Fresh or frozen day 6 blastocyst transfer: is there still a question?

BACKGROUND: The Live Birth Rate (LBR) after day 5 (D5) blastocyst transfer is significantly higher than that with D6 embryos in both fresh and frozen-vitrified embryo transfer cycles, according to the most recently published meta-analyses. Therefore, for women obtaining only D6 blastocysts, the chances of pregnancy may be lower but nonetheless sufficient to warrant transferring such embryos. The best strategy for transfer (i.e., in fresh versus frozen cycles) remains unclear and there is a paucity of data on this subject. METHODS: A total of 896 couples with D6 single blastocyst transfers were retrospectively analyzed: patients receiving a fresh D6 embryo transfer (Fresh D6 transfer group, n = 109) versus those receiving a frozen-thawed D6 embryo transfer (Frozen D6 transfer group, n = 787). A subgroup comprising a freeze-all cycle without any previous fresh or frozen D5 embryo transfers (Elective frozen D6, n = 77) was considered and also compared with the Fresh D6 transfer group. We compared LBR between these two groups. Correlation between D6 blastocyst morphology according to Gardner's classification and live birth occurrence was also evaluated. Statistical analysis was carried out using univariate and multivariate logistic regression models. RESULTS: The LBR was significantly lower after a fresh D6 blastocyst transfer compared to the LBR with a frozen-thawed D6 blastocyst transfer [5.5% (6/109) vs. 12.5% (98/787), p = 0.034]. Comparison between LBR after Elective frozen D6 group to the Fresh D6 blastocyst transfers confirmed the superiority of frozen D6 blastocyst transfers. Statistical analysis of the blastocyst morphology parameters showed that both trophectoderm (TE) and inner cell mass (ICM) grades were significantly associated with the LBR after D6 embryo transfer (p < 0.001, p = 0.037). Multiple logistic regression revealed that frozen D6 thawed transfer was independently associated with a higher LBR compared with fresh D6 transfer (OR = 2.54; 95% CI: [1.05-6.17]; p = 0.038). Our results also show that transferring a good or top-quality D6 blastocyst increased the chances of a live birth by more than threefold. CONCLUSIONS: Our results indicate that transferring D6 blastocysts in frozen cycles improves the LBR, making it the best embryo transfer strategy for these slow-growing embryos. CLINICAL TRIAL NUMBER: Not applicable.

Menstrual Blood Donation for Endometriosis Research: A Cross-Sectional Survey on Women's Willingness and Potential Barriers.

An anonymous online survey in French was used to assess if endometriosis patients would be as ready as unaffected women to donate their menstrual blood for biological research on endometriosis and evaluate potential barriers to such donation. It was distributed in September 2022 by social media and two mailing lists, including a French patient organization. The questionnaire assessed participant age and brief medical history (hormonal contraception, endometriosis diagnosis, type of endometriosis), menstrual experience (menstrual blood abundance, dysmenorrhea), and whether participants would donate menstrual blood. Women who self-declared with an established endometriosis diagnosis versus no endometriosis were compared. Seven hundred seventy-eight women answered the survey. Among women with menstruation (n = 568), 78% are willing to donate menstrual blood for research. Importantly, this proportion was higher in women who declared having an established endometriosis diagnosis (83%, n = 299) compared to self-declared unaffected women (68%, n = 134, p < 0.001). The previous use of a menstrual cup and dysmenorrhea were significantly associated with the willingness to donate menstrual blood, while the use of hormonal contraception was significantly associated with an unwillingness to donate. Only the previous use of the menstrual cup had a predictive value for menstrual blood donation. No significant relationship was observed between menstrual blood donation and age, heavy menstrual bleeding and in endometriosis patients, endometriosis subtypes. In conclusion, women affected or not by endometriosis are largely willing to donate their menstrual blood for research on endometriosis, dysmenorrhea is not a barrier for donation, and women who use a menstrual cup are the more likely to donate.

An integrated multi-tissue approach for endometriosis candidate biomarkers: a systematic review.

