STUDY QUESTION: What is the distribution of endometriosis phenotypes according to age in adult women undergoing surgery? SUMMARY ANSWER: The phenotype of endometriosis did not significantly vary after 24 years old. WHAT IS KNOWN ALREADY: The phenotypic evolution of endometriosis over time remains unclear. While adolescents can exhibit any type of endometriosis lesions, ovarian endometriosis (OMA) and/or deep-infiltrating endometriosis (DIE) tend to increase with age in young adults. In adulthood, understanding the evolution of lesions is crucial for disease management, but the literature on this subject is limited. This study aims to examine the distribution of endometriosis phenotypes in relation to age among adult patients requiring surgical treatment. STUDY DESIGN, SIZE, DURATION: This observational cohort study included patients aged between >= 18 and <= 42 years, who underwent surgery for benign gynecological conditions at our institution between January 2004 and December 2022. A standardized questionnaire was completed for each patient during a face-to-face interview conducted by the surgeon in the month preceding surgery. Women with histologically proven endometriosis were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: The distribution of endometriosis phenotypes (isolated superficial (SUP) endometriosis, OMA +/- SUP, DIE +/- SUP/OMA) was compared between young adults (<= 24 years) and adults (>24 years) and among adults (25-28 years, 29-33 years, 34-38 years, 39 to <= 42 years) using univariate and multivariate analysis. The distribution of different subtypes of DIE (uterosacral ligament(s), vagina, bladder, intestine, and ureter), OMA size, and intensity of pain symptoms were also examined. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1311 adult women with histologically proven endometriosis were included. In women aged 24 years or younger (n = 116), the distribution of endometriosis phenotypes differed significantly from women older than 24 years (n = 1195): The frequency of the DIE +/- SUP/OMA phenotype was lower (41.4% versus 56.1%, respectively), while the rate of isolated superficial lesions was higher (from 32.0% versus 25.9%) (P = 0.001). In the group of women aged >24 years, a significantly higher proportion of vaginal DIE lesions (P = 0.012) and a lower proportion of uterosacral ligament DIE lesions (P = 0.004) were found compared to women aged <= 24 years. No significant differences were observed in terms of endometrioma size. Between the ages of 25 and 42 years, there were no significant changes in the distribution of endometriosis phenotypes after univariate and multivariate analysis. The distribution of subtype of DIE lesions did not significantly change with age between 25 and 42 years. Concerning pain symptom scores, there was a significant decrease with age for dysmenorrhea and dyspareunia. LIMITATIONS, REASONS FOR CAUTION: Inclusion of only surgical patients may have introduced a selection bias. Women referred to our center may have suffered from particularly severe clinical forms of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights that endometriosis presentation did not change with age in adult women. Further research on endometriosis phenotype evolution is necessary to assist practitioners in clinical decisions and treatment strategies.

STUDY QUESTION:Does a reduction in fertility and/or systemic immune cell change occur during the early implantation period in a mouse model of adenomyosis? SUMMARY ANSWER:A reduction in fertility was observed in mice with adenomyosis, coinciding with local and systemic immune changes observed during the implantation period. WHAT IS KNOWN ALREADY:Adenomyosis is a pathology responsible for impaired fertility in humans, with a still unclear pathophysiology. One hypothesis is that changes in immune cells observed in adenomyosis-affected uteri may alter fertility, notably the physiological immune environment necessary for successful implantation and a healthy pregnancy. STUDY DESIGN, SIZE, DURATION:Randomly selected CD-1 female neonatal pups were orally dosed by administration of tamoxifen to induce adenomyosis (TAM group), while others received solvent only (control group). From 6 weeks of life, CD-1 mice of both groups were mated to study impaired fertility and related local and/or systemic immune cell changes during the early implantation period. PARTICIPANTS/MATERIALS, SETTINGS, METHODS:To evaluate fertility and pregnancy outcomes, ultrasound imaging was performed at E (embryonic day) 7.5 and E11.5 to count the number of gestational sacs and the number of resorptions in eight mice of the TAM group and 16 mice of the control group. The mice were sacrificed at E18.5, and morphometric, functional (quantitative reverse transcription PCR; RT-qPCR), and histological analyses were performed on the placentas. To identify local and/or systemic immune changes during the early implantation period, 8 mice of the TAM group and 12 mice of the control group were sacrificed at E4.5. Uterine horns and spleens were collected for flow cytometry and RT-qPCR analyses to study the immune cell populations. To investigate the profile of the cytokines secreted during the early implantation period at the systemic level, supernatants from stimulated spleen cells were analyzed by multiplex immunoassay analysis. MAIN RESULTS AND THE ROLE OF CHANCE:By ultrasound imaging, we observed a lower number of implantation sites (P < 0.005) and a higher number of resorptions (P < 0.001) in the TAM group, leading to smaller litters (average number of fetuses per litter: 1.00 [0.00; 5.25] in the TAM group versus 12.00 [9.50; 13.75] in the control group (P < 0.001). Histological and morphometric analyses of the placentas at E18.5 showed a higher junctional/labyrinthine area ratio in the TAM group (P = 0.005). The expression levels of genes that play a role in vascularization and placental growth (Vegf (P < 0.001), Plgf (P < 0.005), Pecam (P < 0.0001), and Igf2 (P = 0.002)) were reduced in the TAM group. In the TAM group, the percentages of macrophages, natural killer (NK) cells, and dendritic cells (DC) were significantly decreased in the uterus around the implantation period. However, the number of M1 macrophages was increased. Both macrophages and DC had an increased activation profile (higher expression of MCHII, P = 0.012; CD80, P = 0.015; CCR7, P = 0.043 for macrophages, and higher expression of CD206, P = 0.018; CXCR4, P = 0.010; CCR7, P = 0.006, MCHII, P = 0.010; and CD80, P = 0.012 for DC). In spleen, an increase in the activation of macrophages (CCR7, P = 0.002; MCHII, P = 0.001; and CD80, P = 0.034) and DC was observed in the TAM group (CCR7, P = 0.001; MCHII, P = 0.001; Ly6C, P = 0.015). In the uteri and the spleen, we observed increased percentages of CD4+ T lymphocytes (P = 0.0237 and P = 0.0136, respectively) in the TAM group and, in the uteri, an increased number of regulatory T cells (P = 0.036) compared with the controls. LARGE SCALE DATA:Not applicable. LIMITATIONS, REASONS FOR CAUTION:This study is limited by the use of an animal model and the lack of intervention. WIDER IMPLICATIONS OF THE FINDINGS:These data support involvement of innate and adaptive immune cells in the implantation failure and the increased rate of resorption observed in the mouse model of adenomyosis. This substantiates the need for additional research in this domain, with the goal of addressing fertility challenges in women affected by this condition. STUDY FUNDING/COMPETING INTEREST(S):None.

