Bayer AG Research Articles

Oral Contraceptive Pill Pretreatment in Polycystic Ovary Syndrome Patients Undergoing IVF/ICSI Using the Gonadotrophin Releasing Hormone Antagonist Protocol (A Randomized Controlled Trial)

Abstract 700 women with PCOS undergoing IVF/ICSI using flexible GnRH antagonist protocol, were included in the study, and randomized to either OCP pretreatment (n = 350), or no pretreatment (n = 350). The latter group received OCP pretreatment in the form of 30µg ethinyl estradiol / 3mg drospirenone (Yasmin®, Bayer AG, Berlin, Germany) pills for an interval of 21 to 28 days; after which COH was started following a 5-day pill wash-out period. OCP-pretreated PCOS women had more retrieved oocytes, albeit, on the expense of increased gonadotropin consumption. However, this increased oocyte yield did not translate to a significant effect on conception rates among intended-to-treat PCOS woman receiving OCP pretreatment. Conversely, it shifted among OCP-pretreated women who actually started COH cycle, to a significant 18% reduction in the probability of successful pregnancy.

Utilization of healthcare prior to endometriosis diagnosis: a Danish case-control study.

Do women with endometriosis have higher utilization of primary and secondary healthcare prior to diagnosis compared to women without endometriosis? Women with a hospital-based diagnosis of endometriosis had an overall higher utilization of both primary and secondary healthcare in all 10 years prior to diagnosis. Endometriosis is associated with a diagnostic delay, but only a few studies have investigated the potential consequences of this delay with regard to the utilization of healthcare. To the best of our knowledge, no study has investigated it in a period corresponding to the estimated diagnostic delay. This national Danish registry-based case-control study included 129 696 women. Cases were women with a first-time hospital-based diagnosis of endometriosis between 1 January 2000 and 31 December 2017. We identified 21 616 cases using density sampling. Each case was matched on age at the date of diagnosis (index date) to five women without diagnosed endometriosis (n = 108 080). The utilization of healthcare was assessed for the 10 years before the index. Cases had significantly higher use of healthcare in all 10 years preceding the index. The mean number of yearly contacts with the GP was 9.99 for cases and 7.85 for controls, with an adjusted incidence rate ratio of 1.28 (1.27; 1.29). For hospital contacts, the association increased slightly in the first 9 years and was most profound in the last year preceding index when the adjusted incidence rate ratio was 2.26 (95% CI 2.28; 2.31). We were not able to include women with an endometriosis diagnosis from the general practitioner or private gynaecologist. Therefore, our results are only applicable to hospital-based diagnoses of endometriosis. We do not have information on the specific reasons for contacting the healthcare providers and we can therefore only speculate that the higher utilization of healthcare among cases was related to endometriosis. This study is in agreement with the other known studies on the subject. Future studies should include specific reasons for contacting the healthcare system and thereby identify any specific contact patterns for women with endometriosis. With this knowledge, healthcare professionals could be better at relating certain healthcare seeking behaviour to endometriosis earlier and thereby reduce the time from onset of symptoms to diagnosis. This study is supported by grants from the project 'Finding Endometriosis using Machine Learning' (FEMaLe/101017562), which has received funding from The European Union's Horizon 2020 research and innovation program and Helsefonden (21-B-0141). K.Z. report grants from Bayer AG, Roche Inc. and Volition, royalties from Oxford-Bayer scientific collaboration in gynaecological therapies, non-financial collaboration with the World Endometriosis Society and World Endometriosis Research Foundation and is a Wellbeing of Women research advisory committee member. All this is outside the submitted work. The other authors have no conflict of interest to declare. N/A.

Risks of Uterine Perforation and Expulsion Associated With Intrauterine Devices.

The APEX-IUD (Association of Perforation and Expulsion of Intrauterine Devices) study evaluated the association of postpartum timing of intrauterine device (IUD) insertion, breastfeeding, heavy menstrual bleeding, and IUD type (levonorgestrel-releasing vs copper) with risks of uterine perforation and IUD expulsion in usual clinical practice. We summarize the clinically important findings to inform counseling and shared decision making. APEX-IUD was a real-world (using U.S. health care data) retrospective cohort study of individuals aged 50 years and younger with IUD insertions between 2001 and 2018 and with electronic health record data. Cumulative incidences of uterine perforation and IUD expulsion were calculated. Adjusted hazard ratios (aHRs) and 95% CIs were estimated from proportional hazards models with control of confounding. Among the study population of 326,658, absolute risk of uterine perforation was low overall (cumulative incidence, 0.21% [95% CI 0.19-0.23%] at 1 year and 0.61% [95% CI 0.56-0.66% at 5 years]) but was elevated for IUDs inserted during time intervals within 1 year postpartum, particularly among those between 4 days and 6 weeks postpartum (aHR 6.71, 95% CI 4.80-9.38), relative to nonpostpartum insertions. Among postpartum insertions, IUD expulsion risk was greatest for insertions in the immediate postpartum period (0-3 days after delivery) compared with nonpostpartum (aHR 5.34, 95% CI 4.47-6.39). Postpartum individuals who were breastfeeding had a slightly elevated risk of perforation and lowered risk of expulsion than those not breastfeeding. Among nonpostpartum individuals, those with a heavy menstrual bleeding diagnosis were at greater risk of expulsion than those without (aHR 2.84, 95% CI 2.66-3.03); heavy menstrual bleeding also was associated with a slightly elevated perforation risk. There was a slightly elevated perforation risk and slightly lower expulsion risk associated with levonorgestrel-releasing IUDs compared with copper IUDs. Absolute risk of adverse outcomes with IUD insertion is low. Clinicians should be aware of the differences in risks of uterine perforation and expulsion associated with IUD insertion during specific postpartum time periods and with a heavy menstrual bleeding diagnosis. This information should be incorporated into counseling and decision making for patients considering IUD insertion. Bayer AG. EU PAS register, EUPAS33461.