Biomarker identification could help in deciphering endometriosis pathophysiology in addition to their use in the development of non invasive diagnostic and prognostic approaches, that are essential to greatly improve patient care. Despite extensive efforts, no single potential biomarker or combination has been clinically validated for endometriosis.Many studies have investigated endometriosis-associated biological markers in specific tissues, but an integrative approach across tissues is lacking. The aim of this review is to propose a comprehensive overview of identified biomarkers based on tissue or biological compartment, while taking into account endometriosis phenotypes (superficial, ovarian or deep, or rASRM stages), menstrual cycle phases, treatments and symptoms.We searched PubMed and Embase databases for articles matching the following criteria: 'endometriosis' present in the title and the associated term 'biomarkers' found as Medical Subject Headings (MeSH) terms or in all fields. We restricted to publications in English and on human populations. Relevant articles published between 01 January 2005 (when endometriosis phenotypes start to be described in papers) and 01 September 2022 were critically analysed and discussed.Four hundred forty seven articles on endometriosis biomarkers that included a control group without endometriosis and provided specific information on endometriosis phenotypes are included in this review. Presence of information or adjustment controlling for menstrual cycle phase, symptoms and treatments is highlighted, and the results are further summarized by biological compartment. The 9 biological compartments studied for endometriosis biomarker research are in order of frequency: peripheral blood, eutopic endometrium, peritoneal fluid, ovaries, urine, menstrual blood, saliva, feces and cervical mucus. Adjustments of results on disease phenotypes, cycle phases, treatments and symptoms are present in 70%, 29%, 3% and 6% of selected articles, respectively. A total of 1107 biomarkers were identified in these biological compartments. Of these, 74 were found in several biological compartments by at least two independent research teams and only 4 (TNF-a, MMP-9, TIMP-1 and miR-451) are detected in at least 3 tissues with cohorts of 30 women or more.Integrative analysis is a crucial step to highlight potential pitfalls behind the lack of success in the search for clinically relevant endometriosis biomarkers, and to illuminate the physiopathology of this disease.

The "freeze-all" strategy seems to improve the chances of birth in adenomyosis-affected women.

OBJECTIVE: To compare assisted reproductive technologies (ARTs) outcomes between fresh vs. freeze-all strategies in infertile women affected by adenomyosis. DESIGN: A single-center observational study. SETTINGS: University hospital-based research center. PATIENTS: Adenomyosis-affected women undergoing blastocyst embryo transfer after in vitro fertilization and intracytoplasmic sperm injection between January 1, 2018, and November 31, 2021. The diagnosis of adenomyosis was based on imaging criteria (i.e., transvaginal ultrasound and/or magnetic resonance imaging). INTERVENTION(S): Women who underwent a freeze-all strategy were compared with those who underwent a fresh embryo transfer (ET) strategy. MAIN OUTCOME MEASURE(S): Cumulative live birth rate (LBR). RESULTS: A total of 306 women were included in the analysis: 111 in the fresh ET group and 195 in the freeze-all group. The adenomyosis phenotype (internal diffuse adenomyosis, external focal adenomyosis, and adenomyoma) was not significantly different between the two groups. The cumulative LBR (86 [44.1%] vs. 34 [30.6%], respectively), and the cumulative ongoing pregnancy rate (88 [45.1%] vs. 36 [32.4%], respectively) were significantly higher in the freeze-all group compared with the fresh ET group. After multivariate logistic regression analysis, the freeze-all strategy in women with adenomyosis was associated with significantly higher odds of live birth compared with fresh ET (odds ratio = 1.80; 95% confidence interval = 1.02-3.16). CONCLUSION: The freeze-all strategy in women afflicted with adenomyosis undergoing ART was associated with significantly higher cumulative LBRs. Our preliminary results suggest that the freeze-all strategy is an attractive option that increases ART success rates. Additional studies, with a randomized design, should be conducted to further test whether the freeze-all strategy enhances the pregnancy rate in adenomyosis-affected women.

Effects of Ulipristal Acetate on Reactive Oxygen Species and Proinflammatory Cytokine Release by Epithelial and Stromal Cells from Human Endometrium and Endometriosis.

Endometriosis is a condition characterized by increased oxidative stress and chronic inflammation, which can be treated with progestins and other progesterone receptor ligands. However, some patients are refractory to this treatment and the reason is uncertain. Here we investigated the effects of the selective progesterone receptor modulator ulipristal acetate (UPA) on proliferation, reactive oxygen species (ROS), and proinflammatory cytokine production by endometriotic cells and endometrial cells from women with histologically proven endometriosis (n = 22) and endometriosis-free controls (n = 6). Epithelial and stromal cells were isolated and treated in triplicate for 24 h with 1 µM, 10 µM, or 100 µM UPA. Cells were tested for proliferation and ROS production, while cell supernatants were assayed for interleukin (IL)-6, C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α concentrations. Proliferation, ROS production, and IL-6 and CCL2 secretion were increased in non-stimulated epithelial and stromal cells from endometriotic lesions compared to endometrial cells from endometriosis patients and controls. UPA induced a dose-dependent increase of cell proliferation only in endometriosis, while enhancing ROS production by all cell types evaluated. UPA reduced CCL2 production in controls but failed to do that in endometriosis, whereas TNF-α was undetectable. We conclude that treatment of endometriotic cells with UPA stimulated in vitro proliferation and ROS production and failed to revert the proinflammatory cytokine excess that characterized these cells, unravelling possible mechanisms of drug resistance in the treatment of endometriosis.

