bluuebunny/crossref_metadata_2025 huggingface dataset:
OR20-01 AMH Preserves Fertility in Chemotherapy-Treated Mice Through a Mechanism Involving Autophagy
Authors: Beau Isabelle , Sonigo Charlotte , Binart Nadine
Published: May 2020

Chemotherapy-induced ovarian failure and infertility is an important concern in female cancer patients. The follicular ovarian reserve is established early in life then keeps declining regularly along reproductive life. This reserve is constituted by dormant primordial follicles (PMF) which are necessary to maintain female reproductive function. There is a continuous repression of PMF activation in early growing follicle through the balance between factors activating the initiation of follicular growth, mainly actors of the phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, and inhibiting factors such as Anti-Müllerian Hormone (AMH). Any alteration of this equilibrium may induce early follicle depletion and subsequent infertility. Cyclophosphamide (Cy) one of the alkylating agents commonly used for treating breast cancer is able to trigger PMF activation further leading to premature ovarian insufficiency. Preventing chemotherapy-induced ovarian dysfunction might represent an option for preserving optimal chances of natural or medically assisted conceptions after healing.

We showed in a model of Cy-treated pubertal mice, that AMH administration was able to restrain PMF depletion by counting the total PMF number within mouse ovaries. Moreover, the PI3K signaling pathway was evaluated following Cy administration with and without AMH injection. We showed that AMH decreased the phosphorylation of FOXO3A, a transcription factor of PMF activation and induced its nuclear translocation. Altogether, the results support a protective role of AMH against Cy-induced follicular loss. To better understand AMH action in the ovary, we investigated the molecular mechanism to explain the protective effect of this hormone on the PMF pool. It has been reported that autophagy, a lysosomal degradative ubiquitous process implicated in cellular homeostasis, was involved in both ovarian follicular death and survival mostly by PI3K pathway (Gawriluk et al. Reproduction 2011 141, 759–765). We show in mice that Cy inhibits autophagy in the ovary while AMH induces autophagy. In vivo analysis of autophagic flux is currently in progress to dissect this process more finely. Interestingly, FOXO3A was shown to be related to autophagy activation. To investigate the role of FOXO3A in AMH-induced autophagy further, we analyzed mRNA and protein expression of autophagy-related genes controlled by FOXO3A, including BECLIN-1, ATG12, ULK1, BNIP3, GABARAP, and LC3B. These findings establish a close relationship between AMH and autophagy to protect PMF stockpile and to limit follicular depletion induced by Cy.
SAT-293 Osteocalcin and Exercise Improve Mood and Cognition in Female Mice with High-Fat Diet Induced Type 2 Diabetes
Authors: Rentz Jesse , Winberg Jordan , Swardfager Walter , Mitchell Jane
Published: May 2020

The skeleton has been characterized as an endocrine organ, demonstrating a capacity to modulate cognition, mood and energy homeostasis (1,2). These endocrine actions of the skeleton have been attributed to the osteoblast-derived peptide osteocalcin. In mice, uncarboxylated osteocalcin (ucOCN) decreased the acquisition of type 2 diabetes mellitus (T2DM) and ameliorated depressive- and anxiety-like behaviours (1,2). Clinically, T2DM patients present with reduced serum osteocalcin levels and approximately 1 in 4 also suffer from co-morbid depression (3,4). The cognitive and metabolic benefits of ucOCN are similar to the beneficial effects of exercise that is recommended in treatment of both depression and T2DM. Here we compared the effects of ucOCN or exercise in female C57-BL/6J mice under two different metabolic conditions. Mice were fed either a high-fat diet (60% calories from fat) to induce T2DM or a control diet (10% calories from fat). Groups of mice were either sedentary or exercised daily by 30 min treadmill running for two months, with or without daily administration of ucOCN (30 ng/g/day). Mice with T2DM displayed depressive behaviours marked by a higher immobile time in tail suspension tests compared to control mice (97±25 n=11 vs 207±9.0 s n=12; t21=4.21, P=0.0004). Exercise and osteocalcin both improved depressive behaviour (137±8 n=12; t22=5.85, P<0.0001 & 127±15 s n=12; t22=4.46, P=0.0002). Anxiety, measured by the elevated-plus maze revealed the mice with T2DM displayed increased anxiety spending less time in the open arms and had a lower ratio of open to closed arm entries than the control group (0.37±0.03 n=10 vs 0.21±0.032 n=11; t19=3.56, P=0.0021). Neither exercise nor osteocalcin improved anxiety in the T2DM mice. The puzzle box test revealed the negative effects of the high-fat diet in problem solving and memory, where the sedentary mice displayed greater latencies to solve each task compared to control mice. Exercised and mice receiving osteocalcin displayed performances comparable to that of the control group. Under normal metabolic conditions (low fat diet), neither osteocalcin nor exercise altered responses in any of the behavioural tests. Together, these results: 1. The effects of osteocalcin on behaviour and cognition are comparable to that of the effects of exercise in female mice with T2DM; 2. Behaviour and cognition did not improve from exercise or osteocalcin in female mice on a low-fat diet.

References: (1) Ferron et al., Bone. 2012 Feb;50(2):568–575. (2) Oury et al., Cell. 2013 Sep 26:155(1):228–241. (3) Liu et al., Horm Metab Res. 2015 Oct;47(11):813–9. (4) Khaledi et al., Acta Diabetol. 2019 June;56(6):631–650.
SAT-344 Venous Thromboembolism Caused by Primary Hyperparathyroidism
Authors: Kanta Romana , Ansari Mohammad Jamal Uddin , Ali Mariam , Rehman Anis , Jabri Hadoun , Parveen Sanober , Jakoby Michael G
Published: May 2020

Background. Primary hyperparathyroidism (PHPT) is often overlooked as a potential etiology of hypercoagulability and thrombosis. We present a case in which PHPT was the only identifiable risk factor for an episode of venous thromboembolism (VTE).

