Women with endometriosis who undergo IVF: a contemporary review of therapeutic strategies for successful outcomes

Our search used the following databases: Pubmed, Ovid-Medline, The Cochrane Library, and ClinicalTrials.gov. We used the following, database-adapted, phrases for the search which included “Endometriosis AND infertility”, “Endometriosis AND in-vitro fertilization”, “Endometriosis AND IVF”, “Endometriosis AND treatment AND prior to IVF”, “Endometriosis AND weight loss AND IVF”, “Endometriosis AND exercise AND IVF”, “Endometriosis AND pre-treatment AND IVF”, “Endometriosis AND surgery”, “Endometrioma AND surgery”, “Endometriosis AND IVF stimulation”, “Endometriosis AND HCG trigger”, “Endometriosis AND GnRH agonist”, “Endometriosis AND GnRH antagonist”, “Endometriosis AND frozen embryo transfer”, “Endometriosis AND obstetric outcomes”, “Endometriosis AND perinatal outcomes”. The search period was from 1946–2025. 3,550 articles in total were found using the above search strategies. Each of these articles was then assessed based upon title and/or abstract for relevance (AK). Studies not published in English were excluded. 1,558 duplicates were removed. Of the remaining studies, 63 of these articles were included within this review. The references of each cited source were assessed so as not to exclude any other sources relevant to this review. The primary focus was to evaluate the most recent literature on the role of IVF in patients with endometriosis and on how to optimally prepare such patients for IVF, embryo transfer and the risks that may be anticipated in pregnancy. Articles were chosen for inclusion if they were: 1) retrospective or prospective studies involving women with surgically-confirmed endometriosis of reproductive age and involved IVF and/or embryo transfer, 2) Systematic reviews/meta-analyses or 3) incorporated in-vivo or in-vitro animal or cell culture studies in which features of endometriosis were established. We excluded studies that 1) were case reports, case series, abstracts, expert opinion articles, 2) that did not involve patients undergoing IVF and instead undergoing procedures such as intra-uterine insemination (IUI), time intercourse, 3) involved in-vitro maturation (IVM) of oocytes, 4) that did not have surgically-confirmed endometriosis, 6) retrospective or prospective studies that did not have a control group, 7) retrospective or prospective studies that did not report established outcome measures for IVF success including implantation rate, clinical pregnancy rate, miscarriage rate, or live birth rate. In addition, we did not include articles that utilized IVF techniques which are seldom-used due to the availability of newer, more prevalent techniques such as slow-freezing of embryos versus vitrification. This was done to maximize the generalizability of this article and its conclusions. Prior to starting an IVF cycle, it is crucial to determine if any interventions are available which can potentially enhance oocyte yield. This can include optimization of the patient’s general health in addition to synchronization of the follicular pool. A common form of IVF preparation is the use of OCPs (Fig.  1 ). De Zeigler et al. performed a two-center prospective trial of 795 patients examining the effect of 6–8 weeks of OCP use prior to IVF in women with endometriosis compared to controls. The endometriosis group that was treated with OCPs exhibited markedly improved oocyte and frozen embryo yield compared with the non-treated group [ 33 ]. The study also stratified the patients according to endometriosis stage with more advanced-stage patients exhibiting poorer outcomes in both groups. Progestin-only use has also been investigated as a mode of pretreatment for endometriosis patients prior to IVF. A retrospective study reviewed 151 patients who failed a previous IVF cycle and who either went directly into another IVF cycle or was pretreated three months of 2 mg/day of Dienogest. The Dienogest group exhibited higher cumulative implantation, clinical pregnancy and live birth rates (39.7%, 33.3% and 28.6%) compared to the control group (23.9%, 18.2% and 14.8%; P  = 0.049, 0.037 and 0.043, respectively) [ 34 ]. The efficacy of Dienogest was further supported by Khalifa et al. who performed an RCT comparing pretreatment with Dienogest 2 mg/day versus GnRH agonist treatment and noted similar ovarian response parameters and pregnancy outcomes with substantially lower cost [ 35 ]. Despite these encouraging studies, a subsequent meta-analysis of four cohort studies comprising 422 patients did not show a significant improvement in mature oocyte number, pregnancy rate, or live birth rate with Dienogest treatment. This lack of apparent benefit with Dienogest must be cautiously considered since the authors acknowledged substantial heterogeneity ( I 2  > 50%) among the four studies and possible selection bias since