p.Arg853* and a variant of unknown significance in STAT2 c.1301C>T (p.Thr434Met). The panel was performed due to the patient’s history of recurrent sinus infections, hypogammaglobulinemia, and alopecia totalis. The patient did not have symptoms of ACTH deficiency including hypoglycemia and hypotension. After the genetic diagnosis was made, an anterior pituitary hormone evaluation was performed which showed an ACTH <5 pg/ml, AM cortisol <0.2 mcg/dL, TSH 3.48 uIU/ml, FT4 0.82 ng/dL, thyroid peroxidase antibody 29 IU/mL (normal <9), somatomedin-c 44 ng/mL (reference range 152-593), LH 5.36 mIU/mL, and FSH 14.25 mIU/mL. Adrenal insufficiency was diagnosed since the patient did not show incremental cortisol response (serum cortisol <0.2 mcg/dL at 30 and 60 minutes) post Cosyntropin stimulation test. The patient had normal electrolytes. Hydrocortisone replacement therapy was initiated. A growth hormone stimulation test was not performed since the patient had normal height and interval height velocity. The thyroid function remained stable, and the patient attained menarche at age 14. Conclusions: This patient is unique in having asymptomatic, acquired, isolated ACTH deficiency diagnosed in later childhood, despite having frequent sinopulmonary infections since infancy as part of DAVID syndrome. Further research needs to be done to elucidate how NFKB2 variants contribute to acquired, isolated, central ACTH deficiency or autoimmune pituitary disease.

Presentation: Thursday, June 15, 2023
FRI016 Utilizing Game-based Learning In Medical Education
Authors: Daniel Sneha , Bangalore-Krishna Kanthi
Published: October 2023

Disclosure: S. Daniel: None. K. Bangalore-Krishna: None.

In the era of advancing technologies, several apps and software are available for learners that are fun, interactive, innovative, and collaborative. Kahoot! is one such game-based learning platform that facilitates formative assessment and promotes student learning. Kahoot! has been used extensively in higher education and has been successful not only in keeping the learners attentive and engaged but also provided with positive feedback and motivation. The philosophy of learning and education has shifted from being teacher-centered or subject-centered to being learner-centered and current learners tend to lean towards an abstract-active style of learning. We completed a focused discussion with the endocrine fellows and identified topics which were deemed challenging/difficult. We then developed a Kahoot!- based curriculum to review these topics. Each session included 2-3 review questions and 8-10 topic-based questions that were meticulously designed to cover the breadth of the topic followed by a 15-minute didactic session to review core concepts, including multiple clinical correlates to ensure relevance and applicability. Participants used their cellphones to log in and points were awarded (by the app) based on the accuracy and timeliness of responses. After 8 sessions, we conducted a brief survey with qualitative and quantitative questions to assess the effectiveness of the curriculum and contrasted this with the traditional curriculum which involved either a didactic session or watching videos with minimal interaction with an educator. All 8 pediatric endocrine fellows participated in the in-person, weekly sessions (8 total) and the survey. Results showed that 8/8 participants found this platform to be more interesting, easy to use, were motivated to learn during these sessions, engaging and encouraged participation without fear of being incorrect. Participants stated that these sessions helped them ask thought-provoking questions, understand previously complex concepts better and highlighted areas of knowledge deficits. Participants had additional suggestions to enhance deeper learning which we plan to incorporate. Our next step is to assess content retention at 3 months and 6 months after the sessions. With evolving technology and change in learning styles of current learners, game-based learning should be further explored in medical education, to keep learners engaged and make learning more fun, diverse, interactive, and inclusive.

Presentation: Friday, June 16, 2023
FRI595 Two Cases Of Severe Symptomatic Hypocalcemia Secondary To Vitamin D Deficiency Diagnosed Within The Same Week
Authors: Cooper Felicia Ilyssa , Jonsdottir Urdur , Rios Gabriela Guadalupe , Vyas Neha , Gurnurkar Shilpa
Published: October 2023

Disclosure: F.I. Cooper: None. U. Jonsdottir: None. G. Guadalupe Rios: None. N. Vyas: None. S. Gurnurkar: None.