Case. A 64 year old female with no chronic health problems presented to the emergency department for evaluation of dyspnea and right lower extremity pain. Symptoms had steadily increased in severity over approximately one week. The patient denied any long distance travel, sustained immobility, or tobacco use, and she was not taking any prescription or over-the-counter medications. Examination was notable for right distal lower extremity pain to palpation, but no swelling or erythema was observed. Elevated D-dimer (4.00 mg/mL, < 0.50) and hypercalcemia (12.7 mg/dL, 8.8–10.5) were discovered on initial laboratory testing, and an ECG showed sinus tachycardia. CT angiography of the chest revealed extensive, bilateral pulmonary emboli, and lower extremity venous Doppler studies confirmed a right lower extremity deep venous thrombus (DVT). Unequivocally elevated intact parathyroid hormone (PTH) level (235 pg/mL, 12–88) confirmed a diagnosis of PHPT, and an apparent left lower parathyroid adenoma was identified by both Tc99m parathyroid scintigraphy and neck ultrasonography. After hydration, serum calcium remained in the range of 11.5–12.0 mg/dL. The patient was discharged home on the direct factor Xa inhibitor rivaroxaban (Xarelto™) with a plan for six months of anticoagulation before parathyroidectomy.

Conclusions. The skeletal, neuromuscular, cardiovascular, and neuropsychiatric manifestations of PHPT are well described, but little is published regarding PHPT and VTE. In a multivariate analysis of participants in the fourth and fifth Tromsø surveys controlled for age, sex, and BMI, simultaneous elevations of PTH and serum calcium were associated with a nearly 80% increased risk of VTE. PHPT has been linked to several changes that predispose to a hypercoagulable state and thrombosis including dehydration, vasoconstriction, increased platelet count and levels of coagulation factors VII and X, elevated tissue plasminogen activator inhibitor-1 and D-dimer levels, and diminished tissue factor pathway inhibitor levels. Unfortunately, risk of VTE is not addressed in series documenting long-term outcomes for patients undergoing parathyroidectomy for management of PHPT. However, in cases of VTE where PHPT is diagnosed, parathyroidectomy should be considered to potentially improve hypercoagulability and reduce the risk of subsequent VTE.
SUN-646 A Novel Population of FOXO1-Expressing Cells in the Stomach Controls Cell Plasticity by Regulating the Cyclin CCNE1
Authors: McKimpson Wendy M , Kuo Taiyi , Kitamoto Takumi , Higuchi Sei , Haeusler Rebecca , Accili Domenico
Published: May 2020

A promising new therapy for type 1 diabetes is the reprogramming of gut enteroendocrine cells into cells that produce insulin. The mechanism by which gut epithelial cells are converted into cells that make insulin remains unknown. We have previously found that elimination of Foxo1 in neurogenin3 (Ngn3)-expressing cells of the intestine generates glucose-sensing, insulin-producing cells that are capable of reversing streptozotocin-induced diabetes. Others have reported that stomach cells have a similar property when made to express β-cell factors Ngn3, Pdx1, and MafA. Using mice bearing a Foxo1-GFP knock-in allele, we traced Foxo1-expressing cells in the gut to subpopulations of Ngn3+, as well as acid-secreting parietal stomach cells. To study these cells, we established a 2D co-culture method in which primary stomach cells are isolated from mice and cultured with embryonic fibroblasts. Deletion of Foxo1 in this system generated cells immunoreactive for insulin and C-peptide. Interestingly, Foxo1 ablation also altered the abundance of other gastric cell populations, including more parietal cells and decreased expression of stem cell marker, Lgr5. Tissue-specific elimination of Foxo1 in vivo in either Ngn3+ or parietal cells also resulted in the appearance of insulin+ cells, increased parietal cells, and reduced Lgr5 mRNA. To determine how Foxo1 regulated these changes, we used cells isolated from reporter mice that change from red to green after genetic recombination to collect Foxo1-deleted primary stomach cells using FACS. While the mRNA levels of many known Foxo1 targets did not change, cyclin E1 (CCNE1), which regulates G1 to S-phase progression of the cell cycle, was significantly decreased. Conversely, primary stomach cells overexpressing Foxo1 had increased levels of CCNE1. Finally, using ChIP-seq, we found that Foxo1 binds directly to the CCNE promoter in a nutrient-dependent manner. In summary, we show that Foxo1 is expressed in a subpopulation of stomach parietal cells and that it regulates their function through the cell cycle regulator, CCNE1.
SUN-130 Preoperative Hematological Parameters Associated with Recurrence or Regrowth of Meningiomas
Authors: Leães Rech Carolina Garcia Soares , Minuzzi Ricardo Kunde , Silva Camila Batista de Oliveira , Araújo Bruna , Mafalda Tainá , Ferreira Nelson Pires , Oliveira Miriam da Costa , Pereira-Lima Júlia F Semmelmann
Published: May 2020

