#ESHREjc report: diagnosing endometriosis loosens the Gordian knot of infertility treatment

The path to the characterization of endometriosis since its first discovery by Karl von Rokitansky 150 years ago has been a rocky one (von Rokitansky, 1860). Linking histology to clinical observations was perplexed by infamous theories, such as Sigmund Freud’s attributing endometriosis symptoms to ‘hysteria’, but eventually defined a milestone that allowed progress into the development of endometriosis diagnostics. Laparoscopic surgery has been the gold standard to reliably visualize endometriosis lesions for years but non-invasive imaging methods are emerging (Leonardi et al., 2020). The recent ESHRE guidelines call for a refinement of the concept of surgery as the only diagnostic tool, calling it ‘an outdated dogma’ (Members of the Endometriosis Guideline Core Group et al., 2022). If we consider the general lack of awareness, the differences in symptomatology, the many unknown aspects of its pathophysiology, and finally the debate about diagnostic gold standard, it is not surprising that diagnosing endometriosis can take up to 7 years (Arruda et al., 2003). The March edition of #ESHREjc featured a recent Human Reproduction article from Katrina Moss and colleagues that sought to explore whether the delay in the diagnosis of endometriosis altered ART outcomes (Moss et al., 2021). Moss et al. suggest that women who are diagnosed only after entering ART treatment are disadvantaged by a suboptimal choice of insemination method and, ultimately, have a lower chance of achieving a live birth. The March edition of #ESHREjc with 50 participants, patients’ representatives and experts Paola Viganó, Mathew Leonardi, Thomas D’Hooghe and Louise Hull, together with the Authors of the original article, discussed several twists of Moss et al. including the relevance of diagnosis timeliness, the definition of suboptimal insemination method and the reliability of linking national medical records. Figure 1 summarizes the key points discussed. Graphic summary of the #ESHREjc discussion. Moss et al. analysed data collected over two decades. Therefore, it was tempting to question whether delayed diagnosis is still a relevant problem, notwithstanding the substantial increase in endometriosis awareness (França Ferreira and Carneiro, 2021) and advances in ultrasound accuracy (Leonardi et al., 2020). Moss and colleagues shared new, unpublished, data with #ESHREjc showing that in the last 15 years ∼30% of women are still diagnosed with endometriosis only after ART intervention (Fig. 2). This is striking considering the numerous laboratory and imaging tests included in an infertility workup. While we do not know the details of the disease in the delayed diagnosis cohort, the main reasons for this delay are probably the multifaceted symptomatology that is not always correlated to the severity of the disease (Gibson et al., 2021) and the fact that expertise in ultrasound diagnosis varies across centres. Experts in the #ESHREjc pointed out that diagnostic sonography performed by highly trained physicians is becoming increasingly useful in suspecting and mapping endometriosis lesions, even superficial peritoneal endometriosis. With a specificity of 92% and a sensitivity of 79% for pelvic endometriosis, detection of endometriosis by ultrasound scan is relatively diagnostic; however, failure to detect endometriosis on ultrasound cannot exclude its presence (Nisenblat et al., 2016). The quality of the transvaginal ultrasound and the presence of endometriomas and/or deep infiltrating endometriosis also improve the diagnostic capacity of pelvic ultrasounds. Journal Club participants argued in favour of distinguishing between surgery as a diagnostic procedure versus a surgical treatment intervention and agreed that surgery should ideally be reserved for treatment. Recently updated ESHRE guidelines accept that pelvic imaging can identify endometriosis but cannot exclude absence of the condition; laparoscopy may be required for diagnosis in symptomatic women with a negative ultrasound scan (Members of the Endometriosis Guideline Core Group et al., 2022). An oxymoron, but only time will tell if diagnostic imaging combined with clinical examination will have the power to completely dethrone laparoscopy in diagnosing endometriosis with confidence and as early as possible (Pascoal et al., 2022). Patient participants, including Endometriosis UK, actively supported the #ESHREjc discussion and shared their negative experiences with delayed diagnosis, asking for healthcare professionals to improve their skills in non-invasive diagnosis and extend their practice beyond specialized centres with long waiting lists. Delayed diagnosis of endometriosis by the years: no decrease in the percentage of delayed diagnoses since 2005 (Moss et al., unpublished data shared with permission). One key result of Moss et al. was the finding that the chance of obtaining a pregnancy was similar in women with an endometriosis diagnosis prior to the start of ART treatment and women without endometriosis of same age undergoing ART; however, this decreased significantly in women entering an ART cycle with undiagnosed endometriosis (Moss et al., 2021). Moss et al. showed that the number of IUIs was lower in women with early diagnosed endometriosis, associating the diagnostic failure for the high use of IUIs in patients with a late diagnosis, which they considered inappropriate for these patients. Journal Club participants who agreed with Moss et al. reminded everyone of some of the endometriosis-specific disadvantages linked to IUI: it does not change the pro-inflammatory pelvic environment that may hinder fertilization and implantation (Somigliana et al., 2019); there is some evidence of similar outcomes compared to expectant management (Gandhi et al., 2014); and multiple rounds of IUI are usually needed to obtain a pregnancy (ETIC Endometriosis Treatment Italian Club, 2019; Somigliana et al., 2019). Conversely, other Journal Club participants argued that IUI is still feasible in women with endometriosis in the absence of tubal factor and severe male factor infertility referencing a small randomized controlled trial (RCT) and a longitudinal study showing increased success rates with IUI compared to expectant management (Nulsen et al., 1993; Tummon et al., 1997). Similarly, IUI combined with surgical treatment of minimal/mild endometriosis was beneficial, achieving equivalent pregnancy and live birth rates as an ‘unexplained