Risk of endometriosis progression in infertile women trying to conceive naturally or using IVF
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This review examines the risks of endometriosis progression in infertile women attempting natural conception versus undergoing IVF, considering hormonal treatments, estrogen levels, and potential pregnancy complications.
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This paper discusses the balance between pregnancy attempts and the risk that untreated endometriosis may recur or progress during periods when hormonal therapy is stopped, comparing natural conception and IVF strategies at a high level. It synthesizes evidence that endometriosis has an annual recurrence rate of roughly ~10% without medical therapy, with pooled estimates suggesting progression of deep invasive lesions around ~21% over long follow-up (implying a lower ~10% per year at 1 year), while endometrioma growth was observed in about 23% of lesions over ~21 months. The paper’s major caveats are that tools to predict individual recurrence/progression are limited and EFI is primarily intended for post-surgery natural conception, whereas progression risk data are sparse, heterogeneous, and often not annualized. Relevance to endometriosis: the entire paper is focused on recurrence/progression risk in women with endometriosis when trying to conceive naturally or via IVF.
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Abstract
The use of hormonal treatments for endometriosis has increased in recent years. Their effectiveness lies in creating a stable hormonal environment, reducing peripheral estrogen levels, and suppressing ovulation and menstruation. Although these agents do not cure endometriosis and symptoms often return after discontinuation, they effectively relieve pain in most cases and help prevent disease progression or recurrence. Women are therefore typically managed with long-term hormonal treatments, with or without surgery. However, this approach is unsuitable for those seeking natural pregnancy or undergoing IVF, as all hormonal treatments hinder conception. For women pursuing natural pregnancy, these treatments should be discontinued for about 1 year, the time needed to diagnose infertility. However, this suspension exposes women to the risk of recurrence or progression and is therefore clinically acceptable only if the woman has a reasonable likelihood of achieving pregnancy naturally. In women with endometriosis who are infertile and therefore require IVF, ovarian stimulation significantly raises estrogen levels-up to 10 times those of a natural cycle-potentially boosting the risk of endometriosis relapse. Evidence is reassuring on this issue even if some limited data suggest that ovarian stimulation may promote deep invasive endometriosis progression. Overall, physicians and patients must balance the chances of natural or ART-assisted pregnancy against the risk of disease recurrence or progression during treatment discontinuation or IVF. This choice is also complicated by the increased risk of severe pregnancy complications in women with endometriosis, possibly depending on the conception method. This review discusses the available evidence that can be helpful in guiding the decision-making process.
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The
The success of IVF is closely linked to ovarian response. A greater ovarian response to stimulation increases the number of oocytes retrieved, the availability of embryos for transfer, the cumulative chances of success, and, ultimately, the number of babies born. However, a robust ovarian response is accompanied by a significant increase in sex steroid levels, particularly estradiol. In natural cycles, estradiol levels peak at 200–300 pg/ml, whereas in cases of strong ovarian response, these levels can rise to concentrations 10 times higher ( Macklon et al. , 2006 ). This inevitably raises concerns about the safety of IVF in women with endometriosis. Estrogens have a major role for endometriotic tissue ectopic implantation, survival, and growth, and for neo-angiogenesis and synthesis of inflammatory mediators as well. Pathological studies have clearly documented widespread estrogen receptor (ER) expression in endometriotic lesions, particularly in cases of deep endometriosis. An overexpression of ERβ and a downregulation of ERα have also been observed in endometriosis ( Clemenza et al. , 2022 ; Vannuccini et al. , 2022 ).
Understanding the potential risks of IVF in terms of disease recurrence and progression is essential given the current emphasis on ART to treat endometriosis-related infertility. It is vital to establish whether this approach poses additional risks to women, as this information is crucial for effective counseling and shared decision-making. Available evidence is generally reassuring ( Somigliana et al. , 2019 ; Benaglia et al. , 2021a ). A systematic review of 16 studies revealed that ovarian stimulation for IVF has minimal impact on the disease ( Somigliana et al. , 2019 ). IVF does not exacerbate pain symptoms, increase recurrence risk, or significantly affect endometrioma size. However, limited evidence suggests that deep endometriosis may progress with ovarian stimulation ( Somigliana et al. , 2019 ; Benaglia et al. , 2021a ). This concern was supported by five case reports (in total 12 cases) of progression ( Renier et al. , 1995 ; Govaerts et al. , 1998 ; Anaf et al. , 2000 ; Jun and Lathi, 2007 ; Halvorson et al. , 2012 ). This issue is particularly critical because deep endometriosis can lead to serious complications, such as obstructive uropathy or bowel occlusion.
