Publication
Millischer AE, Santulli P, Da Costa S, Bordonne C, Cazaubon E, Marcellin L, Chapron C
• 04/2023
OBJECTIVE: To evaluate the prevalence on magnetic resonance imaging (MRI) of ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE) in adolescents presenting with severe dysmenorrhea. DESIGN: Prospective study. SETTING: Clinic. PATIENT(S): A total of 345 adolescents aged 12-20 years referred to the radiologic MRI department unit between September 2019 and June 2020. INTERVENTION(S): Multiplanar pelvic MRI with cine MRI was performed. Data on the medical history with systematic questioning were collected for each patient before the scan. MAIN OUTCOME MEASURE(S): Data on the endometriosis phenotypes (OMA and/or DIE), distribution of anatomical lesions, and adenomyosis were evaluated and recorded using a dedicated MRI spreadsheet. Myometrial contractions were systematically reported for each case. The data were correlated with the characteristics of the patients and severity of painful symptoms evaluated using a visual analog scale. RESULT(S): The prevalence rates of endometriosis and adenomyosis were 39.3% (121 patients) and 11.4% (35 patients), respectively. Among the adolescents with endometriosis, 25 (20.7%) presented with OMA, and 107 (88.4%) presented with DIE. The odds ratios (confidence intervals) for each pairwise comparison between the age distributions were 2.3 (1.4-3.8) for 15-18 vs. <15 years of age and 3.3 (1.2-8.5) for 18-20 vs. <15 years of age, highlighting a predominance of cases after 18 years of age. Uterine contractions were visualized in 34.4% of cases, with no particular association with endometriosis. No clinical risk factor was identified as being particularly associated with endometriosis. Notably, the visual analog scale score was the same for cases with and without endometriosis. CONCLUSION(S): Severe endometriosis phenotypes (OMA and/or DIE) can be observed in adolescents with intense dysmenorrhea, with a linear increase in prevalence over time resulting in a clear predominance after 18 years of age. Endometriosis in adolescents is a challenging clinical problem with a long delay in diagnosis. Imaging can help reduce this delay in young patients with suggestive symptoms. CLINICAL TRIAL REGISTRATION NUMBER: NCT05153512.
Publication
Collin M, Barat M, Oudjit A, Terris B, Dohan A, Rousset P, Chapron C, Marcellin L, Dousset B, Soyer P
• 04/2023
OBJECTIVE: To compare computed tomography-enterography (CTE) and magnetic resonance-enterography (MRE) in the detection of right-sided bowel deep infiltrating endometriosis (DIE). MATERIALS AND METHODS: Fifty women with DIE who underwent preoperatively CTE and MRE were included. CTE and MRE were first analyzed separately by two independent readers who analyzed five bowel segments (cecum, appendix, ileocecal junction, distal ileum and proximal small bowel [i.e., proximal ileum and jejunum]) for the presence of DIE and then interpreted in consensus. CTE, MRE and CTE with MRE were compared in terms of sensitivity, specificity and accuracy. Interobserver agreement was assessed with kappa (κ) test. RESULTS: Using the reference standard 25 out 250 bowel segments were involved by DIE in 18 women and 225 were free of DIE. Sensitivity, specificity, and accuracy of CTE were 60% (95% confidence interval [CI]: 39-79), 93% (95% CI: 89-96) and 90% (95% CI: 85-93) for Reader 1, respectively, and 52% (95% CI: 31-72), 99% (95% CI: 97-100) and 94% (95% CI: 91-97) for Reader 2, with no differences in sensitivity (P = 0.564) and specificity (P = 0.181) between readers and fair interobserver agreement (κ = 0.37). For MRE these figures were 52% (95% CI: 31-72), 92% (95% CI: 88-95) and 88% (95% CI: 84-92) for Reader 1 and 60% (95% CI: 39-79), 99% (95% CI: 96-100) and 95% (95% CI: 91-97) for Reader 2, with no differences in sensitivity (P = 0.157) and specificity (P = 0.061) between readers and fair interobserver agreement (κ = 0.31). Significant differences in sensitivity (20%; 95% CI: 7-41) were found between CTE + MRE vs. CTE alone for Reader 1 and vs. MRE alone for Reader 2 (P = 0.041 for both) CONCLUSION: CTE and MRE have not different sensitivities and convey only fair interobserver agreement but are highly specific for the diagnosis of right-sided bowel DIE. CTE and MRE are complementary because they improve the detection of DIE implants when used in combination.