infertility’ population (Werbrouck et al., 2006). The new ESHRE guidelines on endometriosis suggest that IUI could be the preferred choice in women with rASRM stage I/II endometriosis (weak recommendation) and could be considered in women with rASRM stage III/IV endometriosis (weak recommendation) though its value is described as ‘uncertain’ (Members of the Endometriosis Guideline Core Group et al., 2022). Contrarily, NICE guidelines (National Institute for Health and Care Excellence (NICE), 2017) do not currently recommend IUI for endometriosis patients but, as it emerged during the #ESHREjc discussion, an update is pending. A heated discussed ensued as Journal Club participants then considered whether or not surgery should be the de facto first choice for those trying to conceive. While keeping in mind individual patient nuances cannot be discussed during a Twitter #ESHREjc, Journal Club participants agreed that ART and surgery could both have a role in the treatment of endometriosis-associated infertility, in line with ESHRE guidelines (Members of the Endometriosis Guideline Core Group et al., 2022). Surgery can be useful when fertility goals are not met with ART, especially when patients also experience pain, when endometriomas make ovaries inaccessible for egg retrieval and when there is complicated deep endometriosis (i.e. bowel obstruction, hydronephrosis). However, surgery for endometriosis-associated infertility alone has no role if ART is required, for example, in the case of tubal factor or severe male factor infertility. Journal Club participants agreed that all other patients must be evaluated on a case-by-case basis and that patient preference should be considered because some patients may wish to avoid surgery while others may prefer a clear surgical diagnosis with the option of a concomitant surgical treatment. #ESHREjc participating clinicians were asked what they would do differently when deciding the course of ART in a patient with endometriosis. The majority answered that they would use a long protocol with GnRH agonists to improve pelvic inflammation. However, it was acknowledged that there is no strong evidence of its absolute benefit over the antagonist protocol (Drakopoulos et al., 2018); both can be used for individual patients. Journal Club participants then discussed specific laboratory proceedings for patients with endometriosis. Embryologists of the Journal Club audience agreed that ICSI, rather than conventional IVF, may be useful in patients with severe endometriosis and a history of poor fertilization rates, even in the absence of strong evidence. Notably, Moss et al. did not report on the use of ICSI in their cohort. Journal Club participants agreed that blastocyst culture strategy needs to be individualized, taking into account the lack of direct effect of endometriosis on embryo quality when assessed by morphology (Dongye et al., 2021), the similar implantation rates of euploid embryos among patients with endometriosis compared with male factor infertility and fertile patients undergoing ART for preimplantation genetic testing purposes (Bishop et al., 2021), and the reality that women with ovarian endometriosis have a reduced number of oocytes and embryos (Alshehre et al., 2021). Relying on large national databases to define the landscape of epidemiology, state-of-the-art and reproductive potential in the context of endometriosis is natural. Moss et al. linked several different national databases to track the clinical outcomes of 1322 patients to study the correlation between timing of endometriosis diagnosis and fertility outcomes. Such approaches are advantageous when compared with single databases when asking complex retrospective questions. However, Journal Club participants highlighted some limitations. For example, in Moss et al. clinical outcomes were not linked to ART cycles; therefore, it was impossible to account for ART treatment for the reported 33% decrease in live birth rates in the delayed diagnosis group. Moreover, the type, severity and method of diagnosis of endometriosis were not reported; other infertility indications were not included in the analysis. Journal Club participants discussed whether the analysis of such data are reliable enough. Considering timely ‘diagnosis’ as a predictor of reproductive success in an observational study, like Moss and colleagues did, is a fascinating concept able to highlight its impact on clinical care and patient-related outcomes. However, Journal Club participants agreed that the most important future research step is an RCT comparing surgery to ART for the improvement of fertility outcomes. The main challenges of such an RCT are the recruitment of a homogeneous population with respect to rASRM endometriosis stage, presence of ovarian endometrioma, associated pain symptoms of endometriosis as well as patient/physician preference for a personalized approach. Moss et al. highlighted the importance of early diagnosis of endometriosis to manage infertility. It is now in the hands of clinicians, embryologists and molecular biologists to collaborate and drive research and innovation towards the realization of this goal. Non-invasive methodologies such as cutting-edge imaging, molecular diagnostics for blood or follicular fluid and difficult but impactful RCTs could all serve the mission. Without credible tools to diagnose endometriosis early and non-invasively, treatment for the associated infertility will never reach its utmost effectiveness. Although endometriosis awareness has significantly increased in the last decade, owing to the work of both professional organizations and support networks, delays in endometriosis diagnosis remain and research funding is still inadequate. The March 2022 #ESHREjc contributed to Endometriosis Awareness Month by promoting discussion characterized by interdisciplinarity, patients’ perspectives, nurturing scientific debate and forging collaborations among different professionals worldwide. The authors thank the authors of the discussed paper, Katrina Moss and Ingrid Rowlands, and all the other participants of the ESHRE journal club on Twitter. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. M.L. reports grants from OZWAC, Endometriosis Australia, AbbVie, CanSAGE, MRFF, HHS; honoraria for lectures/writing from GE Healthcare, Bayer, AbbVie, TerSera, consulting fees from Imagendo, outside the submitted work. All other authors report no conflicts of interest to declare.

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