Intra-individual variability of serum progesterone levels on the day of frozen blastocyst transfer in hormonal replacement therapy cycles.

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. STUDY FUNDING/COMPETING INTEREST(S): No funding or competing interests. TRIAL REGISTRATION NUMBER: N/A.

Progesterone levels do not differ between patients with or without endometriosis/adenomyosis both in those who conceive after hormone replacement therapy-frozen embryo transfer cycles and those who do not.

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.

Endometriosis-related infertility: severe pain symptoms do not impact assisted reproductive technology outcomes.

STUDY QUESTION: Do severe endometriosis-related painful symptoms impact ART live birth rates? SUMMARY ANSWER: Severe pain symptoms are not associated with reduced ART live birth rates in endometriosis patients. WHAT IS KNOWN ALREADY: ART is currently recognized as one of the main therapeutic options to manage endometriosis-related infertility. Presently, no data exist in the literature regarding the association between the core symptom of the disease, e.g. pain and ART reproductive outcomes. STUDY DESIGN, SIZE, DURATION: Observational cohort study of 354 endometriosis patients, who underwent ART at a tertiary care university hospital, between October 2014 and October 2021. Diagnosis of endometriosis was based on published imaging criteria using transvaginal sonography and magnetic resonance imaging, and histologically confirmed in women who had a previous history of endometriosis surgery (n = 127, 35.9%). PARTICIPANTS/MATERIALS, SETTING, METHODS: The intensity of painful symptoms related to dysmenorrhea (DM), dyspareunia (DP), noncyclic chronic pelvic pain, gastrointestinal (GI) pain, or lower urinary tract pain was evaluated using a 10-point visual analog scale (VAS), before ART. Severe pain was defined as having a VAS of 7 or higher for at least one symptom. The main outcome measure was the cumulative live birth rate (CLBR) per patient. We analyzed the impact of endometriosis-related painful symptoms on ART live births using univariable and multivariate analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Three hundred and fifty-four endometriosis patients underwent 711 ART cycles. The mean age of the population was 33.8 ± 3.7 years, and the mean duration of infertility was 3.6 ± 2.1 years. The distribution of the endometriosis phenotypes was 3.1% superficial endometriosis, 8.2% ovarian endometrioma, and 88.7% deep infiltrating endometriosis. The mean VAS scores for DM, DP, and GI pain symptoms were 6.6 ± 2.7, 3.4 ± 3.1, and 3.1 ± 3.6, respectively. Two hundred and forty-two patients (68.4%) had severe pain symptoms. The CLBR per patient was 63.8% (226/354). Neither the mean VAS scores for the various painful symptoms nor the proportion of patients displaying severe pain differed significantly between patients who had a live birth and those who had not, based on univariate and multivariate analyses (P = 0.229). The only significant factors associated with negative ART live births were age >35 years (P < 0.001) and anti-Müllerian hormone levels <1.2 ng/ml (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The diagnosis of endometriosis was based on imaging rather than surgery. This limitation is, however, inherent to the design of most studies on endometriosis patients reverting to ART first. WIDER IMPLICATIONS OF THE FINDINGS: Rather than considering a single argument such as pain, the decision-making process for choosing between ART and surgery in infertile endometriosis patients should be based on a multitude of aspects, including the patient's choice, the associated infertility factors, the endometriosis phenotypes, and the efficiency of medical therapies in regard to pain symptoms, through an individualized approach guided by a multidisciplinary team of experts. STUDY FUNDING/COMPETING INTEREST(S): No funding; no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Reduced fertility in an adenomyosis mouse model is associated with an altered immune profile in the uterus during the implantation period.

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.

Severe pelvic pain is associated with sexual abuse experienced during childhood and/or adolescence irrespective of the presence of endometriosis.

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.

Presence of adenomyosis at MRI reduces live birth rates in ART cycles for endometriosis.

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.

Clinical factors associated with low serum progesterone levels on the day of frozen blastocyst transfer in hormonal replacement therapy cycles.

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.

Development of a core outcome set and outcome definitions for studies on uterus-sparing treatments of adenomyosis (COSAR): an international multistakeholder-modified Delphi consensus study.