STUDY QUESTION: Is there a significant intra-individual variability of serum progesterone levels on the day of single blastocyst Hormone Replacement Therapy-Frozen Embryo Transfer (HRT-FET) between two consecutive cycles? SUMMARY ANSWER: No significant intra-individual variability of serum progesterone (P) levels was noted between two consecutive HRT-FET cycles. WHAT IS KNOWN ALREADY: In HRT-FET cycles, a minimum P level on the day of embryo transfer is necessary to optimise reproductive outcomes. In a previous study by our team, a threshold of 9.8 ng/ml serum P was identified as significantly associated with the live birth rates in single autologous blastocyst transfers under HRT using micronized vaginal progesterone (MVP). Such patients may benefit from an intensive luteal phase support (LPS) using other routes of P administration in addition to MVP. A crucial question in the way towards individualising LPS is whether serum P measurements are reproducible for a given patient in consecutive HRT-FET cycles, using the same LPS. STUDY DESIGN, SIZE, DURATION: We conducted an observational cohort study at the university-based reproductive medicine centre of our institution focusing on women who underwent at least two consecutive single autologous blastocyst HRT-FET cycles between January 2019 and March 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients undergoing two consecutive single autologous blastocyst HRT-FET cycles using exogenous oestradiol and vaginal micronized progesterone for endometrial preparation were included. Serum progesterone levels were measured on the morning of the Frozen Embryo Transfer (FET), by a single laboratory. The two measurements of progesterone levels performed on the day of the first (FET1) and the second FET (FET2) were compared to evaluate the intra-individual variability of serum P levels. Paired statistical analyses were performed, as appropriate. MAIN RESULTS AND THE ROLE OF CHANCE: Two hundred and sixty-four patients undergoing two consecutive single autologous blastocyst HRT-FET were included. The mean age of the included women was 35.0 +/- 4.2 years. No significant intra-individual variability was observed between FET1 and FET2 (mean progesterone level after FET1: 13.4 +/- 5.1 ng/ml vs after FET2: 13.9 +/- 5.0; P = 0.08). The characteristics of the embryo transfers were similar between the first and the second FET. Forty-nine patients (18.6%) had discordant progesterone levels (defined as one progesterone measurement > and one <= to the threshold of 9.8 ng/ml) between FET1 and FET2. There were 37/264 women (14.0%) who had high intra-individual variability (defined as a difference in serum progesterone values >75th percentile (6.0 ng/ml)) between FET1 and FET2. No specific clinical parameter was associated with a high intra-individual variability nor a discordant P measurement. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design. Moreover, only women undergoing autologous blastocyst HRT-FET with MVP were included, thereby limiting the extrapolation of the study findings to other routes of P administration and other kinds of endometrial preparation for FET. WIDER IMPLICATIONS OF THE FINDINGS: No significant intra-individual variability was noted. The serum progesterone level appeared to be reproducible in >80% of cases. These findings suggest that the serum progesterone level measured on the day of the first transfer can be used to individualize luteal phase support in subsequent cycles.

Endometriosis-related infertility remains a therapeutic challenge. A burning issue in this field of research is determining whether pre-assisted reproductive technology (ART) surgery may be of some benefit in terms of reproductive outcomes. This systematic review and meta-analysis aimed at comparing ongoing pregnancy rates (OPR) and/or live birth rates (LBR) in patients who underwent endometriosis surgery before ART (IVF/ICSI) in comparison with patients who underwent first-line ART (IVF/ICSI). Searches were conducted from January 1990 to June 2021 on PubMed, Embase, and Cochrane Library using the following search terms: endometriosis, surgery, reproductive outcomes, and IVF/ICSI. The primary outcomes were OPR or LBR. A total of 19 studies were included in the meta-analysis. No statistically significant differences in LBR [0.91[0.63, 1.30]; I 2 = 66%; n = 11], OPR [1.28[0.66, 2.49]; I 2 = 60%; n = 3], and early pregnancy loss rate [0.88[0.62, 1.25]; I 2 = 0%; n = 7] per cycle were found when comparing patients who underwent endometriosis surgery before IVF/ICSI and those who did not. After the exclusion of the studies with high risks of bias, the LBR per cycle was significantly reduced in the case of surgical treatment before IVF/ICSI [0.53[0.33, 0.86]; I 2 = 30%; n = 4]. These data urge the clinician to carefully weigh the pros and cons before referring infertile patients with endometriosis to surgery before IVF, highlighting the key role of multidisciplinary referral centers.