Meningiomas represent the most frequently diagnosed intracranial tumors. Inflammation and immune processes may play an important role in therapeutic response as well as in anti- and pro-tumor modulating function. In tumors, inflammatory markers have been able to provide useful prognostic information for treatment or clinical evaluation of patients. The aim of this study was to investigate preoperative hematological markers concerning recurrence or regrowth and clinical variables in meningioma. Eighty nine patients with no corticosteroid therapy were included. Blood tests and tumor characteristics were collected from medical records. Recurrence-free survival was evaluated using Cox regression and Kaplan-Meier curves. Of the 89 cases, 73 (82%) were grade I and 16 (18%) grade II. The mean age was 53±13.9 years, with higher frequency in women, 2:1 proportion. The most frequent subtypes were meningothelial (40.4%), transitional (23.5%) and atypical (17.9%), 64% with peripheral location and 64% had a size greater than 3 cm. Regarding tumor resection, 49 (55.1%) underwent complete surgery (40 remained with tumor (81.6%) and 9 relapse (18.3%)) and 40 (44.9%) submitted to partial resection surgery (29 remained with persistent lesion (72.5%) and 11 regrowth (25%)). In total, 20 (22.4%) cases of recurrence or regrowth were observed. The median recurrence-regrowth free survival (RFS) was 62 months, 96.1% at 1 year, 67.4% at 3 years and 51.2% at 5 years. In univariate analysis, anemia (p=0.04), neutrophilia (p=0.02) and neutrophilis/lymphocyts ratio (NLR) (p=0.03) were associated with an increased risk of recurrence or regrowth and poor RFS. In multivariate, the interaction between anemia and NLR >4 represented a higher risk of recurrence or regrowth (p=0.003). The preoperative presence of anemia, neutrophilia, and NLR was associated with an increased risk of recurrence or regrowth in meningiomas, emphasizing the importance of preoperative evaluation of these parameters.
SUN-934 A Rare Case of Hyperparathyroidism - Parathyroid Carcinoma, Atypical Adenoma, or Both?
Authors: Krutilova Petra , Sandhu Harjyot , Salim Michael , Gilden Janice L , Butler Paula
Published: May 2020

Introduction: Parathyroid carcinoma (PC) is a rare endocrine malignancy. It accounts for <1% cases of primary hyperparathyroidism (PHPT). We present a rare case of concurrent PC and atypical parathyroid adenoma (PA).

Case presentation: A 72-year-old woman presented with 1-week history of generalized weakness, confusion, and auditory hallucinations. Her medical history was significant for PHPT known for 5 years, CAD and CHF. The patient appeared mildly volume depleted and was tachycardic (105/min). The rest of her physical exam was unremarkable. Calcium (Ca) was 15.1 mg/dL (8.4–10.2 mg/dL) and intact PTH 451.9 pg/mL (12–88 pg/mL). Her condition improved with aggressive fluid replacement, pamidronate, and cinacalcet. A sestamibi scan revealed increased uptake of bilateral parathyroid tissue. Fine needle aspiration (FNA) revealed PA. Surgical treatment was postponed for control of cardiac comorbidities. One month later, she presented again with symptomatic hypercalcemia. Her Ca was 16.1 md/dL and PTH 761.5 pg/mL. Initial medical management was followed by subtotal parathyroidectomy – three masses were removed (one on the right and two on the left). Final pathology revealed PC within the left parathyroid, the others were consistent with hypercellular parathyroid tissue. One month later, the patient underwent left hemithyroidectomy, right parathyroidectomy, and central neck dissection. PTH level dropped to 2.4 pg/mL and Ca level was 7.6 mg/dL after surgery. She was discharged home on Ca and vitamin D supplements. Pathology was sent to a referral cancer center and revealed PC vs. atypical PA within the right parathyroid.

Discussion: PC is a rare endocrine malignancy. Further, there are not many cases of synchronous PC and PA or multifocal PC. Diagnosing PC preoperatively is challenging since it shares overlapping characteristics with PA. Patients with malignancy commonly present with larger tumor size, higher level of Ca (>14.6 mg/dL), and PTH (5-fold higher than the upper limit of normal). Our patient had a history of multiple admissions due to symptomatic HC. She had no palpable neck masses on exam. Her initial FNA was consistent with PA. Hence, we presumed that her hypercalcemia was caused by PA. Establishing a definitive diagnosis of PC by frozen sections intraoperatively is difficult. Histopathologic findings of atypical cells, high mitotic rate, and cellular invasions can suggest the diagnosis, though they are often negative. Even postoperatively, pathologists often disagree on cytologic interpretation. However, differentiating PA and PC is important since earlier and more aggressive treatment is needed to reduce the morbidity and mortality in case of malignancy.
SAT-637 Patient-Centered Glycemic Management of Type 2 Diabetes with Mobile Applications
Authors: Lau Chap-Kay K , Wu Gloria , Leung Brian , Momen Donia , Luu Shannon
Published: May 2020

BACKGROUND: Ehealth apps have 3.7 billion downloads yearly. The accessibility of diabetes mobile applications allows for patient self-management of diabetes. Renal and cardiovascular complications,1 which play a role in diabetic patient outcomes, are newly highlighted by the 2019 American Diabetes Association’s Standards of Medical Care in Diabetes.2

Purpose: To evaluate free Android mobile apps using the Diabetes Self-Management Education and Support (DSMES) and the 2019 American Diabetes Association (ADA) guidelines for renal and cardiovascular complications.

Methods: Using the search term “diabetes,” Google Play store was accessed. Inclusion criteria: 1) Apps with downloads 1M-100,000; 2) free; 3) DSMES criteria; and 4) medication adherence. Exclusion criteria: 1) Purely educational factual apps on diabetes; 2) no ranking or download information. Google displayed a list of 10 free apps in 2019. The 2019 apps were analyzed for DSMES criteria, renal and cardiovascular complications (ADA 2019), and medication adherence via push notification.

