Endometriosis is a common, benign gynecological disease that is usually associated with pain and/or infertility. It appears likely that chronic inflammation, that is typical of endometriosis lesions, plays a role in chronic pain as well as infertility. It is, therefore, logical to ask if there is a possible link between the severity of endometriosis symptoms and the outcomes of artificial reproductive technology (ART). This was the topic of a recent study that I will be discussing here (1).

The authors looked at 354 infertile patients with severe symptoms of pain, related to their endometriosis, that underwent primary IVF. 711 IVF cycles were recorded between 2014 and 2021. Symptoms of dysmenorrhea (painful periods), dyspareunia (pain during sexual intercourse), gastrointestinal pain and pain during urination were assessed using the Visual Analogue Score (VAS), and pain was recorded as severe when VAS score was higher than 7 in at least one of the aforementioned symptoms.

  Diagnosis of endometriosis was confirmed by histology in only 1/3 of cases (35.9%), whereas in the rest, diagnosis was made by ultrasound or MRI. 89% of cases had deep endometriosis, with 59% of those having bowel involvement. 68% of patients had severe endometriosis symptoms (VAS>7). The primary outcome of interest was cumulative livebirth rate (CLBR).

  The authors found no difference in CLBR following ART between patients with severe endometriosis-related symptoms and those without severe symptoms. No endometriosis-related complications were reported. Severity of symptoms was related to younger patient age and more severe disease. Patients with more severe symptoms had lower pregnancy rates but ,also, higher miscarriage rates, leading to no difference in CLBR.

The only factors independently associated with lowed CLBR were, according to the authors, age> 35 years and anti-mullerian hormone (AMH)  <1.2 ng/ml.

The findings of this study are worth noting for a few reasons. Firstly, this is the only study addressing this question (potential relationship between  severity of endometriosis symptoms and IVF outcome) and the knowledge gained is important to guide our patients. Secondly, one may question the plan of submitting patiens with severe pain due to endometriosis to primary IVF.

Indeed, symptomatic endometriosis patients are more likely to undergo surgery first, followed by attempts for spontaneous conception if deemed likely, or IVF after surgery. Surgery for endometriosis, when performed by clinicians with appropriate expertise, leads to significant improvement in pain symptoms, although there is a risk of operative complications, particularly in cases of deep endometriosis surgery. The risk is lower in experienced hands, however, may be in the region of 5% (2). It is not clear whether complications following deep endometriosis surgery actually have an impact on fertility outcomes (3,4). Spontaneous conception rates after deep endometriosis surgery may be as high as 70% following complete excision of the disease (5), provided that the surgeon deems post-operative conception possible, based on his experience or the use of tools such as the Endometriosis Fertility Index (E.F.I.) (6).

  On the other hand, satisfactory reproductive outcomes may be achieved after 1 to 4 IVF attempts (7). The authors reported no endometriosis- related complications in this study (1), and appropriate regimes may be used to reduce deterioration of endometriosis-related symptoms in the period of ovarian stimulation. However, we need to also acknowledge the, albeit rare, reported cases of rapid progression of deep endometriosis lesions secondary to ovarian stimulation, leading to potentially very severe complications such as ureteral obstruction and bowel stenosis or perforation (8-12). Provided that appropriate information is given to the patients, it may be expected that some of them would decide to undergo primary surgery in order to avoid those risks.

In conclusion, the jury is still out on the most appropriate decision between primary surgery or primary IVF in patients with endometriosis-associated infertility, and this is more so the case in patients with deep endometriosis. Ongoing trials may guide future clinical practice (13). The use of surgery for deep endometriosis as an adjunct to IVF (primary surgery followed by IVF) may be particularly interesting. Until further data are available, we ,as clinicians, should inform our patients on the available options, with their associated risks and benefits, and allow them to make an informed decision. It is my personal opinion though, as an author and a clinician, that, in patients with endometriosis-related infertility and severe pain symptoms, primary surgery (with or without subsequent IVF) remains the preferable approach.   

References:

1. C Maignien, M Bourdon, G Parpex, L Ferreux, C Patrat, C Bordonne, L Marcellin, C Chapron, P Santulli, Endometriosis-related infertility: severe pain symptoms do not impact assisted reproductive technology outcomes, Human Reproduction, 2023;, dead252, https://doi.org/10.1093/humrep/dead252.

2. Roman H, FRIENDS group (French coloRectal Infiltrating ENDometriosis Study group). A national snapshot of the surgical management of deep infiltrating endometriosis of the rectum and colon in France in 2015: a multicenter series of 1135 cases. J Gynecol Obstet Hum Reprod 2017;46:159– 65. Doi: 10.1016/j.jogoh.2016.09.004.

3. Raos M, Mathiasen M, Seyer-Hansen M. Impact of surgery on fertility among patients with deep infiltrating endometriosis. Eur J Obstet Gynecol Reprod Biol. 2023 Jan;280:174-8. doi:10.1016/j.ejogrb.2022.12.004.

        4.   Ferrier C, Roman H, Alzahrani Y, d’Argent EM, Bendifallah S, Marty N, et al. Fertility outcomes in women experiencing severe complications after surgery for colorectal endometriosis. Hum Reprod. 2018 Mar 1;33(3):411- 5. doi: 10.1093/humrep/dex375.

        5.    Soriano D, Bouaziz J, Elizur S, Zolti M, Orvieto R, Seidman D, et al. Reproductive Outcome Is Favorable After Laparoscopic Resection of Bladder Endometriosis. J Minim Invasive Gynecol. 2016 Jul-Aug;23(5):781-6. doi: 10.1016/j.jmig.2016.03.015.

        6. Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2010;94(5):1609–15. doi: 10.1016/j.fertnstert.2009.09.035.

        7.  Maignien C, Santulli P, Marcellin L, Korb D, Bordonne C, Dousset B, et al. Infertility in women with bowel endometriosis: first-line assisted reproductive technology results in satisfactory cumulative live-birth rates. Fertil Steril. 2021 Mar;115(3):692-701. doi: 10.1016/j.fertnstert.2020.09.032.

      8. Horace Roman. Deep rectal shaving using plasma energy for endometriosis causing rectal stenosis. Colorectal Dis (2014) Jul 12. doi: 10.1.0.1.111/codi.12720.

      9. SJ Gordon, PJ Maher, R Woods. Use of the CEEA stapler to avoid ultra-low segmental resection of a full thickness rectal endometriotic nodule. J Am Assoc Gynecol Laparosc 8:312-6 (2001). DOI: 10.1016/S1074-3804(05)60598-1.

     10. Renier M, Verheyden B, Termote L. An unusual coincidence of endometriosis and ovarian stimulation. Eur J Obstet Gynecol Reprod Biol 1995;63:187–9. Doi: 10.1016/0301-2115(95)02234-1.

     11. Antonio Setúbal, Zacharoula Sidiropoulou, Mariana Torgal, Ester Casal, Carlos Lourenço, Philippe Koninckx. Bowel complications of deep endometriosis during pregnancy or in vitro fertilization. Fertil Steril;101: 442-6 (2014). DOI: 10.1016/j.fertnstert.2013.11.001.

     12. Seyer-Hansen M, Egekvist A, Forman A, Riiskjaer M. Risk of bowel obstruction during in vitro fertilization treatment of patients with deep infiltrating endometriosis. Acta Obstet Gynecol Scand. 2018. Jan;97(1):47-52. doi: 10.1111/aogs.13253.