Abstract Study question Are patients receiving hypnosis during oocyte retrieval (OR) satisfied with this support? Summary answer Three-quarters of the women receiving hypnosis during OR were satisfied with this support, considering it beneficial for both pain and anxiety. What is known already OR is a crucial component in the management of assisted reproductive technology (ART). Despite being a safe and efficient procedure, OR is often perceived as the most stressful and painful aspect of ART. OR can be performed under local anesthesia with a paracervical block analgesia but may still cause discomfort for some patients (pain, anxiety related to the procedure). Therefore, exploring non-pharmacological approaches, such as hypnosis, to enhance anesthesia is of major interest. Hypnosis has demonstrated efficacy in pain management across various medical indications, prompting an investigation into its potential benefits during OR. Study design, size, duration A cohort study involving women undergoing an OR under local anesthesia combined with hypnosis at our institution between November 2022 to November 2023. A questionnaire was distributed to patients just after the OR, assessing women’s satisfaction with hypnosis support, along with their experiences of pain (Visual Analogic scale (VAS)) and anxiety (State-Trait Anxiety Inventory (STAI) questionnaire) during the OR procedure. Participants/materials, setting, methods Women for whom hypnosis was administered during the entire OR procedure, using either a virtual reality headset or with a hypnotherapist were included. Exclusions comprised incomplete questionnaires and patients unable to communicate in French. Objectives were (i) to assess the women satisfaction concerning hypnosis during OR on pain and anxiety through specific questions of the survey, (ii) to evaluate pain (VAS) and anxiety (STAI) during the procedure and (iii) to compare the two hypnosis techniques. Main results and the role of chance Two hundred and nine women undergoing OR under local anesthesia fully responded to the questionnaire out of six hundred surveyed. The mean population age was 34.4±4.1 years. Hypnosis support was provided by a hypnotherapist for 79.9% (167/209) of women and using a virtual reality headset for 20.1% (42/209). 73.7% were satisfied of hypnosis for pain, and 86.1% for anxiety. A higher proportion found hypnosis beneficial for anxiety in the therapist group compared to the virtual reality headset group (88.6% (148/167) versus 76.2% (32/42) respectively, p:0.037). For a new oocyte retrieval, 70.8% of women preferred undergoing the procedure under local anesthesia with hypnosis. The mean VAS score was 5.3 ± 2.6 and the mean STAI score was 36.7± 17.8 during oocyte retrieval. No significant differences concerning VAS and STAI scores were found between the therapist and virtual reality headset groups. Limitations, reasons for caution The study evaluates the satisfaction of women with hypnosis support; hence, there is no assessment of long-term benefits on pregnancy chances. Additionally, a potential selection bias exists as not all surveyed women returned the questionnaire. Wider implications of the findings Positive feedback suggests a potential role for hypnosis in enhancing patient well-being during oocyte retrieval, warranting further research and clinical exploration to improve the overall patient experience during what is often perceived as a stressful procedure. Trial registration number NA

Abstract Study question Do endometriosis women who achieve a live birth (LB) after Hormone Replacement Therapy-Frozen Embryo Transfer (HRT-FET) have different transfer-day progesterone levels than controls? Summary answer In women achieving a LB after HRT-FET, serum progesterone levels on the day of the transfer did not differ between endometriosis and unaffected patients. What is known already In HRT-FET, several studies have highlighted the correlation between serum progesterone levels at the time of frozen embryo transfer and LB rates. In the pathophysiology of endometriosis, progesterone resistance is typically described in the eutopic endometrium. This has led to the hypothesis that women with endometriosis may require higher progesterone levels to achieve a LB, especially in HRT-FET cycles without a corpus luteum. Study design, size, duration We conducted an observational cohort study at the university-based reproductive medicine center of our institution, focusing on women who underwent a single autologous frozen blastocyst transfer after HRT using exogenous estradiol and micronized vaginal progesterone for endometrial preparation between January 2019 and December 2021. Women were included only once during the study period. Serum progesterone levels were measured on the morning of the FET by a single laboratory. Participants/materials, setting, methods Patients were divided into groups based on whether they had endometriosis or not and whether they achieved a LB. The diagnosis of endometriosis was based on published imaging criteria (transvaginal sonography/magnetic resonance imaging) and/or confirmed histology. The primary outcome was progesterone levels on the day of the HRT-FET leading to a LB in patients with endometriosis compared to unaffected women. Subgroup analyses were performed based on the presence of deep infiltrating endometriosis or adenomyosis. Main results and the role of chance A total of 1784 patients were included. The mean age of the women was 35.1 ± 4.1 years. Five hundred and sixty women had endometriosis, while 1224 did not. 179/560 (32.0%) with endometriosis and 381/1224 (31.2%) without endometriosis achieved a LB. Among women who achieved a LB after HRT-FET, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (13.6 ± 4.3 ng/mL versus 13.2 ± 4.4 ng/mL, respectively; p = 0.302). In the subgroup of women with deep infiltrating endometriosis (n = 142) and adenomyosis (n = 100), the mean progesterone level was 13.1 ± 4.1 ng/mL and 12.6 ± 3.7 ng/mL, respectively, with no significant difference compared to endometriosis-free patients. After adjustment for BMI, parity, duration of infertility, and tobacco use, neither the presence of endometriosis (coefficient 0.38; 95% CI -0.63 to 1.40; p = 0.457) nor the presence of adenomyosis (coefficient 0.97; 95%CI -0.24 to 2.19; p = 0.114) was associated with the progesterone level on the day of HRT-FET. Among women who did not conceive, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (p = 0.709). Limitations, reasons for caution The primary limitation of our study is associated with its observational design. Extrapolating our results to other laboratories or different routes and/or dosages of administering progesterone also requires validation. Wider implications of the findings This study shows that patients diagnosed with endometriosis do not require higher progesterone levels on the day of a frozen blastocyst transfer to achieve a LB in hormonal replacement therapy cycles. Trial registration number NA