STUDY QUESTION: What outcomes should be reported in all studies investigating uterus-sparing interventions for treating uterine adenomyosis? SUMMARY ANSWER: We identified 24 specific and 26 generic core outcomes in nine domains. WHAT IS KNOWN ALREADY: Research reporting adenomyosis treatment is not patient-centred and shows wide variation in outcome selection, definition, reporting and measurement of quality. STUDY DESIGN, SIZE, DURATION: An international consensus development process was performed between March and December 2021. Participants in round one were 150 healthcare professionals, 17 researchers and 334 individuals or partners with lived experience of adenomyosis from 48 high-, middle- and low-income countries. There were 291 participants in the second round. PARTICIPANTS/MATERIALS, SETTING, METHODS: Stakeholders included active researchers in the field, healthcare professionals involved in diagnosis and treatment, and people and their partners with lived experience of adenomyosis. The core component of the process was a 2-step modified Delphi electronic survey. The Steering Committee analysed the results and created the final core outcome set (COS) in a semi-structured meeting. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 241 outcomes was identified and distilled into a 'long list' of 71 potential outcomes. The final COS comprises 24 specific and 26 generic core outcomes across nine domains, including pain, uterine bleeding, reproductive outcomes, haematology, urinary system, life impact, delivery of care, adverse events and reporting items, all with definitions provided by the Steering Committee. Nineteen of these outcomes will apply only to certain study types. Although not included in the COS, the Steering Committee recommended that three health economic outcomes should be recorded. LIMITATIONS, REASONS FOR CAUTION: Patients from continents other than Europe were under-represented in this survey. A lack of translation of the survey might have limited the active participation of people in non-English speaking countries. Only 58% of participants returned to round two, but analysis did not indicate attrition bias. There is a significant lack of scientific evidence regarding which symptoms are caused by adenomyosis and when they are related to other co-existent disorders such as endometriosis. As future research provides more clarity, the appropriate review and revision of the COS will be necessary. WIDER IMPLICATIONS OF THE FINDINGS: Implementing this COS in future studies on the treatment of adenomyosis will improve the quality of reporting and aid evidence synthesis. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was received for this work. T.T. received a grant (grant number 2020083) from the South Eastern Norwegian Health Authority during the course of this work. T.T. receives personal fees from General Electrics and Medtronic for lectures on ultrasound. E.R.L. is the chairman of the Norwegian Endometriosis Association. M.G.M. is a consultant for Abbvie Inc and Myovant, receives research funding from AbbVie and is Chair of the Women's Health Research Collaborative. S.-W.G. is a board member of the Asian Society of Endometriosis and Adenomyosis, on the scientific advisory board of the endometriosis foundation of America, previous congress chair for the World Endometriosis Society, for none of which he received personal fees. E.S. received outside of this work grants for two multicentre trials on endometriosis from the National Institute for Health Research UK, the Rosetrees Trust, and the Barts and the London Charity, he is a member of the Medicines and Healthcare Products Regulatory Agency (MHRA), Medicines for Women's Health Expert Advisory Group, he is an ambassador for the World Endometriosis Society, and he received personal fees for lectures from Hologic, Olympus, Medtronic, Johnson & Johnson, Intuitive and Karl Storz. M.H. is member of the British Society for Gynaecological Endoscopy subcommittee. No other conflict of interest was declared. TRIAL REGISTRATION NUMBER: N/A.

Immune cells and Notch1 signaling appear to drive the epithelial to mesenchymal transition in the development of adenomyosis in mice.

The epithelial to mesenchymal transition (EMT) has been implicated in the development of adenomyosis, along with dysregulated immune responses. Inflammation potentially induces Notch signaling, which could promote this EMT. The objective of this study was to investigate the involvement of immune cells and Notch1-mediated EMT in the development of adenomyosis. Adenomyosis was induced in 18 CD-1 mice by neonatal oral administration of tamoxifen (TAM group), while 18 neonates received vehicle only (Control group). Their uteri were sampled at 30, 60 or 90 days of age. Immune cell markers (Cd45, Ly6c1, Cd86, Arginine1, Cd19, Cd4, Cd8), Notch1 and its target genes (Hey1, Hey2, Hes1, Hes5) and biomarkers of EMT (E-Cadherin, Vimentin, Tgfb, Snail1, Slug, Snail3) were analyzed by quantitative RT-PCR and immunohistochemistry. Activated-Notch1 protein was measured by western blot. Aberrant expression of immune cell markers was observed in the uteri of mice as they developed adenomyosis. The expression of inflammatory cell markers, notably M1 macrophages and natural killer cells, was increased from Day 30 in the TAM group compared to controls, followed by an increase in the Cd4 marker (T cells) at Day 60. Conversely, expression of the Cd19 marker (B cells) was significantly reduced at all of the stages studied. Notch1 signaling was also highly activated compared to controls at Day 30 and Day 60. Concomitantly, the levels of several markers for EMT were also higher. Therefore, the activation of Notch1 coincides with aberrant expression of immune and EMT markers in the early development of adenomyosis.