Investigating the medical journey of endometriosis-affected women: Results from a cross-sectional web-based survey (EndoVie) on 1,557 French women.

OBJECTIVE: To investigate the medical journey and the quality of life of French endometriosis-affected women, from the onset of the symptoms to the therapeutic management. STUDY DESIGN: Between January 15th 2020 and February 3rd 2020, a prospective cross-sectional web-based survey was conducted among women diagnosed with endometriosis. The questionnaire included 52 questions distributed in five sections (screening, sociodemographic characteristics, impacts on quality of life, SF36 questionnaire, management of endometriosis and proposals for care improvement). RESULTS: One thousand five hundred fifty-seven endometriosis-affected women aged of 42±12.8 years answered the questionnaire. On average, 7 years elapsed between the first symptoms (at 23.8 ± 10.2 years) and the diagnosis (31.0 ± 8.9 years). The mean number of symptoms was 4.6 ± 2.3, with 82 % of women experiencing pain scores between 7 and 10/10. Following diagnosis, 66 % women received a medical treatment, mostly hormonal treatments (45 %), with a significant decrease in pain intensity (VAS scores after treatment = 4.9 ± 2.7, p < 0.001). Most women (62 %) had already been operated, among whom 22 % by laparotomy. Finally, patients reported numerous impacts on their daily lives, particularly on the sexual, psychological, and physical fields. The overall mean score of quality of life was 4.3 ± 2.6 /10. CONCLUSION: This large prospective web-based survey underlines that the journey of women with endometriosis is long and difficult until diagnosis and efficient treatment. It emphasizes the urgent need to reduce the diagnostic delay and thereby the burden of endometriosis on women's lives. Moreover, the creation of referral multidisciplinary centers appears to be crucial to improve the management of the disease.

Oocyte donation outcomes in endometriosis patients with multiple IVF failures.

RESEARCH QUESTION: What are the reproductive outcomes and the prognostic factors of live birth rates in patients with endometriosis referred to oocyte donation after multiple IVF failures? DESIGN: Observational cohort study including all women with endometriosis-related infertility and two or more failed IVF/intracytoplasmic sperm injection (ICSI) cycles referred to oocyte donation between January 2013 and June 2022. Endometriosis was diagnosed based on published imaging criteria, and was confirmed histologically in women who had a history of surgery for endometriosis. The main outcome measured was the cumulative live birth rate (CLBR). The characteristics of women who had a live birth were compared with those who did not using univariate and multivariate analysis to identify determinant factors of fertility outcome. RESULTS: Fifty-seven patients underwent 90 oocyte donation cycles after 244 failed autologous IVF cycles. The mean ± SD age of the population was 36.8 ± 3.3 years, with a mean duration of infertility of 3.6 ± 2.2 years, and a mean number of autologous IVF/ICSI cycles of 4.4 ± 2.3 cycles per patient. Three patients (5.3%) had superficial peritoneal endometriosis, two patients (3.5%) had ovarian endometriomas, and 52 patients (91.2%) had deep infiltrating endometriosis, among which 30 patients (57.7%) had bowel lesions. Thirty patients (52.6%) had associated adenomyosis. Overall, CLBR per patient was 36/57 (63.2%). After multivariate analysis, only being nulligravida (P=0.002) remained an independent negative predictive factor of the live birth rate. Previous surgery did not impact reproductive outcomes. CONCLUSION: This study suggests that oocyte donation appears to be a viable option to optimize the live birth rate in women with endometriosis-related infertility and recurrent IVF failures.

Fertility preservation in women with benign gynaecological conditions.

