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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 Funding/competing Interests: None declared., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Question: Do adolescents and young adult women (YAW) with histologically proven endometriosis present a specific clinical history?, Summary Answer: Questionnaire screening of adolescents and YAW can identify clinical markers associated with histologically proven endometriosis., What Is Known Already: Some validated questionaries can contribute to an earlier endometriosis diagnosis in adults. None of these scores, however, have been validated for adolescents or YAW., Study Design, Size, Duration: This was an observational cross-sectional study using prospectively recorded data performed between January 2005 and January 2020 in a single university tertiary referral centre for endometriosis diagnosis and management. After a thorough surgical examination of the abdomino-pelvic cavity, women with histologically proven endometriosis were allocated to the endometriosis group, and symptomatic women without evidence of endometriosis were allocated to the endometriosis-free control group. The endometriotic patients were allocated into two sub-groups according to their age: adolescent (≤20 years) and YAW (21-24 years)., Participants/materials, Setting, Methods: Adolescents and YAW ≤24 years of age were operated for a symptomatic benign gynaecological condition with signed informed consent. A standardized questionnaire was prospectively completed in the month before the surgery and included epidemiological data, pelvic pain scores, family history of endometriosis, and symptoms experienced during adolescence. The study searched for correlations by univariate analysis to determine clinical markers of endometriosis in adolescents and YAW compared with endometriosis-free control patients., Main Results and the Role of Chance: Of the 262 study participants, 77 women were adolescents (≤20 years of age) and 185 patients (70.6%) were YAW. The endometriosis group included 118 patients (45.0%) and 144 (55.0%) were assigned to the control group. A family history of endometriosis, absenteeism from school during menstruation, history of fainting spells during menstruation, and prescription of oral contraceptive pills for intense dysmenorrhea were significantly more frequently observed in the endometriotic patients. The prevalence and mean pain scores for dysmenorrhea, deep dyspareunia, non-cyclic chronic pelvic pain and gastrointestinal and lower urinary tract symptoms were significantly greater in the endometriosis group, as was experienced rectal bleeding., Limitations, Reasons for Caution: The study was performed in a single referral centre that treats patients with potentially more severe disease. This questionnaire was evaluated on a population of patients with an indication for endometriosis surgery, which can also select patients with more severe disease. Women with asymptomatic endometriosis were not considered in this study. These factors can affect the external validity of this study., Wider Implications of the Findings: Patient interviews are relevant to the diagnosis of endometriosis in adolescents and YAW. Combined with imaging and clinical examination, this approach will enable earlier diagnosis and treatment, while remaining non-invasive and rapid., Study Funding/competing Interest(s): The study received no funding from external sources. There are no conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: No circulating biomarker is available for endometrial carcinoma (EC). We aimed to identify DNA positions universally hypermethylated in EC, and to develop a digital droplet PCR (ddPCR) assay for detection of hypermethylated circulating tumor DNA (meth-ctDNA) in plasma from patients with EC., Methods: DNA positions hypermethylated in EC, and without unspecific hypermethylation in tissue/cell types releasing circulating cell-free DNA in plasma, were identified in silico from TCGA/Gene Expression Omnibus (GEO) data. A methylation-specific ddPCR (meth-ddPCR) assay following bisulfite conversion of DNA extracted from plasma was optimized for detection of meth-ctDNA according to dMIQE guidelines. Performances were validated on a retrospective cohort (n = 78 tumors, n = 30 tumor-adjacent tissues), a prospective pilot cohort (n = 33 stage I-IV patients), and 55 patients/donors without cancer., Results: Hypermethylation of zinc finger and SCAN domain containing 12 (ZSCAN12) and/or oxytocin (OXT) classified EC samples from multiple noncancer samples with high diagnostic specificity/sensitivity [>97%; area under the curve (AUC) = 0.99; TCGA/GEO tissues/blood samples]. These results were confirmed in the independent retrospective cohort (AUC = 0.99). Meth-ddPCR showed a high analytical specificity (limit of blank = 2) and sensitivity (absolute lower threshold of detection = 50 pgmethDNA/mLplasma). In the pilot cohort, meth-ctDNA was detected in pretreatment plasma samples from 9/11 and 5/20 patients with advanced and non-advanced EC, respectively. 2 of 9 patients had ctDNA detected after macroscopic complete surgery and experienced progression within 6 months. No healthy donors had any copy of hypermethylated DNA detected in plasma., Conclusions: Meth-ddPCR of ZSCAN12/OXT allows a highly specific and sensitive detection of ctDNA in plasma from patients with EC and appears promising for personalized approaches for these patients., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Question: Is endometriosis associated with aberrant sialylation patterns and what is the potential impact of such anomalies on cell migratory properties?, Summary Answer: The reduced α-2,6 sialylation patterns in the peritoneal fluid of endometriosis-affected women and in stromal and epithelial cells from endometriotic lesions could be associated with enhanced cell migration., What Is Known Already: Endometriosis is considered to be a benign disease although, like cancer, it has the characteristic of being an invasive disease with cells that have an enhanced capacity to migrate. Aberrant sialylation has been reported in various malignancies and it has been linked to tumour invasion and metastasis., Study Design, Size, Duration: We conducted a prospective laboratory study in a tertiary-care university hospital. We investigated non-pregnant patients who were <42 years of age (n = 273) when they underwent surgery for a benign gynaecological condition., Participants/materials, Setting, Methods: The study population consisted of 102 women with histologically proven endometriosis and 71 endometriosis-free controls, who underwent a complete surgical exploration of the abdominopelvic cavity. Peritoneal fluids were collected during the surgical procedures, and endometrial and endometriotic biopsies were performed on all of the patients to generate stromal and epithelial primary cell cultures. The expression of α-2,6-sialyltransferase (ST6GALNAC1) was studied in eutopic and ectopic endometria of endometriosis patients and in eutopic endometria of controls by reverse transcription followed by quantitative real-time polymerase chain reaction (RT-qPCR). The α-2,6 sialylation levels were measured by ELISA in the peritoneal fluids of patients and controls and by western-blot in primary endometrial and endometriotic cell cultures using Sambucus nigra agglutinin (SNA), an α-2,6 sialic acid-binding lectin. A transwell migration assay after incubation of the cells with neuraminidase was also performed to evaluate the impact of desialylation on eutopic endometrial stromal cell migration., Main Results and the Role of Chance: ST6GALNAC1 gene expression was significantly lower in endometriotic lesions compared to that in eutopic endometrium of endometriosis-affected patients and healthy endometrium (16-fold for both; P < 0.01). We observed a significant reduction in SNA levels in the peritoneal fluids of endometriosis-affected women compared to control women (median optic density (OD), 0.257; range, 0.215-0.279 versus median OD, 0.278; range 0.238-0.285; P < 0.01), as well as in stromal (mean OD, 705 907; standard error of the mean (SEM), 141 549 versus mean OD, 1.16 × 106; SEM, 107,271; P < 0.05) and epithelial (mean OD, 485 706; SEM, 179 681 versus mean OD, 1.25 × 106; SEM, 232 120; P < 0.05) ectopic endometriotic cells compared to control eutopic cells, indicating reduced α-2,6 sialylation. Finally, in the transwell migration assay, the eutopic endometrial cells of endometriosis patients migrated significantly more into the lower chamber after incubation with neuraminidase, indicating enhanced migration by these cells after desialylation., Large Scale Data: N/A., Limitations, Reasons for Caution: Our control group involved patients operated for benign gynaecological conditions (e.g. tubal infertility, uterine fibroids or ovarian cysts) which may also be associated with altered sialylation patterns., Wider Implications of the Findings: The hyposialylation pattern of endometriotic cells appeared to be associated with enhanced migratory abilities, which might contribute to the establishment of early endometriotic implants. Further research is needed to confirm these findings, as this could lead to new potential therapeutic targets for this complex disorder., Study Funding and Competing Interest(s): No external funding was received and there are no conflicts of interest., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Study Question: How does the duration of estrogen (E2) treatment prior to frozen-blastocyst transfers affect the live birth rate (LBR)?, Summary Answer: Prolonged E2 exposure as part of artificial endometrial preparation (AEP) significantly decreases the LBR after autologous frozen-thawed blastocyst transfer., What Is Known Already: One effective method for endometrial preparation prior to frozen embryo transfer is AEP, a sequential regimen with E2 and progesterone, which aims to mimic the endocrine exposure of the endometrium in a normal cycle. Nevertheless, the optimal duration of E2 administration prior to transfer remains unknown., Study Design, Size, Duration: An observational cohort study was conducted in a tertiary care university hospital between 01/07/2012 and 31/12/2015. The main inclusion criteria was having a single frozen-thawed blastocyst transfer with an AEP using exogenous E2., Participants/materials, Setting, Methods: A total of 1377 frozen-thawed blastocyst transfers were assigned to four groups according to the duration of the E2 administration prior to the embryo transfers. These comprised a '≤21 days' group (n = 330), a '22-28 days' group (n = 665), a '29-35 days' group (n = 289) and a '36-48 days' group (n = 93). The '≤21 days' group' was taken as the reference group. The main measured outcome was the LBR following frozen-thawed blastocyst transfers. Statistical analysis was conducted using univariate and multivariate logistic regression models., Main Results and the Role of Chance: LBR significantly decreased when the E2 exposure prior to the frozen-thawed blastocyst transfer exceeded 28 days: OR = 0.66; 95% CI [0.46-0.95]; P = 0.026 and OR = 0.49 [0.27-0.89]; P = 0.018, respectively, for the '29 to 35 days' group and for the '36 to 48 days' group compared to the reference group. Early pregnancy loss rates significantly increased when the E2 exposure lasted more than 35 days prior to the frozen-thawed blastocyst transfer (OR = 2.37 [1.12-5.05]; P = 0.025 vs. the reference group). After multivariate logistic regression, E2 exposure lasting more than 28 days prior to the frozen-thawed blastocyst transfer was associated with a decrease in the LBR, for the '29-35 days' group (OR = 0.65; [0.45-0.95]; P = 0.044) as for the '36-48 days' group (OR = 0.49; [0.26-0.92]; P = 0.035), vs. the reference group., Limitations, Reasons for Caution: One limitation is linked to the observational design of this study., Wider Implications of the Findings: In order to give patients the best chance to obtain a live birth after frozen-thawed blastocyst transfer, the length of E2 exposure prior to the frozen-blastocyst transfer should not exceed 28 days. This study provides new insight in regard to endometrial preparation using AEP prior to frozen-blastocyst transfer., Study Funding/competing Interest(s): No funding and no competing interest.