Adenomyosis of the inner and outer myometrium are associated with different clinical profiles.

STUDY QUESTION: Do adenomyosis phenotypes such as external or internal adenomyosis, as diagnosed by MRI, have the same clinical characteristics? SUMMARY ANSWER: External adenomyosis was found more often in young and nulliparous women and was associated with deep infiltrating endometriosis, whereas, in contrast, internal adenomyosis was more often associated with heavy menstrual bleeding (HMB) but no differences were noted in terms of pain symptoms. WHAT IS KNOWN ALREADY: Adenomyosis is characterized by the presence of endometrial glands and stroma deep within the myometrium, giving rise to dysmenorrhea, pelvic pain and menorrhagia. Various forms have been described, including adenomyosis of the outer myometrium (external adenomyosis), which corresponds to lesions separated from the junctional zone (JZ), and adenomyosis of the inner myometrium (internal adenomyosis), which is mostly characterized by endometrial implants scattered throughout the myometrium and enlargement of the JZ. Although the pathogenesis of adenomyosis is not clearly understood, several lines of evidence suggest that these two phenotypes could have distinct origins. The clinical presentation of different forms of adenomyosis in patients warrants further investigation. STUDY DESIGN, SIZE, DURATION: This was an observational study that used data collected prospectively in non-pregnant patients aged between 18 and 42 years who had undergone surgical exploration for benign gynecological conditions at our institution between May 2005 and May 2018. Only women with a pelvic MRI performed by a senior radiologist during the preoperative work-up were retained for this study. For each patient, a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon in the month preceding the surgery. The women's histories (notably their age, gravidity, history of surgery and associated endometriosis), as well as clinical symptoms such as the pain intensity, presence of menorrhagia and infertility, were noted. PARTICIPANTS/MATERIALS, SETTING, METHODS: A pelvic MRI was performed in 496 women operated at our center for a benign gynecological disease who had provided signed informed consent. Of these, 248 women had a radiological diagnosis of adenomyosis. Based on the MRI findings, the women were diagnosed as having external and/or internal adenomyosis. The women were allocated to two groups according to the adenomyosis phenotype (only external adenomyosis vs only internal adenomyosis). Women exhibiting an association of both adenomyosis forms were analyzed separately. MAIN RESULTS AND THE ROLE OF CHANCE: In all, following the MRI findings, 109 women (44.0%) exhibited only external adenomyosis, while 78 (31.5%) had only internal adenomyosis. The women with external adenomyosis were significantly younger (mean ± SD; 31.9 ± 4.6 vs 33.8 ± 5.2 years; P = 0.006), more often nulligravid (P ≤ 0.001) and more likely to exhibit an associated endometriosis (P < 0.001) compared to the women in the internal adenomyosis group. Moreover, the women exhibiting internal adenomyosis significantly more often had a history of previous uterine surgery (P = 0.002) and HMB (62 (80%) vs 58 (53.2%), P < 0.001) compared to the women with external adenomyosis. No differences in the pain scores (i.e. dysmenorrhea, non-cyclic pelvic pain and dyspareunia) were observed between the two groups. LIMITATIONS, REASONS FOR CAUTION: The exclusive inclusion of surgical patients could constitute a possible selection bias, as the women referred to our center may have suffered from particularly severe clinical symptoms. WIDER IMPLICATIONS OF THE FINDINGS: Further studies are needed to explore the pathogenesis by which these types of adenomyosis occur. This could help with the development of new treatment strategies specific for each entity. STUDY FUNDING/COMPETING INTEREST(S): none. TRIAL REGISTRATION NUMBER: N/A.

B lymphocytes inactivation by Ibrutinib limits endometriosis progression in mice.

