Genetic landscape of a large cohort of Primary Ovarian Insufficiency : New genes and pathways and implications for personalized medicine

Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield-ing infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology.Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromo-somal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link.Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogene-sis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.Funding Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Risk Factors for Recurrent Ectopic Pregnancy: A Case - Control Study

OBJECTIVES: To investigate the role of epidemiological factors in recurrent ectopic pregnancies. STUDY DESIGN: From January 2003 to February 2005, 205 women with single ectopic pregnancy and 20 women with recurrent ectopic pregnancy were identified. The information collected for each woman included socio-demographic characteristics, smoking status, reproductive, sexual, contraceptive and medical histories (including PID). RESULTS: The risk of recurrent ectopic pregnancy was increased with age, mean of gravidity and history of pelvic surgery. After multivariate analysis, there was no significant association between recurrent ectopic pregnancy and any variables. CONCLUSION: Primary prevention of ectopic pregnancy is the best measure against preventing recurrent ectopic pregnancy. Moreover, for successful secondary prevention, identification of modifiable risk factors for recurrent ectopic pregnancy is important

Investigation of the role of serum telomerase levels in patients with occult primary ovarian insufficiency: a prospective cross-sectional study

This study was designed to investigate serum telomerase levels of occult primary ovarian insufficiency (POI) and the relationship between in vitro fertilisation (IVF) results of these patients and serum telomerase levels. A cross-sectional case–control study was conducted between May and October 2017 including 78 patients at University of Health Science, Turkey. Occult POI was defined as women with a history of follicle-stimulating hormone (FSH) elevation between 12 and 25 IU/L and low ovarian reserve before initiation of IVF (n = 39). The control group were patients attending the hospital for contraception, with no history of infertility, having at least one healthy child (n = 39). Telomerase levels in serum samples were determined using enzyme-linked immunosorbent assay method. There was no statistically significant difference in serum telomerase levels in occult POI patients when compared with the control group.Impact statement What is already known on this subject? Clinical studies investigating the role of telomerase on reproductive function and in vitro fertilisation (IVF) outcomes in occult primary ovarian insufficiency (POI) patients are limited with no clear consensus and in all these studies polymerase chain reaction technique was used to evaluate telomere length. Regarding our knowledge, this is the first study in the literature investigating the role of serum telomerase levels in occult POI patients. What do the results of this study add? In contrast to the previous studies, in this study no statistically significant difference was found in serum telomerase levels in occult POI patients when compared with the fertile control patients. What are the implications of these findings for clinical practice and/or further research? The occult POI patients examined in this study are overlooked until they apply with infertility. Serum telomerase measurement is not useful to support the diagnosis of occult POI. Nevertheless, in order to confirm these findings, further studies in larger populations are needed

Is montelukast effective in regression of endometrial implants in an experimentally induced endometriosis model in rats?

Tapisiz, Omer/0000-0002-7128-8086WOS: 000348826200002PubMed: 25462212Objective: Montelukast, a selective antagonist of Type 1 cysteinyl leukotriene receptors (CysLT(1)Rs), antagonizes the proinflammatory and proasthmatic activities of CysLT(1)Rs. We investigated the effect of montelukast on a surgically induced endometriosis rat model. Study design: Thirty-two sexually mature, cycling, female Wistar-Albino rats, in which endometriotic implants were surgically induced, were randomly divided into three groups. Group I [Montelukast (M), 10 rats)] was given 1.6 mg/kg/day of oral montelukast sodium. Group II [Leuprolide acetate (L), 11 rats] was given 1 mg/kg single dose of s.c.leuprolide acetate. Group III [Control (C), 11 rats] received saline solution through an orogastric tube and served as controls. After a 3-weeks medication, the rats were sacrificed to investigate the endometriotic implants for size and morphological and histological characteristics, including immunoreactivity of MMP-2 and VEGF. Results: The mean area of implants decreased from 48.2 +/- 24.7 to 293 +/- 15.8 mm(2) in Group I (M) (P = 0.008) and from 62 +/- 32.1 to 39.9 +/- 18.1 mm(2) in Group II(L) (P = 0.003). In Group III (C), the mean area increased from 41.1 +/- 31.1 to 60.4 +/- 37.1 mm(2) (P = 0.025). Histopathological analysis showed statistically significant lower scores in rats treated with montelukast compared to leuprolide and controls. MMP H scores were not different between the groups in both epithelial and stromal MMP-2 immunostaining. VEGF H scores were statistically lower in Group I (M) in epithelial VEGF immunostaining when compared to Group II(L) and Group III (C) (P = 0.006). Conclusion(s): Montelukast may effectively cause a significant decrease in the area of endometriotic implants. (C) 2014 Elsevier Ireland Ltd. All rights reserved

Effect of the non-specific matrix metalloproteinase inhibitor Doxycycline on endometriotic implants in an experimental rat model.

