Examining the link between endometriosis, fertility and cancer

Published 02 May 2022

A Campus meeting in April focused on many of the recommendations in the newly updated ESHRE guideline on endometriosis, and included associations with cancer risk, pain and infertility, and the role of surgery in their management.

A newly updated ESHRE guideline on endometriosis care underpinned many of the presentations made at this online Campus in April.(1) Published in January, the comprehensive document – described by one speaker as a ‘paradigm shift in endometriosis’ – makes more than 100 recommendations, including on cancer, pain, surgery and infertility.

Indeed, these were the main themes of the Campus, organised by SIG Endometriosis and Endometrial Disorders, which focused specifically on ovarian endometriosis and endometrioma (cystic lesions). The link between endometriosis and cancer has been documented in at least 10,000 studies to date, and it is believed that endometrioma may predispose women to clear cell (CCC) and endometrioid ovarian carcinomas (EnOC), but what remains unclear is whether women with the disease are at higher risk (of cancer) than those in the general population.

The reassuring message delivered by Marina Kvaskoff is that ovarian cancer is rare and ‘most women with endometriosis won’t get endometrial cancer’, an assertion backed up by data from the ESHRE endometriosis guideline which estimates absolute risk in the general female population as 1.3% vs 1.8% for women with endometriosis.
A recent systematic review and metanalysis authored by Kvaskoff and colleagues did find an increased likelihood of ovarian and thyroid cancer, and a minimally greater risk for breast and cervical cancers.(2) However, Kvaskoff said the results should be treated with extreme caution: the majority of evidence was unreliable because of low methodological quality (eg, high heterogeneity). To achieve robust answers, future research must take into account issues such as lack of data on lesion type and the potential for misclassification of endometrioma, said the epidemiologist.

CCC and ENOC are among many subtypes of ovarian cancer that are associated with endometriosis. In his presentation, David Huntsman shared as yet unpublished data which could shed light on why these two different cancers arise from the same benign precursor (endometrioma). The findings suggest cystathionine gamma-lyase (CTH) – an enzyme highly expressed in CCC – could become a potential therapeutic target. Huntsman said this area of research highlights a switch in approach from believing tumour mutations are the ‘whole story’ to considering each cancer type as the endpoint of what he described as a ‘distinct oncogenic journey’ involving cell of origin, mutation and microenvironment. If oncologists took this different path, he suggested, it could help identify new prevention and treatment opportunities.

Endometrioma and pain is another extensive area which is as yet not fully understood. The ESHRE guideline recommends both hormone therapies and surgery to relieve endometriosis-related pain, described during the Campus as an ‘inflammatory soup’ which can cause physical and psychological misery for women. But is medication (analgesia and/or hormones) or surgery more effective (and cost-effective) for endometrioma pain? The first multicentre RCT aims to answer this question, as previewed by Jacques Maas. The primary outcome of the SOMA trial will be 30% reduction in pain (as measured by the numerical rating scale or NRS) after six months. Finding women solely with endometrioma has proved a challenge as has securing of funding, Maas said, but the research team hopes to finalise recruitment by the end of 2022.(3)

Day 2 of the meeting comprised presentations on the association between endometrioma and fertility, and clinical management. What emerged was that women with cysts caused by endometriosis have a lower ovarian reserve, as reflected in lower AMH levels, higher FSH, and lower antral follicle count. Nevertheless, not enough evidence exists to establish if oocyte quality is reduced when endometrioma are present.

Baris Ata presented a comprehensive overview on the impact on ovarian reserve of different surgical approaches. Highlights included data from a recent metanalysis of 14 studies involving 650 women which concluded that AMH is a better measure of ovarian reserve than AFC.(4) Findings showed that endometriotic cystectomies were associated with a significant reduction in AMH but not in the antral follicle count. What happens, Ata explained, is that AFC can be underestimated prior to surgery and this can mask AFC decline post treatment. More evidence is needed on whether other approaches such as laser ablation, bipolar vaporisation, and ethanol sclerotherapy produce the same effect.

Hemostatic techniques (laser energy, bipolar energy or suture) are another potential surgical avenue in need of robust analysis. Ata presented his own unpublished metanalysis data on this approach based on 12 RCTs: results are inconsistent but suggest a lower decline in ovarian reserve with hemostatic vs other approaches. Ovarian suture is his preferred choice, Ata said, because of ‘lower complications’ than with bipolar cauterisation which, he said, ‘should be used judiciously’. Overall, he concluded that ‘a high threshold for surgery’ may be the best way to preserve ovarian reserve.

As to when and how to perform surgery, the ESHRE guideline suggests that cyst removal before fertility treatment does not improve live birth rates, although this approach can relieve pain prior to ART. On the basis that surgery will always be a treatment option, patients and practitioners may have to make a trade-off between pain and fertility. Or a combined approach (stripping the cyst wall then ablation of the surface) may prove optimal in endometrioma management, as outlined by Carla Tomassetti, who is involved in the BLAST (Belgian Laser Study) trial. Results from this multicentre RCT on conservative endometrioma surgery are expected at the end of 2023, with an aim to compare the combined technique with CO2 laser vaporisation only.

1. See ESHRE guideline endometriosis (graphic on absolute ovarian cancer risk page 162)
2. Kvaskoff M, Mahamat-Saleh Y, Farland LV, et al. Endometriosis and cancer: a systematic review and meta-analysis. Hum Reprod Update 2020; 2: 393–420.
3. van Barneveld E, Veth VB, Sampat JM, et al. SOMA-trial: surgery or medication for women with an endometrioma? Study protocol for a randomised controlled trial and cohort study. Hum Reprod Open 2020.
4. Younis JS, Shapso N, Ben-Sira Y, et al. Endometrioma surgery – a systematic review and meta-analysis of the effect on antral follicle count and anti-Müllerian hormone. Am J Obstet Gynecol 2022; 226: 33-51.e7. doi:10.1016/j.ajog.2021.06.102.

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