To further address this concern, we have updated our previous systematic review to include evidence published from January 2018 to December 2024 (the previous review included studies up to January 2018), and focusing specifically on deep endometriosis. Five new studies were identified. These included three additional case reports documenting progression (five cases in total: three involving thoracic endometriosis, one with colon obstruction, and one with ureteral obstruction) ( Seyer-Hansen et al. , 2018 ; Thoreau et al. , 2018 ; Pellerin et al. , 2020 ). More importantly, two cohort studies provided more robust evidence ( Seyer-Hansen et al. , 2018 ; Berlanda et al. , 2019 ). In the first study, Seyer-Hansen et al. examined 77 women with non-operated bowel deep endometriosis who underwent IVF. Severe worsening of symptoms was observed in 10 women (13%, 95% CI: 7–22%). Among these, two experienced colon occlusion, six had sub-occlusion, and two reported worsening pain. All 10 women required a surgical intervention. In contrast, data from Berlanda et al. (2019) painted a less alarming picture. This study reviewed 60 women with deep endometriosis who had failed IVF and compared lesion dimensions before and after treatment. The mean diameter of endometriotic nodules before and after IVF was similar (19 ± 6 and 18 ± 7 mm, respectively). Pain symptoms remained stable across the cohort, and no new nodules were detected. Only one woman (2%, 95% CI: 0.1–8%) experienced a significant complication. She had a transient ureteral stenosis, which resolved with expectant management without requiring surgery. The reasons behind the inconsistency between these two studies are difficult to unravel. One possible explanation is that women in the study by Seyer-Hansen et al. had more severe endometriosis, as it exclusively included cases of deep bowel endometriosis, whereas the study by Berlanda and collaborators included deep endometriosis at any location. Further research is needed to clarify these discrepancies and better understand the risks associated with IVF in women with deep endometriosis.
Finally, the impact of ovarian stimulation on adenomyosis is a neglected but potentially important issue. Unfortunately, we failed to identify informative studies specifically investigating this topic. The evaluation of the transformation of adenomyosis in pregnancy is demanding (myometrium also rapidly expands and changes) and this may explain the lack of evidence.
Intro
Endometriosis is a chronic, inflammatory, and recurrent disease characterized by the presence of endometrial glands, endometrial stroma, and fibrosis in ectopic locations ( Vigano et al. , 2018 ; Becker et al. , 2022 ). The disease can be highly debilitating, severely impacting the quality of life by causing chronic pelvic pain in forms such as dysmenorrhea, dyspareunia, non-menstrual pain, dyschezia, and dysuria. It can also disrupt reproductive mechanisms, leading to infertility ( Zondervan et al. , 2020 ; Al-Lami et al. , 2024 ).
In recent decades, the range of treatment options for endometriosis has expanded, allowing physicians to make increasingly effective use of both new and established therapies. These treatments include laparoscopic surgery, hormonal medical therapies, and ARTs, particularly IVF ( Becker et al. , 2022 ).
The use of hormonal medical therapies has grown over the years, with GnRH antagonists—used with or without add-back therapies—recently entering the market ( Taylor et al. , 2017 ; Giudice et al. , 2022 ; Donnez et al. , 2024 ). Conceptually, these agents are not entirely innovative in treating endometriosis. Their development is based on the old and established rationale of reducing sex steroid levels, creating a steady hormonal state, and preventing ovulation—mechanisms that are not fundamentally different from those of existing treatments like low-dose estroprogestins, progestins alone, or GnRH agonists with or without add-back therapy ( Vercellini et al. , 2024 ).