STUDY QUESTION Do women with endometriosis who achieve a live birth (LB) after HRT-frozen embryo transfer (HRT-FET) have different progesterone levels on the day of transfer compared to unaffected women?SUMMARY ANSWER In women achieving a LB after HRT-FET, serum progesterone levels on the day of the transfer did not differ between patients with endometriosis and unaffected patients.WHAT IS KNOWN ALREADY In HRT-FET, several studies have highlighted the correlation between serum progesterone levels at the time of FET and LB rates. In the pathophysiology of endometriosis, progesterone resistance is typically described in the eutopic endometrium. This has led to the hypothesis that women with endometriosis may require higher progesterone levels to achieve a LB, especially in HRT-FET cycles without a corpus luteum.STUDY DESIGN, SIZE, DURATION We conducted an observational cohort study at the university-based reproductive medicine center of our institution, focusing on women who underwent a single autologous frozen blastocyst transfer after HRT using exogenous estradiol and micronized vaginal progesterone for endometrial preparation between January 2019 and December 2021. Women were included only once during the study period. Serum progesterone levels were measured on the morning of the FET by a single laboratory.PARTICIPANTS/MATERIALS, SETTING, METHODS Patients were divided into groups based on whether they had endometriosis or not and whether they achieved a LB. The diagnosis of endometriosis was based on published imaging criteria (transvaginal sonography/magnetic resonance imaging) and/or confirmed histology. The primary outcome was progesterone levels on the day of the HRT-FET leading to a LB in patients with endometriosis compared to unaffected women. Subgroup analyses were performed based on the presence of deep infiltrating endometriosis or adenomyosis.MAIN RESULTS AND THE ROLE OF CHANCE A total of 1784 patients were included. The mean age of the women was 35.1 +/- 4.1 (SD) years. Five hundred and sixty women had endometriosis, while 1224 did not. About 179/560 (32.0%) with endometriosis and 381/1224 (31.2%) without endometriosis achieved a LB. Among women who achieved a LB after HRT-FET, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (13.6 +/- 4.3 ng/ml vs 13.2 +/- 4.4 ng/ml, respectively; P = 0.302). In the subgroup of women with deep infiltrating endometriosis (n = 142) and adenomyosis (n = 100), the mean progesterone level was 13.1 +/- 4.1 ng/ml and 12.6 +/- 3.7 ng/ml, respectively, with no significant difference compared to endometriosis-free patients. After adjusting for BMI, parity, duration of infertility, tobacco use, and geographic origin, neither the presence of endometriosis (coefficient 0.38; 95% CI: -0.63 to 1.40; P = 0.457) nor the presence of adenomyosis (coefficient 0.97; 95% CI: -0.24 to 2.19; P = 0.114) was associated with the progesterone level on the day of HRT-FET. Among women who did not conceive, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (P = 0.709).LIMITATIONS, REASONS FOR CAUTION The primary limitation of our study is associated with its observational design. Extrapolating our results to other laboratories or different routes and/or dosages of administering progesterone also requires validation. WIDER IMPLICATIONS OF THE FINDINGS This study shows that patients diagnosed with endometriosis do not require higher progesterone levels on the day of a frozen blastocyst transfer to achieve a LB in hormonal replacement therapy cycles.STUDY FUNDING/COMPETING INTEREST(S) None declared.TRIAL REGISTRATION NUMBER N/A.

Abstract Study question Do serum estradiol(E2) levels on the day of frozen blastocyst transfer(FBT) affect the live birth rate (LBR) in hormonal replacement therapy(HRT) cycles using transdermal estrogens? Summary answer E2 levels ≥ 313 pg/mL on the day of FBT are associated with increased early miscarriage rates, but no significant impact on LBR. What is known already E2 plays a crucial role in endometrial receptivity during the periconceptional period and a massive role in placentation. However, the impact of serum E2 levels measured around the time of a FBT in HRT cycles outcomes remains controversial, with some studies showing a detrimental impact of high levels, and others underlining no difference. To this date, there is no study focusing on HRT cycles with transdermal estrogens only, though it is the safest way of estrogen administration regarding thrombo-embolic complications. Study design, size, duration Observational cohort study with 2364 patients undergoing HRT-FBT cycles at a university hospital, between January 2019 and December 2022. Women were only included once during the study period. Participants/materials, setting, methods Patients undergoing single autologous FBT under HRT using transdermal estrogens and vaginal micronized progesterone. The serum E2 level was measured in the morning of the FBT, in a single laboratory. The primary outcome was the LBR, secondary outcomes included clinical pregnancy rates, early miscarriage rates(EMR), and obstetrical outcomes. Patients were divided into three groups based on the 25th and the 75th percentiles of E2 levels and compared using univariate and multivariate logistic regression models. Main results and the role of chance A total of 2364 patients were divided into 3 groups: group A < 122 pg/mL (n = 590), group B 122-312 pg/mL (n = 1184), and group C ≥ 313 pg/mL (n = 590). Mean serum E2 level on the day of FBT was 247.8 pg/mL ± 209.01 pg/ml. The LBR was 32.0% (756/2364), and the early miscarriage rate was 26.3% (280/1075) in the overall population. Multivariate logistic regression showed a negative impact of high E2 levels (≥ 313 pg/mL) on EMR: an increase in the EMR was noted between group C and referent group B (30.3% versus 24.6%, OR 1.5 95%CI (1.06-2.17)). However, no significant impact of E2 levels was noted regarding the LBR (group C vs group B, adjusted OR 0.9 95%CI (0.69-1.10)), the clinical pregnancy rates, or the obstetrical outcomes (birthweight and term of delivery Limitations, reasons for caution The main limitation of our study is linked to its observational design. Extrapolation of our results to other laboratories, or other routes and/or doses of administering estrogens also needs to be validated. Wider implications of the findings Limiting high serum E2 levels on the day of FBT in HRT cycles may improve ART outcomes. Further studies are needed to evaluate if modifications of estrogen doses may improve pregnancy chances, in an approach to individualize the management of ART patients. Trial registration number not applicable

Abstract Study question Is dydrogesterone exposure during early pregnancy associated with the reporting of birth defects ? Summary answer We observed an increased reporting of birth defects, such as congenital heart defects and hypospadias, with dydrogesterone, especially compared to progesterone use. What is known already In assisted reproductive technology (ART), intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation. In the recent years, the Lotus I and Lotus II randomized controlled clinical trials, demonstrated that oral dydrogesterone, a synthetic progesterone derivative, was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone (MVP). Safety profiles in both mother and child were similar. However, concerns have been raised recently regarding an association between dydrogesterone usage during early pregnancy and congenital heart disease in the offspring. Study design, size, duration We performed a case-non case study, similar in the concept to case-control study, using the international pharmacoviligance database, VigiBase. Study cohort consisted in spontaneous reports regarding pregnant women identified using the ad-hoc standardized query (SMQ “Pregnancy and neonatal topics”). Birth defect cases were reports containing a term related to “congenital, familial and genetic disorders” System Organ Classes (SOCs) (excluding genetic, infectious and metabolic abnormalities). Non-cases were reports of any other adverse drug reaction. Participants/materials, setting, methods Through a case–non case study conducted since database inception to 12/31/2021, we first compared the reporting of birth defects with dydrogesterone to that of any other drug, then to any other drug used for ART. Secondly, we performed a comparison on the reporting of birth defects for dydrogesterone with progesterone. Results are presented as reporting odds ratio (ROR) and their 95% confidence interval (95%CI). For each comparison, two sensitivity analyses were performed. Main results and the role of chance Among 29,120,563 individual case safety reports, 50,653 were related to the use of drugs for ART. Of these, 375 were cases of birth defects, including 60 (16%) with dydrogesterone. Dydrogesterone cases were mostly reported from Europe (73%) by physicians (82%). No other teratogenic drug was suspected in the onset of birth defect for dydrogesterone. 44 cases out of 60 (73.3%) were compatible with major birth defect (MBD) cases according to EUROCAT classification. These cases contained a total of 55 MBD, consisting mainly in genital defects such as hypospadias (n = 18, 32.7%), congenital heart defects (n = 15, 27.3%) limb defects (n = 10, 18.2%) and digestive system defects (n = 6, 10.9%). In the primary analysis, a significant disproportionate reporting of birth defects was found with dydrogesterone when compared to any other drug (ROR 5.4, 95%CI [3.9-7.6]) and to any other ART agent (ROR 5.9, 95%CI [4.2-8.4]). In the head-to-head comparison to progesterone, we found an increased reporting of birth defect with dydrogesterone (ROR 5.4, 95%CI [3.7-7.9]).These results were confirmed in both sensitivity analyses. Limitations, reasons for caution First, under-reporting, being inherent to pharmacovigilance systems, impedes the measurement of the incidence of adverse drug reaction and can limit the sensitivity of signal detection. Second, drug causality, not being the same for all cases, is challenging for such events and requires further assessment. However, sensitivity analyses showed consistent results. Wider implications of the findings Physicians should be aware of this potential risk and caution should be used when prescribing dydrogesterone for luteal phase support. Further data are needed to confirm that safety signal. Trial registration number Not applicable