Although a wealth of data has been published regarding fertility preservation (FP) in women with malignant diseases who receive gonadotoxic treatment, the role of FP in non-malignant conditions has been studied to a much lesser extent. These include benign haematological, autoimmune, and genetic disorders, as well as a multitude of benign gynaecological conditions (BGCs) that may compromise ovarian reserve and/or reproductive potential due to pathogenic mechanisms or as a result of medical or surgical treatments. Alongside accumulating data that document the reproductive potential of cryopreserved oocytes and ovarian tissue, there is potential interest in FP for women with BGCs at risk of infertility; however, there are currently insufficient data about FP in women with BGCs to develop guidelines for clinical practice. The purpose of this article is to appraise the available evidence regarding FP for BGC and discuss potential strategies for FP based on estimated ovarian impairment and on short-term and long-term reproductive goals of patients. Cost-effectiveness considerations and patients' perspectives will also be discussed.

Magnetic resonance imaging presentation of diffuse and focal adenomyosis before and after pregnancy.

RESEARCH QUESTION: Is there a change in magnetic resonance imaging (MRI) criteria of diffuse and focal phenotypes of adenomyosis before and after pregnancy? DESIGN: A retrospective, monocentric, observational study in a single academic tertiary referral centre for endometriosis diagnosis and management. Women were followed for symptomatic adenomyosis, and without a prior history of surgery who give birth after 24+0 weeks. For each patient, pelvic MRI pre- and post-pregnancy was performed by two experienced radiologists with the same image acquisition protocol. Diffuse and focal adenomyosis MRI presentation were analysed before and after pregnancy. RESULTS: Between January 2010 and September 2020, of the 139 patients analysed, 96 (69.1%) had adenomyosis at MRI distributed as follow: 22 (15.8%) presented diffuse adenomyosis, 55 (39.6%) focal adenomyosis and 19 (13.7%) both phenotypes. The frequency of isolated diffuse adenomyosis on MRI was significantly lower before versus after pregnancy (n = 22 [15.8%] versus n = 41 [29.5%], P = 0.01). The frequency of isolated focal adenomyosis was significantly higher before pregnancy than after pregnancy (n = 55 [39.6%] versus n = 34 [24.5%], P = 0.01). The mean volume of all focal adenomyosis lesions on MRI decreased significantly after pregnancy, from 6.7 ± 2.5 mm3 to 6.4 ± 2.3 mm3, P = 0.01. CONCLUSION: The current data indicate that, based on MRI, there is an increase in diffuse adenomyosis and a decrease in focal adenomyosis after pregnancy.

[Pelvic exam in gynecology and obstetrics: Guidelines for clinical practice]. / Examen pelvien en gynécologie et obstétrique : recommandations pour la pratique clinique.

OBJECTIVE: To provide guidelines for the pelvic clinical exam in gynecology and obstetrics. MATERIAL AND METHODS: A multidisciplinary experts consensus committee of 45 experts was formed, including representatives of patients' associations and users of the health system. The entire guidelines process was conducted independently of any funding. The authors were advised to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. METHODS: The committee studied 40 questions within 4 fields for symptomatic or asymptomatic women (emergency conditions, gynecological consultation, gynecological diseases, obstetrics, and pregnancy). Each question was formulated in a PICO (Patients, Intervention, Comparison, Outcome) format and the evidence profiles were produced. The literature review and recommendations were made according to the GRADE® methodology. RESULTS: The experts' synthesis work and the application of the GRADE method resulted in 27 recommendations. Among the formalized recommendations, 17 present a strong agreement, 7 a weak agreement and 3 an expert consensus agreement. Thirteen questions resulted in an absence of recommendation due to lack of evidence in the literature. CONCLUSIONS: The need to perform clinical examination in gynecological and obstetrics patients was specified in 27 pre-defined situations based on scientific evidence. More research is required to investigate the benefit in other cases.

Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation.

