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

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

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

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

Management of women with abnormal uterine bleeding: Clinical practice guidelines of the French National College of Gynaecologists and Obstetricians (CNGOF).

OBJECTIVE: To provide French guidelines for the management of women with abnormal uterine bleeding (AUB). DESIGN: A consensus committee of 26 experts was formed. A formal conflict-of-interest policy was developed at the beginning of the process and enforced throughout. The entire guidelines process was conducted independently of any industry funding (i.e. pharmaceutical or medical device companies). The authors were advised to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. METHODS: The last guidelines from the Collège National des Gynécologues et Obstétriciens Français on the management of women with AUB were published in 2008. The literature seems now sufficient for an update. The committee studied questions within 7 fields (diagnosis; adolescents; idiopathic AUB; endometrial hyperplasia and polyps; type 0-2 fibroids; type 3 or higher fibroids; and adenomyosis). Each question was formulated in a PICO (Patients, Intervention, Comparison, Outcome) format and evidence profiles were compiled. The GRADE® methodology was applied to the literature review and the formulation of recommendations. RESULTS: The experts' synthesis work and the application of the GRADE method resulted in 36 recommendations. Among the formalized recommendations, 19 are strong and 17 weak. No response was found in the literature for 14 questions. We chose to abstain from recommendations rather than providing advice based solely on expert clinical experience. CONCLUSIONS: The 36 recommendations make it possible to specify the diagnostic and therapeutic strategies for various clinical situations practitioners encounter, from the simplest to the most complex.

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

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

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

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

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

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

[Management of women with abnormal uterine bleeding: Clinical practice guidelines of the French National College of Gynecologists and Obstetricians (CNGOF)]. / Prise en charge des ménorragies : recommandations pour la pratique clinique du Collège national des gynécologues et obstétriciens français (CNGOF).

OBJECTIVE: To provide French guidelines for the management of women with abnormal uterine bleeding (AUB). DESIGN: A consensus committee of 26 experts was formed. A formal conflict-of-interest (COI) policy was developed at the beginning of the process and enforced throughout. The entire guidelines process was conducted independently of any industrial funding (i.e. pharmaceutical, or medical devices). The authors were advised to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. METHODS: The last guidelines from the Collège national des gynécologues et obstétriciens français (CNGOF) on the management of women with AUB was published in 2008. The literature seems now sufficient for an update. The committee studied questions within 7 fields (diagnosis; adolescent; idiopathic AUB; endometrial hyperplasia and polyps; fibroids type 0 to 2; fibroids type 3 and more; adenomyosis). Each question was formulated in a PICO (Patients, Intervention, Comparison, Outcome) format and the evidence profiles were produced. The literature review and recommendations were made according to the GRADE® methodology. RESULTS: The experts' synthesis work and the application of the GRADE method resulted in 36 recommendations. Among the formalized recommendations, 19 present a strong agreement and 17 a weak agreement. Fourteen questions did not find any response in the literature. We preferred to abstain from recommending instead of providing expert advice. CONCLUSIONS: The 36 recommendations made it possible to specify the diagnostic and therapeutic strategies of various clinical situations managed by the practitioner, from the simplest to the most complex.

[Adenomyosis pathophysiology: An unresolved enigma]. / Physiopathologie de l'adénomyose : une énigme non résolue.

Adenomyosis is a chronic benign uterine disease characterized by the presence of endometrial glands and stroma within the myometrium. It is a heterogeneous disease, presenting various clinical forms, depending on the location of the ectopic lesions within the myometrium. Adenomyosis can be responsible for several symptoms such as dysmenorrhea, abnormal uterine bleeding and/or infertility. Its pathophysiology is a real conundrum and several theories have been proposed: development of adenomyosis lesion could initiate de novo from Mullerian rests or from stem cells. Moreover, multiple factors could be involved in initiating lesions, including specific hormonal, immune and/or genetic changes. The objective of this review is to provide an update on adenomyosis pathophysiology, in particular on the various theories proposed concerning the invasion of the myometrium by endometrial cells and the inducing mechanisms, and to study the link between the physiopathology, the symptoms and the medical treatments.

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

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

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

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

Immunological changes associated with adenomyosis: a systematic review.