Finerenone in Hispanic Patients With CKD and Type 2 Diabetes: A Post Hoc FIDELITY Analysis

In FIDELITY, finerenone improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes. This analysis explores the efficacy and safety of finerenone in Hispanic patients. Post hoc analysis of the FIDELITY prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD randomized control trials. Patients with type 2 diabetes and CKD (urinary albumin-to-creatinine ratio [UACR] of≥30 to<300mg/g and estimated glomerular filtration rate [eGFR]of≥25-≤90mL/min/1.73m2, or UACR of≥300 to≤5,000 and eGFR of≥25mL/min/1.73m2) on optimized renin-angiotensin system blockade. Finerenone or placebo. Cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure); kidney composite (kidney failure, sustained ≥57% eGFR decline, or renal death); change in UACR. Of 13,026 patients, 2,099 (16.1%) self-identified as Hispanic. Median follow-up was 3.0 years. The cardiovascular composite outcome occurred in 10.0% of Hispanic patients receiving Finerenone and in 12.3% of Hispanic patients receiving placebo (HR, 0.80; 95% CI, 0.62-1.04). This was consistent with non-Hispanic patients (HR, 0.87; 95% CI, 0.79-0.97; Pinteraction=0.59). The kidney composite outcome occurred in 6.5% and 6.6% of Hispanic patients with finerenone and placebo, respectively (HR, 0.94; 95% CI, 0.67-1.33). The risk reduction was consistent with that observed in non-Hispanic patients (HR, 0.75; 95% CI, 0.64-0.87; Pinteraction=0.22). Finerenone reduced UACR by 32% at month 4 in both Hispanic and non-Hispanic patients versus placebo (P<0.001 for both patient groups). The safety profile of finerenone and incidence of hyperkalemia was similar between Hispanic and non-Hispanic patient groups. Small sample size, short follow-up time, and lower treatment adherence in the Hispanic population. Overall, the efficacy and safety of finerenone were similar in Hispanic and non-Hispanic patients with CKD and type 2 diabetes. Bayer AG. ClinicalTrials.gov identifier: NCT02540993, NCT02545049. Chronic kidney disease (CKD) in patients with type 2 diabetes occurs more frequently in Hispanic patients than in non-Hispanic patients, with a more rapid progression to kidney failure. Treatment with finerenone reduces the risk of having a kidney or heart event (such as starting dialysis or having a heart attack) in patients with CKD and type 2 diabetes. Because clinical trials that investigate treatments for CKD and type 2 diabetes have not included enough Hispanic patients, the benefits of treatments particularly for Hispanic patients are frequently unknown. This study explores the benefits of finerenone in Hispanic patients. Overall, the study shows that finerenone can provide kidney and heart benefits in Hispanic patients with CKD and type 2 diabetes, as it does in non-Hispanic patients.

Modification of the existing maximum residue level for trifloxystrobin in honey.

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer AG Crop Science Division submitted a request to the competent national authority in the Netherlands to set a maximum residue level (MRL) for the active substance trifloxystrobin in honey. The data submitted in support of the request were found to be sufficient to derive an MRL proposal for the commodity under assessment. An adequate analytical method for enforcement is available to control the residues of trifloxystrobin in honey at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the potential transfer of residues into honey assessed in the present MRL application of trifloxystrobin is unlikely to present a risk to consumer health. The consumer risk assessment shall be regarded as indicative and affected by uncertainties.

A spatiotemporally explicit modeling approach for more realistic exposure and risk assessment of off-field soil organisms.

Natural and seminatural habitats of soil living organisms in cultivated landscapes can be subject to unintended exposure by active substances of plant protection products (PPPs) used in adjacent fields. Spray-drift deposition and runoff are considered major exposure routes into such off-field areas. In this work, we develop a model (xOffFieldSoil) and associated scenarios to estimate exposure of off-field soil habitats. The modular model approach consists of components, each addressing a specific aspect of exposure processes, for example, PPP use, drift deposition, runoff generation and filtering, estimation of soil concentrations. The approach is spatiotemporally explicit and operates at scales ranging from local edge-of-field to large landscapes. The outcome can be aggregated and presented to the risk assessor in a way that addresses the dimensions and scales defined in specific protection goals (SPGs). The approach can be used to assess the effect of mitigation options, for example, field margins, in-field buffers, or drift-reducing technology. The presented provisional scenarios start with a schematic edge-of-field situation and extend to real-world landscapes of up to 5 km × 5 km. A case study was conducted for two active substances of different environmental fate characteristics. Results are presented as a collection of percentiles over time and space, as contour plots, and as maps. The results show that exposure patterns of off-field soil organisms are of a complex nature due to spatial and temporal variabilities combined with landscape structure and event-based processes. Our concepts and analysis demonstrate that more realistic exposure data can be meaningfully consolidated to serve in standard-tier risk assessments. The real-world landscape-scale scenarios indicate risk hot-spots that support the identification of efficient risk mitigation. As a next step, the spatiotemporally explicit exposure data can be directly coupled to ecological effect models (e.g., for earthworms or collembola) to conduct risk assessments at biological entity levels as required by SPGs. Integr Environ Assess Manag 2024;20:263-278. © 2023 Applied Analysis Solutions LLC and WSC Scientific GmbH and Bayer AG and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Assessment of hepatic function employing hepatocyte specific contrast agent concentrations to multifactorially evaluate fibrotic remodeling.

Diffuse parenchymal liver diseases are contributing substantially to global morbidity and represent major causes of deaths worldwide. The aim of our study is to assess whether established hepatic fat and iron quantitation and relaxometry-based quantification of hepatocyte-specific contrast material as surrogate for liver function estimation allows to evaluate liver fibrosis. Retrospective consecutive study. Seventy-two healthy patients (mean age: 53 years) without known liver disease, 21 patients with temporary elevated liver enzymes (mean: 65 years) and 109 patients with biopsy proven liver fibrosis or cirrhosis (mean: 61 years), who underwent liver magnetic resonance imaging (MRI) with a hepatocyte-specific contrast agent [gadoxetate disodium, gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA), 0.25 mmol/mL Primovist, Bayer AG, Leverkusen, Germany] at 1.5 T (n=133) and at 3 T (n=69), were included. Fibrosis was classified using the histopathological meta-analysis of histological data in viral hepatitis (METAVIR) and the clinical Child-Pugh scores. Gd-concentration were quantified using T1 map-based calculations. Gd-concentration mapping was performed by using a Look-Locker approach prior to and 912±159 s after intravenous administration of hepatocyte specific contrast agent. Additionally, parenchymal fat fraction, R2*, bilirubin, gender and age were defined as predicting factors. Diagnostic accuracy was calculated in a monoparametric (linear regression, predictor: Gd-concentration) and multiparametric model (predictors: age, bilirubin level, iron overload, liver fat fraction, Gd concentration in the left and right liver lobe). Mean Gd-concentration in the liver parenchyma was significantly higher for healthy patients ([Gd] =0.51 µmol/L) than for those with liver fibrosis or cirrhosis ([Gd] =0.31 µmol/L; P<0.0001) and with acute liver disease ([Gd] =0.28 µmol/L), though there were no significant differences for the latter two groups. There was a significant moderate negative correlation for the mean Gd-concentration and the METAVIR score (ρ=-0.44, P<0.0001) as well as for the Child-Pugh stage (ρ=-0.35, P<0.0001). There was a significant strong correlation between the bilirubin concentration and the Gd-concentration (ρ=-0.61, P<0.0001). The diagnostic accuracy for the discrimination of healthy patients and patients with known fibrosis or cirrhosis was 0.74 (0.71/0.60 sensitivity/specificity) in a monoparametric and 0.76 (0.85/0.61 sensitivity/specificity) in a machine learning based multiparametric model. T1 mapping-based quantification of hepatic Gd-EOB-DTPA concentrations performed in a multiparametric model shows promising diagnostic accuracy for the detection of fibrotic changes. Liver biopsy might be replaced by imaging examinations.