STUDY QUESTION: What are the effects of B lymphocyte inactivation or depletion on the progression of endometriosis? SUMMARY ANSWER: Skewing activated B cells toward regulatory B cells (Bregs) by Bruton's tyrosine kinase (Btk) inhibition using Ibrutinib prevents endometriosis progression in mice while B cell depletion using an anti-CD20 antibody has no effect. WHAT IS KNOWN ALREADY: A polyclonal activation of B cells and the presence of anti-endometrial autoantibodies have been described in a large proportion of women with endometriosis though their exact role in the disease mechanisms remains unclear. STUDY DESIGN, SIZE, DURATION: This study included comparison of endometriosis progression for 21 days in control mice versus animals treated with the anti-CD20 depleting antibody or with the Btk inhibitor Ibrutinib that prevents B cell activation. PARTICIPANTS/MATERIALS, SETTING, METHODS: After syngeneic endometrial transplantation, murine endometriotic lesions were compared between treated and control mice using volume, weight, ultrasonography, histology and target genes expression in lesions. Phenotyping of activated and regulatory B cells, T lymphocytes and macrophages was performed by flow cytometry on isolated spleen and peritoneal cells. Cytokines were assayed by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Btk inhibitor Ibrutinib prevented lesion growth, reduced mRNA expression of cyclooxygenase-2, alpha smooth muscle actin and type I collagen in the lesions and skewed activated B cells toward Bregs in the spleen and peritoneal cavity of mice with endometriosis. In addition, the number of M2 macrophages decreased in the peritoneal cavity of Ibrutinib-treated mice compared to anti-CD20 and control mice. Depletion of B cells using an anti-CD20 antibody had no effect on activity and growth of endometriotic lesions and neither on the macrophages, compared to control mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: It is still unclear whether B cell depletion by the anti-CD20 or inactivation by Ibrutinib can prevent establishment and/or progression of endometriosis in humans. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation may contribute to clarifying the role of B cell subsets in human endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant of Institut National de la Santé et de la Recherche Médicale and Paris Descartes University. None of the authors has any conflict of interest to disclose.

Associated ileocaecal location is a marker for greater severity of low rectal endometriosis.

OBJECTIVE: To determine whether ileocaecal endometriosis (ICE) is a marker for low rectal endometriosis (LRE) severity. DESIGN: Retrospective cohort study. SETTING: France. POPULATION AND SAMPLE: Analysis of 375 colorectal resections performed in women undergoing complete surgery for LRE from January 1995 to December 2015 in a university centre for endometriosis. METHODS: Univariate and multivariate analysis of anatomical, postoperative clinical, and long-term outcomes according to presence of ICE. MAIN OUTCOMES AND MEASURES: Mean number and type of deep infiltrating endometriosis (DIE) lesions, the existence of an associated endometrioma, and mean total American Society for Reproductive Medicine (ASRM) score. RESULTS: The prevalence of ICE was 25.6%. Primary end-point data showed that women with ICE had a significantly higher adjusted number of DIE lesions (OR = 1.43, 95% CI 1.02-3.03; P = 0.048), higher prevalence of endometriomas (OR = 1.91, 95% CI 1.04-3.51; P = 0.044), more associated DIE sigmoid lesions (OR = 2.12, 95% CI 1.07-3.91; P = 0.025), and a higher mean total ASRM score (OR = 2.07, 95% CI 1.12-4.14; P = 0.025). Women with ICE resected during the surgical procedure for LRE did not have more adverse postoperative clinical outcomes than ICE-negative patients. CONCLUSION: Ileocaecal endometriosis was significantly associated with greater LRE severity. In a complete surgical resection strategy, combining resection of ICE and LRE did not appear to increase postoperative rates of complications, morbidity or recurrence, nor did it seem to impair long-term clinical outcomes. TWEETABLE ABSTRACT: In women with low rectal endometriosis, 25% have an associated ileocaecal location that is a marker for severity.

Recent insights on the genetics and epigenetics of endometriosis.

Endometriosis is a gynecologic disease affecting up to 10% of the women and a major cause of pain and infertility. It is characterized by the implantation of functional endometrial tissue at ectopic positions generally within the peritoneum. This complex disease has an important genetic component with a heritability estimated at around 50%. This review aims at providing recent insights into the genetic bases of endometriosis, and presents a detailed overview of evidence of epigenetic alterations specific to this disease. In the future, these alterations may constitute therapeutic targets for pharmacological compounds able to modify the epigenetic code.

Endometriosis-related infertility: ovarian endometrioma per se is not associated with presentation for infertility.