INTRODUCTION: Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been shown to be involved in Primary Adrenal Insufficiency (PAI). NNT encodes an inner mitochondrial membrane protein that produces large amounts of NADPH. NADPH is used in several biosynthesis pathways and the oxidoreduction of free radicals by the glutathione and thioredoxin systems in mitochondria. Patients with PAI due to NNT deficiency may also exhibit extra-adrenal manifestations, usually including gonadal impairment. CASE REPORT: We present the case of a 35-year-old patient referred to our center for primary infertility with non-obstructive azoospermia, in a context of PAI and obesity. PAI genetic exploration carried out at the age of thirty revealed NNT deficiency due to the presence of two deleterious mutations (one on each allele) in the NNT gene. Scrotal ultrasound revealed a right Testicular Adrenal Rest Tumor (TART). Intensification of glucocorticoid therapy over the course of 8 months failed to reduce the TART volume or improve sperm production and endocrine function. No spermatozoa were found after surgical exploration of both testes, and subsequent histopathological analysis revealed bilateral Sertoli cell-only syndrome. A retrospective review of the hypothalamic-pituitary-gonadic axis hormonal assessment over 20 years showed progressive impairment of testicular function, accelerated during adulthood, leading to hypergonadotropic hypogonadism and non-obstructive azoospermia when the patient reached his thirties, while the PAI remained controlled over the same period. CONCLUSION: This case report provides, for the first time, direct evidence of complete germ line loss in an azoospermic man with NNT deficiency. Additional data further support the hypothesis of a determinant role of oxidative cellular damage due to reactive oxygen species (ROS) imbalance in the severe gonadal impairment observed in this NNT-deficient patient. Early and regular evaluation of gonadal function should be performed in patients with PAI, especially with NNT deficiency, as soon as the patients reach puberty. Fertility preservation options should then be provided in early adulthood for these patients.

RéSUMé: INTRODUCTION: Le gène Nicotinamide Nucleotide Transhydrogenase (NNT) a été récemment impliqué dans l'Insuffisance Surrénalienne Primaire (ISP). Il code pour une protéine de la membrane mitochondriale interne qui produit de fortes quantités de NADPH. Le NADPH est utilisé par plusieurs voies de biosynthèse et dans l'oxydo-réduction de radicaux libres par les voies de signalisation impliquant le glutathion et la thioredoxine dans la mitochondrie. Les patients avec une ISP, en lien avec un déficit du gène NNT, peuvent également présenter des manifestations extra-surrénaliennes, dont une altération gonadique. CAS CLINIQUE: Nous présentons le cas clinique d'un homme de 35 ans adressé à notre centre d'Assistance Médicale à la Procréation pour infertilité primaire avec azoospermie non obstructive, dans un contexte d'ISP et d'obésité. L'exploration génétique effectuée à l'âge de 30 ans a identifié un déficit complet de la protéine NNT dû à la présence de deux mutations hétérozygotes (une sur chaque allèle), délétères. L'échographie scrotale a montré une tumeur testiculaire d'origine surrénalienne à droite. L'intensification du traitement par glucocorticoides pendant 8 mois n'a pas réduit le volume de la tumeur ni amélioré la production spermatique ou la fonction testiculaire endocrine. Aucun spermatozoïde n'a été retrouvé après exploration chirurgicale testiculaire bilatérale, en lien avec un syndrome de Cellules de Sertoli Seules. L'étude rétrospective de l'axe hypothalamo-hypophysaire-gonadique monte une altération progressive de la fonction testiculaire, accélérée à l'âge adulte, aboutissant à un hypogonadisme hypergonadotrope et une azoospermie non-obstructive à 30 ans, alors que l'ISP était contrôlée pendant cette période. CONCLUSION: Ce cas clinique met en évidence pour la première fois une disparition complète de la lignée germinale chez un patient avec un déficit en NNT. Il avance des arguments en faveur de l'hypothèse d'un rôle déterminant des dommages cellulaires, dus à un excès de radicaux oxygénés dans cette atteinte régulière de la fonction gonadique. Cette dernière devrait être suivie à partir de la puberté chez les patients ISP et plus particulièrement ceux ayant un déficit en NNT. Une préservation de la fertilité pourrait leur être proposée lorsqu'ils deviennent adultes.

Decrease of dysmenorrhoea with hormonal treatment is a marker of endometriosis severity.

RESEARCH QUESTION: Is a decrease in dysmenorrhoea after suppressive hormonal therapy a marker of the endometriosis phenotype and of greater disease severity? DESIGN: Retrospective observational cohort study conducted in a French university hospital, between January 2004 and December 2019. Non-pregnant women aged younger than 42 years, who tested for dysmenorrhoea relief after suppressive hormonal therapy before surgery, and who had histological confirmation of endometriosis, were included. The comparisons were carried out according to the results of the suppressive hormonal test. RESULTS: Of the 578 histologically proven endometriosis patients with preoperative pain symptoms, the rate of dysmenorrhoea decrease after suppressive hormonal therapy was 88.2% (n = 510). These patients had a higher incidence of deep infiltrating endometriosis (DIE) intestinal lesions (45.7% [233/510] versus 30.8% [21/68], P = 0.01) and an increased rate of multiple DIE lesions (two or more) (72.8% [287/394] versus 56.4% [22/39], P = 0.02). After multivariate analysis, decrease of dysmenorrhoea after suppressive hormonal therapy remained significantly associated with the severe DIE phenotype (adjusted OR 3.9, 95% CI 2.0 to 7.6, P < 0.001). CONCLUSION: In women with endometriosis, a decrease of dysmenorrhoea after suppressive hormonal therapy is associated with the DIE phenotype and is a marker of greater severity.