158-LB: The Effect of Electronic Nudges on Influenza Vaccination Uptake in Older Adults with Diabetes—A Prespecified Analysis of the NUDGE-FLU Trial

Background: Influenza vaccination is associated with reduced risk of all-cause mortality in patients with diabetes mellitus (DM). However, vaccination rates remain suboptimal. Methods: NUDGE-FLU was a nationwide, pragmatic implementation trial among Danish citizens ≥65 years during the 2022/23 influenza season. Households were randomized in a 9:1:1:1:1:1:1:1:1:1 ratio to usual care or 9 different electronic nudge letters. Baseline and outcome data were obtained via nationwide registries. The endpoint was receipt of a seasonal influenza vaccine before Jan. 1, 2023. In this pre-specified sub-study, effect modification by DM status was assessed in a pooled analysis of all intervention arms vs. usual care, and for individual letters. Results: Of 964,870 participants from 691,820 households, 123,974 had DM. During follow-up, 84.2% with DM vs. 81.5% without DM received a vaccine (p&amp;lt;0.001). In the pooled analysis, DM status modified the effect of any electronic letter compared with usual care on vaccine uptake (p=0.030) such that the effect of any letter was attenuated in participants with DM (82.7% vs. 83.0%; difference, -0.23 percentage points; 99.55%CI: -0.94-0.48; p=0.37) vs. without DM (80.0% vs. 79.7%; difference, +0.36 percentage points; (0.07-0.66); p&amp;lt;0.001). In NUDGE-FLU, 2 of the 9 letters (one emphasizing potential cardiovascular benefits of vaccination and a repeated letter) significantly increased vaccine uptake vs. usual care. Point estimates suggested benefits were more pronounced in participants without DM, but no significant interactions were observed in either case (p&amp;gt;0.10). Conclusion: In a pooled analysis, the effect of any electronic nudge was moderately albeit significantly greater in participants without DM. These findings further suggest that the beneficial effects of specific nudges, including repeated messaging and emphasizing cardiovascular benefits, may be more pronounced in participants without DM. Disclosure M. C. H. Lassen: None. J. S. Jensen: None. C. Martel: None. P. Valentiner-branth: None. T. Biering-sørensen: Advisory Panel; Sanofi, Amgen Inc., GlaxoSmithKline plc., Research Support; Sanofi, Amgen Inc., Boston Scientific Corporation, Novo Nordisk, AstraZeneca, Speaker's Bureau; Sanofi, GlaxoSmithKline plc. N. Johansen: None. M. Vaduganathan: Advisory Panel; American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics,, Research Support; American Regent, Amgen, AstraZeneca, Boehringer Ingelheim, Bayer AG, Galmed, Novartis, Bayer AG, Occlutech, Impulse Dynamics, and Roche Diagnostics, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, Roche Diagnostics. A. Bhatt: None. D. Midin: None. B. Claggett: Consultant; Corvia, Cardurion, Cytokinetics Inc., Novartis, Intellia. S. I. Samson: Employee; Sanofi. M. Loiacono: Employee; Sanofi. P. Sivapalan: None. Funding Sanofi

407-P: Efficacy of Finerenone in Patients with Abnormal Markers of Liver Steatosis and Fibrosis—A FIDELITY Subgroup Analysis

Introduction: Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, showed cardiorenal benefits vs placebo in patients with chronic kidney disease and type 2 diabetes. Here, we analyzed patients with liver function abnormalities in FIDELITY, a prespecified pooled dataset from the FIDELIO-DKD and FIGARO-DKD trials. Methods: Patients with urine albumin-to-creatinine ratio ≥30-≤5000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 and type 2 diabetes were analyzed according to elevated transaminases, high risk of steatosis (hepatic steatosis index [HSI] &amp;gt;36), and risk of intermediate to advanced fibrosis (Fibrosis-4 Index [FIB-4] scores &amp;gt;1.30, &amp;gt;2.67, and &amp;gt;3.25). Changes in liver function and in kidney (kidney failure, sustained 57% eGFR decline, or renal death) and cardiovascular (CV; CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite outcomes were assessed. Results: Across 13,026 patients, finerenone reduced the risk of kidney and CV outcomes compared with placebo in patients with elevated transaminases (HR=0.75; 95% CI 0.50-1.13 and HR=0.81; 95% CI 0.62-1.07, respectively), at high risk of steatosis (HR=0.75; 95% CI 0.64-0.88 and HR=0.85; 95% CI 0.77-0.95, respectively), and at high risk of intermediate fibrosis (HR=0.75; 95% CI 0.60-0.93 and HR=0.76; 95% CI 0.67-0.87, respectively), with stronger reductions in the risk of the CV composite outcome at higher FIB-4 scores (HR=0.61; 95% CI 0.41-0.92; p-value for interaction=0.13 and HR=0.48; 95% CI 0.25-0.90; p-value for interaction=0.03 for FIB-4 &amp;gt;2.67 and &amp;gt;3.25, respectively). Liver transaminase levels remained consistent between treatment groups throughout the study. Conclusions: Finerenone demonstrated robust and consistent cardiorenal benefits in patients with abnormal liver function and even more profound CV benefits in patients with higher FIB-4 scores. Disclosure N.Perakakis: Advisory Panel; Bayer Inc., Other Relationship; Novo Nordisk, Novo Nordisk. P.Kolkhof: Employee; BAYER AG. R.Lawatscheck: Employee; Bayer Inc. C.Scott: None. G.Bakris: Advisory Panel; Janssen Pharmaceuticals, Inc., Consultant; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Other Relationship; Bayer Inc. S.R.Bornstein: None. A.L.Birkenfeld: None. A.Linkermann: None. S.Anker: Advisory Panel; AstraZeneca, Novartis AG, Consultant; Bayer Inc., Boehringer Ingelheim Pharma GmbH&amp;Co.KG, Vifor Pharma Management Ltd., Research Support; Abbott, Vifor Pharma Management Ltd. G.Filippatos: Other Relationship; Boehringer-Ingelheim, Bayer Inc., Amgen Inc., Medtronic, Vifor Pharma Management Ltd., Novartis, Servier Laboratories. B.Pitt: Consultant; Bayer Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Lexicon Pharmaceuticals, Inc., PhaseBio Pharmaceuticals, Inc., KBP Bioscience, Merck &amp; Co., Inc. P.Rossing: Other Relationship; Abbott Diagnostics, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Novo Nordisk, Merck KGaA, Gilead Sciences, Inc., Sanofi. L.M.Ruilope: Advisory Panel; Bayer Inc.