Background: Vitamin D is a fat-soluble vitamin that plays a significant role in intestinal calcium absorption. Humans acquire vitamin D through sun exposure and diet, though few foods naturally contain vitamin D in the amount needed to prevent deficiency. Vitamin D deficiency can result in nutritional rickets, which may present with impaired growth, weakened bones, dental abnormalities, and fractures secondary to decreased calcium absorption. Hypocalcemia can lead to a wide variety of clinical manifestations from mild symptoms such as irritability, tremors, and muscle cramps to life threatening seizures and arrhythmias. Case: This case series describes two children presenting to our pediatric emergency department within the same week with severe hypocalcemia secondary to profound vitamin D deficiency. The first was a 2-year-old female with prior medical history of 29-week prematurity who presented with a first time generalized tonic clonic seizure. She had a limited diet that consisted mostly of non-fortified almond milk. As an infant, she was on breast milk but did not receive vitamin D supplementation. On presentation, she was noted to have exam findings and radiographic evidence of rickets. The second was a 13-year-old male with history of non-verbal autism presenting with one month of diarrhea, agitation, and progressive leg pain. The patient was described as a picky eater and spent minimal time outdoors. Both children were found to have severe hypocalcemia (6.6 mg/dL and 4.8 mg/dL, respectively) in the setting of vitamin D deficiency (vitamin D-25 6.8 ng/dL and 4.9 ng/dL, respectively). They were successfully treated acutely with intravenous calcium gluconate bolus (one dose of 495 mg and three 2,000 mg) and oral calcium, with normalization of ionized calcium levels and improvement of symptoms. They were treated long-term with oral calcium, calcitriol, and vitamin D supplementation. Conclusion: Vitamin D deficiency should be considered in severe symptomatic hypocalcemia in children. Vitamin D supplementation is necessary in all breast-fed babies and a large proportion of other children not meeting vitamin D requirements through diet and sun exposure.

Presentation: Friday, June 16, 2023
OR15-02 Changes In Liver Fat Content By CT 1 Year After Sleeve Gastrectomy In Adolescents With Severe Obesity
Authors: López López Ana Paola , Tuli Shubhangi , Lauze Meghan , Becetti Imen , Pedreira Clarissa C , Huber Florian A , Omeroglu Emre , Misra Madhusmita , Singhal Vibha , Bredella Miriam A
Published: October 2023

Disclosure: A.P. López López: None. S. Tuli: None. M. Lauze: None. I. Becetti: None. C.C. Pedreira: None. F.A. Huber: None. E. Omeroglu: None. M. Misra: None. V. Singhal: None. M.A. Bredella: None.

Introduction: Obesity is associated with non-alcoholic fatty liver disease (NAFLD). Sleeve gastrectomy (SG), the most commonly used metabolic and bariatric surgery, is an effective means of weight loss and has been shown to improve NAFLD in adults but data regarding the efficacy of SG in early stages of NAFLD where steatosis is the only pathology is evolving. We aim to assess the impact of SG on hepatic fat content, one year after SG in youth with severe obesity. Objective: To (i) identify changes in liver fat content using attenuation measurements on non-contrast CT [liver/spleen (L:S) ratio] in youth with obesity before and 12 months after sleeve gastrectomy (SG) compared with non-surgical controls with obesity (NS) and (ii) associations of changes in L:S with changes in body composition. Methods: 52 participants 13-25 years old with obesity were followed for 12 months. 25 subjects had SG (84% female), and 27 were NS (70% female). Non-contrast CT of the abdomen was performed for attenuation measurements of liver and spleen in Hounsfield Units (HU), expressed as L:S ratio. A lower L:S ratio indicates higher liver fat. A single-slice MRI of the abdomen at the level of L4 was performed to assess subcutaneous and visceral adipose tissue (SAT and VAT) cross sectional areas (cm2). Results: Mean age did not differ across groups. Body mass index (BMI) at baseline trended higher in SG vs. NS [44.18 (41.33, 53.72) vs. 42.16 (38.65, 46.96) kg/m2, (p=0.073)], and the mean 1-year decrease in BMI was greater in SG vs. NS (-12.48±0.83 vs. -0.21±0.52 kg/m2, p<0.0001). VAT decreased in SG but increased in NS [-50.77 cm2 (-61.26, -34.09) vs. 13.55 cm2 (-10.27, 34.78), p<0.0001], over 1 year. There was a within group increase in the L:S ratio in SG (0.13± 0.05, p= 0.014) but not NS over 1 year, with a trend for a difference between groups (p=0.055). All SG participants with an L:S ratio <0.9 (threshold for the diagnosis of NAFLD) before surgery had a ratio of >1.0 a year after surgery, consistent with resolution of NAFLD. Within SG, the 1-year change in L:S ratio was negatively associated with 1-year change in visceral fat (ρ=-0.52 p=0.017). Conclusions: Hepatic fat content as assessed by non-contrast CT improved after SG over 1-year in youth with obesity with resolution of NAFLD in all subjects. This was associated with improvements in body composition, especially visceral adiposity.