Results: The top 10 mobile apps in descending order were: 1) mySugr, 2) Onetouch Reveal, 3) OneDrop Diabetes Management, 4) Diabetes: M, 5) Diabetes, 6) Ontrack Diabetes, 7) Health2Sync, 8) Diabetes Connect, 9) Glucose Buddy Diabetes Tracker, 10) Blood Glucose Tracker. All of the mobile apps had the functionality of tracking blood glucose levels. 8/10 had the ability of tracking HbA1C levels. The percent of DSMES incorporation within the apps ranged from 18.2%-81.8%. None of the apps used all the DSMES guidelines or 2019 ADA. Only 1/10 of the mobile apps had the ability to track the presence of heart palpitation and retina/eye issues recommendations. None of the apps had the ability to track cardiovascular and renal complications. 7/10 of the apps had medication reminders (sound notification) and 4/10 of the apps had push notifications.

Conclusion: eHealth mobile apps could be a powerful tool for patient self-management of diabetes. Currently, none of the apps incorporate all of the DSMES or ADA guidelines regarding comorbidities and complications of diabetes. Despite these shortcomings, these apps provide an introduction to the concept of patient-centered tracking of health data. We look for future improvements as more physicians use the apps and provide feedback to the app developers and eHealth commerce space.

References

1.

Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669-2701

2.

American Diabetes Association. 4. Comprehensive medical evaluation and assessment of comorbidities: Standards of Medical Care in Diabetes—2019. Diabetes Care 2019;42(Suppl. 1):S34-S45
SAT-547 Aldosterone-Potassium Ratio Predicts Primary Aldosteronism Subtype
Authors: Puar Troy , Loh Wann Jia , Lim Dawn Shao Ting , Zhang Meifen , Foo Roger S , Lee Lynette , Khoo Joan J C , Tay Donovan , Dekkers Tanja , Velema Marieke Stientje , Deinum Jaap , Kek Peng Chin
Published: May 2020

Objective Prediction models have been developed to predict either unilateral or bilateral primary aldosteronism, and these have not been validated externally. We aimed to develop a simplified score to predict both subtypes and validate this externally.

Methods Our development cohort was taken from 165 patients who underwent adrenal vein sampling (AVS) in two Asian tertiary centres. Unilateral disease was determined using both AVS and post-operative outcome. Multivariable analysis was used to construct prediction models. We validated our tool in a European cohort of 97 patients enrolled in a clinical trial. Previously published prediction models were also tested in our cohorts.

Results Backward stepwise logistic regression analysis yielded a final tool using baseline-aldosterone-to-lowest-potassium ratio (APR, ng/dL/mmol/L), with an area under receiver operating characteristic curve of 0.80 (95% CI: 0.70 - 0.89). In the Asian development cohort, probability of bilateral disease was 90.0% (with APR <5) and probability of unilateral disease was 91.4% (with APR >15). Similar results were seen in the European validation cohort. Combining both cohorts, probability of bilateral disease was 76.7% (with APR <5), and probability for unilateral was 91.7% (with APR >15). Other models had similar predictive ability but required more variables, and were less sensitive for identifying bilateral PA.

Conclusion The novel aldosterone-potassium ratio (APR) is a convenient score to guide clinicians and patients of various ethnicities on the probability of PA subtype. Using APR to identify patients more likely to benefit from AVS may be a cost-effective strategy to manage this common condition.
SAT-298 Integrative Single-Cell Transcriptomic and Epigenomic Landscape of Mouse Anterior Pituitary Cell Types
Authors: Ruf-Zamojski Frederique Murielle , Zamojski Michel A , Nudelman German , Ge Yongchao , Mendelev Natalia , Smith Gregory R , Zhou Xiang , Toufaily Chirine , Schang Gauthier , Gambino Luisina Ongaro , Liu Hanqing , Gomez Castanon Rosa G , Moriwaki Mika , Nair Venugopalan , Pincas Hanna , Nery Joseph R , Bartlett Anna , Alridge Andrew , Odle Angela Katherine , Childs Gwen V , Turgeon Judith L , Welt Corrine Kolka , Ecker Joseph R , Bernard Daniel J , Sealfon Stuart C
Published: May 2020

The pituitary gland is a critical regulator of the neuroendocrine system. To further our understanding of the classification, cellular heterogeneity, and regulatory landscape of pituitary cell types, we performed and computationally integrated single cell (SC)/single nucleus (SN) resolution experiments capturing RNA expression, chromatin accessibility, and DNA methylation state from mouse dissociated whole pituitaries. Both SC and SN transcriptome analysis and promoter accessibility identified the five classical hormone-producing cell types (somatotropes, gonadotropes (GT), lactotropes, thyrotropes, and corticotropes). GT cells distinctively expressed transcripts for Cga, Fshb, Lhb, Nr5a1, and Gnrhr in SC RNA-seq and SN RNA-seq. This was matched in SN ATAC-seq with GTs specifically showing open chromatin at the promoter regions for the same genes. Similarly, the other classically defined anterior pituitary cells displayed transcript expression and chromatin accessibility patterns characteristic of their own cell type. This integrated analysis identified additional cell-types, such as a stem cell cluster expressing transcripts for Sox2, Sox9, Mia, and Rbpms, and a broadly accessible chromatin state. In addition, we performed bulk ATAC-seq in the LβT2b gonadotrope-like cell line. While the FSHB promoter region was closed in the cell line, we identified a region upstream of Fshb that became accessible by the synergistic actions of GnRH and activin A, and that corresponded to a conserved region identified by a polycystic ovary syndrome (PCOS) single nucleotide polymorphism (SNP). Although this locus appears closed in deep sequencing bulk ATAC-seq of dissociated mouse pituitary cells, SN ATAC-seq of the same preparation showed that this site was specifically open in mouse GT, but closed in 14 other pituitary cell type clusters. This discrepancy highlighted the detection limit of a bulk ATAC-seq experiment in a subpopulation, as GT represented ~5% of this dissociated anterior pituitary sample. These results identified this locus as a candidate for explaining the dual dependence of Fshb expression on GnRH and activin/TGFβ signaling, and potential new evidence for upstream regulation of Fshb. The pituitary epigenetic landscape provides a resource for improved cell type identification and for the investigation of the regulatory mechanisms driving cell-to-cell heterogeneity.