214-LB: Plasma Proteomic Markers of Iron and Risk of Diabetes in a Biracial Cohort

Higher levels of iron have been linked to increased diabetes risk among European and European American (EA) populations; whether this is true for other populations where anemia is more common is unknown. Ferritin is an iron storage protein linked to diabetes risk; transferrin transports catalytic iron, reducing its oxidative damage. We tested whether proteomic measurements of ferritin and transferrin were associated with diabetes risk in a biracial cohort of current and former smokers. EA and African American (AA) participants from the COPDGene Cohort who were free of diabetes (n=4,671) at study baseline were followed for the incidence of diabetes. The Somascan was used on plasma measured at followup to determine relative amounts of proteins among participants. Logistic regression was used to calculate OR (95% CIs) of the cross-sectional relationship of natural log transformed ferritin and transferrin with diabetes risk. During an average of 5.6 years of follow-up, the incidence of diabetes was 7.9%. Ferritin was associated with increased diabetes risk (OR=1.29, 1.04-1.61), while higher transferrin linked with decreased risk (OR=0.19, 0.06-0.56) controlling for age, sex, BMI, hepcidin and smoking. When stratified by race, increased risk was associated with higher ferritin only among AA (OR=1.46, 1.07-2.01) and not for EA (OR=1.11, 0.81-1.52). Stratification by sex revealed that the relationship of ferritin was similar among AA men and women and EA women, with non-significant ORs ranging from 1.49-1.55; but null association among EA men (OR = 1.00, 0.65-1.52). Similarly, ORs for transferrin non-significantly ranged from 0.24-0.29 for AA men and women and EA women, but for EA men there was a significant 93% decreased risk for each natural long increase in transferrin (OR=0.07, 0.001-0.60). Our data suggest that higher body iron stores, as measured by ferritin, increases diabetes risk among both AA and EA. Ferritin may be a better marker for AA men and women and EA women while transferrin is a better marker for EU men. Disclosure R. B. Conway: None. K. Young: None. K. A. Pratte: None. G. L. Kinney: None. E. Austin: None. Y. Li: None. R. Bowler: None. D. A. Mcclain: None. J. Crappo: None. Funding National Heart, Lung, and Blood Institute (U01HL089897, U01HL089856); AstraZeneca; Bayer Pharmaceuticals; Boehringer Ingelheim; Genentech; GlaxoSmithKline; Novartis; Pfizer Inc.; Sunovion

Increased Realism in Risk Assessment and Management of Agrochemicals for a Better Balance between Food Production and Environmental Protection

ADVERTISEMENT RETURN TO ARTICLES ASAPPREVViewpointNEXTIncreased Realism in Risk Assessment and Management of Agrochemicals for a Better Balance between Food Production and Environmental ProtectionRobin Sur*Robin SurRegulatory Science − Environmental Safety, Bayer AG Crop Science Division, 40789 Monheim, Germany*Corresponding author: Robin Sur.More by Robin Surhttps://orcid.org/0000-0002-3403-8168, Thomas G. PreussThomas G. PreussRegulatory Science − Environmental Safety, Bayer AG Crop Science Division, 40789 Monheim, GermanyMore by Thomas G. Preuss, and Andrew C. ChappleAndrew C. ChappleRegulatory Science − Environmental Safety, Bayer AG Crop Science Division, 40789 Monheim, GermanyMore by Andrew C. ChappleCite this: ACS Agric. Sci. Technol. 2023, XXXX, XXX, XXX-XXXPublication Date (Web):June 6, 2023Publication History Received14 April 2023Accepted26 May 2023Revised24 May 2023Published online6 June 2023https://doi.org/10.1021/acsagscitech.3c00106© 2023 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views-Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (819 KB) Get e-Alerts Get e-Alerts

Modification of the existing maximum residue levels and setting of import tolerances for fluopyram in various crops.

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer AG Crop Science Division submitted a request to the competent national authority in Italy to modify the existing maximum residue level (MRL) for the active substance fluopyram in kiwi. Additionally, the applicants Bayer Crop Science SA and Bayer SAS Crop Science Division submitted two applications to the competent national authority in Germany to modify the MRLs for fluopyram in certain stem vegetables, seed spices, apples and soyabeans based on intended EU uses as well as to lower the existing EU MRL in pome fruits and to raise the existing EU MRL in peanuts on the basis of authorised use of fluopyram in the USA. The data submitted in support of the request were found to be sufficient to derive MRL proposals for all the crops under assessment except for palm hearts and bamboo shoots. Adequate analytical methods for enforcement are available to control the residues of fluopyram in commodities under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term intake of residues resulting from the use of fluopyram according to the reported agricultural practices is unlikely to present a risk to consumer health. A long-term consumer intake concern is identified if the current MRL of 0.8 mg/kg in pome fruits is maintained and new MRLs for other commodities under consideration are supported, with apples being the highest contributing commodity to the diet for which exposure exceedances were noted. The chronic risk for consumers is unlikely if a lower MRL of 0.6 mg/kg in pome fruits proposed by the applicant is considered. Further risk manager considerations are required.

Abstract ND04: BAY 2965501: A highly selective DGK- ζ inhibitor for cancer immuno-therapy with first-in-class potential