Presentation: Friday, June 16, 2023
SAT352 Reliability Of Two- And Three-dimensional Ultrasonographic Assessments Of Ovarian Morphology In Adolescents
Authors: Rahman Effat , Smith Bailey , Brink Heidi Vanden , Zaman Nabiha , Malik Anushka , Burgert Tania , Barral Romina , Lujan Marla Elaine
Published: October 2023

Disclosure: E. Rahman: None. B. Smith: None. H. Vanden Brink: None. N. Zaman: None. A. Malik: None. T. Burgert: None. R. Barral: None. M.E. Lujan: None.

Background: Distinct features of ovarian morphology using transabdominal ultrasonography (TAUS) have been observed in adolescents with polycystic ovary syndrome (PCOS). Standardized approaches to assess ovarian morphology using transvaginal ultrasonography result in excellent reliability and close agreement among multiple raters, which can lead to more precise estimates of follicle counts and ovarian size. The degree to which these methods translate to TAUS is unknown. Establishing standardized methods to analyze ovarian features via TAUS are needed to clarify the utility of ovarian morphology in the clinical evaluation of PCOS in adolescence. Objectives: To determine the reliability of follicle counts and ovarian size assessments obtained using 2D and 3D TAUS in early adolescence. Methods: Three raters evaluated images of 30 ovaries garnered from adolescents via TAUS (n=19, 6 - 20 months post-menarche) for the following 2D parameters: follicle number per ovary (2D FNPO), follicle number per cross-section (FNPS), ovarian volume (2D OV), ovarian area (OA) and stromal area (SA). Three dimensional assessments of follicle counts (3D FNPO) and ovarian volume (3D OV) were also performed using SonoAVCantralTM and VOCALTM software (GE Healthcare), respectively. Intraclass correlation coefficients (ICCs) were used to determine interrater reliability for each variable. An ICC <0.5 was defined as poor, 0.50-0.75 as moderate, 0.75-0.90 as good, and >0.900 as excellent reliability. Results: Across 2D measures of ovarian morphology, interrater reliability was highest for 2D FNPO (ICC = 0.698), followed by OA (0.655), SA (0.619), and FNPS (0.516). Ovarian volume measurements by 2D methods demonstrated poor reliability (0.297). Three-dimensional assessments of follicle counts were not associated with improved interrater agreement (0.609). By contrast, better reliability was detected for 3D OV versus 2D OV - albeit 3D measures still met criteria for poor reliability (0.397 vs 0.297). Conclusions: Assessments of ovarian morphology using TAUS are associated with moderate-to-poor reliability using standardized approaches. Follicle counts per ovary were moderately reliable with 2D and 3D TAUS, in contrast to OV which demonstrated poor reliability across raters irrespectively of modality. Poor reliability for measures of OV is concerning given current practice guidelines for the ultrasonographic assessment of PCOS advocate for measures of OV over FNPO when using TAUS. Factors impacting reliability, such as gynecological age, body habitus, and image quality will be evaluated in subsequent investigations to refine training, image acquisition protocols, and method development.

Presentation: Saturday, June 17, 2023
THU625 Med12 Mutation Activates Tryptophan-Kynurenine-ahr Pathway To Promote Growth Of Uterine Leiomyoma
Authors: Zuberi Azna , Huang Yongchao , Dotts Ariel J , Wei Helen , Coon V John S , Lizuka Takashi , Wu Olivia , Sotos Olivia , Chakravarti Debabrata , Dai Yang , Bulun Serdar Ekrem , Yin Ping
Published: October 2023

Disclosure: A. Zuberi: None. Y. Huang: None. A. Dotts: None. H. Wei: None. J. Coon V: None. T. Lizuka: None. O. Wu: None. O. Sotos: None. D. Chakravarti: None. Y. Dai: None. S.E. Bulun: None. P. Yin: None.

A.Z. and Y.H. contributed equally to this work.† Y.D., S.E.B., and P.Y. are co-senior authors.