Additional authors not listed due to abstract submission restrictions: N. Seenarine, M. Amper, N. Jain (ISMMS).
SAT-562 Angiotensin II Induces Aldosterone Synthesis in the Rat Heart Stressed by Angiotensin II
Authors: Bose Himangshu S , Whittal Randy M , Rajapaksha Maheshinie , Marshall Brendan , Wang Ning-Ping , Perry Elizabeth W , Zhao Zhi-qing , Miller Walter L
Published: May 2020

Aldosterone (Aldo) causes myocardial injury and fibrosis. While most Aldo is made by the adrenal zona glomerulosa; there have been controversial reports that Aldo is also synthesized in the heart; such myocardial synthesis of Aldo might contribute to myocardial injury. We induced cardiac fibrosis in rats by infusing angiotensin II (AngII) @ 500 ng/kg/min via subcutaneous pumps. After 4 weeks, circulating corticosterone increased about 400-fold from ~29 nM to ~11 μM. Aldo synthesis in isolated mitochondria (mito) was assessed by conversion of tritiated deoxycorticosterone to Aldo; AngII infusion doubled Aldo synthesis, and this augmented synthesis was inhibited in mito from rats receiving AngII + telmisartan, which inhibits the binding of AngII to the AT1 receptor. Western blotting showed P450c11AS (Aldo synthase) was also stimulated by AngII and inhibited by telmisartan in both rat heart and H9c2 myocardial cells. 2-dimentional native PAGE and mass spectrometry showed that a 290-kDa complex on the inner mitochondrial membrane (IMM) contained P450c11AS, Tom22 (a translocase associated with the outer mitochondrial membrane, OMM), and StAR (the steroidogenic acute regulatory protein). Immunocytochemistry and transmission electron microscopy monitoring of immune-gold particles confirmed that P450c11AS, Tom22, and StAR were associated with the mito, that P450c11AS and StAR were associated with the IMM and that P450c11AS and StAR, but not Tom22, were increased by AngII. Cardiac Aldo synthesis required myocardial expression of P450c11AS, but expression of P450scc, the initial steroidogenic enzyme that converts cholesterol to pregnenolone, was undetectable, indicating the heart cannot make Aldo de novo from cholesterol. The only known action of StAR is to promote the movement of cholesterol from the OMM to IMM; nevertheless, we found that intramitochondrial StAR is required for Aldo synthesis; protein crosslinking with BS3 showed that Tom22 forms a bridge between StAR and P450c11AS. This is the first activity ascribed to intramitochondrial StAR, but the manner by which StAR promotes P450c11AS activity is unclear. As P450scc was undetectable, and circulating concentrations of corticosterone approached the Km (~28 μM) for the use of corticosterone as a substrate for P450c11AS, we suggest that cardiac P450c11AS uses circulating steroids for substrate. Thus the stressed heart produces aldosterone using a previously undescribed intramitochondrial mechanism that involves P450c11AS, Tom22 and StAR
SAT-747 A Prospective Non-surgical Treatment for Inguinal Hernias
Authors: Potluri Tanvi , Zhao Hong , Taylor Matthew Joseph , Bulun Serdar E
Published: May 2020

BACKGROUND: Inguinal hernias are a widespread public health issue and typically diagnosed in one-fourth of all men. Despite hernia repair being the most commonly performed surgery in the US, the mechanisms causing this disease are currently unknown. We previously developed a mouse model that expresses the human aromatase gene (Aromhum) wherein all male mice develop inguinal hernias. We further showed that high production of estradiol by aromatase in the lower abdominal muscle (LAM) via binding to estrogen receptor caused increased fibroblast proliferation and muscle atrophy which leads to inguinal hernia formation (1).

Hypothesis: Disruption of estrogen signaling via ablation of estrogen production using an aromatase inhibitor or inhibition of estrogen receptor by an estradiol antagonist can prevent or reverse the formation of inguinal hernias.

Results: We previously demonstrated that aromatase inhibitor, letrozole, completely prevented the formation of inguinal hernias in Aromhum mice (1). Here we show that ER-dependent estradiol antagonist fulvestrant can also prevent LAM tissue fibrosis, muscle atrophy and hernia formation in Aromhum mice (n=4, p=0.0007). WT littermates did not show hernia formation with or without fulvestrant treatment (n=4). Furthermore, we demonstrate that aromatase inhibitor letrozole can reverse mild to moderate size of hernia (150-160 mm2), while placebo-treated mice had progressively enlarged hernias (n=7, p=0.04). We subsequently show a reduction in muscle fibrosis and a restoration of myocyte size in Aromhum mice with letrozole treatment.

Conclusion: Estrogen produced as a result of aromatase expression in estrogen-sensitive LAM tissue stimulates the proliferation of estrogen receptor-expressing fibroblasts, fibrosis, muscle atrophy, and hernia formation. Ablation of estrogen production or its signaling not only completely prevents this phenotype but also reverses mild to moderate-sized hernias. Our findings pave the pathway for developing the first potential preventive and therapeutic pharmacological approach for combating recurrent inguinal hernias in elderly men through modulation of estrogen signaling in abdominal muscle tissue.