The aim of this study was to investigate the possible therapeutic effects of Doxycycline (Dox) on endometriotic lesions in an experimental rat model. Thirty-seven female Wistar albino rats with surgically induced endometriosis were randomized and divided into four groups. The rats were administered 5 mg/kg/day oral Dox in Group 1 (low-dose Dox group, n=9), 20 mg/kg/day oral Dox in Group 2 (high-dose Dox group, n=10) and 1 mg/kg single dose, subcutaneous leuprolide acetate in Group 3 (leuprolide acetate group, n=9). The rats in Group 4 (control group, n=9) were given no medication. The rats received medication for three weeks and were then sacrificed to evaluate the morphological and histological features of the implants. Matrix metalloproteinase (MMP)-9 immunoreactivity of the implants was also evaluated. The size of the endometriotic implants decreased in Groups 1-3 but statistically significant differences were not observed among the groups. The mean surface area of the endometriotic implants decreased from 69.3±30.8 to 52.1±27.0 mm² in Group 1 (P>0.05), from 60.2±18.9 to 38.6±28.7 mm² in Group 2 (P>0.05) and from 58.1±33.1 to 26±9.0 mm² in Group 3 (P=0.03). The epithelial MMP-9 immunohistochemical score was significantly higher in Group 1 and lower in Group 3 when compared with the control group (Group 4) (P=0.042 and P=0.014, respectively). When the stromal MMP-9 immunohistochemical and histopathological scores of the endometriotic implants were compared, no statistically significant differences were found among the groups. Although there was no statistically significant difference, Dox reduced the endometriotic implant area in the rat endometriosis model. Further studies are required to investigate the potential efficacy of Dox in endometriosis due to its widespread use and tolerability

Maternal Serum Nitric Oxide Levels in Adolescent Pregnancies

OBLECTIVE: We aimed to evaluate maternal serum nitric oxide (MSNO) levels in adolescent pregnancies. STUDY DESIGN: A total of forty five pregnancies were included to the study, of these eight were adolescent pregnancies (age range, 18-19 years old). Factors analyzed between adolescent pregnancies and reproductive age pregnancies (age range 20-35 years old) were; age, gravidity, parity, gestational weeks, umbilical and middle cerebral artery Doppler velocimetry values, birth weigts, APGAR 5. minute scores and MSNO levels. Statistical analyses were carried out by using the statistical packages for SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA) with Chi-square (χ2) test and Student’s t test. The receiver operator characteristic (ROC) curve analysis was used to establish the cutoff values for MSNO levels. RESULTS: Demographic and clinical characteristics showed no statistically significant difference among the groups (p>0.05). MSNO levels were statistically significantly lower in adolescent age pregnancies.                                               CONCLUSION: According to current study, MSNO levels were statistically significantly different from reproductive age pregnancies. MSNO levels may be a discriminative marker in adolescent age pregnancies but further studies with larger participants are needed to get more definite results

When Should the Labor Induction be Started For Late-term Pregnancies, in the Morning or in the Evening?

Aim: We aimed to investigate the labor outcomes of late-term pregnancies underwent intravenous oxytocin induction starting in the morning compared with starting in the evening. Material and Method: 266 women with a singleton pregnancy in cephalic presentation, at gestational age of 41 0/7 through 41 6/7 weeks were enrolled in this retrospective study. Labor inductions with intravenous oxytocin were started in the morning hours (08.00-12.00) or in the evening hours (16.00-20.00). Labor outcomes and night-time (20.00-08.00) deliveries were recorded. Results: In primiparae group, labor duration and active phase length of labor were significantly shorter in the evening group than in the morning group. In multiparae women, the ratio of night-time delivery was significantly higher in evening group as compared to morning group. And also night-time delivery was found as a significant risk factor for neonatal intensive care unit admission. Discussion: Induction of labour with intravenous oxytocin starting in the evening shortens labor duration in primiparae women, but not in multiparae women. Night-time delivery may be a risk for poor perinatal outcome. As the labor induction is planned, parity, start time of induction and estimated delivery time should be taken into account to reduce the risk of poor neonatal outcome in late-term pregnancies

Analysis of factors that influence the outcomes of labor induction with intravenous synthetic oxytocin infusion in term pregnancy with favourable bishop score

Purpose: To investigate the factors that influence the success of labor induction with synthetic intravenous oxytocin infusion in term pregnancies with favourable Bishop score. Material and Methods: 150 pregnant women with completed 37 weeks of gestation and Bishop score>6 who had single and cephalic presentation of pregnancy and were decided to underwent labor induction with intravenous oxytocin infusion were included in the study. Labor induction was considered unsuccessful if a vaginal delivery did not occur within 24 hours after the onset of loxytocin infusion or a cesarean section was performed during oxytocin infusion due to foetal distress, cephalopelvic disproportion or failure to progress in labor. Multivariable regression were used to identify odds of induction success. Results: Out of 150 women, induction of labor was unsuccessful in 23 (15.3%). Multivariate analysis demonstrated that nulliparity, shorter gestation period, persistent occiput posterior presentation and greater birth weight were independent risk factors for the induction failure. ROC curve analysis stated that gestation period of 3445-gram-birth weight has a sensitivity of 82.6% and a spesificity of 71.7% for the prediction of failure. Conclusion: Nulliparity, shorter gestation period, persistent occiput posterior presentation and greater birth weight increase the failure risk of labor induction with intravenous synthetic oxytocin infusion. [Cukurova Med J 2015; 40(2.000): 317-325