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36] and was similar (22 million [13.8 -35]) at 3 months follow up. Overall, after 3 months of treatment 30.6% of the men had a concentration increase by >20%, and 42.8% had decrease by >20%. Higher sperm concentration at baseline predicted a >20% decrease in sperm concentration. No other clinical, demographic, endocrinological, and semen analysis characteristics were associated with change in sperm concentration (p > 0.05) (Table ).CONCLUSIONS: Although 43% of men who received Natesto had a decline in sperm concentration, only 5% of them became azoospermic. There does not appear to be any baseline characteristics that can predict who adversely reacts to Natesto. SUPPORT:This was an investigator-initiated trial sponsored in part by Aytu BioSciences

Study question Do genetic components and functional annotation/s in eutopic endometrium share significant difference to influence diagnosis in adenomyosis? Summary answer An integrated clinico-transcriptomic approach chalk the chief individual as well as hub genes in women with adenomyosis to set the algorithm for improved diagnosis. What is known already Adenomyosis often document similar presentation/s to other gynecological diseases including endometriosis making the diagnosis difficult. Differentially expressed transcripts and proteins were identified by transcriptomic analysis and genome-wide profiling of eutopic and ectopic endometrial samples in women with endometriosis. Biological networking and functional enrichment analysis enable prioritization of candidate genes for validation purpose in target tissue. Recently, key pathways in proliferative stage of adenomyosis at transcriptome level were documented in eutopic endometrium. However, characterization of functional annotations may assist clinicians to evaluate if they share systematic correlations predictive of ultrasonographic finding/s for help in everyday practice in diagnosing adenomyosis . Study design, size, duration Microarray datasets (GSE7307 and GSE78851) were selected from Gene Expression Omnibus database (GEO), which contains endometriosis, adenomyosis and normal endometrial tissues. An in-depth bioinformatic analysis was done to determine differentially expressed genes (DEGs) on GEO2R platform; followed by gene ontology (GO), KEGG pathway enrichment and protein-protein interaction (PPI) analysis by DAVID (http://david.ncifcrf.gov) and Cytoscape (version 3.8.2) respectively. PPI network was predicted further using a search tool, STRING (http://string-db.org; version 11.0) for retrieval of interacting genes. Participants/materials, setting, methods Eutopic endometrial samples were obtained during window of implantation from women (n = 10) with endometriosis, adenomyosis and adenomyosis-associated-endometriosis as diagnosed by laparoscopy, and, trans-vaginal ultrasound (TVUS) between March to December 2021 from Institute of Reproductive Medicine, Kolkata. Counterpart/s of male sub-fertility, defined by World-Health-Organization criteria (5th edition) was treated as control (n = 10). In-silico findings were validated by quantitative-real-time PCR (qRT-PCR). TVUS findings and gene expression/s were correlated by Spermann-rank correlation test. P < 0.05 was considered statistically significant. Main results and the role of chance A total of 4474 and 1061, significant DEGs (log fold-change>1, p < 0.05) were identified from datasets of endometriosis and adenomyosis respectively. GO function/s included common biological processes and molecular function/s, namely, epithelial-to-mesenchymal transition (EMT), metallopeptidase activity and extracellular matrix remodelling. EMT and Wnt signaling ranked top position/s in KEGG pathway enrichment. Among sixty-four common DEGs, four genes, namely, SERPINA1, MMP11, THBS1, MMP7 have maximal node degree (>2) and MCODE (k = 2) in PPI network and were prioritized as hub genes. STRING analysis computed the network of common hub genes between adenomyosis and endometriosis. qRT-PCR findings confirmed down-regulation (p < 0.02) of SERPINA1, and MMP11 in adenomyosis compared to endometriosis and MMP7, and THBS1 in both endometriosis and adenomyosis (p < 0.03) compared to control. Down-regulation (p < 0.003) of SNORD116, MYH11 and PIGR was simultaneously observed in adenomyosis only as compared to endometriosis. Similar gene expression/s as to adenomyosis was documented in combined cohort because of possible presence of common pathology. Interestingly, posterior-wall thickness (PWT) on TVUS was positively correlated with MMP11 (r = 0.88; p<0.03) and SERPINA1 (r = 0.94; p<0.01) in adenomyosis. MMP-11 also exhibited positive correlation with PWT (r = 0.85; p<0.03) and uterine-size (r = 0.88; p<0.03) in endometriosis and combined cohort respectively while MYH11 negatively correlated (r=-0.97; p<0.02) with uterine-size in adenomyosis associated endometriosis. Limitations, reasons for caution The heterogeneous nature of data for bioinformatic analysis is a major limitation. Moreover, only mild adenomyosis was considered in the study; hence, results could differ in women with co-occurrence of other gynecological condition/s and/or in severe cases of adenomyosis. The observed differences need to be replicated in larger study cohort/s. Wider implications of the findings We identify a set of novel hub genes and enrichment pathways in receptive phase which provide an in-depth discriminative understanding between pathogenesis of endometriosis and adenomyosis. Our results suggest a dys-regulated micro-environment run an algorithmic cascade for perturbed uterine preparation (in adenomyosis), thus providing platform for newer therapeutic targets. Trial registration number Not Applicable