Study Question: The aim of this study was to evaluate the live birth rate (LBR) after frozen-thawed Day 5 (D5) and Day 6 (D6) blastocyst transfers., Summary Answer: LBR following frozen-thawed blastocyst transfer is significantly lower with D6 than with D5 blastocyst regardless of embryo quality., What Is Known Already: During fresh embryo transfer cycles, pregnancy rates (PR) are significantly higher when transferring blastocysts expanded on D5 compared with slow developing blastocysts (D6). In programmed thawed blastocyst transfer (TBT) cycles, the same clinical outcomes should be expected when transferring D5 or D6 blastocysts because of endometrial/embryonic synchronization due to hormonal priming of endometrial receptivity. However, the impact of delayed blastocyst expansion at D6 on clinical outcomes remains unclear. Some reports have shown higher PRs after D5 TBT compared with those of D6, while others have shown equivalent TBT outcomes after D5 and D6 cryopreserved blastocysts transfers., Study, Design, Size, Duration: This retrospective cohort follow-up study included 1347 single autologous frozen-thawed blastocyst transfers performed between January 2012 and December 2015 at a tertiary care university hospital., Participants/materials, Setting, Methods: All of the patients scheduled for TBT were allocated to two groups according to the day of blastocyst expansion: on D5 (n = 994) or on D6 (n = 353). The primary outcome was LBR per embryo transfer in the first blastocyst thawing cycle. Secondary outcomes were clinical pregnancy rate (cPR), early miscarriage rate and neonatal outcomes following TBT for the two groups. Statistical analyses were conducted using univariate and multivariate logistic regression model., Main Results and the Role of Chance: The LBR was significantly increased in the D5 group compared to the D6 group [294/994 (29.6%) versus 60/353 (17.0%); P < 0.001]. The cPR was also higher when blastocysts were vitrified on D5 compared with those vitrified on D6 [429/994 (43.2%) versus 95/353 (26.9%); P < 0.001]. No significant differences were found between groups in terms of early miscarriage rate (P = 0.862). More good-quality embryos (defined as an B3-B4 or B5 embryo ≥BB according to the grading scale proposed by Gardner) were transferred in the D5 group than in the D6 group [807 (81.2%) versus 214 (60.6%); P < 0.001]. However, a comparison of TBT cycles with equal embryo quality (good versus low) also supported the superiority of D5 blastocysts. Concerning neonatal outcomes, the D5 group infants had a lower mean birth weight compared to those of the D6 group (P = 0.001). In addition, a significantly shorter gestational age at birth is reported in the D5 blastocyst group as compared to the D6 group (P = 0.004). After multivariate logistic regression taking into account potential confounders such as the women's age, number of previous IVF/ICSI procedures, the day of the blastocyst vitrification (D5 or D6) and embryo quality, blastocyst expansion at D6 was independently associated with a significant decrease in LBR compared to D5 expanded-blastocysts (OR 0.52; 95% CI 0.38-0.72; P < 0.001)., Limitations, Reasons for Caution: The poor predictive value of the morphological approach in embryo selection could constitute a limitation in this study. However, blastocyst quality was evaluated similarly in both groups., Wider Implications of the Findings: The LBR following frozen-thawed blastocyst transfer was significantly lower with D6 than with D5 blastocysts, regardless of their quality. These results could affect cryopreservation procedures as they suggest that the use of D5-expanded blastocysts for TBT may be preferred in order to shorten the time of conceiving., Study Funding/competing Interest(s): No specific funding was obtained for this study. None of the authors have any competing interests to declare., Trial Registration Number: Not applicable.

Study Question: What is the relationship between endometriosis phenotypes superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA), deep infiltrating endometriosis (DIE) and the adenomyosis appearance by magnetic resonance imaging (MRI)?, Summary Answer: Focal adenomyosis located in the outer myometrium (FAOM) was observed more frequently in women with endometriosis, and was significantly associated with the DIE phenotype., What Is Known Already: An association between endometriosis and adenomyosis has been reported previously, although data regarding the association between MRI appearance of adenomyosis and the endometriosis phenotype are currently still lacking., Study Design, Size, Duration: This was an observational, cross-sectional study using data prospectively collected from non-pregnant patients who were between 18 and 42 years of age, and who underwent surgery for symptomatic benign gynecological conditions between January 2011 and December 2014. For each patient, a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding the surgery. Only women with preoperative standardized uterine MRIs were retained for this study., Participants/materials, Setting, Methods: Surgery was performed on 292 patients with signed consent and available preoperative MRIs. After a thorough surgical examination of the abdomino-pelvic cavity, 237 women with histologically proven endometriosis were allocated to the endometriosis group and 55 symptomatic women without evidence of endometriosis to the endometriosis free group. The existence of diffuse or FAOM was studied in both groups and according to surgical endometriosis phenotypes (SUP, OMA and DIE)., Main Results and the Role of Chance: Adenomyosis was observed in 59.9% (n = 175) of the total sample population (n = 292). Based on MRI, the distribution of adenomyosis was as follows: isolated diffuse adenomyosis (53 patients; 18.2%), isolated FAOM (74 patients; 25.3%), associated diffuse and FAOM (48 patients; 16.4%). Diffuse adenomyosis (isolated and associated to FAOM) was observed in one-third of the patients regardless of whether they were endometriotic patients or endometriosis free women taken as controls (34.2% (81 cases) versus 36.4% (20 cases)); P = 0.764. Among endometriotic women, diffuse adenomyosis (isolated and associated to FAOM) failed to reach significant correlation with the endometriosis phenotypes (SUP, 20.0% (8 cases); OMA, 45.2% (14 cases) and DIE, 35.5% (59 cases); P = 0.068). In striking contrast, there was a significant increase in the frequency of FAOM in endometriosis-affected women than in controls (119 cases (50.2%) versus 5.4% (3 cases); P < 0.001). FAOM correlated with the endometriosis phenotypes, significantly with DIE (SUP, 7.5% (3 cases); OMA, 19.3% (6 cases) and DIE, 66.3% (110 cases); P < 0.001)., Limitations, Reasons for Caution: There was a possible selection bias due to the specificity of the study design, as it only included surgical patients in a referral center that specializes in endometriosis surgery. Therefore, women referred to our center may have suffered from particularly severe forms of endometriosis. This could explain the high number of women with DIE (166/237-70%) in our study group. This referral bias for women with severe lesions may have amplified the difference in association of FAOM with the endometriosis-affected patients compared to women without endometriosis. Furthermore, according to inclusion criteria, women in the endometriosis free group were symptomatic women. This may introduce some bias as symptomatic women may be more prone to have associated adenomyosis that in turn could have been overrepresented in the endometriosis free group. Whether this selection could have introduced a bias in the relationship between endometriosis and adenomyosis remains unknown., Wider Implications of the Findings: This study opens the door to future epidemiological, clinical and mechanistic studies aimed at better characterizing diffuse and focal adenomyosis. Further studies are necessary to adequately determine if diffuse and focal adenomyosis are two separate entities that differ in terms of pathogenesis., Study Funding/competing Interest(s): No funding supported this study. The authors have no conflict of interest to declare., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

