Publication
Maignien C, Bourdon M, Parpex G, Ferreux L, Patrat C, Bordonne C, Marcellin L, Chapron C, Santulli P
• 02/2024
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.
Publication
Bourdon M, Maget AS, Jeljeli M, Doridot L, Marcellin L, Thomas M, Chêne C, Chouzenoux S, Batteux F, Chapron C, Santullli P
• 01/2024
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.
Publication
Reis FM, Chouzenoux S, Bourdon M, Jeljeli M, Chapron C, Batteux F
• 01/2024
Endometriosis is a condition characterized by increased oxidative stress and chronic inflammation, which can be treated with progestins and other progesterone receptor ligands. However, some patients are refractory to this treatment and the reason is uncertain. Here we investigated the effects of the selective progesterone receptor modulator ulipristal acetate (UPA) on proliferation, reactive oxygen species (ROS), and proinflammatory cytokine production by endometriotic cells and endometrial cells from women with histologically proven endometriosis (n = 22) and endometriosis-free controls (n = 6). Epithelial and stromal cells were isolated and treated in triplicate for 24 h with 1 μM, 10 μM, or 100 μM UPA. Cells were tested for proliferation and ROS production, while cell supernatants were assayed for interleukin (IL)-6, C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α concentrations. Proliferation, ROS production, and IL-6 and CCL2 secretion were increased in non-stimulated epithelial and stromal cells from endometriotic lesions compared to endometrial cells from endometriosis patients and controls. UPA induced a dose-dependent increase of cell proliferation only in endometriosis, while enhancing ROS production by all cell types evaluated. UPA reduced CCL2 production in controls but failed to do that in endometriosis, whereas TNF-α was undetectable. We conclude that treatment of endometriotic cells with UPA stimulated in vitro proliferation and ROS production and failed to revert the proinflammatory cytokine excess that characterized these cells, unravelling possible mechanisms of drug resistance in the treatment of endometriosis.
Publication
Fernandez H, Agostini A, Baffet H, ChabbertBuffet N, Descamps P, Estrade JP, Giraudet G, Hocke C, Salle B, Tremollieres F, Chapron C
• 11/2023
The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of new pharmacological therapies and a review that was published in 2021, most national and international guidelines now suggest a new therapeutic approach. In addition, a novel validated screening method based on patient questionnaires and analysis of 109-miRNA saliva signatures, which combines biomarkers and artificial intelligence, opens up new avenues for overcoming diagnostic challenges in patients with pelvic pain and for avoiding laparoscopic surgery when sonography and MRI are not conclusive. Dienogest (DNG) 2 mg has been a reimbursable healthcare expense in France since 2020, and, according to recent studies, it is at least as effective as combined hormonal contraception (CHC) and can be used as an alternative to CHC for first-line treatment of endometriosis-associated pain. Since 2018, the literature concerning the use of DNG has grown considerably, and the French guidelines should be modified accordingly. The levonorgestrel intrauterine system (LNG IUS) and other available progestins per os, including DNG, or the subcutaneous implant, can be offered as first-line therapy, gonadotropin-releasing hormone (GnRH) agonists with add-back therapy (ABT) as second-line therapy. Oral GnRH antagonists are promising new medical treatments for women with endometriosis-associated pain. They competitively bind to GnRH receptors in the anterior pituitary, preventing native GnRH from binding to GnRH receptors and from stimulating the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, estradiol and progesterone production is reduced. Oral GnRH antagonists will soon be on the market in France. Given their mode of action, their efficacy is comparable to that of GnRH agonists, with the advantage of oral administration and rapid action with no flare-up effect. Combination therapy with ABT is likely to allow long-term treatment with minimal impact on bone mass. GnRH antagonists with ABT may thus be offered as second-line treatment as an alternative to GnRH agonists with ABT. This article presents an update on the management of endometriosis-associated pain in women who do not have an immediate desire for pregnancy.
Publication
Hilpert J, GroettrupWolfers E, Kosturski H, Bennett L, Barnes CLK, Gude K, Gashaw I, Reif S, StegerHartmann T, Scheerans C, Solms A, Rottmann A, Mao G, Chapron C
• 09/2023
INTRODUCTION: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa. OBJECTIVE: This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period. METHODS: Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated. RESULTS: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed. CONCLUSIONS: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required. CLINICAL TRIAL REGISTRATION: NCT03373422 (date registered: November 23, 2017).
Publication
Maignien C, Hachem RE, Bourdon M, Marcellin L, Chalas C, Patrat C, GonzàlezForuria I, Chapron C, Santulli P
• 08/2023
RESEARCH QUESTION: What are the reproductive outcomes and the prognostic factors of live birth rates in patients with endometriosis referred to oocyte donation after multiple IVF failures? DESIGN: Observational cohort study including all women with endometriosis-related infertility and two or more failed IVF/intracytoplasmic sperm injection (ICSI) cycles referred to oocyte donation between January 2013 and June 2022. Endometriosis was diagnosed based on published imaging criteria, and was confirmed histologically in women who had a history of surgery for endometriosis. The main outcome measured was the cumulative live birth rate (CLBR). The characteristics of women who had a live birth were compared with those who did not using univariate and multivariate analysis to identify determinant factors of fertility outcome. RESULTS: Fifty-seven patients underwent 90 oocyte donation cycles after 244 failed autologous IVF cycles. The mean ± SD age of the population was 36.8 ± 3.3 years, with a mean duration of infertility of 3.6 ± 2.2 years, and a mean number of autologous IVF/ICSI cycles of 4.4 ± 2.3 cycles per patient. Three patients (5.3%) had superficial peritoneal endometriosis, two patients (3.5%) had ovarian endometriomas, and 52 patients (91.2%) had deep infiltrating endometriosis, among which 30 patients (57.7%) had bowel lesions. Thirty patients (52.6%) had associated adenomyosis. Overall, CLBR per patient was 36/57 (63.2%). After multivariate analysis, only being nulligravida (P=0.002) remained an independent negative predictive factor of the live birth rate. Previous surgery did not impact reproductive outcomes. CONCLUSION: This study suggests that oocyte donation appears to be a viable option to optimize the live birth rate in women with endometriosis-related infertility and recurrent IVF failures.