Abstract Study question Does the freeze all strategy improve cumulative live birth rates in infertile women affected with adenomyosis? Summary answer The freeze all strategy in adenomyosis-affected women is associated with significantly higher cumulative live birth rates. What is known already Controlled ovarian stimulation enhances the efficacy of assisted reproductive technology (ART) by permitting multiple-oocyte yields, but also may alter endometrial receptivity by an earlier endometrial development which could in turn contribute to diminished pregnancy chances. Technical improvements in vitrification made deferred frozen-thawed embryo transfer (freeze –all strategy) a feasible alternative to fresh embryo transfer (ET). In adenomyosis, the eutopic endometrium is abnormal and its functional alterations are seen as likely to alter the quality of endometrial receptivity. One question in the adenomyosis ART-management is to know whether a freeze all strategy could lead to an increase in reproductive outcomes. Study design, size, duration This cohort study conducted in a tertiary care university hospital included adenomyosis-affected women undergoing blastocyst embryo transfer following in vitro fertilization / intracytoplasmic sperm injection (IVF/ICSI) between 01/01/2018 to 31/11/2021. The diagnosis of adenomyosis was based on imaging criteria (e.g. transvaginal ultrasound and/or magnetic resonance imaging). Participants/materials, setting, methods Women who underwent a freeze all strategy were compared to those who underwent a fresh ET strategy. Statistical analyses were conducted using univariate and multivariate logistic regression models. The primary outcome was the cumulative live birth rate (LBR). Main results and the role of chance A total of 306 women were included in the analysis: 111 in the fresh ET group and 195 in the freeze all group. The phenotype of adenomyosis (internal diffuse adenomyosis, external focal adenomyosis and adenomyomas) was not significantly different between the two groups. The cumulative live birth rate was significantly increased in the freeze all group compared to the fresh ET group [86 (44.1%) vs. 34 (30.6%), p = 0.020]. The cumulative OPR [89 (45.6%) versus 37 (33.3%), p = 0.035] and the cumulative CPR [122 (62.6%) vs. 53 (47.7%), p = 0.011] were significantly higher in freeze all group compared to the fresh group, whereas the early miscarriage rate was not significantly different between the two groups. After multivariate logistic regression analysis, the freeze all strategy in women with adenomyosis was associated with a significant increase in the live birth rate as compared to fresh ET (OR = 1.85; 95% CI = 1.06 – 3.24; p = 0.031). Limitations, reasons for caution This analysis consists in a retrospective cohort study. The inclusion of patients from a referral center specialized in the management of adenomyosis and endometriosis could constitute a selection bias, as these women may have had particularly severe forms of adenomyosis. Wider implications of the findings The freeze all strategy could be an attractive option to increase ART success rates, in adenomyosis-affected womenundergoing IVF/ICSI. Trial registration number NA

Abstract Study question Whether slow developing expanded day 6 (D6) blastocysts should be either transferred during fresh cycle or systematically vitrified at D6 Summary answer Fresh D6 blastocyst transfer is independently associated with reduced live birth rate compared to frozen thawed D6 transfer What is known already Live birth rate (LBR) after D5 blastocyst transfers are significantly higher when compared with D6 embryos in both fresh and frozen-vitrified embryo transfer cycles according to the last published meta-analyses. Therefore, for women obtaining only D6 blastocysts, chances of pregnancy may be lower but still persist and these embryos should be transferred. The question of the best strategy for transfer (i.e. in fresh or frozen cycles) remains unclear while data on this subject are scarce. Study design, size, duration Retrospective observational cohort study. Patients having only embryos reaching blastocyst stage at D6 were included between January 2018 and May 2021. Two groups were compared : patients having a fresh D6 transfer (D6 fresh transfer group) and patients having a frozen thawed D6 transfer ( D6 frozen transfer group). Participants/materials, setting, methods 830 D6 single blastocyst transfers (736 frozen blastocysts and 94 fresh blastocysts) were analyzed. LBR and neonatal outcome were compared between groups, as well as the influence of clinical characteristics and data related to COS protocols. Correlation between D6 blastocyst morphology according to Gardner’s classification and livebirth occurrence was also evaluated. Statistical analysis of the data was carried out using univariate and multivariate logistic regression models. Main results and the role of chance LBR was significantly lower after D6 fresh blastocyst transfer compared to D6 frozen thawed blastocyst transfer [5.3% (5/96) vs 12.2% (90/736), p < 0.05]. Moreover, when comparing a subgroup of 68 first D6 frozen embryo transfers (1st D6 frozen transfer group) to the 94 fresh D6 blastocyst transfers (D6 fresh elective group), the superiority of D6 frozen blastocyst transfers regarding LBR was also confirmed (17.6% vs 5.3% p < 0.001, respectively). Concerning neonatal outcomes, the mean birth weight was comparable between the two groups. Univariate logistic regression analysis taking into account blastocyst morphology parameters showed that TE grade was the only parameter significantly associated with LBR after D6 embryo transfer (p < 0.001). Multiple logistic regression revealed that D6 embryo fresh transfer was independently associated with reduced LBR compared to frozen thawed D6 transfer (OR 0.367; 95%IC 0.143-0.945; p = 0.038). Moreover, our results showed that transferring a good or top quality D6 blastocyst increases 3 fold chances of live birth. Limitations, reasons for caution The number of fresh cycles seems relatively small, but the consistency of our results was guaranteed by the homogeneity of the 2 subgroups, standardization of all biological and clinical procedures and the robust statistical analysis methodology used in this study. Wider implications of the findings Despite their lower potential, D6 blastocysts have to be transferred with the objective to improve LBR, especially in women obtaining only these type of embryos. Our results recommend to transfer D6 blastocysts in frozen cycles. However, these findings have to be confirmed on larger series in prospective randomized trials. Trial registration number not applicable

