bluuebunny/crossref_metadata_2025_split huggingface dataset:
PMON230 Pancreatic Exocrine Cells are Altered during the Progression of Ovarian Cancer-Driven Cachexia in Female Mice
Authors: Elesh Ibrahim , Kim So-Youn , Lele Subodh , Luan Yi , Yu Seok-Yeong 
Published: November 2022

Abstract
Cancer-associated cachexia (CAC) is a progressive debilitating syndrome that frequently complicates metabolic function in body vital organs and subsequently causes a high mortality rate in cancer patients. However, the underlying mechanisms and the functional consequences of organs dysfunction during CAC are not fully elucidated. Recently, we have developed a preclinical model characterized by oocyte-specific knockin for constitutively active Pi3k (Pik3ca*) which induces ovarian granulosa cell tumor (GCT) and mimics the stagewise progression of CAC in humans. Here, we aim to characterize the pathophysiological effect of cachexia on pancreatic dysfunction and investigate the potential role of the pancreas in the development and complication of cachexia in transgenic female mice with ovarian cancer. Notably, we found that cachectic mice showed a drastic loss in the pancreatic volume (PV) before death. Histological and morphometric assays revealed that exocrine pancreatic acinar atrophy (PAA) is drastic in the pancreas of cachectic PIK3CA* mice. The pancreas appeared to have an increased number of pancreatic stellate-shaped cells between acini. No significant changes were observed in the morphology of endocrine islets. Immunohistochemical assay confirmed a high level of TNF-a in atrophied pancreatic tissue and decreased intensity of pancreatic amylase in the cytoplasm of atrophied pancreatic acinar cells. Additionally, moderate fibrosis was also observed in the wall of pancreatic ducts and blood vessels, but not between the pancreatic acini. Masson trichrome and histochemical staining confirmed expression of extracellular matrix proteins including collagen I, II, IV, and a -smooth muscle actin in ducts and vessel walls. Overall, our preliminary findings in this novel CAC mouse model strongly suggest potential signs of exhausted exocrine pancreatic cells during the progression of ovarian cancer-driven cachexia. This mouse line could be an ideal preclinical model to aid in clarifying molecular mediators of pancreatic pathophysiology and metabolic dysfunction during CAC.
Keywords: Ovarian cancer-driven cachexia, pancreas, atrophy, amylase.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON238 Bone mineral density in middle-aged women with reproductive disorders
Authors: van Zwol - Janssens Charissa , Hage Aglaia , van der Ham K , Velthuis B K , Budde R P J , Koster M P H , Louwers Y V , Franx A , Fauser B C J M , Boersma E , Laven J S E 
Published: November 2022

Abstract

Objective
Reproductive disorders, such as premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS), are associated with hormonal and metabolic changes, which might lead to changes in bone mineral density (BMD). On the one hand women with POI enter menopause too early and have less estrogen exposure rendering them more prone to develop low BMD. On the other hand women with PCOS, who often have a delayed menopause and therefore experience longer estrogen exposure, may have an increased BMD. A third reproductive disorder, preeclampsia (PE) does not seem to affect BMD or menopausal age. The effect of these reproductive disorders, with different menopausal ages, on BMD could be most evident in middle-aged women. We hypothesized that the duration of estrogen exposure is a key factor in BMD.

Materials and methods
In this cross-sectional study we compared the BMD of 258 women with a history of PE as a reference group (age 46.0; 40% postmenopausal) to 90 women with POI (age 48.1; 100% postmenopausal) and 84 women with PCOS (age 48.3; 26% postmenopausal). BMD was measured using non-contrast coronary CT scans in three consecutive thoracic vertebrae (in the T7-T10 range). Secondary outcomes included T-scores, prevalence of osteoporosis and osteopenia and the comparison of measured BMD to predicted BMD, calculated by a formula based on age. We performed linear regression analysis to assess differences in BMD between groups, adjusted for age and BMI.