Reference: (1) Zhao H, et al.,PNAS. 2018 Oct 30;115(44):E10427-36.
MON-265 Once-Weekly Somapacitan in Japanese Adults with GH Deficiency Was Well Tolerated, with Similar Efficacy to Daily GH: A Randomized Trial
Authors: Otsuka Fumio , Takahashi Yutaka , Tahara Shigeyuki , Rasmussen Michael Højby , Ogawa Yoshihisa , Takano Koji
Published: May 2020

Somapacitan is a long-acting, reversible albumin-binding human growth hormone (GH) derivative based on a proven protraction technology. The objective of this trial was to evaluate the safety, efficacy and treatment satisfaction of once-weekly somapacitan compared with daily GH (Norditropin®) over 52 weeks in Japanese patients with adult GH deficiency (AGHD).

This was a phase 3, multicenter, randomized, open-label, parallel-group, active-controlled trial (NCT03075644). Patients previously treated with human GH were randomized 1:3 to either daily GH or somapacitan, respectively, to undergo 20 weeks of dose titration and 32 weeks of fixed-dose treatment. The primary endpoint was the incidence of adverse events (AEs) from baseline to week 53. Secondary endpoints included change from baseline in visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT, respectively) assessed with computerized tomography scans; change from baseline in treatment satisfaction evaluated using Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores; and occurrence of anti-somapacitan antibodies.

In total, 62 patients were randomized (16 to the daily GH and 46 to the somapacitan treatment arm), of which 60 completed the trial. Baseline characteristics for daily GH vs somapacitan groups, respectively, were: 43.8% vs 47.8% female, 87.5% vs 80.4% adult-onset GH deficiency, mean (SD) age 49.3 (11.5) vs 54.1 (12.1) years, weight 67.9 (12.0) vs 69.4 (22.7) kg, body mass index 24.8 (3.7) vs 26.4 (6.7) kg/m2, and GH dose at screening 0.29 (0.14) vs 0.31 (0.17) mg. Rate of AEs per 100 patient-years was similar between treatment arms (309.8 for daily GH, 312.7 for once-weekly somapacitan); most AEs were mild (97.9% and 93.1%, respectively) and none were severe. Four AEs in the somapacitan arm were serious; all were considered unlikely related to treatment. No anti-somapacitan antibodies were detected during treatment. Mean insulin-like growth factor-I standard deviation score (IGF-I SDS) at baseline was maintained with both treatments. The majority of the patients had IGF-I SDS values below +2. No significant differences in VAT, SAT and TAT were seen in both treatment groups after 52 weeks (estimated difference, somapacitan – daily GH [95% CI]): –1.74 [–18.13; 14.66], –11.53 [–35.54; 12.48], and –12.85 [–47.31; 21.62] cm2, respectively. TSQM-9 scores were not significantly different between treatments, but showed a tendency in favor of somapacitan (estimated difference [95% CI]): 4.87 [–3.46; 13.20] for effectiveness, 6.79 [–1.04; 14.61] for convenience, and 6.88 [–1.08; 14.85] for overall satisfaction.

No new safety concerns were identified. Improvements in body composition were similar in the GH and somapacitan cohorts. The safety and tolerability of somapacitan in Japanese patients with AGHD were consistent with results from the global phase 3 trial (REAL 1).
OR22-01 NF-κB Pathway Is Implicated in Thyroid Embryogenesis
Authors: Vanier Stéphanie Larrivée , Magne Fabien , Jean-Louis Martineau , Samuels Mark E , Van Vliet Guy , Deladoey Johnny Yvan
Published: May 2020

BACKGROUND: Congenital hypothyroidism due to thyroid dysgenesis (CHTD) is the most common congenital endocrine disease with a prevalence of 1:4,000 live births. We have suggested a two-hit hypothesis to explain CHTD, combining an inherited or de novo variant with a post-zygotic event. This model could explain the sporadicity of the disease (99%), its ethnic predominance and the high discordance rate between monozygotic twins. Despite years of research, more than 95% of cases of CHTD remain unexplained, especially those with thyroid ectopy. This suggests that research on genes and/or pathways not previously associated with thyroid development need to be pursued. Inactivation of the NF-κB pathway can cause deficient anterior pituitary and variable immunodeficiency, or DAVID syndrome. Whether this pathway is also involved in CHTD remains to be established. Objective: To evaluate the implication of the NF-κB pathway during thyroid migration. Methods: Knock down experiments using morpholinos in a zebrafish model were carried out to investigate the roles of certain genes related to the NF-kB pathway during thyroid development. Rescue experiment was also performed to evaluate the specificity of the morpholino. The first gene to be tested was IKBKE, a member of the inhibitor of κB kinase (IKK) family. Thyroid location was assessed by microscopy of live larvae. Results:ikbke depletion in zebrafish caused defective aortic arch artery formation and abnormal thyroid migration. The thyroid phenotype was partially rescued by injection of human IKBKE RNA in ikbke morphants. Conclusion:IKBKE seems important for normal thyroid migration suggesting that the non-canonical NF-kB pathway might be implicated. Further studies targeting other genes in this pathway are ongoing to extend these results.
SAT-035 In Vitro Effect of Different Follicle-Stimulating Hormone Preparations on Sertoli Cells
Authors: Grande Giuseppe , Iva Arato , Barrachina Ferran , Bellucci Catia , Cinzia Lilli , Jodar Meritxell , Chiara Aglietti Maria , Mancini Francesca , Vincenzoni Federica , Pontecorvi Alfredo , Calafiore Riccardo , Oliva Rafael , Luca Giovanni , Mancuso Francesca , Milardi Domenico
Published: May 2020