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., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: Were spontaneous miscarriages more frequent in women with histologically proven endometriosis when compared with endometriosis-free controls?, Summary Answer: Endometriosis-affected women display a significantly higher rate of previous spontaneous miscarriages than endometriosis-free controls., What Is Known Already: The association between endometriosis and miscarriages has long been debated without reaching a consensus., Study Design, Size, Duration: We conducted a retrospective cohort study comparing exposed women (endometriosis) and control (without endometriosis) regarding the incidence of miscarriages. All study participants underwent surgery for benign gynaecological conditions in a tertiary-care university hospital between January 2004 and March 2013. After thorough surgical examination of the abdominopelvic cavity, 870 women with histologically proven endometriosis were allocated to the endometriosis group and 981 unaffected women to the control group. Only previously pregnant women were finally included for the study analysis: 284 women in the endometriosis group and 466 in the control group., Participants/materials, Setting, Methods: Data were collected preoperatively using a structured questionnaire. Among women with at least one pregnancy before the surgery, the type and number of the different previous first trimester pregnancies outcomes were studied. Previous history of miscarriage was studied according to the existence of previous infertility history and the disease severity (revised American Fertility Society and surgical classification)., Main Results and the Role of Chance: Four hundred and seventy-eight pregnancies in endometriosis-affected women and 964 pregnancies in controls were analysed. The previous miscarriage rate was significantly higher in women with endometriosis compared with the controls (139/478 [29] versus 187/964 [19%], respectively; ITALIC! P < 0.001). After a subgroup analysis, the miscarriage rates of women with endometriosis and the controls were, respectively: 20 versus 12% ( ITALIC! P = 0.003) among women without a previous history of infertility and 53 versus 30% ( ITALIC! P < 0.001) for women with a previous history of infertility. After using a random-effects Poisson regression and adjusting for confounding factors, we found a significantly increased incidence rate ratio (IRR) for miscarriages in women with endometriosis (adjusted IRR: 1.70, 95% confidence interval: 1.34-2.16)., Limitations, Reasons for Caution: There is a possible selection bias due to the specificity of the study design which included only surgical patients. In the control group, certain of the surgical gynaecological conditions, such as fibroids, ovarian cysts or tubal pathologies, might be associated with higher spontaneous miscarriage rates. In the endometriosis group, asymptomatic women were less likely to be referred for surgery and might therefore be underrepresented., Wider Implications of the Findings: This study opens the doors to future, more mechanistic studies to establish the exact link between endometriosis and spontaneous miscarriage rates., Study Funding/competing Interests: No external funding was used for this study. The authors have no conflicts of interest to declare., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: Are protein oxidative stress markers [thiols, advanced oxidation protein products (AOPP), protein carbonyls and nitrates/nitrites] in perioperative peritoneal fluid higher in women with histologically proven endometriosis when compared with endometriosis-free controls?, Summary Answer: Protein oxidative stress markers are significantly increased in peritoneal fluids from women with deep infiltrating endometriosis with intestinal involvement when compared with endometriosis-free controls., What Is Known Already: Endometriosis is a common gynaecologic condition characterized by an important inflammatory process. Various source of evidence support the role of oxidative stress in the development of endometriosis., Study Design, Size, Duration: We conducted a prospective laboratory study in a tertiary-care university hospital between January 2011 and December 2012, and included 235 non-pregnant women, younger than 42 year old, undergoing surgery for a benign gynaecological condition., Participants/materials, Setting, Methods: After complete surgical exploration of the abdomino-pelvic cavity, 150 women with histologically proven endometriosis and 85 endometriosis-free controls women were enrolled. Women with endometriosis were staged according to a surgical classification in three different phenotypes of endometriosis: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) and deeply infiltrating endometriosis (DIE). Perioperative peritoneal fluids samples were obtained from all study participants. Thiols, AOPP, protein carbonyls and nitrates/nitrites were assayed in all peritoneal samples., Main Results and the Role of Chance: Concentrations of peritoneal AOPP were significantly higher in endometriosis patients than in the control group (median, 128.9 µmol/l; range, 0.3-1180.1 versus median, 77.8 µmol/l; range, 0.8-616.1; P < 0.001). In a similar manner concentrations of peritoneal nitrates/nitrites were higher in endometriosis patients than in the control group (median, 24.8 µmol/l; range, 1.6-681.6 versus median, 18.5 µmol/l; range, 1.6-184.5; P < 0.05). According to the surgical classification, peritoneal fluids protein AOPP and nitrates/nitrites were significantly increased only in DIE samples when compared with controls (P < 0.001 and P < 0.05; respectively), whereas the others forms of endometriosis (SUP and OMA) showed non-statistically significant increases. We found positive correlations between peritoneal fluids AOPP concentrations, nitrites/nitrates levels and the total number of intestinal DIE lesions (r = 0.464; P < 0.001 and r = 0.366; P = 0.007; respectively)., Limitations, Reasons for Caution: Inclusion of only surgical patients may constitute a possible selection bias. In fact, our control group involved women who underwent surgery for benign gynaecological conditions. This specificity of our control group may lead to biases stemming from the fact that some of these conditions, such as fibroids, ovarian cysts or tubal infertility, might be associated with altered peritoneal proteins oxidative stress markers., Wider Implications of the Findings: We demonstrate the existence of a significantly increased protein oxidative stress status in peritoneal fluid from women with endometriosis especially in cases of DIE with intestinal involvement. This study opens the way to future more mechanistics studies to determine the exact role of protein oxidative stress in the pathogenesis of endometriosis. Even if an association does not establish proof of cause and effect, these intrinsic biochemical characteristics of endometriosis may lead to the evaluation of therapeutic approaches targeting oxidative imbalance., Study Funding/competing Interests: No funding was used for this study. The authors have no conflict of interest., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Endometriosis is a common gynecologic condition characterized by an important inflammatory process mediated by the prostaglandin pathway. Oral contraceptives are the treatment of choice for symptomatic endometriotic women. However the effects of oral contraceptives use and prostaglandin pathway in endometriotic women are actually still unknown., Objective: To investigate the expression of prostaglandin pathway key genes in endometriotic tissue, affected or not by hormonal therapy, as compared with healthy endometrial tissue., Design: This was a comparative laboratory study., Setting: This study was conducted in a tertiary-care university hospital., Patients: Seventy-six women, with (n = 46) and without (n = 30) histologically proven endometriosis., Main Outcome Measures: Prostaglandin-endoperoxidase synthase (PTGS)1, PTGS2, prostaglandin E receptor (PTGER)1, PTGER2, PTGER3, and PTGER4 mRNA levels in endometrium of disease-free women and in eutopic and ectopic endometrium of endometriosis-affected women. PTGS2 expression was further investigated by immunohistochemistry, using specific monoclonal antibodies. PTGS2 expression was analyzed at mRNA and protein levels and correlated with taking hormonal treatment., Results: PTGS2 expression was significantly increased in eutopic and ectopic endometrium as compared with healthy tissue (induction of 9.6- and 6.3-fold, respectively; P = .001). PTGS2 immunoreactivity increased gradually from normal endometrium to eutopic and ectopic endometrium (h-score of 96.7 ± 55.0, 128.3 ± 66.1, and 226.7 ± 62.6, respectively, P < .001). PTGER2, PTGER3, and PTGER4 expression increased significantly and gradually from normal to eutopic and ectopic endometrium, whereas PTGER1 remained unchanged. Patients under hormonal treatment had a higher PTGS2 expression at transcriptional and protein levels as compared with those without treatment (P = .002 and P = .025, respectively)., Conclusions: Prostaglandin pathway is strongly deregulated in eutopic and ectopic endometrium of women suffering from endometriosis for the benefit of an increased PTGS2 expression. We show for the first time that hormonal treatment appears to enhance even more PTGS2 expression. These results contribute to explain why medical treatment could fail to control endometriosis progression.