Results
Compared to women with a history of PE, women with POI had lower BMD (p&lt;0.001) and women with PCOS had higher BMD (p=0.003). Prevalence of osteoporosis was higher in women with POI (12.2%) compared to PE (0.8%; P=0.002) and none of the women with PCOS fulfilled the criteria for osteoporosis. Prevalence of osteopenia was significantly higher in the POI group and lower in the PCOS group compared to the PE group (57.8%, 17.9% and 26.4% respectively; p&lt;0.01). As expected, measured BMD of women with POI was significantly lower than the predicted BMD. On the contrary, the measured BMD of women with PCOS was significantly higher than the predicted BMD. Interestingly, the measured BMD of women with a history of PE was also higher than the predicted BMD.

Conclusion
Our results imply that prolonged estrogen exposure as in PCOS is associated with a higher BMD. A lower estrogen exposure associated with an early menopause in POI is associated with a lower BMD and osteoporosis. Patients with a history of PE could be seen as an intermediate group in terms of BMD and estrogen exposure, however, the measured BMD of women with a history of PE was higher than the predicted BMD. This study emphasizes the importance of adequate counseling on long term health issues when diagnosing a reproductive disorder.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON246 Prevalence of Hypertension and Metabolic Syndrome in Women with PCOS from France and Brazil
Authors: Spritzer Poli Mara , Marchesan Lucas B , Perol Sandrine , Allgayer Roberta M , Plu-Bureau Geneviève 
Published: November 2022

Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting women of reproductive age and has been associated with metabolic and reproductive abnormalities. Evidence from different geographic regions indicates that the metabolic features of PCOS may be influenced by ethnicity, lifestyle and sociocultural backgrounds. Also, metabolic disturbances seem to be found in higher frequency in referral than in unselected populations and from a clinical practice point of view, data from referral samples may be relevant for adjusting effective primary and secondary prevention strategies. Therefore, the aim of this study was to determine the prevalence of systemic arterial hypertension and metabolic syndrome (MBS) in women with PCOS from France and Brazil. We retrospectively assessed 314 French (FR) women and 236 Brazilian (BR) women with PCOS, according to the Rotterdam criteria, aging between 18 and 42 years and not using combined oral contraceptives or metformin. These women had been referred to the respective University Hospitals between 2014 to 2021 in France and 2014 to 2020 in Brazil. BR women had participated in previous studies conducted at our research center. Hypertension was defined according to the ACC/AHA 2017 and MBS according to the Joint Scientific Statement, 2009. Mean age was 26.0 (SD 5.9) years FR and 25.9 (SD 5.8) BR, p=0.87, and mean body mass index (BMI) was 27.1 (SD 6.8) FR and 31.3 (SD 7.5) BR P&lt;0.001. The frequency of classical phenotype (A/B) was 83.7% in FR (n=262) and 77.1% in BR (n=182), p =0.071. Subsequent analyses were done including only women presenting the classical phenotype from each center. FR women with PCOS presented lower prevalence of overweight/obesity (53.7% FR vs. 84.6% BR, p&lt;0.001), hypertension (32.6% FR vs. 71.6% BR, p&lt;0.001) and MBS (12.5% FR vs. 38.5% BR, p&lt; 0.001) than BR women with PCOS. Using logistic regression models for hypertension and MBS, it was found that both BMI and country contributed significantly for these prevalence results. In conclusion, women with PCOS living in France presented a less severe metabolic profile than those living in south Brazil. Differences in dietary pattern, lifestyle, socio-cultural features and ethnicity may have contributed to these results. Further studies are warranted to deeper characterize the influence of dietary composition and lifestyle on prevalence ratios of metabolic features in women living in France.
Sources of Research Support: INCT-CNPq /FAPERGS
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP066 Impact of Comorbid Adrenal Insufficiency on Outcomes of Infective Endocarditis Hospitalizations
Authors: Akaho Elikplim , Kumi Dennis , Ramirez Marcelo , Karki Sadicchya , Shrestha Prajwal , Nissan Ninos , Patel Birju , Soon-shiong Raquel 
Published: November 2022