STUDY QUESTION:Is endometriosis associated with childhood and/or adolescent sexual abuse? SUMMARY ANSWER:Endometriosis is not associated with a history of sexual abuse, unlike the presence of severe pelvic pain. WHAT IS KNOWN ALREADY:Several studies have highlighted a link between pelvic pain and sexual abuse during childhood/adolescence. Moreover, an inflammatory state has been described in patients with a history of childhood maltreatment. Given that inflammation and pelvic pain are two entities often encountered with endometriosis, several teams have investigated whether endometriosis is associated with abuse during childhood/adolescence. However, the results are conflicting, and the link between sexual abuse and the presence of endometriosis and/or pain is hard to disentangle. STUDY DESIGN, SIZE, DURATION:A survey nested in a cohort study of women surgically explored for benign gynecological indications at our institution between January 2013 and January 2017. For each patient, a standardized questionnaire was completed during a face-to-face interview with the surgeon in the month preceding the surgery. Pelvic pain symptoms (dysmenorrhea, deep dyspareunia, non-cyclic chronic pelvic pain, and gastrointestinal or lower urinary tract symptoms) and their intensities were assessed with a 10 cm visual analog scale (VAS). Pain was considered to be severe when the VAS score was ≥7. PARTICIPANTS/MATERIALS, SETTING, METHODS:A 52-question survey was sent in September of 2017 to evaluate abuses, especially sexual abuse during childhood and/or adolescence, and the psychological state during childhood and adolescence. The survey was structured to cover the following sections: (i) abuses and other life events during childhood and adolescence; (ii) puberty and body changes; (iii) onset of sexuality; and (iv) family relationships during childhood and adolescence. The patients were divided into groups according to whether or not they exhibited histologically proven endometriosis. Statistical analyses were conducted using univariate and multivariate logistic regression models. MAIN RESULTS AND THE ROLE OF CHANCE:Two hundred and seventy-one patients answered all the questions of the survey: 168 with (endometriosis group) and 103 without endometriosis (control group). The mean ± SD overall population age was 32.2 ± 5.1 years. There were 136 (80.9%) and 48 (46.6%) women who experienced at least one severe pelvic pain symptom in the endometriosis and the control groups, respectively (P < 0.001). No differences were found between the two study groups regarding the following characteristics: (i) a history of sexual, physical, or emotional abuse; (ii) a history of abandonment or bereavement; (iii) the psychological state regarding puberty; and (iv) the family relationships. After multivariable analysis, we found no significant association between endometriosis and a history of sexual abuse during childhood and/or adolescence (P = 0.550). However, the presence of at least one severe pelvic pain symptom was independently associated with a history of sexual abuse (odds ratio = 3.6, 95% CI (1.2-10.4)). LIMITATIONS, REASONS FOR CAUTION:Evaluation of the psychological state during childhood and/or adolescence can be subject to recall bias. In addition, selection bias is also a possibility given that some of the patients surveyed did not return the questionnaire. WIDER IMPLICATIONS OF THE FINDINGS:Severe gynecological painful symptoms in women with or without histologically proven endometriosis may be linked to sexual abuse experienced during childhood and/or adolescence. Patient questioning about painful symptoms and abuses is important to provide comprehensive care to the patients, from a psychological to a somatic point of view. STUDY FUNDING/COMPETING INTEREST(S):No funding or competing interests. TRIAL REGISTRATION NUMBER:N/A.