IVF/ICSI Outcomes After a Freeze-All Strategy: an Observational Cohort Study.

In order to inform patients undergoing ART regarding their chances for motherhood, it seems useful to describe "freeze all" outcomes according to the different potential indications. The goal of this study was to examine the impact of a "freeze-all approach" on the cumulative live birth rate (cLBR) according to the indication. It is a cohort study including women who had undergone ovarian stimulation (OS) using an antagonist protocol with GnRH agonist triggering between 09.2016 and 09.2018 followed by a freeze-all cycle of blastocyst embryos. The ART outcomes were compared between the two main indications of the freeze-all strategy which were in our cohort: risk of ovarian hyperstimulation syndrome (OHSS) and endometriosis. The ART outcomes were also described for the others indications (inadequate endometrium and/or premature progesterone elevation at trigger day, two or more previous ART failures, and autoimmune disease and/or a high risk of thromboembolic disease (AI and/or TE risk)). In total, 658 women were included. The cLBR in the total population was 37.7% (248/658). The cLBR was significantly higher in the "OHSS risk" group (133/281, 47.3%) than in the "endometriosis" group (69/190, 36.3%) (p = 0.017). No significant differences were noted regarding perinatal outcomes, except a significantly higher risk of placenta praevia (PP) observed in the "endometriosis" group (10.1%) (p = 0.002). The "freeze-all approach" yielded good results in terms of the cLBR and especially in case of OHSS risk. These data should be taken into account when informing patients about the ART strategy and their chances of motherhood.

Embryo transfer learning using medical simulation tools: a comparison of two embryo transfer simulators.

INTRODUCTION: Embryo transfer(ET) is one of the main procedures to become pregnant by assisted reproductive technology(ART). Simulation training is a way to improve the skills of clinicians. The objective of this study was to evaluate the interest of trainees in learning embryo transfer using simulators. MATERIAL AND METHODS: An observational study was conducted at the University hospital-based research center. Trainees, comprising midwives and resident or graduated gynecologists, who attended the medical training for infertility and ART in June 2019, were included. They trained on two ET simulators (Simulator A and B) and complete an anonymously online questionnaire. A sub-group analysis focusing on graduated gynecologists not performing ET in current practice, was performed. RESULTS: Thirty-two trainees were included. Trainees felt that ET simulators should be used in medical education to promote learning how to perform the ET procedure (n=26, 81.3% for Simulator A and n=21, 65.5% for Simulator B; p=0.31). The use of both simulators improved the level of self-confidence (81.3% and 75.0% respectively; p=0.55). Significant differences in the global and in the subgroup analysis (n=24) in favor of Simulator A were observed regarding learning the precision of the ET procedure (p<0.01), the pathway to introduce the catheter into the uterine cavity (p<0.05), and the guidance for proper placement of the catheter into the uterine cavity (p=0.03). In the subgroup analysis of graduated gynecologists not performing ET in current practice, Simulator A was found more realistic for the visualization of the introduction of the catheter into the uterine cavity (p=0.01) and more useful to learn about difficult cases (p=0.03). CONCLUSION: Students expressed a high level of interest in ET simulators to improve their skills. Although the simulators displayed some differences regarding learning the precision of the ET procedure, both improved the level of self-confidence. This new learning method needs to be further developed in order to offer to trainees the most realistic simulators. TRIAL REGISTRATION: This study was approved for publication by the Ethics Review Committee of the Cochin University Hospital (CLEP) (n° AAA-2020-08016) retrospectively registered.

Influence of endometrioma size on ART outcomes.