Publication
Bourdon M, Ouazana M, Maignien C, Pocate Cheriet K, Patrat C, Marcellin L, Gonnot J, Cervantes C, Laviron E, Blanchet V, Chapron C, Santulli P
• 03/2023
INTRODUCTION: Embryo transfer(ET) is one of the main procedures to become pregnant by assisted reproductive technology(ART). Simulation training is a way to improve the skills of clinicians. The objective of this study was to evaluate the interest of trainees in learning embryo transfer using simulators. MATERIAL AND METHODS: An observational study was conducted at the University hospital-based research center. Trainees, comprising midwives and resident or graduated gynecologists, who attended the medical training for infertility and ART in June 2019, were included. They trained on two ET simulators (Simulator A and B) and complete an anonymously online questionnaire. A sub-group analysis focusing on graduated gynecologists not performing ET in current practice, was performed. RESULTS: Thirty-two trainees were included. Trainees felt that ET simulators should be used in medical education to promote learning how to perform the ET procedure (n=26, 81.3% for Simulator A and n=21, 65.5% for Simulator B; p=0.31). The use of both simulators improved the level of self-confidence (81.3% and 75.0% respectively; p=0.55). Significant differences in the global and in the subgroup analysis (n=24) in favor of Simulator A were observed regarding learning the precision of the ET procedure (p<0.01), the pathway to introduce the catheter into the uterine cavity (p<0.05), and the guidance for proper placement of the catheter into the uterine cavity (p=0.03). In the subgroup analysis of graduated gynecologists not performing ET in current practice, Simulator A was found more realistic for the visualization of the introduction of the catheter into the uterine cavity (p=0.01) and more useful to learn about difficult cases (p=0.03). CONCLUSION: Students expressed a high level of interest in ET simulators to improve their skills. Although the simulators displayed some differences regarding learning the precision of the ET procedure, both improved the level of self-confidence. This new learning method needs to be further developed in order to offer to trainees the most realistic simulators. TRIAL REGISTRATION: This study was approved for publication by the Ethics Review Committee of the Cochin University Hospital (CLEP) (n° AAA-2020-08016) retrospectively registered.
Publication
Barrière P, Hamamah S, Arbo E, Avril C, Salle B, Pouly JL, Jenkins J; REOLA study group
• 01/2023
BACKGROUND: Since the first launch of a biosimilar recombinant follicle stimulating hormone (rFSH), Bemfola®, in Europe in 2014, it has been possible to study in routine clinical care throughout France the effectiveness of a biosimilar rFSH including according to different rFSH starting doses. METHODS: REOLA was a non-interventional, retrospective, real world study using anonymized data from 17 Assisted Reproductive Technology (ART) centres' data management systems across France including 2,319 ART ovarian stimulation cycles with Bemfola® and 4,287 ART ovarian stimulation cycles with Gonal-f®. For both products, four populations were studied according to starting dose of rFSH: < 150 IU, 150 - 224 IU, 225 - 299 IU and ≥ 300 IU. The primary endpoint was the cumulative live birth rate (cLBR) per commenced ART ovarian stimulation cycle including all subsequent fresh and frozen-thawed embryo transfers starting during a follow up period of at least 1 year following oocyte retrieval. RESULTS: A direct relationship of increasing rFSH starting dose with increasing age, increasing basal FSH, decreasing AMH and increasing body mass index was noted. No clinically relevant differences were seen in all outcomes reported, including the cLBR, between Bemfola® and Gonal-f®, but for both drugs, an association was seen with increasing rFSH starting dose and decreasing cLBR. CONCLUSIONS: The REOLA study demonstrates that the cLBR with Bemfola® is very similar to Gonal-f® across all patient subpopulations. The cLBR is inversely related to the rFSH starting dose irrespective of the drug used, and the REOLA study provides reassurance of the clinical effectiveness of a biosimilar rFSH used in a real world setting.