Study Question: Are interleukin-33 (IL-33) serum levels higher in women with uterine leiomyoma compared with controls without leiomyoma?, Summary Answer: Serum IL-33 is elevated in women with uterine leiomyoma and correlated with features of uterine leiomyoma tumour burden, namely fibroid number, size and weight., What Is Known Already: Uterine leiomyomas are the most common benign tumours in premenopausal women associated with major tissue fibrosis. IL-33 is a cytokine involved in fibrotic disorders. The potential role of IL-33 in leiomyoma has not been reported before., Study Design, Size, Duration: This is a prospective laboratory study conducted in a tertiary-care university hospital between January 2005 and December 2010. We investigated non-pregnant, 42-year-old patients (n = 151) during surgery for a benign gynaecological condition., Participants/materials, Setting, Methods: After complete surgical exploration of the abdominopelvic cavity, 59 women with histologically proved uterine leiomyoma and 92 leiomyoma-free control women were enrolled. Women with endometriosis or past history of ovarian malignancy and borderline tumours were not included. The control group included women with benign ovarian cysts, paratubal cysts or tubal defects without any evidence of uterine leiomyoma. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. Serum samples were obtained in the month preceding the surgical procedures according to the menstrual phase or hormonal therapy. IL-33 was measured in sera by enzyme-linked immunosorbent assay, and correlation of IL-33 concentration with the extent and severity of the disease was investigated., Main Results and the Role of Chance: IL-33 was detected in 32 (54.2%) women with leiomyoma and 18 (19.6%) controls (P < 0.001). Serum IL-33 was higher in women with leiomyoma (median, 140.1 pg/ml; range, 7.5-2247.7) than in controls (median, 27.8 pg/ml; range, 7.5-71.6; P = 0.002). We found positive correlations between serum IL-33 concentration and leiomyoma features, such as fibroid weight (r = 0.630; P = 0.001) and size (r = 0.511; P = 0.018) and the number of fibroids (r = 0.503; P = 0.003)., Limitations, Reasons for Caution: There was a possible selection bias due to inclusion of only surgical patients. Therefore our control group consisted of women who underwent surgery for benign gynaecological conditions. This may lead to biases stemming from the fact that certain of these conditions, such as tubal infertility or ovarian cysts, might be associated with altered serum IL-33 levels., Wider Implications of the Findings: We demonstrate for the first time that elevated serum IL-33 levels are associated with the existence of uterine leiomyoma. However, even if an association does not constitute proof of cause and effect, investigating the mechanisms that underlie fibrogenesis associated with leiomyomas is a step towards understanding this enigmatic disease. This study opens the doors to future, more mechanistics studies to establish the exact role of IL-33 in uterine leiomyomas pathogenesis., Study Funding/competing Interest(s): No funding, no conflict of interest.

Study Question: Are anti-Müllerian hormone (AMH) levels lower in women with endometriosis, notably those with endometriomas (OMAs) and deep infiltrating lesions, compared with controls without endometriosis?, Summary Answer: Endometriosis and OMAs per se do not result in lower AMH levels. AMH levels are decreased in women with previous OMA surgery independently of the presence of current OMAs., What Is Known Already: The impact of endometriosis and OMAs per se on the ovarian reserve is controversial. Most previous studies have been conducted in infertile women. The strength of our study lies in the following points: (i) the selection of women undergoing surgery and not only according to the presence of infertility, (ii) the classification of women with endometriosis and controls based on strict surgical and histological criteria., Study Design, Size, Duration: Cross-sectional study using data prospectively collected in all non-pregnant <42-year-old patients, who were surgically explored for a benign gynaecological condition at a university tertiary referral centre between 2004 and 2008. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. AMH levels were measured in serum samples drawn in the month preceding surgery, without regard to menstrual phase or hormonal therapy., Participants/materials, Setting, Methods: Operations were done on 1262 women between 2004 and 2008, of which 1133 signed the informed consent. Of the 566 women with a visual diagnosis of endometriosis, 411 had histologically proven endometriosis. Frozen serum samples for the AMH measurement were available in 313 of them. Out of the 554 women without visual endometriosis and without past endometriosis surgery, 413 had a frozen serum sample for the AMH measurement. Univariate analysis examined AMH levels according to baseline patient characteristics, the presence and type of endometriosis (superficial lesion, OMA, deep infiltrating lesion) and previous OMA surgery. Analysis of variance-covariance then examined the effects of co-variables on AMH levels. Finally, logistic regressions were conducted to examine the odds ratio (OR) of having AMH levels <1 ng/ml according to the same co-variables., Main Results and the Role of Chance: The difference in AMH levels between women with endometriosis and controls did not reach significance (3.6 ± 3.1 versus 4.1 ± 3.4 ng/ml, P = 0.06). Analysis of variance-covariance demonstrated that AMH levels significantly decreased with age (P < 0.001) and in women with prior OMA surgery irrespective of whether OMAs were present or not at the time of study (P < 0.05). Logistic regression revealed that two major factors were related to AMH levels <1 ng/ml: (i) age (compared with <29 years; 30-34 years OR = 3.1, 95% CI: 1.5-6.4, P = 0.01; 35-39 years OR = 7.0, 95% CI: 3.5-14.1, P = 0.001; ≥40 years OR = 20.8, 95% CI: 9.1-47.4, P = 0.001) and (ii) prior OMA surgery (OR = 3.0, 95% CI: 1.4-6.41, P = 0.01)., Limitations, Reasons for Caution: The selection of our study population was based on a surgical diagnosis. Women with an asymptomatic form of endometriosis are therefore not included in our study. We cannot exclude that infertile women with OMAs associated with a diminished ovarian reserve, as assessed during their infertility work-up, were less likely to be referred for surgery and might therefore be underrepresented., Wider Implications of the Findings: Our findings suggest that OMAs per se do not diminish the ovarian reserve reflected by AMH levels but that alterations seen in women with endometriosis are a deleterious consequence of OMA surgery. These findings should be taken into account in the decision to operate OMAs in women with a desire for future pregnancy., Study Funding: none. Potential competing interests: none.