RESEARCH QUESTION: Does endometrioma size affect the number of oocytes retrieved after ovarian stimulation in women with endometriosis-related infertility undergoing IVF/intracytoplasmic sperm injection (ICSI)? DESIGN: Cohort study of infertile women with unilateral or bilateral endometrioma(s) associated with deep infiltrating endometriosis, undergoing their first IVF/ICSI cycle between January 2014 and November 2021. A total of 326 women with an adequate imaging work-up with transvaginal ultrasound and/or magnetic resonance imaging performed by senior radiologists before the start of ovarian stimulation was included. Prognostic factors associated with the number of oocytes retrieved were analysed. IVF/ICSI outcomes were compared between five groups defined according to the largest endometrioma diameter (<2, 2 to <4, 4 to <6, 6 to <8 and ≥8 cm). RESULTS: Factors that significantly reduced the number of oocytes retrieved after adjustment by multiple linear regression were women's age (regression coefficient -0.18; 95% confidence interval [95% CI] -0.31 to-0.06; P = 0.005), smoking habit (-2.02; 95% CI -3.42 to -0.62; P = 0.005), day 3 FSH concentration (-0.20; 95% CI -0.39 to -0.02; P = 0.031) and a previous history of surgery for ovarian endometriosis (-1.32; 95% CI -2.63 to -0.02; P = 0.047). Antral follicle count and oestradiol concentration on the trigger day were positively correlated with the number of oocytes retrieved (0.14; 95% CI 0.08 to 0.19; P < 0.001 and 0.003; 95% CI 0.002 to 0.004; P < 0.001, respectively). The mean number of oocytes retrieved was not significantly different between the five groups (P = 0.413), nor were the cumulative live birth rate, the number of cancelled cycles and perinatal outcomes. CONCLUSIONS: No significant difference in the number of oocytes retrieved was observed according to endometrioma size. This study suggests that ovarian stimulation can be of benefit to women irrespective of the endometrioma size.

Low serum progesterone affects live birth rate in cryopreserved blastocyst transfer cycles using hormone replacement therapy.

RESEARCH QUESTION: Does serum progesterone concentration on the day of vitrified-warmed embryo transfer affect live birth rate (LBR) with hormonal replacement therapy (HRT) cycles? DESIGN: Observational cohort study of patients (n = 915) undergoing single autologous vitrified-warmed blastocyst transfer under HRT using vaginal micronized progesterone. Women were included once, between January 2019 and March 2020. Serum progesterone concentration was measured by a single laboratory on the morning of embryo transfer. The primary end point was LBR. Univariate and multivariate logistic regression models were used for statistical analyses. RESULTS: Median (25th-75th percentile) serum progesterone concentration on the day of embryo transfer was 12.5 ng/ml (9.8-15.3). The LBR was 31.5% (288/915) in the overall population. No significant differences were found in implantation rates (40.7% versus 44.9%); LBR was significantly lower in women with a progesterone concentration ≤25th percentile (≤9.8 ng/ml) (26.1% versus 33.2%, P = 0.045) versus women with a progesterone concentration >25th percentile. This correlated with a significantly higher early miscarriage rate (35.9% versus 21.6%, P = 0.005). After adjusting for potential confounding factors in multivariate analysis, low serum progesterone levels (≤9.8 ng/ml) remained significantly associated with lower LBR (OR 0.68 95% CI 0.48 to 0.97). CONCLUSION: A minimum serum progesterone concentration is needed to optimize reproductive outcomes in HRT cycles with single autologous vitrified-warmed blastocyst transfer. Whether modifications of progesterone administration routes, dosage, or both, can improve pregnancy rates needs further study so that treatment of patients undergoing HRT cycles can be further individualized.

A new validated screening method for endometriosis diagnosis based on patient questionnaires.