Abstract The second messenger diacyl glycerol (DAG) plays a key role in T cell receptor downstream signaling and thereby in T-cell activation. Diacylglycerol kinase zeta (DGK-ζ) is a lipid kinase that can down-modulate T-cell activation by catalyzing the conversion of DAG to phosphatidic acid, thereby acting as a ligand independent, intracellular immune checkpoint. Inhibition of DGK- ζ offers the potential to enhance T cell priming against suboptimal tumor antigens and to overcome multiple immune-suppressive mechanisms in the tumor microenvironment. Bayer AG in collaboration with the German Cancer Research Center (DKFZ) have developed BAY 2965501, a highly selective, orally available DGK-ζ inhibitor which shows a unique binding mode and good DMPK profile. The compound enhances the reactivity of human and mouse T-cells, both in the priming and the effector phase, and overcomes the inhibitory impact of suppressive factors, such as adenosine and prostaglandin E2. Oral dosing of BAY 2965501 shows T cell dependent efficacy in syngeneic, murine tumor models. Furthermore, this results in reactivation of exhausted T cells in vivo. Preclinical safety studies showed only mild findings, so that good clinical tolerability is expected. Collectively, the preclinical data support first in human (FiH) phase I testing of therapeutic potential. A FiH trial with BAY 2965501 in patients with advanced solid tumors including NSCLC, gastric/GEJ AdCa, ccRCC, and melanoma patients, is currently enrolling patients (NCT05614102). This study will evaluate the safety, tolerability, maximum tolerated or administered dose, pharmacokinetics, pharmacodynamics, and tumor response profile of BAY 2965501. Citation Format: Rienk Offringa, Catherine Olesch, Frederik Cichon, Mareike Grees, Norbert Schmees, Ulrike Roehn, Florian Prinz, Judith Guenther, Detlef Stoeckigt, Michael Erkelenz, Thi Thanh Uyen Nguyen, Ulf Boemer, Nicolas Werbeck, Marc Kunze, Kirstin Petersen, Dennis Kirchhoff. BAY 2965501: A highly selective DGK- ζ inhibitor for cancer immuno-therapy with first-in-class potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND04.

(076) Effects of Long-term Testosterone Therapy on Erectile Function, Sexual Activity, and Quality of Life in Hypogonadal Men with Type 2 Diabetes – Results from a Registry Study

Abstract Introduction Treatment of erectile function (EF) in men with type 2 diabetes (T2DM) remains challenging. EF and sexual activity contribute to quality of life (QoL) in aging men. Objective to investigate effects of long-term TTh up to 13 years in men with hypogonadism and T2DM compared to an untreated control group. Methods In an ongoing registry study in men with hypogonadism (total testosterone ≤350 ng/mL and at least moderate symptoms on the Aging Males’ Symptoms scale, AMS) in a single urology office, 370 men had type 2 diabetes. 190 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 180 opted against TTh and served as controls (CTRL). IIEF-EF (5+1 questions, maximum score: 30) and AMS were assessed at each visit. Patients were asked at each visit about sexual activity per month. Absolute measures with standard deviations (SDs) as well as changes over time, adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids, and quality of life to account for baseline differences between groups, are reported for a duration of 13 years. Results Mean (median) follow-up: T-group 9.0±3.4 (9), CTRL 9.7±3.2 (11) years, total observation time: T-group 1703, CTRL 1747 patient-years. Baseline age was 60.0±6.4 (T-group) and 63.0±4.9 years (CTRL) (p&amp;lt;0.0001). 71 patients (37.4%) in the T-group and 74 (41.1%) in CTRL had a history of cardiovascular disease (myocardial infarction MI, stroke, or coronary artery disease diagnosis) (p&amp;lt;0.05). Baseline smoking prevalence was 41.6% (79 men) in the T-group and 37.4% (67 men) in CTRL (p=0.415). At baseline, PDE5-Inhibitors were used by 29.5% (T-group) and 35.0% (CTRL) (p=0.255). T-group: IIEF-EF increased from 15.8±6.0 (means ± SD) at baseline to 29.5±0.9 after 13 years. Changes: IIEF-EF increased by 12.1±0.3 (least squares means ± standard errors) in year 13, p&amp;lt;0.0001 vs. baseline. CTRL: IIEF-EF decreased from 19.2±3.8 at baseline to 6.9±1.0 after 13 years. Changes: IIEF-EF declined by 14.7±0.3 after 13 years. T-group: sex frequency increased from 3.4±1.3 (means ± SD) at baseline to 12.0±5.4 after 13 years. Changes: sex frequency increased by 6.6±0.5 (least squares means ± standard errors) in year 13, p&amp;lt;0.0001 vs. baseline. CTRL: sex frequency decreased from 7.7±3.4 at baseline to 0.0±0.2. Changes: sex frequency declined by 10.5±0.5 (p&amp;lt;0.0001). T-group: AMS decreased from 55.3±9.3 (means ± SD) at baseline to 17.1±0.2 after 13 years. Changes: AMS decreased by 31.4±0.7 (least squares means ± standard errors) in year 13, p&amp;lt;0.0001 vs. baseline. CTRL: AMS increased from 40.1±5.7 at baseline to 65.8±4.6 after 13 years. Changes: AMS increased by 25.8±0.7. Conclusions Long-term TTh in men with type 2 diabetes improved erectile function, sexual activity, and QoL despite advancing age. In the untreated control group, sexual function and QoL deteriorated progressively. Disclosure Yes, this is sponsored by industry/sponsor: Bayer AG, Berlin, Germany Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Bayer AG, Berlin, Germany

(496) Effects of Long-term Testosterone Therapy in Men with Functional Hypogonadism and Obesity on the Lipid Pattern – Results from a Registry Study