Background: Interleukin 33 (IL-33) is a cytokine involved in fibrotic disorders. We have analyzed IL-33 levels in the sera and peritoneal fluids of women with various forms of endometriosis and investigated the correlation with disease activity., Methods: We conducted a prospective laboratory study in a tertiary-care university hospital between January 2005 and December 2010. Five hundred and ten women with histologically proven endometriosis and 132 endometriosis-free controls were enrolled in this study. Complete surgical exploration of the abdominopelvic cavity was performed in each patient. Blood samples and peritoneal fluids were obtained before and during surgical procedures, respectively. IL-33 was measured by an enzyme-linked immunosorbent assay in sera and peritoneal fluids, and the concentrations correlated with the extent and the severity of endometriotic lesions., Results: IL-33 was detectable in 23.1% of serum samples from all 642 women studied and 75.0% of peritoneal fluid samples studied (44 women with endometriosis and 36 controls). Serum IL-33 was higher in deeply infiltrating endometriosis (DIE) (median, 104.9 pg/ml; range, 8.0-104.9) than in endometriosis-free women (median, 61.3 pg/ml; range, 7.5-526.0; P = 0.022) or in women affected by superficial endometriosis (median, 36.8 pg/ml; range, 7.5-179.0; P < 0.001). Peritoneal IL-33 was higher in DIE than in endometriosis-free women (median, 642.0 pg/ml; range, 25.9-3350.6 versus median, 194.2 pg/ml; range, 12.7-1818.2, respectively; P = 0.003). We found positive correlations between serum IL-33 concentration and intensity of dysmenorrhea (r = 0.174; P = 0.028) and gastrointestinal symptoms (r = 0.199; P = 0.027), total number of DIE lesions (r = 0.224; P = 0.016) and the worst DIE lesion (r = 0.299; P < 0.001)., Conclusions: In spite of the number of samples with undetectable levels, serum IL-33 is abnormally elevated in women with endometriosis and principally in DIE. Elevated serum IL-33 is correlated with the intensity of preoperative painful symptoms, and with the extent and severity of the DIE. IL-33 may be considered as a novel cytokine involved in the pathogenesis of DIE.

Background: The objective of this study was to evaluate the significance of severe preoperative pain for patients presenting with ovarian endometrioma (OMA)., Methods: Three hundred consecutive patients with histologically proven OMA were enrolled at a single university tertiary referral centre between January 2004 and May 2010. Complete surgical excision of all recognizable endometriotic lesions was performed for each patient. Pain intensity was assessed with a 10-cm visual analogue scale (VAS). Pain was considered as severe when VAS was ≥ 7. Prospective preoperative assessment of type and severity of pain symptoms (VAS) was compared with the peroperative findings (surgical removal and histological analysis) of endometriomas and associated deeply infiltrating endometriosis. Correlations were sought with univariate analysis and a multiple regression logistic model., Results: After multiple logistic regression analysis, uterosacral ligaments involvement was related with a high severity of chronic pelvic pain [odds ratios (OR) = 2.1; 95% confidence interval (CI): 1.1-4.3] and deep dyspareunia (OR = 2.0; 95% CI: 1.1-3.5); vaginal involvement was related with a higher intensity of lower urinary symptoms (OR = 13.4; 95% CI: 3.2-55.8); intestinal involvement was related with an increased severity of dysmenorrhoea (OR = 5.2; 95% CI: 2.7-10.3) and gastro-intestinal symptoms (OR = 7.1; 95% CI: 3.3-15.3)., Conclusions: In case of OMA, severe pelvic pain is significantly associated with deeply infiltrating lesions. In this situation, the practitioner should perform an appropriate preoperative imaging work-up in order to evaluate the existence of associated deep nodules and inform the patient in order to plan the surgical intervention strategy.

Background: An inverse association between BMI and endometriosis has been reported but remains controversial. We decided to evaluate the association between BMI and the different types of endometriosis, classified as superficial endometriosis (SUP), deep infiltrating endometriosis (DIE) and ovarian endometrioma (OMA)., Methods: From a prospective database of patients who underwent gynecological surgery between February 2005 and October 2008, we compared 238 patients with a histological diagnosis of endometriosis to 238 age- and smoking-status-matched controls using a prospective preoperative questionnaire and surgical data. Numerical variables means were compared for matched pairs, and non-parametric variables using Wilcoxon test. The Odds ratios for all types of endometriosis adjusted for confounding variables were computed according to predefined BMI groups [1(<18.5), 2 (≥18.5 and <22), 3(≥22 and <25), 4(≥25)], taking Group 3 as the reference population., Results: BMI was significantly lower for all 238 patients (21.70 ± 3.7 versus 23.29 ± 4.1, P < 0.001), for 101 OMA patients (21.88 ± 3.8 versus 22.99 ± 4, P < 0.038), and for 97 DIE patients (21.35 ± 3.4 versus 23.35 ± 3.8, P < 0.001) compared with their own controls, but not for the 40 SUP patients. Patients in Group 1 had adjusted odds ratios as high as 3.3 [95% confidence interval (CI): 1.6-6.8] for DIE and 2.7 (95% CI: 1.1-6.8) for OMA; in Group 2, the adjusted oddd ratios were 2.6 (95% CI: 1.3-5.5) for DIE and 2.9 (95% CI: 1.5-5.4) for OMA., Conclusions: Endometriotic patients have lower BMI than age- and smoking-status-matched controls, independent of confounding variables. Patients with the lowest BMI (<18.5) are at a high risk of DIE.

Background: Gynaecological laparoscopic surgery outcomes can be compromised by the formation of de novo adhesions. This randomized, double-blind study was designed to assess the efficacy and safety of 4% icodextrin solution (Adept(®)) in the reduction of de novo adhesion incidence compared to lactated Ringer's solution (LRS)., Methods: Patients undergoing laparoscopic surgery for removal of myomas or endometriotic cysts were treated with randomized solution as an intra-operative irrigant and 1l post-operative instillate. De novo adhesion incidence (number of sites with adhesions), severity and extent were independently scored at a second-look procedure and the efficacy of the two solutions compared. The effect of surgical covariates on adhesion formation was also investigated. Initial exploratory analysis of individual anatomical sites of clinical importance was progressed. RESULTS Of 498 patients randomized, 330 were evaluable (160 LRS--75% myomectomy/25% endometriotic cysts; 170 Adept--79% myomectomy/21% endometriotic cysts). At study completion, 76.2% LRS and 77.6% Adept had ≥ 1 de novo adhesion. The mean (SD) number of de novo adhesions was 2.58 (2.11) for Adept and 2.58 (2.38) for LRS. The treatment effect difference was not significant (P = 0.909). Assessment of surgical covariates identified significant influences on the mean number of de novo adhesions regardless of treatment, including surgery duration (P = 0.048), blood loss in myomectomy patients (P = 0.019), length of uterine incision in myomectomy patients (P < 0.001) and number of suture knots (P < 0.001). There were 15 adverse events considered treatment-related in the LRS patients (7.2%) and 18 in the Adept group (8.3%). Of 17 reported serious adverse events (9 LRS; 8 Adept) none were considered treatment-related., Conclusions: The study confirmed the safety of Adept in laparoscopic surgery. The proportion of patients with de novo adhesion formation was considerably higher than previous literature suggested. Overall there was no evidence of a clinical effect but various surgical covariates including surgery duration, blood loss, number and size of incisions, suturing and number of knots were found to influence de novo adhesion formation. The study provides direction for future research into adhesion reduction strategies in site specific surgery.

Background: The relationship between the use of oral contraception (OC) and endometriosis remains controversial. We therefore compared various characteristics of OC use and the surgical diagnosis of endometriosis histologically graded as superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) or deep infiltrating endometriosis (DIE)., Methods: This cross-sectional study included 566 patients without visible endometriosis at surgery as controls, and 410 patients with histologically proven endometriosis, categorized by their worst lesions as SUP n = 47, OMA n = 120 and DIE n = 243. Personal data, including on OC use, were prospectively collected during standardized interviews. Statistical analysis was performed using unconditional logistic regression., Results: Past OC users had an increased incidence of endometriosis (adjusted odd ratios (OR) = 2.79, 95% confidence interval (CI) 1.74-5.12, P = 0.002) of any revised American Fertility Society stage. Women who had previously used OC for severe primary dysmenorrhea were even more frequently diagnosed with endometriosis (adjusted OR = 5.6, 95% CI 3.2-9.8), especially for DIE (adjusted OR = 16.2, 95% CI 7.8-35.3). Women who had previously used OC for other reasons also had an increased risk of endometriosis, but to a lesser extent (adjusted OR = 2.6, 95% CI 1.8-4.1). The age at which OC was initiated, duration of OC use and free interval from last OC use were not significantly different between control and endometriosis women, irrespective of histological grading. Current OC users did not show an increased prevalence of endometriosis (OR = 1.22, 95% CI 0.6-2.52)., Conclusions: Our data indicate that a history of OC use for severe primary dysmenorrhea is associated with surgical diagnosis of endometriosis, especially DIE, later in life. However, this does not necessarily mean that use of OC increases the risk of developing endometriosis. Past use of OC for primary dysmenorrhea may serve as a marker for women with endometriosis and DIE.