BACKGROUND: The time between symptoms onset and endometriosis diagnosis is usually long. The negative impacts of delayed endometriosis diagnosis can affect patients and health outcomes. METHODS: We conducted a case-control study using clinical symptoms and epidemiological data extracted from a prospective pre-operative patient questionnaire compared between patients with histologically proven endometriosis and patients with no endometriosis at surgical exploration from 2005 to 2018, in a French referral center. We used the beta coefficients of the significant variables introduced in a multiple regression model to devise a score (score 1), evaluated by the area under the curve (or C-index), with three levels, defined by a score between 1 and ≥ 25: (i) highly specific, identifying correctly the patients without the disease; (ii) highly sensitive, identifying the patients with the disease; and (iii) a level maximizing sensitivity and specificity for the best classification of the whole population. To minimize patient self-evaluation of pain, we devised a second score (score 2) with the same method and levels and scores definition, excluding visual analog scale pain scores, except for dysmenorrhea. These scores were validated on an internal and external population. FINDINGS: Score 1 had a C-index of 0.81 (95% CI [0.79-0.83]). Results for the three score 1 levels were: ≥ 25: specificity of 91% (95% CI [89-93]); < 11: sensitivity of 91% (95% CI [89-93]); ≥ 18: specificity of 75% (95% CI [72-78]) and sensitivity of 73% (95% CI [70-76]). Score 2 had a C-index of 0.75 (95% CI [73-77]). The three levels of score 2 were: ≥ 24: specificity of 82% (95% CI [80-85]); < 7: sensitivity of 92% (95% CI [90-94]); ≥ 17: specificity of 62% (95% CI [58-65]) and sensitivity of 78% (95% CI [75-81]). The two scores were internally and externally validated. INTERPRETATION: A score based only on a patient questionnaire could allow identification of a population at high risk of endometriosis. This strategy might help referral to specialized radiologists for a non-surgical endometriosis scan. FUNDING: None.

Endometriosis increases the rate of spontaneous early miscarriage in women who have adenomyosis lesions.

RESEARCH QUESTION: In women with radiologically diagnosed adenomyosis, is the presence of endometriosis associated with a higher rate of miscarriage? DESIGN: An observational cohort study of women who received medical care for benign gynaecological conditions between May 2005 and May 2018. Women who had adenomyosis lesions visualized by uterine magnetic resonance imaging (MRI) were included. Women who had never been pregnant were excluded. Women with adenomyosis identified by MRI but who did not have endometriosis lesions (control group) were compared with women with adenomyosis and endometriosis lesions (study group). Primary outcome was rate of a previous history of early miscarriage. RESULTS: A total of 214 pregnancies in the study group and 53 pregnancies in the control group were analysed. The rate of a previous miscarriage was significantly higher among women with adenomyosis and endometriosis lesions compared with women in the control group (61/214 [28.5%] versus 6/53 [11.3%], respectively, P = 0.009). A multivariable generalized estimating equation logistic regression model, adjusted for adenomyosis and endometriosis phenotypes, found that the association between endometriosis and adenomyosis significantly increased the risk of miscarriage (OR 3.2, 95% CI 1.1 to 9.65). The risk was significantly higher with deep infiltrating endometriosis (OR 4.37, 95% CI 1.32 to 14.53). CONCLUSIONS: Women affected by endometriosis had a significantly higher rate of previous spontaneous miscarriage than women without endometriosis with adenomyosis lesions identified by MRI. Mechanistic studies are needed to establish the complex link between the presence of endometriosis and adenomyosis and the rate of spontaneous miscarriage.

ART Outcomes After Hysteroscopic Proximal Tubal Occlusion Versus Laparoscopic Salpingectomy for Hydrosalpinx Management in Endometriosis Patients.

The objective of this paper is to compare assisted reproductive technology (ART) cumulative live birth rates after hysteroscopic proximal tubal occlusion and laparoscopic salpingectomy in endometriosis patients, for management of hydrosalpinx. This is an observational cohort study at a university hospital, including all endometriosis patients with hydrosalpinges undergoing ART, between January 2013 and December 2018. The patients underwent either laparoscopic salpingectomy or hysteroscopic proximal tubal occlusion with Essure® when laparoscopy was not an option (extensive pelvic adhesions at exploratory laparoscopy or a history of multiple abdominal surgeries with frozen pelvis). The diagnosis of endometriosis was based on published imaging criteria using transvaginal sonography (TVUS) and magnetic resonance imaging (MRI). Endometriosis patients with hydrosalpinges diagnosed by hysterosalpingography and/or TVUS and/or MRI were included. The primary outcome was the cumulative live birth rate. A total of 104 patients were included in the study; 74 underwent laparoscopic salpingectomy and 30 underwent proximal tubal occlusion with Essure®. The Essure® group had longer infertility durations (58.9 ± 30.0 months vs. 39.5 ± 19.1 months, p = 0.002) and a higher incidence of associated adenomyosis (76.7% vs. 39.1%, p < 0.001) than the salpingectomy group. The cumulative live birth rate was 56.6% after 44 ART cycles in the Essure® group and 40.5% after 99 ART cycles in the salpingectomy group (p = 0.13). In a population of endometriosis patients undergoing ART, women treated by Essure® for management of hydrosalpinx have similar cumulative live birth rates as women treated by laparoscopic salpingectomy.