Follicle-stimulating hormone (FSH) is the main regulator of spermatogenesis and plays a key role in the development and function of the reproductive system. To assess the effects of different FSH preparations in combination with testosterone on porcine pre-pubertal Sertoli cells, we performed Real Time PCR analysis of AMH, inhibin B and FSH-r, Western blotting analysis of AKT-posphoAKT, ERK1/2-posphoERK1/2, ELISA assay for AMH and inhibin B and a high-throughput proteomic analysis.We observed that all three preparations induced a reduction of AMH in terms of mRNA and secreted protein and, an increase of inhibin B in terms of mRNA in all the formulations while, only α-follitropin induced an increase of inhibin B secreted in the culture medium. Proteomic analysis permitted us to identify 46 secreted proteins.Of those, the SPARC protein was down-regulated after the treatment with testosterone associated with α-follitropin, β-follitropin and urofollitropin (vs group stimulated with T alone). 11 proteins were up-regulated by the different FSH preparations. In detail, Hemoglobin subunit beta, TPA and TPI have been observed to be up-regulated by stimulation with testosterone in addition with α-follitropin or with β-follitropin and or with urofollitropin. All preparations induced an increase in the secreted inhibin beta A chain, but in the medium after stimulation with urofollitropin we observed an higher increase in the levels of this protein. β-follitropin, associated with testosterone, specifically induces an up-regulation of 8 specific secreted proteins.Our study, showing that the three FSH preparations were associated with different effects, could offer the opportunity to shed light inside applications to personalized reproductive medicine.
SUN-419 Monitoring Thyroid Function Tests in Patients on Lithium: Adherence to Recommended Guidelines and Comparison of Practice Patterns in a Health Care System
Authors: Aliyeva Sevil , Kirloskar Kunal , Anant Kedaari , Schroeder Pamela
Published: May 2020

It is well known that Lithium causes various types of thyroid dysfunction. Thus, multiple professional guidelines, for example the American Psychiatry Association, recommend that thyroid function be assessed before starting lithium therapy, within the first 6 months of initiation, and then every 6 to 12 months. We hypothesized that these recommendations are not consistently followed by all types of providers.

Methods

A total of 796 patients were identified by chart review with age ≥18 years and ICD 9/10 codes for bipolar disorder or on lithium in outpatient clinics in our multicenter system from January 2013 to December 2017.

Results

Lithium start date was known in 472 (59.3%) of 796 patients. Of these 796 patients, 518 (65 %) were followed by psychiatry, 25 (3%) by family medicine, 60 (7.5%) by internal medicine, and 193 (24%) by other specialties including endocrinology and emergency department. Patients with unknown start date were excluded from analysis of baseline and follow-up TSH. Baseline TSH was done in 178 (37%) of patients with known start date. Of these patients, 141 (79%) were followed by psychiatry, 13 (7%) by internal medicine, and 8 (4%) by family medicine. Of the 472 patients, 76 (16%) had 6-month TSH by psychiatry (42; 60.5%), internal medicine (17; 22%), and family medicine (3; 4%). Of the 796 patients on lithium, 568 (71%) had random TSH values, 200 (25%) had abnormal thyroid function tests (TFTs), and only 69 (34%) had baseline TFTs before lithium was started. Of the 200 patients with abnormal TFTs, 90 (45%) developed thyroid disease. The odds of baseline TSH for family practice and internal medicine were not significantly different than for psychiatry, (OR = 1.3 p = 0.6, and OR = 0.7, p = 0.3, respectively). Internal medicine had 5.1 times higher odds of TSH at 6 months compared with psychiatry (p <0.001). The odds of 6-month TSH for family practice were not significantly different than for psychiatry.

Conclusion

Our findings revealed that TSH was not checked in most patients before starting lithium therapy and TSH values were not followed at recommended intervals. This raises the concern that a large number of patients may have undiagnosed thyroid dysfunction due to inappropriate follow up. Future plans include a quality improvement project to focus on improving practice patterns, such as EMR reminders to prompt providers when TFTs are due and educating providers about the guidelines.
SAT-034 The Effect of Natesto on Spermatogenesis, Reproductive Hormones, and Hypogonadal Symptoms. A Phase IV Study
Authors: Masterson Thomas A , Best Jordan , Bitran Josh , Molina Manuel L , Ibrahim Emad , Kaiser Ursula B , Ramasamy Ranjith
Published: May 2020

INTRODUCTION AND OBJECTIVE: Exogenous testosterone (T) therapy is typically long-acting and causes azoospermia in up to 65% of the men. Natesto, dosed three times a day, is a short-acting, FDA approved nasal testosterone available since 2015. We hypothesized that Natesto can preserve spermatogenesis due to its short-acting property.

METHODS: We prospectively enrolled hypogonadal men aged 18-55 years with two serum T levels < 300 ng/dL (drawn before 10 AM), symptoms, and 2 semen analyses (SA) with total motile sperm counts (TMSC) > 5 million in a phase IV clinical trial. Eligible men received Natesto for 6 months. Serum T, luteinizing hormone (LH), follicle stimulating hormone (FSH), 17-hydroxyprogesterone (17-OHP), 2 SA, and testis volume were collected at baseline and after 3 and 6 months of therapy. Symptoms were evaluated using the international index of erectile function 6 (IIEF-6) and the short form 36 (SF-36) questionnaires. The primary endpoints were change in T, LH, FSH, sperm concentration, sperm motility, and TMSC. Secondary end points were change in symptoms, testis volume, and adverse events (AEs). Data are presented as means (SD), t-test was used to compare changes after 3 and 6 months, p<0.05 was considered significant.