The growing role of hormonal therapies reflects a rethinking of the role of surgery, which was once considered the first-line treatment for endometriosis. This shift is driven by increased awareness of the complications and long-term adverse effects of surgical intervention. For instance, removing ovarian endometriomas can severely damage ovarian reserve ( Baraki et al. , 2024 ), while excising deep invasive endometriosis can compromise the integrity of nearby organs, potentially causing long-term bowel or bladder dysfunctions ( Schneyer et al. , 2024 ). Currently, surgery must be considered for patients who are refractory to medical therapy and for those who cannot be prescribed these drugs; it is mandatory for cases of ureteral or colorectal endometriosis causing clinically significant stenosis ( Vercellini et al. , 2024 ). Furthermore, even when a surgical intervention is decided, the disease’s tendency to return has led to the widespread use of hormonal medical therapy as a tertiary prevention measure ( Somigliana et al. , 2014 ). There is growing consensus that long-term progestins or estroprogestins should be used post-surgery to prevent recurrences ( Zakhari et al. , 2020 ; Petraglia et al. , 2024 ; Vercellini et al. , 2024 ). Importantly, the protective effects of these therapies last only as long as they are used. This is especially evident for endometriomas, likely due to ovulation’s key role in their pathogenesis ( Vercellini et al. , 2010 ; Wattanayingcharoenchai et al. , 2021 ). Once hormonal treatment is discontinued, endometriosis can recur, exposing women to an increasing risk over time. The overall cumulative risk is directly related to the duration of time without medical treatment ( Vercellini et al. , 2008 ; Zakhari et al. , 2021 ).
The role of surgery in restoring fertility is even more contentious ( Vercellini et al. , 2009 ; Becker et al. , 2022 ; Ottolina et al. , 2022 ). Women undergoing surgery are exposed to the above-mentioned complications, yet the benefits for natural fertility are uncertain ( Vercellini et al. , 2009 ; Ottolina et al. , 2022 ). Consequently, ART has gained increasing acceptance as the preferred approach for managing endometriosis-related infertility ( Becker et al. , 2022 ).
Conclusions
The choice between attempting natural conception and proceeding directly to IVF is complex and requires careful consideration of several critical, yet often poorly defined, factors. These include evaluating the likelihood of achieving a natural pregnancy, the probability of success with ART, the effect on pain symptoms, the risk of endometriosis progression associated with repeated natural cycles or ART, and the potential impact on pregnancy complications. In general, pursuing natural pregnancy may expose women to a slightly higher risk of endometriosis progression or recurrence compared to ART, but this risk is relatively low—∼10% over the typical 1-year timeframe. On the other hand, ART is more costly and carries its own specific risks. The decision-making process cannot be rigid or one-size-fits-all. Instead, management should be personalized and tailored to the individual woman’s preferences and clinical condition. Factors such as her medical history, sonographic findings, semen analysis results, and the presence of pain symptoms must all be carefully considered. Tailored approaches might include adjusting the duration of natural conception attempts (e.g. shortening to 6 months or extending beyond 12 months), closely monitoring the condition during attempts at natural conception, and initiating medical therapy promptly in cases of endometriosis recurrence or progression.
In ART cycles, evidence is too weak for strong recommendations. However, some speculative suggestions may be drawn. Strategies such as mandatory eSET, transfer at blastocyst stage to lower the number of transfers, avoiding fresh embryo transfers to avoid a pregnancy in a hyper-stimulated hormonal context that could facilitate decidualization, or using artificial endometrial preparation to avoid ovulation may be considered. For the two latest interventions, one must balance the decision with the drawbacks of a policy of systematic freeze all and the potential beneficial effects of embryo transfer in a natural cycle on pregnancy complications (lowering the risk of hypertensive disorders of pregnancy, preeclampsia, postpartum hemorrhage, and cesarean section). Even if still debated because of the risk of discarding valuable embryos, the use of preimplantation genetic testing for aneuploidy (PGT-A) might be considered here because it can reduce the number of transfers and shorten exposure to ovulations ( Viville and Aboulghar, 2025 ). Finally, when planning for ovarian stimulation one could consider a progesterone-primed ovarian stimulation treatment. In this protocol, women receive progesterone or a progestin to prevent ovulation all along the stimulation and this could theoretically be beneficial for endometriosis. However, this protocol is incompatible with fresh embryo transfer. Even if the benefits are theoretical, it seems wise to consider this approach when fresh transfer is excluded a priori . Noteworthy, in most extreme scenarios when risks are deemed excessive, one could opt straight for oocytes donation or even refraining from conceiving ( Vercellini et al. , 2018 ).
In conclusion, the impact of discontinuing medical therapy to pursue natural conception or ART is an under-researched area with limited and indirect evidence. Nevertheless, this is a critical issue for women with endometriosis and warrants greater attention in the future. In the meantime, a shared decision-making approach is essential, incorporating all aspects of this multifaceted clinical issue to ensure that decisions align with the individual’s preferences and condition.