BACKGROUND: Adenomyosis is a benign gynecological disorder associated with subfertility, pelvic pain and abnormal uterine bleeding that have significant consequences for the health and quality of life of women. Histologically, it is defined as the presence of ectopic endometrial islets within the myometrium. Its pathogenesis has not yet been elucidated and several pieces of the puzzle are still missing. One process involved in the development of adenomyosis is the increased capacity of some endometrial cells to infiltrate the myometrium. Moreover, the local and systemic immune systems are associated with the onset of the disease and with maintaining it. Numerous observations have highlighted the activation of immune cells and the release of immune soluble factors in adenomyosis. The contribution of immunity occurs in conjunction with hormonal aberrations and activation of the epithelial to mesenchymal transition (EMT) pathway, which promotes migration of endometrial cells. Here, we review current knowledge on the immunological changes in adenomyosis, with the aim of further elucidation of the pathogenesis of this disease. OBJECTIVE AND RATIONALE: The objective was to systematically review the literature regarding the role of the immune system in development of adenomyosis in the inner and the outer myometrium, in humans. SEARCH METHODS: A systematic review of published human studies was performed in MEDLINE, EMBASE and Cochrane Library databases from 1970 to February 2019 using the combination of Medical Subject Headings (MeSH): Adenomyosis AND ('Immune System' OR 'Gonadal Steroid Hormones'), and free-text terms for the following search terms (and their variants): Adenomyosis AND (immunity OR immune OR macrophage OR 'natural killer cell' OR lymphocyte* OR leucocyte* OR HLA OR inflammation OR 'sex steroid' OR 'epithelial to mesenchymal transition' OR 'EMT'). Studies in which no comparison was made with control patients, without adenomyosis (systemic sample and/or eutopic endometrium), were excluded. OUTCOMES: A total of 42 articles were included in our systematic review. Changes in innate and adaptive immune cell numbers were described in the eutopic and/or ectopic endometrium of women with adenomyosis compared to disease-free counterparts. They mostly described an increase in lymphocyte and macrophage cell populations in adenomyosis eutopic endometrium compared to controls. These observations underscore the immune contributions to the disease pathogenesis. Thirty-one cytokines and other markers involved in immune pathways were studied in the included articles. Pro-inflammatory cytokines (interleukin (IL) 6, IL1ß, interferon (IFN) α, tumor necrosis factor α, IFNγ) as well as anti-inflammatory or regulatory mediators (IL10, transforming growth factor ߅) were found to be elevated in the eutopic endometrium and/or in the ectopic endometrium of the myometrium in women with adenomyosis compared to controls. Moreover, in women affected by adenomyosis, immunity was reported to be directly or indirectly linked to sex steroid hormone aberrations (notably changes in progesterone receptor in eutopic and ectopic endometrium) in three studies and to EMT in four studies. WIDER IMPLICATIONS: The available literature clearly depicts immunological changes that are associated with adenomyosis. Both systemic and local immune changes have been described in women affected by adenomyosis, with the coexistence of changes in inflammatory as well as anti-inflammatory signals. It is likely that these immune changes, through an EMT mechanism, stimulate the migration of endometrial cells into the myometrium that, together with an endocrine imbalance, promote this inflammatory process. In light of the considerable impact of adenomyosis on women's health, a better understanding of the role played by the immune system in adenomyosis is likely to yield new research opportunities to better understand its pathogenesis.

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

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

Metastatic mediastinal mature teratoma with malignant transformation in a young man with an adenocarcinoma in a Klinefelter's syndrome: Case report and review of the literature.

Malignant transformation of mediastinal mature teratoma is extremely rare and worsens the prognosis of the disease. Transformation can appear synchronously to or several years after the initial diagnosis. Clinical and radiological signs can orientate the clinician but the definitive diagnosis is obtained thanks to histology. An 11 year-old boy presented with a mediastinal mature teratoma and bone and pulmonary metastases. He received six cycles of chemotherapy combining etoposide, ifosfamide, cisplatin, followed by resection of a 16×14×9cm mediastinal mass. Karyotype analysis revealed the presence of an additional sex chromosome X (47 XXY) pathognomonic of Klinefelter's syndrome. Ten years later, sciatalgia revealed malignant transformation of a pre-existing sacral bone metastasis into gastrointestinal adenocarcinoma. The patient received four cycles of chemotherapy combining oxaliplatin, 5-fluorouracil and cetuximab. This treatment was followed by a complete resection of the sacral metastasis and completed with adjuvant irradiation of 54Gy in 30 daily fractions. Twelve months after the diagnosis of relapse, the patient remained alive without disease. To our knowledge, this is the first case of adenocarcinoma developed in bone metastases of a mediastinal mature teratoma in a boy with a Klinefelter's syndrome. We propose a review of the literature and an analysis of 20 others published cases of mediastinal teratoma with malignant transformation into adenocarcinoma.

[Definition, description, clinicopathological features, pathogenesis and natural history of endometriosis: CNGOF-HAS Endometriosis Guidelines]. / Définition, description, formes anatomo-cliniques, pathogenèse et histoire naturelle de l'endométriose, RPC Endométriose CNGOF-HAS.