STUDY QUESTION: Is there an association between the endometriosis phenotype and presentation with infertility? SUMMARY ANSWER: In a population of operated patients with histologically proven endometriosis, ovarian endometrioma (OMA) per se is not associated with an increased risk of presentation with infertility, while previous surgery for endometriosis was identified as a risk factor for infertility. WHAT IS KNOWN ALREADY: The increased prevalence of endometriosis among subfertile women indicates that endometriosis impairs reproduction for reasons that are not completely understood. STUDY DESIGN, SIZE, DURATION: This was an observational, cross-sectional study using data prospectively collected in all non-pregnant patients aged between 18 and 42 years, who were surgically explored for benign gynaecological conditions at our institution between January 2004 and March 2013. For each patient, a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS: Surgery was performed in 2208 patients, of which 2066 signed their informed consent. Of the 1059 women with a visual diagnosis of endometriosis, 870 had histologically proven endometriosis and complete treatment for their endometriotic lesions, including 307 who presented with infertility. Univariate analysis and multiple logistic regression analysis were performed to determine factors associated with infertility. MAIN RESULTS AND THE ROLE OF CHANCE: The following variables were identified as risk factors for endometriosis-related infertility: age >32 years (odds ratio [OR] = 1.9; 95% confidence interval [CI]: 1.4-2.4), previous surgery for endometriosis (OR = 1.9; 95% CI: 1.3-2.2), as well as peritoneal superficial endometriosis (OR = 3.1; 95% CI: 1.9-4.9); Conversely, previous pregnancy was associated with a lower rate of infertility (OR = 0.7; 95% CI: 0.6-0.9 and OR = 0.6; 95% CI: 0.4-0.9, respectively). OMA is not selected as a significant risk factor for infertility. LIMITATIONS, REASON FOR CAUTION: The selection of our study population was based on a surgical diagnosis. We cannot exclude that infertile women with OMA associated with a diminished ovarian reserve, as assessed during their infertility work-up, were referred less frequently to surgery and might therefore be underrepresented. In addition we cannot exclude that our group of infertile women present associated other causes of infertility. WIDER IMPLICATIONS OF THE FINDINGS: Identification of risk and preventive factors of endometriosis-related infertility can help improve clinical and surgical management of endometriosis in the setting of infertility. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: None.

Consensus on Recording Deep Endometriosis Surgery: the CORDES statement.

STUDY QUESTION: Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? SUMMARY ANSWER: A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. WHAT IS KNOWN ALREADY: Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. STUDY DESIGN, SIZE, DURATION: International expert consensus based on a systematic review of literature. PARTICIPANTS/MATERIALS, SETTING, METHODS: Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. MAIN RESULTS AND THE ROLE OF CHANCE: We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. LIMITATIONS, REASONS FOR CAUTION: The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. WIDER IMPLICATIONS OF THE FINDINGS: This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. STUDY FUNDING/COMPETING INTERESTS: None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. TRIAL REGISTRATION NUMBER: N/A.

Endometriosis also affects the decidua in contact with the fetal membranes during pregnancy.

STUDY QUESTION: Are the fetal membranes of women affected with endometriosis similar to those from disease-free women? SUMMARY ANSWER: Decidua of women with endometriosis is able to generate endometriotic-like lesions in contact with the fetal membranes. WHAT IS KNOWN ALREADY: Eutopic endometrium of women affected with endometriosis presents compromised properties. Endometrium undergoes decidualisation to accept and to further control the conceptus development during pregnancy. Decidualized endometrium is in close contact with the chorionic membrane and forms the choriodecidual layer, a major maternal-fetal interface. STUDY DESIGN, SIZE, DURATION: This is a laboratory case-control study involving diseased versus control samples. Eleven case samples and 11 control samples were collected from women in a tertiary care/research center between November 2011 and December 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were consecutive pregnant women affected with confirmed endometriosis and disease free women, who underwent Cesarean section before labor for obstetrical indication. The choriodecidual tissues were characterized using histology, immunohistochemistry, transcriptomic and whole genome CpG methylation analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We demonstrate for the first time the presence of endometriotic-like lesions within the decidual side of the choriodecidua of the fetal membranes from women affected with severe endometriosis. Fetal membranes from women affected with endometriosis exhibited glandular components in the choriodecidual layer surrounded by enlarged decidualized cells disseminated along the entire membrane surface. Significant deregulation (variation of expression ≥2, P-value ≤0.05) was observed for 2773 genes known to be enriched in processes involved in glandular function, endocrine and nervous system, neoangiogenesis, and autoimmune disease. CpG methylation analysis revealed 5999 differentially methylated regions with a P-value ≤0.05. LIMITATIONS, REASONS FOR CAUTION: We studied women who delivered at term by Cesarean section before labor, following an uneventful pregnancy. Notwithstanding this, one cannot exclude that the presence of disseminated endometriotic lesions within the choriodecidual layer of the fetal membranes may disturb the anatomical integrity and/or the function of the membranes in some women with endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: Our results shed new light on the capability of the diseased decidua to develop lesions not only at ectopic autologous locations, but also on the semi-allogenous fetal membranes, a particularly immunotolerant environment.