Endometriosis
Concerns about the impact of ovarian stimulation on endometriosis growth should not be limited to the time of IVF treatment. It is also essential to consider the potential additive or amplifying effects of a pregnancy achieved through a fresh ART cycle, i.e. immediately following ovarian stimulation. The combined influences of multiple corpora lutea and the ability of hCG to sustain their activity for several weeks may exacerbate endometriosis. In other words, it is necessary to clarify whether pregnancy outcomes differ between women with endometriosis who conceive naturally and those who require ART.
The effect of hormonal, biochemical, and metabolic changes associated with pregnancy on endometriotic lesions has been extensively studied in recent years, with most evidence focusing on ovarian endometriomas. Research has consistently shown that these lesions can undergo decidualization early in pregnancy, adopting a sonographic appearance that can mimic malignancy ( Bean et al. , 2022 , 2023 ; Filippi et al. , 2022 ). The impact of pregnancy on deep invasive endometriosis has been harder to study and has received less attention, but emerging evidence offers some insights ( Bean et al. , 2022 , 2023 ; Filippi et al. , 2022 ; Zajicek et al. , 2024 ). Deep nodules can also decidualize, becoming hyperechoic with moderate to high vascularity on color Doppler imaging. However, this transformation tends to occur later in pregnancy. Recent findings suggest that the frequency of decidualization in endometriomas and deep nodules is higher than previously thought, occurring in up to 50% of cases ( Filippi et al. , 2022 ; Bean et al. , 2023 ; Zajicek et al. , 2024 ).
Unfortunately, there is currently insufficient evidence to determine whether the frequency or severity of decidualization is influenced by ART. The presence of multiple corpora lutea and elevated peripheral sex steroid levels in ART cycles could potentially amplify this effect. Although a trend in this direction has been noted, the available evidence is insufficient for definitive conclusions ( Filippi et al. , 2022 ). Moreover, what are the clinical consequences of this ectopic decidualization?
Endometriosis has been linked to several obstetric complications. Although the evidence is not entirely consistent, studies suggest a modest increase in risks for gestational hypertension, gestational diabetes, preeclampsia, preterm premature rupture of membranes, preterm delivery, cesarean section rates, antepartum bleeding, postpartum hemorrhage, and adverse neonatal outcomes ( Salmeri et al. , 2023 ; Vercellini et al. , 2023 ; Busnelli et al. , 2024 ; Enzelsberger et al. , 2024 ). The most pronounced association, however, is with placenta previa, where women with severe endometriosis face a 5- to 10-fold increased risk ( Vercellini et al. , 2023 ). However, a direct influence of ectopic lesions on these obstetric disorders, including placenta previa, is unlikely. Instead, these effects are likely mediated by the strong association between endometriosis and adenomyosis ( Vercellini et al. , 2023 ). Consequently, concerns about obstetric complications should not heavily influence the decision to pursue natural conception versus ART.
On the other hand, women with endometriosis face a higher risk of spontaneous hemoperitoneum during pregnancy, a rare but severe complication associated with a significant risk of fetal loss and even maternal death ( Brosens et al. , 2016 ; Lier et al. , 2017 ; Benaglia et al. , 2021b ; Schreurs et al. , 2023 ). This severe complication is extremely rare (<1%), develops progressively due to persistent bleeding from venous vessels, and sometimes without clear, pathognomonic symptoms, thus potentially hampering a prompt diagnosis. Women must be informed about it. The risk appears to be higher in pregnancies achieved through ART and in the presence of deep invasive endometriosis ( Brosens et al. , 2016 ; Lier et al. , 2017 ; Benaglia et al. , 2021b ). The decidualization of deep invasive lesions may contribute to this risk. While firm conclusions are difficult to draw due to the rarity of the condition, it may be prudent to consider avoiding fresh embryo transfers in women with unoperated deep invasive endometriosis to minimize the impact of multiple corpora lutea. However, a firm recommendation for freeze all in women with deep invasive endometriosis cannot be drawn. Our considerations are speculative, robust data are not available.
Finally, it is worth emphasizing that other potential complications of ectopic decidualization, such as intestinal or ureteral obstruction, intestinal perforation or fistula, can occur during pregnancy. Their frequency is presumably very rare and only supported by case reports ( Leone Roberti Maggiore et al. , 2017 ). However, a detrimental additional effect of ART is not demonstrated here.
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