Endometriosis and adenomyosis are histologically defined. The frequency of endometriosis cannot be precisely estimated in the general population. Endometriosis is considered a disease when it causes pain and/or infertility. Endometriosis is a heterogeneous disease with three well-recognized subtypes that are often associated with each other: superficial endometriosis (SUP), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE). DIE is frequently multifocal and mainly affects the following structures: the uterosacral ligaments, the posterior vaginal cul-de-sac, the bladder, the ureters, and the digestive tract (rectum, recto-sigmoid junction, appendix). The role of menstrual reflux in the pathophysiology of endometriosis is major and explains the asymmetric distribution of lesions, which predominate in the posterior compartment of the pelvis and on the left (NP3). All factors favoring menstrual reflux increase the risk of endometriosis (early menarche, short cycles, AUB, etc.). Inflammation and biosteroid hormones synthesis are the main mechanisms favoring the implantation and the growth of the lesions. Pain associated with endometriosis can be explained by nociception, hyperalgia, and central sensitization, associated to varying degrees in a single patient. Typology of pain (dysmenorrhea, deep dyspareunia, digestive or urinary symptoms) is correlated with the location of the lesions. Infertility associated with endometriosis can be explained by several non-exclusive mechanisms: a pelvic factor (inflammation), disrupting natural fertilization; an ovarian factor, related to oocyte quality and/or quantity; a uterine factor disrupting implantation. The pelvic factor can be fixed by surgical excision of the lesions that improves the chance of natural conception (NP2). The uterine factor can be corrected by an ovulation-blocking treatment that improves the chances of getting pregnant by in vitro fertilization (NP2). The impact of endometrioma exeresis on the ovarian reserve (NP2) should be considered when a surgery is scheduled. Endometriosis is a multifactorial disease, resulting from combined action of genetic and environmental factors. The risk of developing endometriosis for a first-degree relative is five times higher than in the general population (NP2). Identification of genetic variants involved in the disease has no implication for clinical practice for the moment. The role of environmental factors, particularly endocrine disrupters, is plausible but not demonstrated. Literature review does not support the progression of endometriosis over time, either in terms of the volume or the number of the lesions (NP3). The risk of acute digestive occlusion or functional loss of a kidney in patients followed for endometriosis seems exceptional. These complications were revealing the disease in the majority of cases. IVF does not increase the intensity of pain associated with endometriosis (NP2). There is few data on the influence of pregnancy on the lesions, except the possibility of a decidualization of the lesions that may give them a suspicious aspect on imaging. The impact of endometriosis on pregnancy is debated. There is an epidemiological association between endometriosis and rare subtypes of ovarian cancer (endometrioid and clear cell carcinomas) (NP2). However, the relative risk is moderate (around 1.3) (NP2) and the causal relationship between endometriosis and ovarian cancer is not demonstrated so far. Considering the low incidence of endometriosis-associated ovarian cancer, there is no argument to propose a screening or a risk reducing strategy for the patients.

Conservative management of an atypical intra-sinusal ossifying fibroma associated to an aneurysmal bone cyst.

Ossifying fibroma (OF) is a benign fibro-osseous lesion mainly occurring in young adults and seems to originate from the periodontal ligament. Aneurysmal bone cyst (ABC) is a benign intraosseous lesion characterized by blood-filled spaces of various sizes. These two lesions can specifically affect the jaws and are commonly described in the literature. However, few cases describing an association of OF and ABC have been reported in the literature, especially in the maxillary sinus. We report the case of a 40-year-old male patient affected with an asymptomatic lesion with a dual component of OF and ABC laying in the maxillary sinus. Our aim is to discuss its clinical and morphological features as well as treatment results.

[Bowel endometriosis and infertility: Do we need to operate?] / Infertilité et endométriose digestive : faut-il opérer ?

Endometriosis is a benign chronic inflammatory disease, whose pathogenesis is still unclear. Endometriosis is responsible for infertility and/or pelvic pain. One of the most important features of the disease is the heterogeneity (clinical and anatomical: superficial peritoneal, ovarian and/or deep infiltrating lesions). Bowel involvement constitutes one particularly severe form of the disease, affecting 8-12% of women with deep endometriosis. In case of associated infertility, bowel endometriosis constitutes a real therapeutic challenge for gynecologists. Indeed, while complete resection of the lesions alleviates pain and seems to improve spontaneous fertility, surgery remains technically challenging and may cause severe complications. Reverting to assisted Reproductive Technology (ART) is another valuable therapeutic option regarding pregnancy rates. Thus, the choice between surgical management or ART is still debated. Benefits and risks of these two options should be considered and discussed before planning treatment. In the present study, we aimed to answer the question: Bowel endometriosis and infertility: do we need to operate?

rFSH in medically assisted procreation: Evidence for ovarian follicular hyperplasia and interest of mass spectrometry to measure 17-hydroxyprogesterone and Δ4-androstenedione in serum.