STUDY QUESTION:What is the impact of adenomyosis on the live birth rate (LBR) in women affected by endometriosis women undergoing ART?SUMMARY ANSWER:For women undergoing ART, the presence of adenomyosis at MRI, especially T2 high-signal intensity spots within the myometrium, has a negative impact on the LBR.WHAT IS KNOWN ALREADY:Adenomyosis is a common gynecological disease. The development of imaging techniques for the diagnosis has led to several adenomyosis phenotypes being described, and fertility issues appear to vary according to the characteristics of the lesions. What makes assessment of the impact of adenomyosis on fertility issues even more difficult is its frequent association with endometriosis, which is another known risk factor of infertility. Although data suggest that adenomyosis may worsen the ART prognosis, there is no clear consensus regarding the impact of adenomyosis on ART outcomes in women affected by endometriosis.STUDY DESIGN, SIZE, DURATION:This was an observational study that included phenotyped patients with endometriosis, aged between 18 and 42 years, who underwent IVF/ICSI treatment in a tertiary care center between June 2015 and July 2018. Only women who had undergone a pelvic MRI during the pre-therapeutic ART workup were retained for this study. The MRI data were interpreted by radiologists who had expertise in gynecological MRI.PARTICIPANTS/MATERIALS, SETTING, METHODS:A continuous series of 202 women affected by endometriosis was included. The women were monitored until four ART cycles had been completed, until delivery, or until discontinuation of treatment before the completion of four cycles. The primary outcome was the delivery of at least one live infant after up to four IVF/ICSI cycles. The patient and the MRI characteristics were compared between the women who achieved a live birth versus those who did not.MAIN RESULTS AND THE ROLE OF CHANCE:The patients' mean age was 32.5 ± 3.7 years. Deep infiltrating endometriosis was present in 90.1% (182/202) of the included population. Adenomyosis (lesions of the internal and/or the external myometrium) was found in 71.8% (145/202) of the included women. The cumulative LBR was 57.4% (116/202). The women who gave birth were significantly younger (32.0 ± 3.3 versus 33.3 ± 4.1, P = 0.026) and had significantly better ovarian reserve parameters (anti-Müllerian hormone levels, antral follicle count) than those who did not. The presence of adenomyosis, irrespective of the phenotype (76/116 (65.5%) versus 69/86 (80.2%), respectively, P = 0.022) and the presence of T2 high-signal intensity myometrial spots (27/116 (23.3%) and 37/86 (43.0%), respectively, P = 0.003) was significantly less frequent in the group of women who gave birth versus those who did not. After multivariate analysis, the presence of adenomyosis (odds ratio (OR): 0.48, 95% CI (0.29-0.99), P = 0.048) and the presence of T2 high-signal intensity myometrial spots (OR: 0.43, 95% CI (0.22-0.86), P = 0.018) were independently found to be associated with a decrease in the cumulative chance of live birth.LIMITATIONS, REASONS FOR CAUTION:The inclusion of patients from a referral center specialized in the management of women affected by endometriosis could constitute a selection bias, as these women may have had particularly severe forms of adenomyosis and/or endometriosis. A sensitive issue is that there is no consensual classification of adenomyosis and several lesions of adenomyosis can co-exist. Therefore, a comparison of fertility outcomes between women with and without adenomyosis is difficult to perform in practice.WIDER IMPLICATIONS OF THE FINDINGS:In women exhibiting endometriosis, the practitioner should perform an appropriate imaging workup to search for adenomyosis, identify prognostic factors, and personalize the patient management strategy in the setting of ART.STUDY FUNDING/COMPETING INTEREST(S):No funding was obtained and there were no conflicts of interest.TRIAL REGISTRATION NUMBER:N/A.

STUDY QUESTION:Which factors are associated with low serum progesterone (P) levels on the day of frozen embryo transfer (FET), in HRT cycles?SUMMARY ANSWER:BMI, parity and non-European geographic origin are factors associated with low serum P levels on the day of FET in HRT cycles.WHAT IS KNOWN ALREADY:The detrimental impact of low serum P concentrations on HRT-FET outcomes is commonly recognized. However, the factors accounting for P level disparities among patients receiving the same luteal phase support treatment remain to be elucidated, to help clinicians predicting which subgroups of patients would benefit from a tailored P supplementation.STUDY DESIGN, SIZE, DURATION:Observational cohort study with 915 patients undergoing HRT-FET at a tertiary care university hospital, between January 2019 and March 2020.PARTICIPANTS/MATERIALS, SETTING, METHODS:Patients undergoing single autologous blastocyst FET under HRT using exogenous estradiol and vaginal micronized progesterone for endometrial preparation. Women were only included once during the study period. The serum progesterone level was measured in the morning of the FET, in a single laboratory. Independent factors associated with low serum P levels (defined as ≤9.8 ng/ml, according to a previous published study) were analyzed using univariate and multivariate logistic regression models.MAIN RESULTS AND THE ROLE OF CHANCE:Two hundred and twenty-six patients (24.7%) had a low serum P level, on the day of the FET. Patients with a serum P level ≤9.8 ng/ml had a lower live birth rate (26.1% vs 33.2%, P = 0.045) and a higher rate of early miscarriage (35.2% vs 21.5%, P = 0.008). Univariate analysis showed that BMI (P < 0.001), parity (P = 0.001), non-European geographic origin (P = 0.001), the duration of infertility (P = 0.018) and the use of oral estradiol for endometrial preparation (P = 0.009) were significantly associated with low serum P levels. Moreover, the proportion of active smokers was significantly lower in the 'low P concentrations' group (P = 0.002). After multivariate analysis, BMI (odds ratio (OR) 1.06 95% CI (1.02-1.11), P = 0.002), parity (OR 1.32 95% CI (1.04-1.66), P = 0.022), non-European geographic origin (OR 1.70 95% CI (1.21-2.39), P = 0.002) and active smoking (OR 0.43 95% CI (0.22-0.87), P = 0.018) remained independent factors associated with serum P levels ≤9.8 ng/ml.LIMITATIONS, REASONS FOR CAUTION:The main limitation of this study is its observational design, leading to a risk of selection and confusion bias that cannot be ruled out, although a multivariable analysis was performed to minimize this.WIDER IMPLICATIONS OF THE FINDINGS:Extrapolation of our results to other laboratories, or other routes and/or doses of administering progesterone also needs to be validated. There is urgent need for future research on clinical factors affecting P concentrations and the underlying pathophysiological mechanisms, to help clinicians in predicting which subgroups of patients would benefit from individualized luteal phase support.STUDY FUNDING/COMPETING INTEREST(S):No funding/no conflicts of interest.TRIAL REGISTRATION NUMBER:N/A.