Publication
Bourdon M, Antoine V, Combes U, MaitrotMantelet L, Marcellin L, Maignien C, Chapron C, Santulli P
• 08/2023
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.
Publication
Bourdon M, Alwohaibi A, Maignien C, Marcellin L, Chargui A, Pocate Cheriet K, Patrat C, Chapron C, Santulli P
• 07/2023
In order to inform patients undergoing ART regarding their chances for motherhood, it seems useful to describe -'freeze all-' outcomes according to the different potential indications. The goal of this study was to examine the impact of a -'freeze-all approach-' on the cumulative live birth rate (cLBR) according to the indication. It is a cohort study including women who had undergone ovarian stimulation (OS) using an antagonist protocol with GnRH agonist triggering between 09.2016 and 09.2018 followed by a freeze-all cycle of blastocyst embryos. The ART outcomes were compared between the two main indications of the freeze-all strategy which were in our cohort: risk of ovarian hyperstimulation syndrome (OHSS) and endometriosis. The ART outcomes were also described for the others indications (inadequate endometrium and/or premature progesterone elevation at trigger day, two or more previous ART failures, and autoimmune disease and/or a high risk of thromboembolic disease (AI and/or TE risk)). In total, 658 women were included. The cLBR in the total population was 37.7% (248/658). The cLBR was significantly higher in the -'OHSS risk-' group (133/281, 47.3%) than in the -'endometriosis-' group (69/190, 36.3%) (p = 0.017). No significant differences were noted regarding perinatal outcomes, except a significantly higher risk of placenta praevia (PP) observed in the -'endometriosis-' group (10.1%) (p = 0.002). The -'freeze-all approach-' yielded good results in terms of the cLBR and especially in case of OHSS risk. These data should be taken into account when informing patients about the ART strategy and their chances of motherhood.
Publication
Marcellin L, Legay L, Santulli P, Millischer AE, Bordonne C, Maitrot Mantelet L, Maignien C, Bourdon M, Gaudet Chardonnet A, Borghese B, Goffinet F, Chapron C
• 07/2023
RESEARCH QUESTION: Is there a change in magnetic resonance imaging (MRI) criteria of diffuse and focal phenotypes of adenomyosis before and after pregnancy? DESIGN: A retrospective, monocentric, observational study in a single academic tertiary referral centre for endometriosis diagnosis and management. Women were followed for symptomatic adenomyosis, and without a prior history of surgery who give birth after 24+0 weeks. For each patient, pelvic MRI pre- and post-pregnancy was performed by two experienced radiologists with the same image acquisition protocol. Diffuse and focal adenomyosis MRI presentation were analysed before and after pregnancy. RESULTS: Between January 2010 and September 2020, of the 139 patients analysed, 96 (69.1%) had adenomyosis at MRI distributed as follow: 22 (15.8%) presented diffuse adenomyosis, 55 (39.6%) focal adenomyosis and 19 (13.7%) both phenotypes. The frequency of isolated diffuse adenomyosis on MRI was significantly lower before versus after pregnancy (n = 22 [15.8%] versus n = 41 [29.5%], P = 0.01). The frequency of isolated focal adenomyosis was significantly higher before pregnancy than after pregnancy (n = 55 [39.6%] versus n = 34 [24.5%], P = 0.01). The mean volume of all focal adenomyosis lesions on MRI decreased significantly after pregnancy, from 6.7 ± 2.5 mm3 to 6.4 ± 2.3 mm3, P = 0.01. CONCLUSION: The current data indicate that, based on MRI, there is an increase in diffuse adenomyosis and a decrease in focal adenomyosis after pregnancy.
Publication
Marcellin L, Bourdon M, Houdre D, Maignien C, Chardonnet AG, Borghese B, Mantelet LM, Santulli P, Chapron C
• 05/2023
RESEARCH QUESTION: Is a decrease in dysmenorrhoea after suppressive hormonal therapy a marker of the endometriosis phenotype and of greater disease severity? DESIGN: Retrospective observational cohort study conducted in a French university hospital, between January 2004 and December 2019. Non-pregnant women aged younger than 42 years, who tested for dysmenorrhoea relief after suppressive hormonal therapy before surgery, and who had histological confirmation of endometriosis, were included. The comparisons were carried out according to the results of the suppressive hormonal test. RESULTS: Of the 578 histologically proven endometriosis patients with preoperative pain symptoms, the rate of dysmenorrhoea decrease after suppressive hormonal therapy was 88.2% (n = 510). These patients had a higher incidence of deep infiltrating endometriosis (DIE) intestinal lesions (45.7% [233/510] versus 30.8% [21/68], P = 0.01) and an increased rate of multiple DIE lesions (two or more) (72.8% [287/394] versus 56.4% [22/39], P = 0.02). After multivariate analysis, decrease of dysmenorrhoea after suppressive hormonal therapy remained significantly associated with the severe DIE phenotype (adjusted OR 3.9, 95% CI 2.0 to 7.6, P < 0.001). CONCLUSION: In women with endometriosis, a decrease of dysmenorrhoea after suppressive hormonal therapy is associated with the DIE phenotype and is a marker of greater severity.