Background: Deep infiltrating endometriosis (DIE) is presented as a disease with high recurrence risk. Bladder DIE is the most frequent location in cases of urinary endometriosis. Surgical removal has been recommended for bladder DIE but long-term outcomes remains unevaluated. The objectives of this study are to evaluate the rate of recurrence after partial cystectomy for patients presenting with bladder DIE and to outline the surgical modalities for handling associated posterior DIE nodules., Methods: Seventy-five consecutive patients with histologically proved bladder DIE were enrolled at a single tertiary academic center between June 1992 and December 2007. A partial cystectomy was performed for each patient. Complete surgical exeresis of all associated symptomatic DIE lesions was carried out during the same surgical procedure. Bladder DIE patients were classified into three groups: patients with isolated bladder DIE (Group A); patients with associated symptomatic posterior DIE (Group B); patients with associated asymptomatic posterior DIE (Group C). Bladder DIE recurrence was defined as a clinical reappearance of the disease or radiological evidence that mandated a new surgical procedure. We assessed pelvic pain symptoms pre- and post-operatively using a 10-cm visual analogue scale., Results: In a series of 627 patients with DIE, we observed 75 patients (12%) with bladder DIE. With a 50.9 +/- 44.6 months mean follow-up after partial cystectomy no patient presented evidence of bladder DIE recurrence. Post-operatively, we observed a significant improvement with respect to pain symptoms, with only two patients (2.7%) developing major complications during follow-up. Among patients with non-operated associated asymptomatic posterior DIE lesions (n = 15), a second surgical procedure indicated for pain symptoms was necessary in only one patient (6.7%)., Conclusions: For patients presenting with bladder DIE, no patients required further surgery for bladder recurrence after radical surgery consisting in partial cystectomy. Exeresis of associated posterior DIE nodules is indicated only when they are symptomatic.

Background: This study was designed to investigate the intra-operative characteristics and the risk of intra- and post-operative complications in cases of total laparoscopic hysterectomy (TLH) in overweight, obese and non-obese patients., Methods: This cohort study includes all patients undergoing TLH for benign pathologies between January 1993 and June 2007 in Cochin university hospital (Paris). Demographic and surgical data were analysed. A comparison between overweight and obese patients versus non-obese patients and multivariate analyses were performed., Results: Of 1460 patients undergoing TLH, 101 patients (6.9%) had a BMI of 30 or higher and 338 (23.2%) were overweight. After adjustment with respect to the patients' characteristics and past history (age, parity, past history of laparotomies, previous Cesarean section, menopausal status), no significant difference was found whether in terms of intra-operative (haemorrhage, transfusion, thrombosis, ureter, bladder or bowel injuries) or post-operative complications (hyperthermia, infections, fistula). Concerning the intra- and post-operative characteristics of these patients, only a significantly longer operating time was noted in the case of obesity (RR = 1.80; CI 95%: 1.16-2.81)., Conclusions: In our experience, provided that the operating technique is meticulous, the intra- and post-operative complications are not increased in the case of obesity, although the operating time is longer.

Background: Laparoscopic hysterectomy is indicated as an alternative to laparotomy when the vaginal route is potentially difficult because of an immobile uterus and a poor vaginal accessibility. The aim of this study was to evaluate the rate, the risk factors for bladder injuries in a series of 1501 laparoscopic hysterectomies indicated for benign uterine pathologies., Methods: This study was conducted retrospectively from January 1993 to 2000 and prospectively from 2001 to July 2007.The indications, patients' characteristics and complications were recorded. The overall rate of bladder injuries, the comparison of means (t test) and percentages (exact chi(2) test) between the cases and the population with no injury, the odd ratios (OR) and multivariate analysis were performed using the statistical package for the social sciences software., Results: The rate of bladder injuries was 1% (15 patients). Risks factors were previous Caesarian section [OR: 4.33, 95% confidence interval (CI): 1.53-12.30] and previous laparotomy (OR: 4.69, 95% CI: 1.59-13.8). The rate of injury decreases with the surgeons' experience and reaches a plateau of 0.4% after 100 hysterectomies performed., Conclusions: The rate of bladder injury during total laparoscopic hysterectomy is low and decreases with the surgeon's experience. Bladder injury is not linked to an increase of post-operative morbidity when recognized and repaired during the same laparoscopic procedure. The comparison with other routes of hysterectomies should take into account these risk factors.

Background: Transvaginal ultrasonography (TVUS) has important advantages compared with transrectal ultrasonography (TRUS): it is less invasive, is cost-effective, is a familiar and well-accepted approach, and anesthesia is not required. We compared the accuracy of TVUS and TRUS for diagnosing rectal wall involvement in patients presenting with histologically proved deeply infiltrating endometriosis (DIE)., Methods: Prospective study of 134 patients with histologically proved DIE underwent preoperative investigations using both TVUS and TRUS. The radiologist (TVUS) and sonographer (TRUS) were unaware of the clinical findings but knew that DIE was suspected., Results: DIE was confirmed histologically for all the patients. A rectal wall involvement was histologically proved for 75 patients (56%). For the diagnosis of infiltration of the intestinal wall, TVUS and TRUS, respectively, had a sensitivity of 90.7% and 96.0%, a specificity of 96.5% and 100.0%, a positive predictive value of 97.1% and 100.0% and a negative predictive value of 88.9% and 95.2%., Conclusions: TVUS and TRUS have similar degrees of accuracy for predicting intestinal involvement. TVUS must be the first-line imaging process to perform for patients presenting with clinically suspected DIE. The question for the coming years is to define if it is necessary for TRUS to be carried out systematically in cases of clinically suspected DIE.

Background: Matrix metalloproteinases (MMPs) may contribute to endometriosis. We tested whether eight functional polymorphisms of these genes could modify the risk of endometriosis., Methods: In this case-control study, 227 endometriosis and 241 controls were genotyped for MMP1 -1607 1G/2G, MMP2 -1575 G/A (MMP2.1), -1306 C/T (MMP2.2), MMP3 -1612 5A/6A, MMP7 -153 C/T (MMP7.1), -181 A/G (MMP7.2), MMP12 -82 A/G and MMP13-77 A/G. Association between MMP genotypes and superficial (SUP), deep infiltrating (DIE) and endometriomas (OMA) was tested for each polymorphism separately, using unconditional logistic regression and then for combined genotypes, using the combination test., Results: When considering all cases, MMP2 polymorphisms were found to be significant, mainly due to DIE (P = 0.023). A small difference between SUP and controls was found for MMP7.2 (P = 0.032) and MMP12 (P = 0.035), in the absence of correction for multiple testing. Using the combination test, the best association when comparing SUP with controls was obtained for MMP12-MMP13 (P = 0.004) for the combined genotype A/G-A/A (odds ratio = 27.60, 95% confidence interval: 2.80-272.40)., Conclusions: These data show a potential role for MMP12 -82 A/G and MMP13 -77 A/G combined polymorphisms in superficial endometriosis. As no association was found with deep infiltrating endometriosis, this combination of polymorphisms might protect from a more in-depth penetration of tissues.