Abstract Introduction The lipid pattern plays a role in the assessment of cardiometabolic risks such as atherogenicity (non-HDL), arteriosclerotic cardiovascular disease (remnant cholesterol), or insulin resistance (TG:HDL ratio). A recent meta-analysis suggested that, in patients with metabolic disorders, only a reduction of triglycerides achieved statistical significance across controlled and uncontrolled studies (Corona G et al. Exp Rev Clin Pharmacol 2021;14:1091-1103). The lipid pattern plays a role in the assessment of cardiometabolic risks such as atherogenicity (non-HDL), arteriosclerotic cardiovascular disease (remnant cholesterol), or insulin resistance (TG:HDL ratio). A recent meta-analysis suggested that, in patients with metabolic disorders, only a reduction of triglycerides achieved statistical significance across controlled and uncontrolled studies (Corona G et al. Exp Rev Clin Pharmacol 2021;14:1091-1103). Another recent meta-analysis suggested significant reductions of total cholesterol, LDL, HDL and triglycerides (Hudson J et al. Lancet Healthy Longev 2022;3:e381–93). Objective to investigate effects of long-term TTh up to 13 years on the lipid pattern in men with functional hypogonadism and obesity compared to an untreated control group. Methods In an ongoing registry study in men with hypogonadism (total testosterone ≤350 ng/mL and at least moderate symptoms on the Aging Males’ Symptoms scale, AMS) in a single urology office, 491 men had functional hypogonadism and obesity (BMI ≥30 kg/m2). 292 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 199 opted against TTh and served as controls (CTRL). Total cholesterol, LDL, HDL, and triglycerides were assessed at each visit. Absolute measures with standard deviations (SDs) as well as changes over time, adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids, and quality of life to account for baseline differences between groups, are reported for a duration of 13 years. Results Mean (median) follow-up: T-group 10.1±3.1 (11), CTRL 9.4±3.3 (10) years, total observation time: T-group 2944, CTRL 1861 patient-years. Baseline age: 59.5±6.0 (T-group) and 63.0±5.0 years (CTRL) (p&amp;lt;0.0001). Total cholesterol (TC) (mmol/L for all lipids) decreased by 2.9±0.1 (least squares means ± SEs) from 8.2±1.0 to 5.1±0.3 (means ± SDs) in T-group and increased by 1.38±0.1 from 7.3±1.0 to 8.6±1.2 in CTRL (p&amp;lt;0.0001 for all). HDL increased by 0.5±0.0 from 1.0±0.4 to 1.6±0.3 in T-group and decreased by 0.4±0.0 from 1.1±0.5 to 0.8±0.4 in CTRL (p&amp;lt;0.0001 for all). The TC:HDL ratio decreased by 5.4±0.2 from 9.2±3.8 to 3.4±0.6 in T-group and increased by 6.5±0.3 from 8.0±3.8 to 12.6±5.8 in CTRL (p&amp;lt;0.0001 for all). LDL decreased by 1.9±0.0 from 4.5±0.9 to 2.5±0.3 in T-group and increased by 1.2±0.1 from 4.2±1.3 to 5.4±1.3 in CTRL (p&amp;lt;0.0001 for all). Triglycerides (TG) decreased by 1.1±0.0 from 3.4±0.5 to 2.2±0.1 in T-group and increased by 0.7±0.0 from 3.2±0.5 to 3.9±0.5 in CTRL (p&amp;lt;0.0001 for all). Non-HDL decreased by 3.4±0.1 from 7.2±1.0 to 3.5±0.2 in T-group and increased by 1.6±0.1 from 6.2±1.1 to 7.8±1.3 in CTRL (p&amp;lt;0.0001 for both). Remnant cholesterol decreased by 1.5±0.1 from 2.7±0.9 to 1.0±0.3 in T-group and increased by 0.5±0.1 from 2.1±1.0 to 2.4±0.7 in CTRL (p&amp;lt;0.0001 for both). The TG:HDL ratio decreased by 5.0±0.2 from 8.7±3.9 to 3.2±0.6 in T-group and increased by 6.8±0.3 from 8.1±3.9 to 13.6±6.7 in CTRL (p&amp;lt;0.0001 for both). Conclusions Long-term TTh in men with functional hypogonadism and obesity improved all components of the lipid pattern. In the untreated control group, the lipid pattern deteriorated. Disclosure Yes, this is sponsored by industry/sponsor: Bayer AG, Berlin, Germany. Clarification Industry funding only - investigator initiated and executed study. Any of the authors act as a consultant, employee or shareholder of an industry for: Bayer AG.

(397) Long-term Testosterone Therapy in Men with Functional Hypogonadism and Obesity Improves Surrogate Parameters of Liver Function in a Urological Registry Study

Abstract Introduction Hepatic steatosis is highly prevalent in patients with hypogonadism and obesity. Fatty liver is increasingly recognized as cardiovascular risk factor. The gold standard assessment – histological evaluation of liver biopsies – cannot be performed in routine clinical practice. However, the fatty liver index (FLI) can be calculated using the formula by Bedogni: FLI = (e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745) / (1 + e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745) * 100 (Bedogni G et al. BMC Gastroenterol 2006;6:33). A FLI &amp;lt;30 rules out and a FLI ≥60 rules in fatty liver. Objective to investigate effects of long-term testosterone therapy (TTh) up to 13 years on surrogate parameters of liver function in men with functional hypogonadism and obesity in comparison to an untreated control group. Methods In an ongoing registry study in men with hypogonadism (total testosterone ≤350 ng/mL and at least moderate symptoms on the Aging Males’ Symptoms scale, AMS) in a single urology office, 491 men had functional hypogonadism and obesity (BMI ≥30 kg/m2). 292 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 199 opted against TTh and served as controls (CTRL). Height was measured at baseline, weight, waist circumference, triglycerides and γ-GT were assessed at each visit and the fatty liver index (FLI) calculated. AST, ALT, and bilirubin were also measured at each visit. Mean absolute measures with standard deviations (SDs) are reported for a duration of 13 years. Results Mean (median) follow-up: T-group 10.1±3.1 (11), CTRL 9.4±3.3 (10) years. Baseline age was 59.5±6.0 (T-group) and 63.0±5.0 years (CTRL) (p&amp;lt;0.0001). Triglycerides decreased from 3.4±0.5 to 2.2±0.1 in the T-group and increased from 3.2±0.5 to 3.9±0.5 in CTRL (p&amp;lt;0.0001 for both). γ-GT (U/L) decreased from 42.9±22.8 to 20.5±6.4 in the T-group and increased from 35.5±11.6 to 61.7±5.9 in CTRL (p&amp;lt;0.0001 for both). AST (U/L) decreased from 38.4±13.3 to 20.8±1.9 in the T-group and increased from 28.6±9.0 to 54.1±11.9 in CTRL (p&amp;lt;0.0001 for both). ALT (U/L) decreased from 41.4±13.7 to 24.7±2.1 in the T-group and increased from 32.7±9.4 to 60.2±13.8 in CTRL (p&amp;lt;0.0001 for both). Bilirubin decreased from 0.53±0.27 to 0.18±0.05 mg/dL in the T-group and increased from 0.44±0.23 to 1.09±0.27 mg/dL in CTRL (p&amp;lt;0.0001 for both). Waist circumference from 115.0±13.2 to 97.5±4.6 cm in the T-group and increased from 118.6±11.4 to 121.2±6.1 cm in CTRL (p&amp;lt;0.0001 for all). BMI decreased from 36.8±3.6 to 28.3±2.1 kg/m2 in the T-group and increased from 33.9±3.3 to 34.9±2.2 kg/m2 in CTRL (p&amp;lt;0.0001 for all). FLI decreased from 95.1±4.6 to 61.3±11.2 in the T-group and increased from 94.1±4.4 to 98.0±1.3 in CTRL (p&amp;lt;0.0001 for both). Conclusions Long-term testosterone therapy in men with functional hypogonadism and obesity improved surrogate parameters of liver function indicating an improvement in hepatic steatosis. All measures deteriorated over time in untreated obese hypogonadal control patients. Disclosure Yes, this is sponsored by industry/sponsor: Bayer AG, Berlin, Germany. Clarification Industry funding only - investigator initiated and executed study. Any of the authors act as a consultant, employee or shareholder of an industry for: Bayer AG.