Fusion imaging for evaluation of deep infiltrating endometriosis: feasibility and preliminary results.

OBJECTIVE: Magnetic resonance imaging (MRI) and ultrasound scanning complement each other in screening for and diagnosis of endometriosis. Fusion imaging, also known as real-time virtual sonography, is a new technique that uses magnetic navigation and computer software for the synchronized display of real-time ultrasound and multiplanar reconstructed MR images. Our aim was to evaluate the feasibility and ability of fusion imaging to assess the main anatomical sites of deep infiltrating endometriosis (DIE) in patients with suspected active endometriosis. METHODS: This prospective study was conducted over a 1-month period in patients referred to a trained radiologist for an ultrasound-based evaluation for endometriosis. Patients with a prior pelvic MRI examination within the past year were offered fusion imaging, in addition to the standard evaluation. All MRI examinations were performed on a 1.5-T MRI machine equipped with a body phased-array coil. The MRI protocol included acquisition of at least two fast spin-echo T2-weighted orthogonal planes. The Digital Imaging Communications in Medicine dataset acquired at the time of the MRI examination was loaded into the fusion system and displayed together with the ultrasound image on the same monitor. The sets of images were then synchronized manually using one plane and one anatomical reference point. The ability of this combined image to identify and assess the main anatomical sites of pelvic endometriosis (uterosacral ligaments, posterior vaginal fornix, rectum, ureters and bladder) was evaluated and compared with that of standard B-mode ultrasound and MRI. RESULTS: Over the study period, 100 patients were referred for ultrasound examination because of endometriosis. Among them were 20 patients (median age, 35 (range, 27-49) years) who had undergone MRI examination within the past year, with a median (range) time interval between MRI and ultrasound examination of 171 (1-350) days. All 20 patients consented to undergo additional evaluation by fusion imaging. However, in three (15%) cases, fusion imaging was not technically possible because of changes since the initial MRI examination resulting from either interval surgery (n = 2; 10%) or pregnancy (n = 1; 5%). Data acquisition, matching and fusion imaging were performed in under 10 min in each of the other 17 cases. The overall ability of each technique to identify and assess the main anatomical landmarks of endometriosis was as follows: uterosacral ligaments: ultrasound, 88% (30/34); MRI, 100% (34/34); fusion imaging, 100% (34/34); posterior vaginal fornix: ultrasound, 88% (30/34); MRI, 100% (34/34); fusion imaging, 100% (34/34); rectum: ultrasound, 100% (17/17); MRI, 82.3% (14/17); fusion imaging, 100% (17/17); ureters: ultrasound, 0%; MRI, 100% (34/34); fusion imaging, 100% (34/34); and bladder: ultrasound, 100%; MRI, 100%; fusion imaging, 100%. CONCLUSION: Fusion imaging is feasible for the assessment of endometriotic lesions. Because it combines information from both ultrasound and MRI techniques, fusion imaging allows better identification of the main anatomical sites of DIE and has the potential to improve the performance of ultrasound and MRI examination.

In vitro activity and resistance profile of samatasvir, a novel NS5A replication inhibitor of hepatitis C virus.