Background: The aim of this study was to evaluate the risk of ureteral injuries and to discuss how to avoid their occurence after laparoscopic hysterectomy indicated for benign uterine pathologies., Methods: This observational study covers the period from January 1993 to December 2005 (retrospective study from 1993 to 2000 and prospective from 2001). We reviewed incidence, methods of diagnosis and management of ureteral injuries., Results: The rate of ureteral injuries was 0.3% (four patients). Three patients presented a ureteral fistula diagnosed secondarily some time after the operation. The fourth patient presented a ureteral injury that was diagnosed peroperatively. Three out of four of the lesions were observed on the right side. In every case, there were preoperative risk factors connected with a past history of surgery, or the lateral location of uterine myomas. All four patients needed ureterovesical reimplantation. The outcome was good in all four cases., Conclusions: The rate of ureter complications after laparoscopic hysterectomy is low and comparable to that observed after hysterectomy by laparotomy. The risk should not prevent laparoscopic hysterectomy being used more widely. Prevention depends on training in the technique and the surgeon's experience.

Background: Despite the advantages of the vaginal and laparoscopic approaches, most hysterectomies carried out involve laparotomy. The objective of this prospective observational multicentre study was to examine the routes and complications of hysterectomy for benign disorders., Methods: Of the 15 university hospitals belonging to Collégiale de Gynécologie-Obstétrique de Paris-Ile de France, 12 participated in this study that took place between June and December 2004. We analysed the characteristics of the patients, the indications for hysterectomy and intra- and post-operative complications (and their determinants) according to the surgical approach., Results: In total, 634 women underwent hysterectomy for benign disorders during the study period. The patients' mean age (+/-SD), BMI, parity and previous Caesarean sections were 51.4 +/- 10.3 years, 25 +/- 5.7 kg/m(2), 2 +/- 1.6 children and 0.2 +/- 0.6, respectively. Hysterectomy was performed by the laparoscopic, laparoscopically assisted vaginal hysterectomy (LAVH), laparotomic and vaginal routes in 19.1, 8.2, 24.4 and 48.3% of cases, respectively. The operating time was shorter with the vaginal route than with laparoscopy, laparotomy and LAVH (P < 0.0001). Intra- and post-operative complications were significantly more frequent in the laparotomic group (18%) compared with the vaginal group (8.2%), the laparoscopic group (5.8%) and the LAVH group (8.2%) (P < 0.0001). In a multivariate logistic regression model, obesity [odds ratio (OR): 2.84, 95% confidence interval (CI): 1.53-5.27, P = 0.001], history of pelvic surgery (OR: 2.47, 95% CI: 1.39-4.39, P = 0.002) and history of Caesarean section (OR: 2.04, 95% CI: 1.01-4.1, P = 0.046) were significantly associated with intra- and post-operative complications. Laparoconversion was necessary in 36 cases (7.5%) overall and was more frequent with laparoscopy and LAVH than with the vaginal route (P < 0.0001)., Conclusions: This study confirms that the vaginal route is increasingly used for hysterectomy in France and that it is the route of choice for benign disorders.

Background: To investigate whether knowledge of the anatomical distribution of histologically proven deeply infiltrating endometriosis (DIE) lesions contributes to understanding the pathogenesis., Methods: Observational study between June 1992 and December 2004 (retrospective study between 1992 and 2000; prospective study between 2001 and 2004). Continuous series of 426 patients suffering from pelvic pain who underwent complete surgical exeresis of DIE. DIE lesions were classified according to four different possibilities: (i) Firstly, DIE lesions were classified as located in the anterior or posterior pelvic compartment. (ii) Secondly, DIE were classified as left, median and right. (iii) Thirdly, DIE lesions were classified as pelvic or abdominal. (iv) Fourthly, DIE lesions that could present in a right and/or left location were classified as unilateral or bilateral., Results: These 426 patients presented 759 histologically proven DIE lesions: bladder (48 lesions; 6.3%); uterosacral (USL) (400 lesions; 52.7%); vagina (123 lesions; 16.2%); ureter (16 lesions; 2.1%) and intestine (172, 22.7%). DIE lesions are significantly more often located in the pelvis (n=730 lesions) than in the abdomen (n=29 lesions) (P<0.0001). Pelvic DIE lesions are significantly more often located in the posterior compartment of the pelvis [682 DIE lesions (93.4%) versus 48 DIE lesions (6.6%); P<0.0001]. Pelvic DIE lesions are significantly more frequently located on the left side. For patients with unilateral pelvic DIE lesions, the anatomical distribution is significantly different in the three groups: left (172 lesions; 32.0%), median (284 lesions; 52.8%) and right (82 lesions; 15.2%) (P<0.0001). For patients with lateral lesions, left DIE lesions (172 lesions; 67.8%) were found significantly more frequently than right DIE lesions (82 lesions; 32.2%) (P<0.0001). A similar predisposition was observed when we included patients with bilateral pelvic DIE lesions (P=0.0031). The same significantly asymmetric distribution is observed for total (pelvic and abdominal) DIE lesions., Conclusions: Our results demonstrate that distribution of DIE lesions is asymmetric. It is possible that this is related to the anatomical difference between the left and right hemipelvis and to the flow of peritoneal fluid. These findings support the hypothesis that retrograde menstruation of regurgitated endometrial cells is implicated in the pathogenesis of DIE.

The objective was to develop recommendations for the diagnosis and treatment of endometriosis and its associated symptoms. A working group was convened comprised of practising gynaecologists and experts in evidence-based medicine from Europe, as well as an endometriosis self-help group representative. After reviewing existing evidence-based guidelines and systematic reviews, the expert panel met on three occasions for a day during which the guideline was developed and refined. Recommendations based solely on the clinical experience of the panel were avoided as much as possible. The entire ESHRE Special Interest Group for Endometriosis and Endometrium was given the opportunity to comment on the draft guideline, after which it was available for comment on the ESHRE website for 3 months. The working group then ratified the guideline by unanimous or near-unanimous voting; finally, it was approved by the ESHRE Executive Committee. The guideline will be updated regularly, and will be made available at http://www.endometriosis.org/guidelines.html with hyperlinks to the supporting evidence, and the relevant references and abstracts. For women presenting with symptoms suggestive of endometriosis, a definitive diagnosis of most forms of endometriosis requires visual inspection of the pelvis at laparoscopy as the 'gold standard' investigation. However, pain symptoms suggestive of the disease can be treated without a definitive diagnosis using a therapeutic trial of a hormonal drug to reduce menstrual flow. In women with laparoscopically confirmed disease, suppression of ovarian function for 6 months reduces endometriosis-associated pain; all hormonal drugs studied are equally effective although their side-effects and cost profiles differ. Ablation of endometriotic lesions reduces endometriosis-associated pain and the smallest effect is seen in patients with minimal disease; there is no evidence that also performing laparoscopic uterine nerve ablation (LUNA) is necessary. In minimal-mild endometriosis, suppression of ovarian function to improve fertility is not effective, but ablation of endometriotic lesions plus adhesiolysis is effective compared to diagnostic laparoscopy alone. There is insufficient evidence available to determine whether surgical excision of moderate-severe endometriosis enhances pregnancy rates. IVF is appropriate treatment especially if there are coexisting causes of infertility and/or other treatments have failed, but IVF pregnancy rates are lower in women with endometriosis than in those with tubal infertility. The management of severe/deeply infiltrating endometriosis is complex and referral to a centre with the necessary expertise is strongly recommended. Patient self-help groups can provide invaluable counselling, support and advice.

Background: To derive a diagnostic model based on symptoms and history as assessed by a standardized questionnaire to predict posterior deep infiltrating endometriosis (DIE) among women with chronic pelvic pain symptoms., Methods: 134 women scheduled for laparoscopy for chronic pelvic pain symptoms completed a standardized self-administered questionnaire, specifically designed for the study. We compared the symptoms of the women with posterior DIE diagnosed at laparoscopy with those of the women with other disorders, and used multiple logistic regression analysis to select the best combination of symptoms for predicting posterior DIE. Cross-validation was performed with the jackknife method., Results: 51 women (38.1%) were diagnosed with posterior DIE and 83 with other disorders (61.9%). The following variables were independent predictors for posterior DIE: painful defecation during menses, severe dyspareunia (visual analogic scale > or =8), pain other than noncyclic, and previous surgery for endometriosis. The cross-validation procedure leads to a simplified diagnostic model that uses two independent predictors: painful defecation during menses and severe dyspareunia. The sensitivity of this model for diagnosing posterior DIE was 74.5%, its specificity was 68.7%, its positive likelihood ratio was 2.4, and its negative likelihood ratio was 0.4. It correctly classified 70.9% of our sample into a high-risk (with either severe dyspareunia or painful defecation during menses) and a low-risk (neither symptom) group., Conclusions: Standardized evaluation of painful symptoms is useful for screening women so that they may have adequate exploration and counselling before laparoscopic surgery for pelvic pain symptoms.