(396) Effects of Long-term Testosterone Therapy in Men with Functional Hypogonadism and Obesity on Weight, Waist Circumference, and Erectile Function – Results from a Registry Study

Abstract Introduction Obesity is a risk factor for erectile dysfunction (ED). Long-term testosterone therapy (TTh) has been shown to improve anthropometric parameters as well as erectile function. Objective to investigate effects of long-term TTh up to 13 years in men with functional hypogonadism and obesity compared to an untreated control group. Methods In an ongoing registry study in men with hypogonadism (total testosterone ≤350 ng/mL and at least moderate symptoms on the Aging Males’ Symptoms scale, AMS) in a single urology office, 491 men had functional hypogonadism and obesity (BMI ≥30 kg/m2). 292 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 199 opted against TTh and served as controls (CTRL). Weight, waist circumference, and IIEF-EF (5+1 questions, maximum score: 30) were assessed at each visit. Absolute measures with standard deviations (SDs) as well as changes over time, adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids, and quality of life to account for baseline differences between groups, are reported for a duration of 13 years. Results Mean (median) follow-up: T-group 10.1±3.1 (11), CTRL 9.4±3.3 (10) years, total observation time: T-group 2944, CTRL 1861 patient-years. Baseline age was 59.5±6.0 (T-group) and 63.0±5.0 years (CTRL) (p&amp;lt;0.0001). In the T-group, 35.3%, 44.9% and 19.9% had obesity class I (BMI 30.0-34.4), II (BMI 35.0-39.9) and III (BMI ≥40 kg/m2), respectively. In CTRL, 71.9%, 22.1%, and 6%, had obesity class I, II, and III, respectively. At baseline, PDE5-Inhibitors were used by 25.0% (T-group) and 25.6% (CTRL) (p=0.875). T-group: weight (kg) decreased by 23.9±0.4 (least squares means ± standard errors) from 114.5±11.8 to 87.5±6.7 (means ± standard deviations) after 13 years. CTRL: weight increased by 8.4±0.6 from 105.6±10.5 to 107.9±6.2 (p&amp;lt;0.0001 for all). T-group: waist circumference (cm) decreased by 13.8±0.3 (least squares means ± SEs) from 115.0±13.2 to 97.5±4.6 (means ± SDs) after 13 years CTRL: waist circumference increased by 9.3±0.4 from 118.6±11.4 to 121.2±6.1 (p&amp;lt;0.0001 for all). T-group: BMI (kg/m2) decreased by 7.7±0.1 (least squares means ± SEs) from 36.8±3.6 to 28.3±2.1 after 13 years CTRL: BMI increased by 2.7±0.2 from 33.9±3.3 to 34.9±2.2 (p&amp;lt;0.0001 for all). Per cent weight loss from baseline was 22.8±4.9% in the T-group, per cent weight gain was 8.4±3.7% in CTRL (p&amp;lt;0.0001 for both). In the T-group, 118 patients (40.4%) achieved weight loss of ≥20% after a mean observation time of 92 months (minimum: 27, maximum: 189). No patient in CTRL achieved weight loss of ≥20%. 290 men (99.3%) in the T-group vs. 8 men (4.0%) in CTRL achieved weight loss of ≥5%. T-group: IIEF-EF increased by 11.4±0.3 (least squares means ± SEs) from 17.2±5.9 (means ± SD) at baseline to 29.4±1.0 after 13 years. CTRL: IIEF-EF decreased by 15.1±0.4 from 19.0±3.9 at baseline to 7.0±1.0 after 13 years (p&amp;lt;0.0001 for all). Conclusions Long-term TTh in men with functional hypogonadism and obesity improved weight, waist circumference and erectile function. In the untreated control group, anthropometric measures and erectile function deteriorated. Disclosure Yes, this is sponsored by industry/sponsor: Bayer AG, Berlin, Germany Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Bayer AG

(398) Remission of Type 2 Diabetes, Mortality, and Major Adverse Cardiovascular Events in Men with Hypogonadism and Type 2 Diabetes Receiving Long-term Testosterone Therapy in Comparison to an Untreated Control Group in a Urological Registry Study

Abstract Introduction We had reported previously that 34.3% of patients with hypogonadism and type 2 diabetes (T2DM) receiving testosterone therapy (TTh) up to 11 years in our registry study achieved remission of their T2DM after a mean time of 8.6±2.9 years (Haider KS et al. Diabet Obes Metab 2020;22:2055-2068). Remission is defined as discontinuation of anti-diabetic medication while maintaining HbA1c within the non-diabetic range for at least three months. Objective to investigate effects of long-term TTh up to 13 years in men with hypogonadism and T2DM on glycemic control, remission of T2DM, mortality, and major adverse cardiovascular events (MACE). Methods In an ongoing registry study in men with hypogonadism (total testosterone ≤350 ng/mL and at least moderate symptoms on the Aging Males’ Symptoms scale, AMS) in a single urology office, 370 men had type 2 diabetes. 190 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 180 opted against TTh and served as controls (CTRL). Patients’ T2DM was treated at the local diabetes center which included mandatory lifestyle education. Glycemic control (HbA1c) was measured and insulin resistance (HOMA-IR) calculated at each or each other visit. Absolute measures with standard deviations (SDs) as well as changes over time, adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids, and quality of life to account for baseline differences between groups, are reported for a duration of 13 years. Results Mean (median) follow-up: T-group 9.0±3.4 (9), CTRL 9.7±3.2 (11) years, total observation time: T-group 1703, CTRL 1747 patient-years. Baseline age was 60.0±6.4 (T-group) and 63.0±4.9 years (CTRL) (p&amp;lt;0.0001). 71 patients (37.4%) in the T-group and 74 (41.1%) in CTRL had a history of cardiovascular disease (myocardial infarction MI, stroke, or coronary artery disease diagnosis) (p&amp;lt;0.05). Baseline smoking prevalence was 41.6% (79 men) in the T-group and 37.4% (67 men) in CTRL (p=0.415). HbA1c decreased from 9.5±1.4% to 5.5±1.2% in the T-group and increased from 7.8±0.7% to 10.5±1.2% in CTRL (means ± SDs). Mean adjusted change from baseline (least squares means ± SEs) at 13 years was -3.7±0.2 (T-group) and +3.4±1.2 (CTRL) (p&amp;lt;0.0001 for all). HOMA-IR decreased from 10.2±2.1 to 1.5±0.3 in the T-group and increased from 7.3±1.3 to 14.8±2.5 in CTRL. Mean adjusted change from baseline at 13 years was -8.3±0.3 (T-group) and +6.8±0.4 (CTRL) (p&amp;lt;0.0001 for all). In the T-group, 108 patients (56.8%) went into remission. The median time to remission was 87 months. During the entire observation period, 21 patients (11.1%) died in the T-group vs. 62 (34.4%) in CTRL (p&amp;lt;0.0001). Major adverse cardiovascular events (MACE): in the T-group, there were no cases of MI or stroke. In CTRL, there were 62 cases of MI (34.4%) and 51 cases of stroke (28.3%). Conclusions Long-term TTh in men with hypogonadism and T2DM improves glycemic control and insulin resistance and reduces mortality and MACE, compared to untreated controls. Every other patient receiving TTh achieves remission of T2DM. Disclosure Yes, this is sponsored by industry/sponsor: Bayer AG, Berlin, Germany. Clarification Industry funding only - investigator initiated and executed study. Any of the authors act as a consultant, employee or shareholder of an industry for: Bayer AG.