‡To whom correspondence should be addressed: Serdar E. Bulun, M.D.Division of Reproductive Science in MedicineDepartment of Obstetrics and Gynecology Feinberg School of Medicine at Northwestern University 250 E. Superior Street, Suite 03-2306 Chicago, Illinois 60611-2914 Tel: 312-472-3636 Fax: 312-472-3740 Email: s-bulun@northwestern.edu Ping Yin, M.D., Ph.D. Division of Reproductive Science in Medicine Department of Obstetrics and Gynecology Feinberg School of Medicine at Northwestern University 303 E. Superior Street, Suite 10-111 Chicago, Illinois 60611 Tel: 312-503-1831 Fax: 312-503-0095 Email: p-yin@northwestern.edu. Conflict of interest: The authors have declared that no conflict of interest exists. Uterine leiomyomas (LM) cause heavy menstrual bleeding, anemia and pregnancy loss in approximately 10 million US women. Driver mutations in the mediator complex subunit 12 (MED12) gene in uterine myometrial cells initiate 70% LM tumors that grow in a progesterone-dependent manner. We showed a distinct chromatin occupancy landscape of MED12 and a shift of binding sites from proximal promoters to intronic/intergenic regions in mutant (mut-MED12) vs wild-type LM tissues. Integration of cistrome and transcriptome data identified tryptophan 2,3-dioxygenase (TDO2) as the top mut-MED12 target gene, which was massively upregulated in mut-MED12 LM. TDO2 catalyzes the conversion of tryptophan to kynurenine, which is an aryl hydrocarbon receptor (AHR) ligand and significantly elevated in mut-MED12 LM. Incubation of primary mut-MED12 LM cells with tryptophan or kynurenine stimulated AHR nuclear translocation, increased proliferation, inhibited apoptosis and induced AHR-target gene expression, whereas blocking the TDO2-kynurenine-AHR pathway by siRNA or pharmacologically abolished these effects. Progesterone receptor regulated the expression of AHR and its target genes. In vivo, TDO2 expression positively correlated with the expression of genes crucial for LM growth. In summary, activation of the TDO2-kynurenine-AHR pathway selectively in mut-MED12 LM induces tumor growth and may inform the development of targeted treatments and precision medicine.

Presentation: Thursday, June 15, 2023
THU632 Musculoskeletal Composition And Function In Polycystic Ovary Syndrome: Early Evidence From A Prospective Study
Authors: Kazemi Maryam , Michalak Julia , Xavier Isabella B , Parry Stephen A , Lujan Marla E
Published: October 2023

Disclosure: M. Kazemi: None. J. Michalak: None. I.B. Xavier: None. S.A. Parry: None. M.E. Lujan: None.

Current evidence on the body composition of women with polycystic ovary syndrome (PCOS) is primarily focused on fat accumulation and impaired fat function. The relevance of PCOS to non-fat (skeletal muscle, bone) components of body composition remains unknown, despite the clinical and prognostic value for musculoskeletal function and healthy aging. We recently showed a link between PCOS and the loss of skeletal muscle mass and bone concurrent with fat infiltration. While our observations reflect an aberrant musculoskeletal composition in PCOS, any impact on function is unknown. The objective of the current study was to test the hypothesis that musculoskeletal function and composition are poorer in PCOS vs. controls without PCOS. This work represented early evidence from a prospective case-control study (N=25, age 18-35y; BMI 18.2-41.5 kg/m2). Cases were defined as those with PCOS (NIH criteria; n=12). Controls were those without PCOS (n=13). Musculoskeletal composition traits (bone mineral density [BMD], lean body mass [LBM]) were evaluated by dual-energy X-ray absorptiometry. Furthermore, musculoskeletal function traits (maximum and average isometric strength of the hand and forearm muscles in 3 trials) were evaluated with a hydraulic dynamometer. Associations between PCOS status and traits were evaluated using generalized linear regression models. All p-values were BMI adjusted. Analyses of the musculoskeletal composition traits revealed comparable BMD between PCOS cases and controls (mean [SD]: 1.13 [0.03] vs. 1.11 [0.02] g/cm2; P=0.30). In contrast, PCOS cases showed an association with lower LBM vs. controls (40.98 [26.71] vs. 43.86 [24.10] kg; P<0.001). Regarding musculoskeletal function, PCOS cases showed an association with lower maximum (29.10 [1.89] vs. 34.46 [1.88] kg; P=0.007) and average (27.33 [1.84] vs. 32.35 [1.88] kg; P=0.008) isometric strength of the dominant hand vs. controls. Similarly, PCOS cases showed an association with lower maximum (28.10 [2.15] vs. 32.25 [1.69] kg; P<0.001) and average (26.93 [2.04] vs. 30.42 [1.61] kg; P<0.001) isometric strength of the non-dominant hand vs. controls. Quantitative musculoskeletal traits, including lower LBM and hand grip strength differ in PCOS vs. controls. These findings reflect poorer skeletal muscle mass, physical fitness, and overall health status in PCOS. If confirmed by longitudinal studies, these observations may translate to a greater risk for musculoskeletal derangements in later life stages. Potential mechanisms underlying these aberrations are being investigated and will likely reveal environmental and biological pathways (assuming interactive) beyond obesity per se. Future studies should also delineate causal pathways of PCOS to musculoskeletal aberrations.