Background: Little is known about the precise nature of the relationship between dysmenorrhoea (DM) and endometriosis. Our aim was to evaluate the relationship between the severity of DM in women with posterior deep infiltrating endometriosis (DIE) and indicators of the extent of their disease., Methods: Various indicators of the extent of DIE were recorded during surgery in 209 women. The severity of their DM was assessed with a pain scale. The scale was retrospective for 155 women and prospective for 54. Correlations were sought with an ordinal logistic regression model with cumulative odds., Results: On univariate analysis the following variables were related to the severity of DM: number of previous surgical procedures for endometriosis; revised American Fertility society classification; extensiveness of adnexal adhesion; Douglas obliteration; size of the posterior DIE implant; extent of the sub-peritoneal infiltration by the posterior DIE (rectal, vaginal or both versus sub-peritoneal only). Current infertility was associated with less severe DM. After multiple regression analysis, presence of a rectal or vaginal infiltration by the posterior DIE and extensiveness of adnexal adhesion were the only factors that remained related to DM severity., Conclusions: The concept of 'very deep infiltrating endometriosis', defined as implants invading the wall of the pelvic organ, should be tested in future classification systems specifically addressed to the prediction of endometriosis-related pain.

Background: Deeply infiltrating endometriosis (DIE) is recognized as a specific entity responsible for pain. The distribution of locations and their contribution to surgical management has not been previously studied., Methods: Medical, operative and pathological reports of 241 consecutive patients with histologically proven DIE were analysed. DIE lesions were classified as: (i). bladder, defined as infiltration of the muscularis propria; (ii). uterosacral ligaments (USL), as DIE of the USL alone; (iii). vagina, as DIE of the anterior rectovaginal pouch, the posterior vaginal fornix and the retroperitoneal area in between, and (iv). intestine, as DIE of the muscularis propria., Results: A total of 241 patients presented 344 DIE lesions: USL (69.2%; 238); vaginal (14.5%; 50); bladder (6.4%; 22); intestinal (9.9%; 34). The proportion of isolated lesions differed significantly according to the DIE location: 83.2% (198) for USL DIE; 56.0% (28) for vaginal DIE; 59.0% (13) for bladder DIE; 29.4% (10) for intestinal DIE (P < 0.0001). The total number of DIE lesions varied significantly according to the location (P < 0.0001). In 39.1% of cases (9/23) intestinal lesions were multifocal. Only 20.6% (seven cases) of intestinal DIE were isolated and unifocal., Conclusions: Multifocality must be considered during the pre-operative work-up and surgical treatment of DIE. We propose a surgical classification based on the locations of DIE. Operative laparoscopy is efficient for bladder, USL and vaginal DIE. However, indications for laparotomy still exist, notably for bowel lesions.

Background: Laparoscopic surgery presents a large number of advantages over laparotomy. The goal of this work was to check whether these benefits outweigh any greater risk of complications., Methods: The study design was a meta-analysis of published data from prospective randomized clinical trials (RCT). For the period 1966 to June 2000 we searched Medline and Cochrane Controlled Trial Registers and asked the investigators for further details. Meta-analysis was carried out with the Cochrane review manager software RevMan 4.1., Results: A total of 27 prospective RCT including 3611 women (1809 treated by operative laparoscopy and 1802 treated by laparotomy) were enrolled in the meta-analysis. The overall risk of complications was significantly lower for patients operated by laparoscopic surgery [relative risk (RR) 0.59; 95% confidence interval (CI) 0.50-0.70]. There was no statistically significant difference concerning the risk of major complications with respect to the approach used (RR 1.0; 95% CI 0.60-1.65). The risk of minor complications was significantly lower for patients operated by laparoscopic surgery (RR 0.55; 95% CI 0.45-0.66). Concerning the risks of readmission, second procedure and blood transfusion, there was no difference between the two groups. Identical results were found when we performed a sensitivity analysis including or excluding studies according to the methodological score. Subgroup analysis according to how serious the surgery was (minor, major, advanced) showed a significant increase in the risk of transfusion for advanced procedures performed by laparotomy., Conclusions: Laparoscopic surgery is not inherently dangerous for patients presenting benign gynaecological pathologies. The potential risk of complications should no longer be advanced as an argument against using laparoscopic surgery rather than laparotomy for an operation when the indication allows the choice.

Background: Laparoscopic myomectomy (LM) has some advantages over laparotomy; however, it is reputed to be technically difficult, and the risk of conversion to laparotomy might be an obstacle in using this procedure. The aim of this study was to identify the pre-operative factors affecting the risk of conversion to an open procedure (either laparoscopic assisted myomectomy or laparotomy), and to develop a simple prediction model based on available pre-operative data with the use of multiple logistic regression., Methods: A total of 426 women presenting with a subserous or intramural myoma measuring 20 mm or more underwent LM between March 1989 and October 1999. Of these patients, 378 had successful LM. Forty eight patients [11.3%, 95% confidence interval (CI) 8.3--14.3] had a conversion to an open procedure. A total of 265 women had adequate pre-operative ultrasonography (US) and were used for the analysis., Results: The best prediction model included four pre-operative factors that were found to be independently related to the risk of conversion: size > or = 50 mm at US (adjusted OR = 10.3; 95% CI = 2.8--37.9), intramural type (adjusted OR = 4.3; 95% CI = 1.3--14.5), anterior location (adjusted OR = 3.4; 95% CI = 1.3-9.0) and pre-operative use of gonadotrophin-releasing hormone (GnRH) agonists (adjusted OR = 5.4; 95% CI = 2.0--14.2). The regression coefficients were then scaled and rounded to integers to provide an estimate of the risk for conversion. For a given patient with selected characteristics the predicted risk varied from 0--73%., Conclusions: This prediction model provides a useful tool that enables multiple criteria to be taken into account simultaneously to help select cases for LM. GnRH agonists should been used only in selected cases. US evaluation is essential before performing LM.

Objective: Factors responsible for the abnormal proliferation of myometrial cells that accompanies leiomyoma formation are unknown, although steroid hormones and peptide growth factors have been implicated. We hypothesized that endothelin-1 (ET-1) is a physiological regulator of tumor growth., Design: In this study, we investigated the role of ET-1 on growth of human leiomyoma cells and its synergistic effect with growth factors, as well as the signaling pathway involved in this interaction., Methods: Leiomyoma cell proliferation was assayed by [H]thymidine incorporation and cell number. Protein kinase C (PKC) isoforms were analyzed by Western blot using specific antibodies., Results: ET-1 on its own was unable to stimulate DNA synthesis but potentiated the leiomyoma cell growth effects of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), IGF-I and IGF-II. The failure of a protein tyrosine kinase (PTK) inhibitor, tyrphostin 51, to affect the potentiating effect of ET-1, supports the hypothesis of non-involvement of PTK in this process. The inhibition of PKC by calphostin C or its down-regulation by phorbol 12,13-dibutyrate (PDB) eliminated the potentiating effect of ET-1, but did not block cell proliferation induced by the growth factors alone. Five PKC isoforms (alpha, beta1, epsilon, delta and zeta) were detected in leiomyoma cells, but only phorbol ester-sensitive PKC isoforms (PKCalpha, epsilon and delta) contribute to the potentiating effect of leiomyoma cell growth by ET-1., Conclusions: We have demonstrated that ET-1 potentiates leiomyoma cell proliferation to growth factors through a PKC-dependent pathway. These findings suggest a possible involvement of ET-1 in the pathogenesis of leiomyomas.