Publication
Kim MR, Chapron C, Römer T, Aguilar A, Chalermchockcharoenkit A, Chatterjee S, Dao LTA, Fong YF, Hendarto H, Hidayat ST, Khong SY, Ma L, Kumar P, Primariawan RY, Siow A, Sophonsritsuk A, Devi Thirunavukarasu R, Thuong BC, Yen CF
• 12/2022
This work provides consensus guidance regarding clinical diagnosis and early medical management of endometriosis within Asia. Clinicians with expertise in endometriosis critically evaluated available evidence on clinical diagnosis and early medical management and their applicability to current clinical practices. Clinical diagnosis should focus on symptom recognition, which can be presumed to be endometriosis without laparoscopic confirmation. Transvaginal sonography can be appropriate for diagnosing pelvic endometriosis in select patients. For early empiric treatment, management of women with clinical presentation suggestive of endometriosis should be individualized and consider presentation and therapeutic need. Medical treatment is recommended to reduce endometriosis-associated pelvic pain for patients with no immediate pregnancy desires. Hormonal treatment can be considered for pelvic pain with a clinical endometriosis diagnosis; progestins are a first-line management option for early medical treatment, with oral progestin-based therapies generally a better option compared with combined oral contraceptives because of their safety profile. Dienogest can be used long-term if needed and a larger evidence base supports dienogest use compared with gonadotropin-releasing hormone agonists (GnRHa) as first-line medical therapy. GnRHa may be considered for first-line therapy in some specific situations or as short-term therapy before dienogest and non-steroidal anti-inflammatory drugs as add-on therapy for endometriosis-associated pelvic pain.
Publication
Bourdon M, Dahan Y, Maignien C, Patrat C, Bordonne C, Marcellin L, Chapron C, Santulli P
• 12/2022
RESEARCH QUESTION: Does endometrioma size affect the number of oocytes retrieved after ovarian stimulation in women with endometriosis-related infertility undergoing IVF/intracytoplasmic sperm injection (ICSI)? DESIGN: Cohort study of infertile women with unilateral or bilateral endometrioma(s) associated with deep infiltrating endometriosis, undergoing their first IVF/ICSI cycle between January 2014 and November 2021. A total of 326 women with an adequate imaging work-up with transvaginal ultrasound and/or magnetic resonance imaging performed by senior radiologists before the start of ovarian stimulation was included. Prognostic factors associated with the number of oocytes retrieved were analysed. IVF/ICSI outcomes were compared between five groups defined according to the largest endometrioma diameter (<2, 2 to <4, 4 to <6, 6 to <8 and ≥8 cm). RESULTS: Factors that significantly reduced the number of oocytes retrieved after adjustment by multiple linear regression were women's age (regression coefficient -0.18; 95% confidence interval [95% CI] -0.31 to-0.06; P = 0.005), smoking habit (-2.02; 95% CI -3.42 to -0.62; P = 0.005), day 3 FSH concentration (-0.20; 95% CI -0.39 to -0.02; P = 0.031) and a previous history of surgery for ovarian endometriosis (-1.32; 95% CI -2.63 to -0.02; P = 0.047). Antral follicle count and oestradiol concentration on the trigger day were positively correlated with the number of oocytes retrieved (0.14; 95% CI 0.08 to 0.19; P < 0.001 and 0.003; 95% CI 0.002 to 0.004; P < 0.001, respectively). The mean number of oocytes retrieved was not significantly different between the five groups (P = 0.413), nor were the cumulative live birth rate, the number of cancelled cycles and perinatal outcomes. CONCLUSIONS: No significant difference in the number of oocytes retrieved was observed according to endometrioma size. This study suggests that ovarian stimulation can be of benefit to women irrespective of the endometrioma size.