Presentation: Thursday, June 15, 2023
THU635 Metabolic Characteristics Among Polycystic Ovary Syndrome-Phenotypes In A Sample Of Hispanic Patients
Authors: Gonzalez-Rodriguez Loida Alejandra , Arroyo Isabel C , Diaz-Rios Beatriz , González-Sepúlveda Lorena , Casas-Loyola Cristina M , Bermúdez-Santos Jadailine , Pérez-Cardona Cynthia , Romaguera Josefina , Azziz Ricardo
Published: October 2023

Disclosure: L.A. Gonzalez-Rodriguez: Research Investigator; Self; Eli Lilly & Company. I.C. Arroyo: None. B. Diaz-Rios: None. L. González-Sepúlveda: None. C.M. Casas-Loyola: None. J. Bermúdez-Santos: None. C. Pérez-Cardona: None. J. Romaguera: None. R. Azziz, MD, MBA, MPH: Advisory Board Member; Self; Arora Forge. Consulting Fee; Self; Rani Therapeutics, Spruce Biosciences, Fortress Biotech, Core Access Surgical Technologies. Grant Recipient; Self; Ferring Pharmaceuticals. Stock Owner; Self; Martin Imaging.

PURPOSE: Polycystic Ovary Syndrome (PCOS), a common endocrinopathy affecting women in their reproductive years, is associated with an increased risk for cardiometabolic comorbidities. Even though PCOS is a common condition, there is often a delay in diagnosis and treatment due to several proposed diagnostic criteria. Due to the complexity of this syndrome and different clinical manifestations, it has been recommended to identify their 4 phenotypes. This study aimed to compare the clinical and metabolic characteristics among PCOS-phenotypes in a sample of Hispanic patients. METHODS: This is a cross-sectional study of females between 21-45 years of age with confirmed PCOS using the Rotterdam criteria. Patients were classified according to phenotypes: A, hyperandrogenism (HA), oligoovulation/menstrual dysfunction (OA/MD), and polycystic ovarian morphology (PCOM); B, HA + OA/MD; C, HA + PCOM; D, OA/MD + PCOM. Metabolic Syndrome (MetS) was diagnosed using ATP III criteria. Metabolic characteristics were compared between groups. RESULTS: Sixty-three patients with PCOS were evaluated with phenotypes A (60%), B (21%), C (5%), and D (14%). Only 26 patients (41%) had a previous diagnosis of PCOS. The prevalence of MetS in this sample was 52.4%. Among the phenotypes, phenotype B had the higher prevalence of MetS (61.5%) followed by phenotype D (55.6%) and phenotype A (52.6%). Significant differences in obesity, waist, and hip circumference were found, with phenotype-C having lower parameters (p ≤ 0.05). A tendency for lower BMI, waist-to-hip-ratio, HOMA-IR, and hs-CRP levels was also observed in phenotype-C. CONCLUSION: Our study found a high prevalence of MetS in this sample of patients with PCOS; phenotypes affected by menstrual dysregulation having a higher prevalence. Less than half of patients with PCOS were previously diagnosed despite multiple medical evaluations for symptoms, which emphasizes the importance of an early diagnosis to avoid cardiometabolic complications.

Presentation: Thursday, June 15, 2023
THU636 Prevalence Of Metabolic Syndrome In A Sample Of Hispanic Patients With Polycystic Ovary Syndrome
Authors: Arroyo Isabel C , Gonzalez-Rodriguez Loida , Rios Beatriz Diaz , Rivera-Rodriguez Yanni , Garcia-Irizarry Adriana , Cabrera-Martinez Hilary , Gonzalez-sepulveda Lorena , Perez-Cardona Cynthia , Romaguera Josefina , Azziz Ricardo
Published: October 2023

Disclosure: I.C. Arroyo: None. L. Gonzalez-Rodriguez: None. B. Diaz Rios: None. Y. Rivera-Rodriguez: None. A. Garcia-Irizarry: None. H. Cabrera-Martinez: None. L. Gonzalez-sepulveda: None. C. Perez-Cardona: None. J. Romaguera: None. R. Azziz, MD, MBA, MPH: Advisory Board Member; Self; Arora Forge. Consulting Fee; Self; Rani Therapeutics, Spruce Biosciences, Fortress Biotech, Core Access Surgical Technologies. Grant Recipient; Self; Ferring Pharmaceuticals. Stock Owner; Self; Martin Imaging.