(071) Effects of Long-term Testosterone Therapy on Erectile Function, Sexual Activity, and Quality of Life in Men with Functional Hypogonadism – results from a registry study

Abstract Introduction Erectile function (EF) and sexual activity contribute to quality of life (QoL) in aging men. Testosterone therapy (TTh) has well-established beneficial effects on EF and QoL while there is less information on sexual activity. Objective to investigate effects of long-term TTh up to 13 years in men with functional hypogonadism compared to an untreated control group. Methods In an ongoing registry study in men with hypogonadism (total testosterone ≤350 ng/mL and at least moderate symptoms on the Aging Males’ Symptoms scale, AMS) in a single urology office, men with primary hypogonadism were excluded from the analysis. 797 men had functional hypogonadism. 394 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 403 opted against TTh and served as controls (CTRL). IIEF-EF (5+1 questions, maximum score: 30) and AMS were assessed at each visit. Patients were asked at each visit about sexual activity per month. Absolute measures with standard deviations (SDs) as well as changes over time, adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between groups, are reported for a duration of 13 years. Results Mean (median) follow-up: T-group 10.1±3.1 (11), CTRL 10.5±3.0 (12) years, total observation time: T-group 3975, CTRL 4220 patient-years. Baseline age was 58.1±6.6 (T-group) and 63.2±4.8 years (CTRL) (p&amp;lt;0.0001). At baseline, PDE5-Inhibitors were used by 27.2% (T-group) and 22.1% (CTRL) (p=0.096). T-group: IIEF-EF increased from 17.2±5.8 (means ± SD) at baseline to 29.4±1.0 after 13 years. Changes: IIEF-EF increased by 11.0±0.2 (least squares means ± standard errors) in year 13, p&amp;lt;0.0001 vs. baseline. For the entire observation time, the year-to-year changes were always statistically significant vs. previous year. CTRL: IIEF-EF decreased from 19.8±3.4 at baseline to 7.1±1.1 after 13 years. Changes: IIEF-EF declined by 13.9±0.2 after 13 years. For the entire observation time, year-to-year changes were always statistically significant vs. previous year. T-group: sex frequency increased from 3.6±1.4 (means ± SD) at baseline to 11.0±4.3 after 13 years. Changes: sex frequency increased by 6.2±0.3 (least squares means ± standard errors) in year 13, p&amp;lt;0.0001 vs. baseline. For the first four years, year-to-year changes were statistically significant vs. previous year. CTRL: sex frequency decreased from 8.4±3.1 at baseline to 0.0±0.3. Changes: sex frequency declined by 10.3±0.3 (p&amp;lt;0.0001). For the first ten years, year-to-year changes were always statistically significant vs. previous year. T-group: AMS decreased from 53.3±9.6 (means ± SD) at baseline to 17.0±0.1 after 13 years. Changes: AMS decreased by 29.9±0.4 (least squares means ± standard errors) in year 13, p&amp;lt;0.0001 vs. baseline. For the first four years, the year-to-year changes were statistically significant vs. previous year. CTRL: AMS increased from 40.4±5.6 at baseline to 65.8±4.3 after 13 years. Changes: AMS increased by 23.6±0.4. For the entire observation time, the year-to-year changes were statistically significant vs. previous year. Conclusions Long-term TTh in men with functional hypogonadism improved erectile function, sexual activity, and QoL despite advancing age. In the untreated control group, these parameters deteriorated progressively. Disclosure Yes, this is sponsored by industry/sponsor: Bayer AG, Berlin, Germany Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Bayer AG, Berlin, Germany

(004) Are Endogenous Androgens Linked to Female Sexual Function? A Systemic Review and Meta-Analysis

Abstract Introduction The benefits of treatment with testosterone (T) in women with loss of desire suggest that low androgens may distinguish women with sexual dysfunction (SD) from others; however, evidence on this point is lacking. Objective Our aim was to answer the question: is there an association between endogenous levels of androgens and sexual function in women? Methods An extensive search was performed in MEDLINE, Embase and PsycInfo. Four separate meta-analyses were conducted for total T, free T, Free Androgen Index (FAI), and Dehydroepiandrosterone sulphate (DHEAS). Cohort, cross-sectional, and prospective studies were included. The main outcome was the association between endogenous androgens and sexual desire. Global sexual function was considered as a secondary outcome. The effect measure was expressed as standardized mean difference (SMD). Results The meta-analysis on total T included 34 studies involving 3,268 women, mean age 36.5 years. In 11 studies, a significant association was found between sexual desire, measured by validated psychometric instruments, and total T (SMD = 0.59 [0.29;0.88], P &amp;lt; 0.0001), with a moderate effect. The association with global sexual function (n = 12 studies) was also significant (SMD = 0.44 [0.21;0.67], P &amp;lt;0.0001). Overall, total T was associated with a better sexual function (SMD = 0.55 [0.28,0.82)], P &amp;lt; 0.0001), with similar results obtained when poor quality studies were removed. Age showed a negative relationship with the overall outcome. No differences were found when stratifying the studies according to menopausal status, type of menopause, age at menopause, use of hormonal replacement therapy, relationship status, method for T measurement, phase of the menstrual cycle or use of hormonal contraception. The meta-analysis of T derivatives (free T and FAI) also showed a significant, moderate association with sexual desire. In contrast, DHEAS seems not to exert any significant influence on desire, whilst showing a positive association with global sexual function. Conclusions There appears to be a moderate association between total T and sexual desire/global sexual function, which is confirmed, although weak, in studies employing liquid chromatography-mass spectrometry (LC-MS). Similar results on desire were obtained for free T and FAI. DHEAS only showed a positive association with global sexual function. A significant publication bias was found for total T. Our results suggest that endogenous androgens show a moderate association with a better sexual function in women; however, the role of psychological, relational and other hormonal factors should not be overlooked. More research is needed. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: LV received scientific research grants, advisory board attendance and speaker honoraria from Therascience, Theramex, Bayer Schering Pharma, Intercept, Lipocine, Ibsa.