Abstract

Background
Adrenocortical integrity is vital to mounting an appropriate response to a potentially deleterious endovascular infection such as infectious endocarditis. Likewise, adrenocortical hormones affect how cytokine storms lead to secondhand injuries that complicate sepsis. Data on the clinical outcomes of infective endocarditis in patients with adrenal insufficiency is limited and thus our attempt to study this topic was perhaps a worthwhile venture. Method: A retrospective cohort study was designed using data obtained from the 2016 to 2018 combined National Inpatient Sample (NIS) database. Adult patients (age &gt;18) admitted with a principal diagnosis of acute and subacute infective endocarditis were identified using the international diseases classification code, tenth revision (ICD-10). They were then stratified into two cohorts based on the presence of adrenal insufficiency. Primary outcomes assessed were, mortality, length of stay (LOS) and total hospital charge. Secondary outcomes included septic shock, embolic stroke, cardiogenic shock, and septic arterial embolization. Multivariate linear and logistic regressions were used to adjust for confounders.

Results
There was a total of 36,669.97 adult hospitalizations for infective endocarditis, among which 0.67% had a secondary diagnosis of adrenal insufficiency. The presence of adrenal insufficiency led to an increased length of stay (19.66 days vs 13. 05 days, adjusted mean difference of 7.17 days, 95%CI: 1.41 to 12.92 days, p: 0. 015) and an increased total charge (342,312.3 USD vs 147,887.6 USD, adjusted mean difference: 189,447.6 USD, 95%CI: 32,509.7USD to 346,385.5 USD, p: 0. 018) compared with patients without adrenal insufficiency. There was no significant difference in the odds of mortality between the two groups (4. 00% vs 4. 01%, AOR: 0.87, 95% CI: 0.99 to 7.57, p: 0.898). Similarly, other secondary clinical outcomes including septic shock, cardiogenic shock, septic arterial embolization, and embolic strokes were not different between the two cohort groups.

Conclusion
The presence of adrenal insufficiency among patients admitted with infective endocarditis led to an increased length of stay and a commensurate increased total charge. However, it did not significantly impact the outcomes in terms of mortality, rate of septic shock, cardiogenic shock, septic arterial embolization, or embolic strokes.
Presentation: No date and time listed
PMON267 Comparison Between Single Time Point Testing and 24-Hour Average Concentration of Total Testosterone in Hypogonadal Men Treated with an Oral Testosterone Undecanoate Softgel (JATENZO®)
Authors: Swerdloff Ronald , Wang Christina , Gittelman Marc , Newmark Jay , Woun Seo B , Rohowsky Nestor , Dudley Robert 
Published: November 2022

Abstract
In 2019, a novel, first-in-class testosterone (T) replacement therapy (TRT), oral testosterone undecanoate (TU) was approved by the U.S. FDA for the treatment of male hypogonadism. During clinical trials, dose adjustments were based on 24-hr average T concentration (Cavg) because single T measurements were considered less accurate. Subsequent, concordance analyses for this oral TU product have shown that a single total T value 6-hrs after the morning oral TU dose best corresponds to Cavg. Nonetheless, a conversion factor for T values obtained at other post-dose time points would be useful for healthcare providers (HCPs) and ease potential scheduling challenges for patients. Consequently, the relationship between other T sampling time points and Cavg was examined to determine if a reliable conversion factor could be derived to help HCPs monitor a patient's serum T concentration at times other than 6-hrs after oral TU administration. Hypogonadal men, age 18–65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. Overall, 166 men were randomized into the oral TU arm. Dose titration was based on Cavg calculated from serial pharmacokinetic (PK) samples. There were three pre-designated PK visits, to individualize the appropriate TU dose and to achieve a eugonadal T Cavg by the final study visit. Ratios between different timepoints and Cavg were determined for PK samples following morning drug administration. Overall, 87.3% (95% CI: 81.3%, 92.0%) of hypogonadal men had a final Cavg in the eugonadal range, with a mean serum total T = 488.7 ± 154.5 ng/dL (16.95 ± 5.37 nmol/L). Pooled values from all PK days demonstrated a linear relationship between T concentrations at 4, 6, and 9-hrs and Cavg (p &lt; 0.0001). Visit and time of sampling interaction were not statistically significant (p &gt;&gt; 0.50), indicating consistency in results among PK visits and among sampling timepoints. A factor was derived to enable conversion of T values assessed at a time other than 6-hrs (post oral TU dose) into a close approximation of Cavg: 1/[1.870–0.14×(hours after AM dose)]. Therefore, a sample drawn at 4-hrs after the morning oral TU dose would be multiplied by 0.75; while one drawn at 8-hrs would be multiplied by 1.33. Hence, T Cavg can be approximated after morning JATENZO administration if a blood sample cannot be collected precisely 6-hrs thereafter.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF34 | PMON202 The Human Metabolic Profile of Estetrol
Authors: Gérard Céline , Apter Dan , Chatel Guillaume , Nollevaux Fabrice , Jost Maud , Gaspard Ulysse , Foidart Jean-Michel 
Published: November 2022