PURPOSE: Polycystic ovary syndrome (PCOS) is an endocrinopathy affecting women of reproductive age. It confers an increased risk of comorbidities such as metabolic syndrome (MetS), cardiovascular (CV) disease, diabetes mellitus, and cancer. There is limited information about how this association impacts Hispanic women, a high-risk group for cardiometabolic disease. This study aimed to evaluate the association between PCOS and MetS in a sample of Hispanic patients. METHODS: This is a cross-sectional study of female patients between 21-45 years of age who underwent evaluation for PCOS and MetS. Patients underwent clinical, laboratory, and imaging studies. PCOS was diagnosed using the Rotterdam criteria and MetS was diagnosed using ATP III criteria. Prevalence of MetS and associated variables were compared between groups. RESULTS: Seventy-eight patients were included in this study (63 patients with PCOS+ and 15 patients with PCOS-). Mean age was 31 ± 6 years. PCOS+ patients were younger. MetS were observed in 52.4% of patients PCOS+ vs 40% of patients PCOS- (p>0.05). No significant differences were found in BMI, waist circumference, blood pressures, triglycerides, HDL, fasting glucose levels, insulin levels, and A1c among groups (p>0.05). A higher prevalence of elevated hs-CRP was observed in patients with PCOS+ (60.3%) vs PCOS- (42.9%). CONCLUSION: Our study found a prevalence of 52.4% of MetS in a sample of patients with PCOS+. Previous studies have shown a 41% prevalence of MetS among Puerto Rican women and 44% prevalence in women with PCOS. PCOS is associated with an increased risk of CV disease, cancer, and diabetes, the leading causes of death in PR. Strategies to decrease this prevalence and avoid its complications in our population are imperative.

Presentation: Thursday, June 15, 2023
OR03-01 Functional Rescue Of Trafficking-Defective Mutant Follicle-Stimulating Hormone Receptors (FSHR) Leading To Premature Ovarian Failure With The Pharmacoperone CAN1405
Authors: Ulloa-Aguirre Alfredo , Zariñán Teresa , Gutiérrez-Sagal Rubén , Nataraja Selvaraj , Yu Henry N , Jardón-Valadez Eduardo
Published: October 2023

Disclosure: A. Ulloa-Aguirre: None. T. Zariñán: None. R. Gutiérrez-Sagal: None. S. Nataraja: None. H.N. Yu: None. E. Jardón-Valadez: None.

Inactivating mutations in the follicle-stimulating hormone (FSH) receptor (FSHR) cause premature ovarian failure. Approximately 30% of mutant FSHRs (mutFSHR) are misfolded proteins unable to route to the plasma membrane (PM). We herein tested the effect of a small molecule FSHR ago-allosteric modulator (CAN1405) on the functional rescue of several inactivating mutFSHR. Wild-type (WT) and mutFSHRs A189V, A191I and D224V (at the ectodomain), and four FSHRs with mutations in the serpentine region (SR) of the receptor (D408Y, A419I, I423T, and P519T) were expressed in HEK-293 cells and stimulated with recombinant FSH in the presence of vehicle or CAN1405. Changes in plasma membrane expression and function provoked by CAN1405 exposure were analyzed by immunoblotting and by activation of the cAMP-sensitive pSOMLuc reporter plasmid and ERK1/2 phosphoryation, respectively. Molecular interactions between FSHR and CAN1405, were predicted in silico by computational docking. Exposure of WT and mutFSHR-expressing cells to CAN1405 increased the ratio of mature (PM-expressed) to immature (intracellular) FSHR forms (m/i ratio) of all SR mutant FSHRs (from 0.5 to 3.0) as disclosed by immunoblotting. Similar results were observed when activation of the cAMP-sensitive pSOMLuc reporter and ERK1/2 phosphorylation were examined in FSH-stimulated cells. PM expression of FSHR WT and the activation-defective mutFSHR I423T, but not the FSHRs with mutations in the ectodomain, were also increased by CAN1405. Interesting, in the presence of CAN1405, signaling of the mutFSHR I423T was marginal in terms of activation of the pSOMLuc reporter but not of pERK1/2, suggesting that binding of CAN1405 to the mutFSHR changed the conformation of the receptor allowing functional selectivity on FSH-stimulated signaling. CAN1405 was located in a binding pocket at interhelical upper half of the FSHR. Side chains of residues Y530, A450, T449 S453, L415, H615, M585, V612, I588, and K608 were detected in close interaction with the CAN1045 and the FSHR-CAN1405 complex was likely stabilized by hydrophobic interactions. It is concluded that the small molecule CAN1405 with ago-allosteric properties is an effective pharmacological chaperone that corrects trafﬁcking of SR misfolded mutFSHRs and also increases WT FSHR expression and function. These data demonstrate that allosteric modulators of the FSHR may serve as an effective therapeutic approach for the treatment of infertility in women bearing the WT FSHR or in heterozygous carriers of mutations at the transmembrane domain of this receptor.