Abstract Study question Are there any fertility disorders and related local and/or systemic immune changes during the early implantation period in a mouse model of adenomyosis? Summary answer An increase in fertility disorders was observed in adenomyosis mice and coincide with local and systemic immune changes observed during the period of implantation. What is known already Adenomyosis is as a common pathology that could be responsible for fertility alteration. Immune changes in uterus are implicated in adenomyosis physiopathology. One hypothesis is that the physiological immune environment necessary for a successful implantation can be altered in adenomyosis, leading to fertility disorders. Study design, size, duration Randomly selected CD-1 female neonatal pups were orally dosed with oral administration of tamoxifen in order to induce adenomyosis (TAM group), while other received solvent only (control group). At 3 months, CD-1 mice (F1) of both group were put into mating. 36 pregnant mice were included in the TAM group and 30 in the control group. Participants/materials, setting, methods Ultrasounds were performed during pregnancy at E(E=embryonic day)7.5 and E12.5 to evaluate fertility outcomes in mice of the TAM and control group. Mice were sacrificed at E18.5 and histological,morphometric and functional analysis were performed on the placentas. In order to identify local and/or systemic immune changes in the uterus, mice of both group were sacrificed at E4.5 of pregnancy, during the implantation period. Uterine horns and spleen were collected for flow cytometry and RT-qPCR analyzes. Main results and the role of chance We observed a significantly lower number of implantation sites and a significantly higher number of resorption (3.88±2.36 versus 1.00±0.82(p < 0.001)) in TAM compared to control group. Analysis of placentas showed a significantly higher junctional/labyrinthic area ratio (0.60±0.09 versus 0.30±0.05(p = 0.0052)) and a significantly lower expression of Vascular Endothelial Growth-Factor(GF), Platelet endothelial cell adhesion molecule, Insulin-like GF2 and Placental GF in the TAM group compared to the control group, indicating an altered placental vascularization compared to controls. To characterize the immune change during the early implantation period, we analyzed some immune cells populations in the uteri and the spleen: In the TAM group, the number of macrophages(F4/80), Natural Killers(NK) cells(NKP46+/NKG2D+) and dendritic cells (DC)(CD11b+) were significantly decreased compared to control uteri. However, the number of M1 macrophages(Ly6c+hight) and their activation were significantly increased. DC activation was also increased in TAM group. In the spleen, a significant increase in the activation macrophages and DC was observed in adenomyosis group compared to control. In the uteri, the number of LT4(CD4+) cells and number of LTreg cells(CD25+/FOXP3+) were significantly increased in the TAM group compared to control group. In the spleen, a significant increase in LT4 cells count was observed in TAM compared to control group. Limitations, reasons for caution This study is limited by the use of an animal model and the lack of intervention. Wider implications of the findings This study provides evidence that adenomyotic lesions in mice induced fertility disorders and immune modifications at a local and at a systemic level during the early implantation period. These data support the involvement of innate and adaptive immune cells in implantation failure observed in the mouse model of adenomyosis. Trial registration number not applicable

Abstract Study question Is there an impact of CFTR (cystic fibrosis transmembrane-conductance regulator) gene mutation type and/or general health condition of men with CF and the ICSI outcomes? Summary answer Neither genetic severity nor clinical severity seems to have a negative impact on the biological or clinical ICSI issues for cystic fibrosis men patients. What is known already CFTR protein regulates electrolyte and fluid transport in many tissues with exocrine function, including male reproductive tract. Mutation of CFTR gene causes CF, which affects the function of several organs, and impairs male fertility. CF is generally associated to an obstructive azoospermia because of bilateral absence of vas deferens and seminal vesicles degeneration. CFTR protein is detected in human fetus at the early developmental stages and highly expressed in testis and epididymis. CFTR provides establishment of specific fluid environment for germ cell differentiation and maturation. According to literature, it seems likely that CFTR mutations affect sperm quality and embryo development. Study design, size, duration This cohort study was conducted in the Assisted Reproduction Center of an university hospital on 52 patients, for whom a CF has been diagnosed and monitored in the same hospital. The CF diagnosis was based on CFTR genetic tests and clinical symptoms. All men were azoospermic and underwent on a microscopic epididymal sperm aspiration (MESA) and/or a testicular sperm extraction (TESE). 52 couples underwent in total 107 ICSI with frozen sperm between 1999 and 2019. Participants/materials, setting, methods Clinical data- one year preceding surgical sperm collection and freeze - related to the severity of the CF were collected: respiratory spirometry data, Pseudomonas aeruginosa colonization, number of antibiotic treatment, BMI and Pancreatic insufficiency, as well as CFTR mutations. Linear regression tests (fisher and χ²) were carried out to establish or not correlation between biological and clinical ICSI outcomes and on the other hand genotype and/ or each clinical parameter. Main results and the role of chance The mean age of patients at sperm retrieval was 31.3 years [21-55]. Mean BMI was 21.3. Patients with severe genotype represented 67.8% and likely (67.3%) with external pancreatic deficiency. P.aeroginosa colonization was revealed in 30% of cases and 45.6% patients received at least one IV antibiotic treatment. Respiratory function has been impaired in 18 cases, with a maximal expiratory volume per second < 40%. Spermatozoa were found and frozen for all patients after surgical sperm retrieval (20 MESA and 32 MESA + TESE). The mean number of epididymal motile progressive spermatozoa was satisfactory (10.2±18.83 million). Women mean age was 30 years at ICSI and female infertility was associated in 15.4%. Fertilization and cleavage rates were 66% both. Mean number of transferred and/or frozen embryos per attempt was 3. Implantation rate was 20%. A total of 50 pregnancies and 44 live births were obtained (35.5% of cumulative clinical pregnancy rate per ICSI and 29.1% of live birth rate per transfer). Fertilization rate, absence of pregnancy or absence of live birth were not affected by the genetic severity (p = 0.63, p = 0.46 and p = 0.16 respectively). Likewise, and after several univariate analyses there was no statistically significant correlation between clinical severity and ICSI outcomes. Limitations, reasons for caution Practices of assisted reproduction have constantly evolved during the study period, this concerns the controlled ovarian stimulation protocols, IVF techniques, equipment and culture media used. Our study needs to be completed by a multivariate analyse Wider implications of the findings Regarding to better quality of life of CF patients nowadays and to our results- with no significant correlation between genetic and/or clinical severity and ICSI outcomes, surgical sperm collection can be proposed only in case of a conceptional project or before transplantation and immunosuppressive agents in order to perform ICSI. Trial registration number for non-clinical trials

L’adénomyose est une pathologie chronique bénigne de l’utérus caractérisée par la présence de glandes endométriales et de stroma au sein du myomètre. C’est une maladie hétérogène, présentant des formes cliniques distinctes selon la localisation des lésions dans le myomètre. Cette maladie fréquente peut être responsable de symptômes invalidants comme des dysménorrhées, des ménométrorragies et/ou une infertilité. Sa physiopathologie est encore mal élucidée et plusieurs théories sont proposées. Certaines suggèrent que le développement de l’adénomyose se ferait de novo, à partir de reliquats Mülleriens ou de cellules souches. Par ailleurs, de multiples facteurs pourraient être impliqués dans le développement des lésions, notamment des modifications hormonales, immunitaires ou encore génétiques. L’objectif de cette revue est de faire une mise au point sur la physiopathologie de l’adénomyose, notamment sur les différentes théories proposées concernant l’envahissement du myomètre par les cellules endométriales et les mécanismes inducteurs et d’étudier le lien entre la physiopathologie, les symptômes et les thérapeutiques médicales.