Abstract

Objectives
Estetrol (E4), a native estrogen produced by the fetal human liver, has four hydroxyl-groups, making it structurally distinct from other estrogens. We determined the human metabolic profile of E4, which is recently marketed combined with drospirenone as a novel contraceptive and is currently in development for the relief of menopausal symptoms.
Method: We studied the in vitro metabolism of E4 using human hepatocytes, human liver microsomes and recombinant CYP enzymes in reaction phenotyping studies to evaluate the role of human cytochrome P450 enzymes, UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT). Furthermore, we evaluated the in vivo metabolism of E4 in an open-label, non-randomised phase 1 human absorption, distribution, metabolism, and excretion study, in which six healthy postmenopausal participants received a single oral solution containing 15 mg [14C]-E4. We analysed blood (up to 240h), urine and faecal samples (up to 312h). Metabolite profiling and identification was performed using liquid chromatography with tandem mass spectrometry.

Results
The in vitro studies showed that E4 undergoes extensive phase 2 metabolism to form glucuronide and sulphate conjugates. UGT2B7 is the key enzyme catalysing the direct glucuronidation of E4 and SULT1E1 is the dominant sulfotransferase for sulphate conjugation in vitro. Unlike for other estrogens, oxidative phase 1 metabolism by P450 enzymes does not play a major role in the metabolism of E4. Following oral administration of E4 to humans, the major metabolites observed in human plasma were E4-16-glucuronide, E4-3-glucuronide and E4-glucuronide-sulfate (respectively 62%, 17% and 9% of radioactivity at the time of maximum plasma concentration [Tmax]). At Tmax, unchanged E4 accounts for only 7.5% of plasma radioactivity. Main metabolites quantified in urine during the first 6 hours after administration were E4-16-glucuronide and E4-3-glucuronide (respectively 77.4% and 16.5% of urine radioactivity). Approximately 69% of the total administered radioactivity was recovered in urine and 22% in faeces. Mass spectrometry showed that E4 was not present in urine but was detected in faeces and that E4 is not converted back into one of the other natural estrogens (estriol, estradiol, estrone).

Conclusions
Altogether, these data suggest that E4 has a unique metabolic profile. E4 is a terminal end-product of estrogen metabolism, which is not converted back, in vivo, into active metabolites like estriol, estradiol or estrone. Unlike for other estrogens, CYP450 enzymes do not play a major role in the metabolic pathway of E4.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:48 p.m. - 12:53 p.m.
RF34 | PMON203 Copy Number Variant Analysis Reveals Novel Candidate Genes Associated with Primary Ovarian Insufficiency
Authors: Franca Monica , Moraes Daniela , Franca Monica , Krepischi Ana , Faria-Jr Jose , Costa Elaine , Hayashida Sylvia , Maciel Gustavo , Costa Silvia , Kulikowski Leslie , Jorge Alexsander , Mendonca Berenice , Domenice Sorahia 
Published: November 2022

Abstract

Primary ovarian insufficiency (POI) is characterized by a heterogeneous genetic background. Moreover, the etiology of most POI cases remains unclear. Herein, our goal was to investigate the presence of rare deletions or duplications in patients presenting with POI, which could lead to identification of novel chromosomal regions and/or genes potentially associated with disease risk.