Presentation: Thursday, June 15, 2023
OR04-01 Single Nucleus RNA Sequencing Reveals Diet Induced Obesity And SGLT2 Inhibitor Therapy Modulate the Testes Transcriptome In Male Mice
Authors: Ozturk Berkcan , Efthymiou Vissarion , Ali Waqar , Ferraz-Bannitz Rafael , Erika Pacheco , Navarrete Valerie , Dreyfuss Jonathan M , Pan Hui , Patti Mary-Elizabeth
Published: October 2023

Disclosure: B. Ozturk: None. V. Efthymiou: None. W. Ali: None. R. Ferraz-Bannitz: None. P. Erika: None. V. Navarrete: None. J.M. Dreyfuss: None. H. Pan: None. M. Patti: Consulting Fee; Self; AstraZeneca, MBX-Biosciences, Hanmi Pharmaceutical. Other; Self; DSMB: Fractyl Health, Inc.

Paternal environmental exposures during postnatal life can influence health of their offsprings, modulating risk of metabolic disease. We have previously shown that pharmacologic interventions to improve the health of fathers may also reduce metabolic disease risk of offsprings. To identify potential mechanisms responsible for paternally-mediated intergenerational metabolic disease risk, we analyzed the transcriptome in testes using single-nucleus RNA sequencing. C57BL/6J male mice, age 8 weeks, were treated with low fat (10% fat) or high fat diet (HFD, 60% fat) diet to induce obesity and hyperglycemia; after 4 weeks, HFD-fed mice were randomized to continued HFD or HFD containing the SGLT2 inhibitor canagliflozin (250 mg/ kg/ day) (CANA). After 20 weeks, we dissected testes for single nucleus RNA sequencing (LFD, HFD, CANA n=3,4,4 respectively). Unsupervised clustering revealed 35 distinct clusters. We employed supervised cell-calling and identified 13 distinct canonical testis-residing cell types and 2 novel subtypes. The magnitude of differential expression between groups was most pronounced in Leydig cells, pachytene-stage cells, and round spermatids, suggesting that the transcriptome of particular cell types in testis is more robustly affected in response to obesity. Ontology analysis of differentially expressed genes (DEG) in those 3 cell types (FDR≤0.1 for input genes and p≤0.05 for enrichment analysis) revealed that downregulated genes in HFD as compared to LFD were enriched in cytoskeletal element organization, posttransciptional and posttranslational modifications respectively. Importantly, upregulated genes in CANA compared to HFD were also enriched in similar ontology terms. In addition, ontology analysis of DEGs in CANA compared to HFD showed enrichment in mitochondrial oxidative phosphorylation in Leydig cells and round spermatids which suggests unique transcriptomic changes driven by canagliflozin in these cell types. Thus, diet-induced obesity has striking effects to remodel the testicular transcriptome, with substantial reversal by SGLT2i. Transcriptomic differences induced by high fat diet and reversed by SGLT2i may reveal molecular mechanisms that mediate the reduction in risk of metabolic disease to offspring.

Presentation: Thursday, June 15, 2023
OR09-02 Chemogenetic Manipulation Of Brainstem Noradrenergic Neurons Modulates The Activity Of The Kisspeptin GnRH Pulse Generator In Mice
Authors: Vas Szilvia , Ruiz-Cruz Miguel , Han Su Young , Hwa-Yeo Shel , Herbison Allan Edward
Published: October 2023

Disclosure: S. Vas: None. M. Ruiz-Cruz: None. S. Han: None. S. Hwa-Yeo: None. A.E. Herbison: None.

The kisspeptin neurons in the arcuate nucleus (ARNKISS) represent the GnRH pulse generator that drives pulsatile luteinizing hormone secretion. These neurons serve as a hub to integrate multiple cues, such as the negative feedback control from steroid hormones, as well as metabolic, and stress-related inputs. Brainstem noradrenergic (NA) neurons have long been implicated in the control of GnRH pulse generator frequency and fertility but the precise mechanisms through which they operate, and their roles remain unclear. Here we used intersectional Cre-lox and FLP-FRT recombination approaches to couple ARNKISS neuron GCaMP6 fiber photometry with the brainstem NA DREADD (Designer Receptor Exclusively Activated by Designer Drug) modulation to investigate the role that NA may play in controlling ARNKISS pulse generator activity. Kiss1-Cre,GCaMP6s mice were crossed with a mouse line in which FLP recombinase is expressed selectively in dopamine β-hydroxylase (NA) neurons. Adult female mice were injected bilaterally with a FLP-dependent retrograde viral vector (AAVrg-hSyn-fDIO-hM3D(Gq)-mCherry-WPREpA) into the mid-caudal ARN to express excitatory (hM3Dq) DREADD receptors selectively in brainstem NA neurons that project to the ARN. An optical fiber was then implanted to detect the calcium-dependent population activity of KISSARN neurons. Histology revealed m-Cherry/DREADD expression in small sub-populations of tyrosine-hydroxylase neurons located in the brainstem A1, A2 and A6, confirming direct innervation from these regions to the ARN. Selective activation of these NA neurons with 1.5 and 3 mg/kg CNO (s.c.) in diestrous-stage mice, dose-dependently inhibited the frequency of the pulse generator synchronization episodes by 48-76% over 4 hours. These observations demonstrate that, when activated, brainstem NA neurons exert an inhibitory influence on the kisspeptin GnRH pulse generator in intact female mice. The new data may help to dissect how key components of the stress-responsive circuitry impact the central regulation of fertility.