Study question Is serum homocysteine combined with uterine-artery Doppler were effective in predicting preeclampsia (≥140mmHg/≥90mmHg blood pressure) in singleton pregnancy during 11–15 weeks of gestation? Summary answer Combination of serum homocysteine levels with uterine-artery Doppler is superior to individual presence of biochemical/ultrasound marker/s making the duo effective for early screening in preeclampsia. What is known already American College of Obstetricians and Gynecologists and National Institute for Care and Health Excellence recommend identifying patients who are at high risk of developing preeclampsia based on medical history. Recently, biochemical and ultrasound markers were investigated for prediction of preeclampsia, but none of them were predictably reliable, valid, and suitable for routine clinical use. Increased levels of homocysteine in 1st-trimester, seems to signal onset of preeclampsia later in pregnancy portraying severity of the disease as well. We aimed to identify predictive value of serum homocysteine combined with uterine-artery Doppler in singleton pregnancy during 11–15 weeks of gestation for preeclampsia. Study design, size, duration One hundred forty-two consented singleton pregnant women (28-45 years) at gestational age of 11–15 weeks, recruited between January to December 2021 from Institute of Reproductive Medicine, Kolkata were enrolled in the study. Women who used aspirin as a prophylaxis for preeclampsia or were diagnosed to have fetal, structural or chromosomal abnormalities were excluded from the study (n = 7). Maternal age, weight and height, mean arterial pressure, parity, and obstetric history were documented. Participants/materials, setting, methods Uterine-artery Doppler ultrasound and serum homocysteine levels were performed transabdominally and using ELISA respectively. Pregnancy outcomes were recorded. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) at optimal cut-off values were determined to predict preeclampsia. Optimal cut-off values for homocysteine levels were calculated using receiver operator characteristic curve (ROC). Chi-square test, Fisher’s exact test, unpaired t test, and Mann–Whitney U test were used when appropriate. P-value <0.05 was considered statistically significant. Main results and the role of chance 16 cases had preeclampsia (11.26%) of whom 9 had early-onset preeclampsia (6.33%). Baseline characteristics including maternal-age (>35 or<), parity, body-mass- index, and gestational-age at measurement were not significantly different between two groups excepting higher (p < 0.001) mean arterial blood pressure (mmHg) at first trimester (97.2±6.4 vs. 81.1±7.2) in preeclampsia. Preeclamptic women had significantly higher (p < 0.001) serum homocysteine levels (μmol/l) (26.1±3.5 vs 10.2± 5.6) than normotensive pregnant women (n = 119). No difference in mean pulsatility (PI) of uterine-artery was observed (1.78±0.64 vs. 1.72±0.48) excluding significantly high (p > 0.02) in women with early-onset preeclampsia than control (2.11±0.81 vs. 1.39±0.92). However, lower (p < 0.01) gestational age (weeks) (35.4±2.1 vs. 37.6±1.4), and neonatal birth weight (gms) (2937.3±578.2 vs. 3227.6±421.5) with higher (p < 0.001) preterm delivery (25% vs 5.04%), low birth weight (25% vs 5.04%) and neonatal respiratory distress syndrome (12.5% vs. 0.84%) was documented in preeclampsia than control/s. The optimal cut-off value of serum homocysteine with PI levels, from ROC (AUC=0.735, p < 0.001) was superior to individual ROC (AUC=0.451; AUC=0.268). The sensitivity, specificity, PPV, and NPV were 67.7%, 70.5%, 1.7%, and 98.5%, respectively using a combination of abnormal serum homocysteine levels with abnormal uterine artery Doppler PI (above 95th percentile) and used as a predictive value for preeclampsia. Limitations, reasons for caution The limitation of this study was that there were small cases of early-onset preeclampsia. Additional studies with a larger sample size of early-onset preeclampsia and other models using serum homocysteine, combined with uterine artery Doppler, and maternal characteristic risk factors should be conducted. Wider implications of the findings Early screening of preeclampsia by using combination of serum homocysteine and uterine artery Doppler during first trimester (11–15 weeks) at the same visit may be more effective and allows the timing for using early low-dose aspirin prophylaxis in order to prevent preeclampsia. Trial registration number Not applicable