The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a clinically validated target for drugs designed to treat chronic HCV infection. This study evaluated the in vitro activity, selectivity, and resistance profile of a novel anti-HCV compound, samatasvir (IDX719), alone and in combination with other antiviral agents. Samatasvir was effective and selective against infectious HCV and replicons, with 50% effective concentrations (EC50s) falling within a tight range of 2 to 24 pM in genotype 1 through 5 replicons and with a 10-fold EC50 shift in the presence of 40% human serum in the genotype 1b replicon. The EC90/EC50 ratio was low (2.6). A 50% cytotoxic concentration (CC50) of >100 µM provided a selectivity index of >5 × 10(7). Resistance selection experiments (with genotype 1a replicons) and testing against replicons bearing site-directed mutations (with genotype 1a and 1b replicons) identified NS5A amino acids 28, 30, 31, 32, and 93 as potential resistance loci, suggesting that samatasvir affects NS5A function. Samatasvir demonstrated an overall additive effect when combined with interferon alfa (IFN-α), ribavirin, representative HCV protease, and nonnucleoside polymerase inhibitors or the nucleotide prodrug IDX184. Samatasvir retained full activity in the presence of HIV and hepatitis B virus (HBV) antivirals and was not cross-resistant with HCV protease, nucleotide, and nonnucleoside polymerase inhibitor classes. Thus, samatasvir is a selective low-picomolar inhibitor of HCV replication in vitro and is a promising candidate for future combination therapies with other direct-acting antiviral drugs in HCV-infected patients.

A clinical score can predict associated deep infiltrating endometriosis before surgery for an endometrioma.

STUDY QUESTION: Is it possible to detect associated deep infiltrating endometriosis (DIE) before surgery for patients operated on for endometriomas using a preoperative clinical symptoms questionnaire? SUMMARY ANSWER: A diagnostic score of DIE associated with endometriomas using four clinical symptoms defined a high-risk group where the probability of DIE was 88% and a low-risk group with a 10% probability of DIE. WHAT IS KNOWN ALREADY: Many clinical symptoms are already known to be associated with DIE but they have not yet been used to build a clinical prediction model. STUDY DESIGN, SIZE, DURATION: We built a diagnostic score of DIE based on a case control study of 326 consecutive patients operated on for an endometrioma between January 2005 and October 2011: 164 had associated DIE (DIE+) and 162 had no DIE (DIE-). We derived the score on a training sample obtained from a random selection of 2/3 of the population (211 patients, 101 DIE+, 110 DIE-), and validated the results on the remaining third (115 patients, 63 DIE+, 52 DIE-). The gold standard for the diagnosis of DIE was based on surgical exploration and histological diagnosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were consecutive patients aged 18-42 years who underwent surgery for an endometrioma with histological confirmation and complete treatment of their endometriotic lesions: data for these women were extracted from a prospective database including a standardized preoperative questionnaire. On the training dataset, variables associated with DIE in a univariate analysis were introduced in a multiple logistic regression and selected by a backward stepwise procedure and a Jackknife procedure. A diagnostic score of DIE was built with the scaled/rounded coefficients of the multiple regression. Two cut-off values delimitated a high and a low risk group, and their diagnostic accuracy was tested on the validation dataset. MAIN RESULTS AND THE ROLE OF CHANCE: Four variables were independently associated with DIE: visual analogue scale of gastro-intestinal symptoms ≥5 or of deep dyspareunia >5 (adjusted diagnostic odds ratio (aDOR) = 6.0, 95% confidence interval (CI) [2.9-12.1]), duration of pain greater than 24 months (aDOR = 3.8, 95% CI [1.9-7.7]), severe dysmenorrhoea (defined as the prescription of the oral contraceptive pill for the treatment of a primary dysmenorrhoea or the worsening of a secondary dysmenorrhoea) (aDOR = 3.8, 95% CI [1.9-7.6]) and primary or secondary infertility (aDOR = 2.5, 95% CI [1.2-4.9]). The sum of these variables weighted by their rounded/scaled coefficients constituted the score ranging from 0 to 53. A score <13 defined a low-risk group where the probability of DIE was 10% (95% CI [7-15] with a sensitivity of 95% (95% CI [89-98]) and a negative likelihood ratio of 0.1 (95% CI [0.0-0.3]). A score ≥35 defined a high-risk group where the probability of DIE was 88% (95% CI [83-92%]), with a specificity of 94% (95% CI [87-97]), and a positive likelihood ratio of 8.1 (95% CI [3.9-17.0]). The performance of the score was confirmed on the validation dataset with 11% of DIE+ patients having a score <13 (sensibility: 95%) and 90% of DIE+ patients having a score ≥35 (specificity: 94%). LIMITATION, REASONS FOR CAUTION: This study was performed in a department specialized in DIE management. Score accuracy could be different in less specialized centres. WIDER IMPLICATIONS OF THE FINDINGS: This score could have a major clinical impact on the time of diagnosis, the management of DIE and could reduce the cost of investigations by helping to identify high-risk patients, while preserving the quality of care. STUDY FUNDING/COMPETING INTERESTS: The authors have no competing interests to declare. No grant supported the study.