RESULTS: In total, 102 men were screened, and 60 men (age 19-55 years) enrolled. Of the 60 men, 44 completed 3 months, 33 completed 6 months, and 17 dropped out. Mean serum T increased from hypogonadal at baseline to 3 and 6 months (p=0.005), LH and FSH decreased (p=0.03) but remained within the normal range (2-5 IU/mL). Most importantly, semen parameters remained unchanged after 3 and 6 months of T therapy. Only 3 (7.5%) men had severe oligospermia and one (2.5%) became azoospermic but recovered at 6 months after discontinuation. Testis volume and intratesticular T (serum 17-OHP) were maintained at 3 and 6 months. There was improvement across all sub-domains of the IIEF as well as improvement in questions related to energy in the SF-36. A total of 10 men dropped out due to nasal irritation.

CONCLUSIONS: This phase IV clinical trial demonstrated that Natesto increased serum T, improved hypogonadal symptoms, maintained gonadotropins, testis volume, intratesticular testosterone and semen parameters. Natesto, and other short acting forms of testosterone therapy may help hypogonadal men maintain fertility.
MON-180 Risk for Hypercoagulability Among Patients with Cushing Syndrome. From the National Inpatient Sample
Authors: Ahmed Fatima , Abugroun Ashraf , Elhassan Manar , Seyoum Berhane , Taha Wael
Published: May 2020

Background: Patients with Cushing syndrome are at higher risk for hypercoagulability due to elevated levels of pro-coagulants and impaired fibrinolysis. Objective: We aimed to examine the association of Cushing syndrome and hypercoagulability using a large national database. Methods: The National Inpatient Sample (NIS) was queried for all patients diagnosed with Cushing syndrome during the year 2011-2015. Patients with Cushing syndrome were identified using the international classification of diseases (ICD-9) code “2550”. The control group was randomly selected from the same database in a 4:1 ratio matched by age and gender. Hypercoagulable state was defined by presence of either ICD-9 codes “28981 or 28982” for primary and secondary hypercoagulable state as well as personal history of venous thrombosis or pulmonary embolism identifed with ICD-9 codes “V1251 and V1255” respectively. Patients who were diagnosed with autoimmune diseases, solid tumors, metastatic cancer, as well as those who were bed-bound were excluded. Multivariable logistic regression with adjustment for patient’s demographics, socioeconomic factors, comorbidities and hospital factors was used to obtain Cushing syndrome related risk for hypercoagulability. Subgroup analysis was performed based on gender, race and age groups; young adults (aged 18-35 years), middle-aged (> 35-<55 years) and older adults (aged > 55 years). Results: A total of 43,157 patients diagnosed with Cushing syndrome were identified. The mean age was 53.9 years (standard error of the mean 0.1). Majority of patients were females (75.2%) and of Caucasian race (74.6%). The prevalence of hypercoagulability was markedly higher among patients with Cushing syndrome 10 % vs 4%, p <0.001. On multivariable analysis, presence of Cushing syndrome correlated with significanlty higher risk for hypercoagulability with adjusted odd ratio (a OR) 2.20 [95%CI: 1.98-2.44] p <0.001. The risk for hypercoagulability was highest among young patients (age ≤ 35) with a OR 6.02 [95%CI: 4.06-8.94] p<0.001 and among Hispanics with a OR 3.66 [95%CI: 2.38-5.64] p<0.001. No significant gender difference on risk for hypercoagulability. Conclusion: Patients with Cushing syndrome are at higher risk for hypercoagulability. This risk is markedly higher among young patients and among Hispanics. Particular attention for early detection and prevention of venous thromboembolism in patients with Cushing Syndrome is advisable.
SUN-057 Endocrine Dysfunction After Pediatric Epilepsy Surgery: A Report from the Global Pediatric Epilepsy Surgery Registry
Authors: Jones Monika , Zeitler Philip Scott
Published: May 2020

RATIONALE: Epilepsy surgery in children is no longer considered a last resort for drug-resistant seizures; however, there are no studies that address the impact of pediatric epilepsy surgery on endocrine function. We reviewed patients in the Global Pediatric Epilepsy Surgery Registry to assess the prevalence of various endocrinopathies after epilepsy surgery in childhood.

METHODS: Retrospective data was collected for 122 patients, via parent proxy, who had epilepsy surgery before age 18. Data were collected on age, height, weight, seizure etiology, and surgery type, as well as reported endocrine diagnoses. Descriptive statistics were tabulated and group differences assessed.

RESULTS: 22.7% of patients were followed by an endocrinologist after surgery, but not before. 9.8% of patients reported one diagnosed endocrine disorder post-operatively, including precocious puberty (5.7%) and diabetes insipidus (0.8%); 3.3% had more than one diagnosed endocrine disorder. A higher incidence of diagnosed endocrinopathies was found in children after hemispherectomy surgery (12.64%) or who acquired hydrocephalus after surgery (30%) than in other forms of surgery. 16.4% of parents report that the child had “excessive weight gain” after surgery and 9.8% report “excessive weight loss” after surgery.

CONCLUSION: Endocrine dysfunction, including precocious puberty and disorders of water balance, appears to be common after epilepsy surgery in childhood, especially hemispherectomy. Longitudinal studies are needed to better understand the etiology and true prevalence of these disorders. The Global Pediatric Epilepsy Surgery Registry is the first longitudinal study with this aim.