Publication
Maignien C, Bourdon M, Marcellin L, Guibourdenche J, Chargui A, Patrat C, PluBureau G, Chapron C, Santulli P
• 10/2022
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.
Publication
Beinse G, Just PA(#), Le Frere Belda MA(#), LaurentPuig P, Jacques S, Koual M, Garinet S, Leroy K, Delanoy N, Blons H, Gervais C, Durdux C, Chapron C, Goldwasser F, Terris B, Badoual C, Taly V, Bats AS(#), Borghese B(#), Alexandre J(#)
• 10/2022
BACKGROUND: Molecular alterations leading to homologous recombination deficiency (HRD) are heterogeneous. We aimed to identify a transcriptional profile shared by endometrial (UCEC), breast (BRCA) and ovarian (OV) cancers with HRD. METHODS: Genes differentially expressed with HRD genomic score (continuous gHRD score) in UCEC/BRCA/OV were identified using edgeR, and used to train a RNAseq score (ridge-regression model) predictive of the gHRD score (PanCanAtlas, N = 1684 samples). The RNAseq score was applied in independent gynaecological datasets (CARPEM/CPTAC/SCAN/TCGA, N = 4038 samples). Validations used ROC curves, linear regressions and Pearson correlations. Overall survival (OS) analyses used Kaplan-Meier curves and Cox models. RESULTS: In total, 656 genes were commonly up/downregulated with gHRD score in UCEC/BRCA/OV. Upregulated genes were enriched for nuclear/chromatin/DNA-repair processes, while downregulated genes for cytoskeleton (gene ontologies). The RNAseq score correlated with gHRD score in independent gynaecological cancers (R² = 0.4-0.7, Pearson correlation = 0.64-0.86, all P < 10-11), and was predictive of gHRD score >42 (RNAseq HRD profile; AUC = 0.95/0.92/0.78 in UCEC/BRCA/OV). RNAseq HRD profile was associated (i) with better OS in platinum-treated advanced TP53-mutated-UCEC (P < 0.001) and OV (P = 0.013), and (ii) with poorer OS (P < 0.001) and higher benefit of adjuvant chemotherapy in Stage I-III BRCA (interaction test, P < 0.001). CONCLUSIONS: UCEC/BRCA/OV with HRD-associated genomic scars share a common transcriptional profile. RNAseq signatures might be relevant for identifying HRD-gynaecological cancers, for prognostication and for therapeutic decision.
Publication
Donnez J, Carmona F, MaitrotMantelet L, Dolmans MM, Chapron C
• 10/2022
Abnormal uterine bleeding (AUB) is a clinical entity which can lead to iron deficiency anemia. Classification according to the acronym PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy, and hyperplasia; coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not otherwise classified) provides a structured approach to establish the cause of AUB. The goal of this review is to discuss the different mechanisms and the relationship between uterine disorders and AUB. Heavy menstrual bleeding, a subgroup of AUB, is more closely related to the presence of uterine fibroids. The relationship between heavy menstrual bleeding and uterine fibroids remains poorly characterized, particularly the understanding of endometrial function in women with structural myometrial features such as leiomyomas. A number of theories have been proposed in the literature and are discussed in this review. Uterine adenomyosis is also a frequent cause of AUB, and its pathogenesis is still far from being fully elucidated. The mechanisms contributing to its development are multifactorial. Many theories lean toward invasion of the myometrium by endometrial cells. Both clinical and basic studies favor the theory of direct invasion, although de novo development of adenomyosis from Müllerian rests or stem cells has not been ruled out. Development of adenomyotic lesions involves repeated tissue injury and repair. In addition, this review describes the other causes of AUB such as endometrial polyps, cesarean scar defects, and uterine vascular abnormalities. Endometrial polyps are often asymptomatic, but approximately 68% of women have concomitant AUB. Histologic alterations in the lower uterine segment in patients who had undergone cesarean sections were identified and may explain the cause of AUB.
Publication
Tellum T, Naftalin J, Chapron C, Dueholm M, Guo SW, Hirsch M, Larby ER, Munro MG, Saridogan E, van der Spuy ZM, Jurkovic D
• 08/2022
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.