Patients and Methods
Sixty-six patients presenting idiopathic POI were evaluated; 44 had primary amenorrhea and 22 secondary amenorrhea. Chromosomal microarray analysis was performed to detect copy number variants (CNVs) using array-CGH or SNP-array. Identified CNVs were validated by population databases of either health individuals (Database of Genomic Variants - DGV) or patients carrying chromosomal structural alterations (DECIPHER). A set of rare CNVs was selected and annotated in regard to gene content and clinical associations using bioinformatic tools (RefSeq, OMIM, PubMed, Ovarian Kaleidoscope Database, and Mouse Genome Informatics).

Results
Fifteen rare CNVs were found in 13 patients, ten of them with primary amenorrhea. The identified CNVs comprised four deleted and 11 duplicated regions, in which the break points occurred intragenic in 8 of them. Most of the CNVs were mapped in the autosomes. Seven CNVs identified in 5 patients were classified as pathogenic or probably pathogenic; three were novel variants containing candidate genes associated with ovarian development [19q13.43 (NLRP5) and Xq13.2 (XIST)] or function [(2q37.3 (PER2)]. The other pathogenic CNVs were previously implicated in POI etiology; two of them [Xq27.2q28 del (14.5 Mb) and Xq22.1q27.1 dup (41.4 Mb)] were encompassed in a complex chromosome rearrangement, associated with 20p13 dup (2.7 Mb), and the last region was 15q25.2 deletion. Four VUS containing genes associated with ovarian development [2p23.1 (XDH and EHD3), 9p24.1 (KDM4C), 22q12.1 (ZNRF3)] or function [1p31.1 (PTGFR)] were identified.

Conclusion
CNVs analysis indicated a genetic etiology in 10% of these POI patients. New candidate genes associated with ovarian development and function were revealed.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:54 p.m. - 12:59 p.m.
ODP435 11-Ketotestosterone is One of the Major Androgens in Pigs
Authors: Yazawa Takashi , Sato Takahiro , Ida Takanori 
Published: November 2022

Abstract
11-ketotestosterone (11-KT) is one of the active androgens, which belongs to the novel 11-oxygenated class of androgens. Although 11-KT has been regarded as a teleost-specific androgen, it was recently demonstrated that 11-KT is a major human androgen. However, the details of its functions and dynamics remain unknown. Deficiency of proper animal model is one of the reasons for this. Although rodent models have contributed to reveal synthesis and functions of steroid hormones, only small amounts of 11-KT are synthesized in mice and rats (Yazawa et al. Endocrinology, 2008). In mammal, 11-KT is abundant in limited animal species, such as non-human primates, pig and guinea pig. This suggest that these animal species are valuable models for determining the functions of 11-KT in mammals. In the present study, we evaluated the production and potential functions of 11-KT in pig. In previous studies, we studied human and murine steroidogenesis using steroidogenic cells-derived from mesenchymal stem cells (MSCs, Yazawa et al. Endocrinology 2006, 2009; Mol Endo, 2010; Endocrine J 2016). Therefore, we first induced steroidogenic cells from porcine subcutaneous preadipocytes (PSPA cells), which originate from MSCs. With the aid of cAMP, adenovirus-mediated introduction of SF-1/Ad4BP induced the differentiation of PSPA cells into 11-KT-producing cells. Using PSPA cell-derived steroidogenic cells and our previously established method (Yazawa et al. JSBMB, 2020), we found that porcine AKR1C1 can convert androstenedione into testosterone (T) and is expressed in adrenal, testis and ovary. In addition, we showed that HSD11B2, one of the essential genes to produce 11-KT from T was expressed in testicular Leydig cells and the adrenal cortex. 11-KT was present in the plasma of both immature male and female pigs, with slightly higher levels in males than in females. T levels were much higher in male pigs. It is noteworthy that 11-KT levels were &gt;10-fold higher than T levels in female pigs. However, castration altered the plasma profiles of 11-KT and T in male pigs to the female-like profiles. 11-KT induced endothelial nitric oxide synthase (eNOS) in porcine vascular endothelial cells. These results indicate that 11-KT is produced in porcine adrenal glands and testes. It can potentially be involved in the regulation of cardiovascular functions through eNOS expression. In addition, these findings indicate that pigs (especially female) represent an ideal model for analyzing the functions of 11-KT in mammal.
Presentation: No date and time listed