Presentation: Friday, June 16, 2023
OR09-03 Loss of Inhibin Negative Feedback In The Pituitary Leads To Enhanced Ovulation But Pregnancy Failure In Mice
Authors: (Claire) Lin Yeu-Farn , Brule Emilie , Cowan Mitra , Boehm Ulrich , Bernard Daniel J
Published: October 2023

Disclosure: Y. Lin: None. E. Brule: None. M. Cowan: None. U. Boehm: None. D.J. Bernard: None.

Loss of inhibin negative feedback in the pituitary leads to enhanced ovulation but pregnancy failure in mice

Follicle-stimulating hormone (FSH) is an essential regulator of gonadal function, particularly in females. Inhibins are TGFβ family ligands made in the gonads that suppress FSH synthesis. Inhibins require a co-receptor, betaglycan or TGFBR3L, to mediate their actions in pituitary gonadotrope cells. Female mice with a gonadotrope-specific knockout of betaglycan or global deletion of Tgfbr3l exhibit increased ovarian follicle development, numbers of ovulated eggs, and litter sizes compared to controls. Females with both co-receptors knocked out (hereafter dKO) show dramatic increases in FSH levels, numbers of antral follicles and corpora lutea, serum progesterone levels, and ovarian aromatase expression. They ovulate 3-4 times as many eggs in natural cycles compared to control females. dKO females can become pregnant and show an increased number of implanted embryos at 7.5 days post coitum (7.5 dpc). Nevertheless, dKO females do not give birth to live offspring. By 10.5 dpc, the weight of the fetoplacental unit is decreased in dKO females, and many embryos display morphological abnormalities. By 14.5 dpc, most embryos in dKO females are either dead or resorbing. Wild-type surrogates give birth to live young following transplantation of embryos from control or dKO females. Conversely, control but not dKO females carry wild-type embryos to term. These data suggest that the maternal environment in dKO mice cannot support full-term pregnancies. Based on the hormonal profile of the cycling females, we suspected a deleterious effect of elevated estrogens. Consistent with this idea, treatment with the aromatase inhibitor anastrozole increased fetal survival in some dKO mice, suggesting a role for estrogens in embryo death. We are currently more thoroughly characterizing the maternal hormonal environment throughout gestation and investigating placental structure/function to gain more insight into the precise nature of the pregnancy failure. Our results will show how loss of inhibin action in the pituitary impede embryo survival and whether pregnancy loss is linked to increases in FSH.

Presentation: Friday, June 16, 2023
FRI381 Melanocortin 4 Receptor Signaling In Sim-1 Neurons Permits Sexual Receptivity In Female Mice
Authors: Harberson Mitchell Thomas , Semple Erin , Hill Jennifer W
Published: October 2023

Disclosure: M.T. Harberson: None. E. Semple: None. J.W. Hill: None.

Female sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear. In this study, female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) paired with males were found to approach males less and have reduced receptivity to copulation, as indicated by a low lordosis quotient. The mice were then bred to express MC4Rs exclusively on Sim1 neurons (tbMC4RSim1 mice) or on oxytocin neurons (tbMC4ROxt mice). Lordosis behavior was normalized in tbMC4RSim1 mice and improved in tbMC4ROxt mice. In contrast, approach behavior was unchanged in tbMC4RSim1 mice but greatly increased in tbMC4ROxt animals. The changes were independent of melanocortin-driven metabolic effects. These results implicate MC4R signaling in Oxt neurons in appetitive behaviors and MC4R signaling in Sim1 neurons in female sexual receptivity, while suggesting melanocortin-driven sexual function does not rely on metabolic neural circuits.

Presentation: Friday, June 16, 2023