Ovarian monitoring requires the determination of serum estradiol and progesterone levels. We investigated whole follicular steroidogenesis under rFSH in medically assisted procreation (MAP: 26 IVF, 24 ICSI) compared to 11 controls (IUI). Estrone, estradiol, Δ4-androstenedione, testosterone, progesterone and 17-hydroxyprogesterone were measured by immunoassay and mass spectrometry except for estrogens. At the start of a spontaneous or induced cycle, steroids levels fluctuated within normal ranges: estradiol (314-585 pmol/L), estrone (165-379 pmol/L) testosterone (1.3-1.6 nmol/L), Δ4-androstenedione (4.5-5.6 nmol/L), 17-hydroxyprogesterone (2.1-2.2 nmol/L) and progesterone (1.8-1.9 nmol/L). 17-hydroxyprogesterone, Δ 4-androstenedione and estradiol predominated. Then estradiol and oestrone levels rise, but less markedly for oestrone in IUI. In MAP, rFSH injections induce a sharp increase in estrogens associated with a rise in 17-hydroxyprogesterone and Δ4-androstenedione levels, disrupting oestrogen/androgen ratios. rFSH stimulation induces an ovarian hyperplasia and Δ4pathway which could become abnormal. Determining 17-hydroxyprogesterone and Δ4-androstenedione levels with LC-MS/MS may therefore be useful in managing recurrent MAP failures.

Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis.

The redox-sensitive nuclear factor erythroid-derived 2-like 2 (NRF2) controls endogenous antioxidant enzymes' transcription and protects against oxidative damage which is triggered by inflammation and known to favor progression of endometriosis. Glutamate Cysteine Ligase (GCL), a target gene of NRF2, is the first enzyme in the synthesis cascade of glutathione, an important endogenous antioxidant. Sixty-one patients, with thorough surgical examination of the abdominopelvic cavity, were recruited for the study: 31 with histologically-proven endometriosis and 30 disease-free women taken as controls. Expressions of NRF2 and GCL were investigated by quantitative RT-PCR and immunohistochemistry in eutopic and ectopic endometria from endometriosis-affected women and in endometrium of disease-free women. Ex vivo stromal and epithelial cells were extracted and purified from endometrial and endometriotic biopsies to explore expression of NRF2 and GCL in both stromal and epithelial compartments by western blot. Finally, in order to strengthen the role of NRF2 in endometriosis pathogenesis, we evaluated the drop of NRF2 expression in a mouse model of endometriosis using NRF2 knockout (NRF2-/-) mice. The mRNA levels of NRF2 and GCL were significantly lower in ectopic endometria of endometriosis-affected women compared to eutopic endometria of disease-free women. The immunohistochemical analysis confirmed the decreased expression of both NRF2 and GCL in ectopic endometriotic tissues compared to eutopic endometria of endometriosis-affected and disease-free women. Immunoblotting revealed a significant decreased of NRF2 and GCL expression in epithelial and stroma cells from ectopic lesions of endometriosis-affected women compared to eutopic endometria from controls. Using a murine model of endometriosis, NRF2-/- implants were more fibrotic compared to wild-type with an increased weight and volume. These findings indicate that expression of the transcription factor NRF2 and its effector GCL are both profoundly deregulated in endometriotic lesions towards increased growth and fibrogenetic processes.

[Conservative management of endometrioma in women undergoing in vitro fertilization]. / Traitement conservateur des endométriomes chez les patientes prises en charge en FIV.

Endometriosis is a chronic disease. The pathogenesis is actually still unclear. Endometriosis is responsible for infertility and/or pelvic pain. One of the most important features of the disease is the heterogeneity (clinical and anatomical). Among the different phenotypes of endometriosis, the ovarian endometrioma seems to most important lesion in the management of endometriosis-related infertility. Surgical treatment is associated to a decrease of the ovarian reserve and a potential detrimental effect on in vitro fecondation (IVF) outcomes. Thus, the choice between conservative or surgical management of endometrioma before IVF is actually debated. The advantages and drawback of surgical and conservative management should be discussed before to plan the treatment. In the present review, we aimed at assessing the risks of a conservative management of endometrioma as compared to surgery before IVF.