the Dienogest group may have had more severe symptoms at presentation. [ 36 ]. Overall, pretreatment with OCPs or progestins remains a promising area for clinical application in addition to for further study given the variety of OCPs and Progestin formulations. This is in addition to the reduction in cost compared to other pre-treatment options to be discussed below. Fig. 1 Potential interventions for a retrieval cycle Potential interventions for a retrieval cycle While an area of great general interest, it is unfortunate that no high-quality studies have been done to determine if any particular lifestyle changes (i.e. diet, exercise) can impact fertility or the course of IVF in women with endometriosis. A recent meta-analysis of six RCTs comprising 457 patients looking at various dietary interventions did not indicate any intervention being associated with a clinically significant outcome (e.g. ≥ 30% reduction in pain scores). This is likely due to the significant heterogeneity in the included studies [ 37 ]. With regards to exercise, very limited studies have been done on the role of exercise in treating endometriosis and none in relation to preparation for IVF. Overall, many of the studies indicate a positive effect especially for aerobic exercise and exercise that has been practiced over longer periods of a woman’s life [ 38 , 39 ]. In general, until larger, better-quality studies are published, patients with endometriosis planning IVF engaging in any dietary interventions and/or regularly scheduled exercise should be counseled that these interventions are unlikely to influence their IVF course. Surgical removal of endometriosis and endometriomas is a mainstay of therapy for this condition particularly when associated with pelvic pain or large endometriomas (≥ 5 cm) precluding follicle access for retrieval. However, the role and timing of surgery for patients with moderate to severe endometriosis, especially with endometrioma(s), who are planning IVF has evolved. It is currently believed that resection of endometriomas should be deferred until after egg or embryo cryopreservation is performed. As surgical removal of endometriomas is likely to contribute and accelerate diminished ovarian reserve and a greater depletion of egg quantity/quality that is ultimately irreversible as time progresses with age [ 40 ]. One rare exception to this approach is if a large endometrioma will encumber oocyte retrieval (Fig.  1 ) [ 41 ]. It must be noted that antibiotic prophylaxis should be used during oocyte retrieval in women with endometrioma(s). This is due to the higher risk of inadvertent puncture of the endometrioma followed by a greater risk of an ensuing infection from a post-operative ovarian abscess [ 42 ]. In a randomized trial, Demirol et al. assessed the effect of endometrioma excision on 99 patients proceeding to IVF. Compared to patients who went straight to IVF, the endometrioma excision group exhibited a longer course of stimulation with greater total gonadotropin usage (4575 IU in the endometrioma excision group versus 3675 IU in the controls; p  = 0.001). Although, they noted a lower oocyte yield for the excision group (7.6 vs 8.6, p  = 0.032), they found equivalent fertilization, implantation, and pregnancy rates [ 43 ]. These results were corroborated by a subsequent retrospective cohort study of Bourdon et al. showing a higher rate of poor ovarian response among patients who underwent endometrioma excision versus controls, (30.8%) vs (22.3%), respectively; p  = 0.02 [ 44 ]. A decrease in ovarian reserve following endometrioma excision is the likely cause for this poor response which has been confirmed in numerous studies [ 18 , 19 , 44 , 45 ]. Recently a meta-analysis of 22 studies comparing patients who underwent surgery for endometriomas or deep-infiltrating endometriosis (DIE) prior to IVF/ICSI versus those who immediately proceeded to IVF showed no improvement in clinical pregnancy or live birth rates [ 46 ]. This study also noted a significant lower AMH levels and oocyte yield for patients who underwent initial endometrioma excision. A randomized clinical trial is underway in Italy looking at the live birth rates and cost profile for patients with DIE allocated to surgery or IVF [ 47 ]. Overall excisional surgery, especially for endometriomas, appears to harm more than help. Given the decrease in ovarian reserve and lower oocyte yields, patients would be better served proceeding straight to IVF. The only exception remains if the endometrioma would encumber oocyte retrieval. More recently, ethanol-based sclerotherapy has been investigated as a potential alternative excision to address the treatment of endometriomas. A retrospective review of 37 patients that underwent ethanol sclerotherapy and 37 controls, noted a greater cumulative live birth rate (CLBR) compared to controls (OR of 2.68 (95% confidence interval, CI: 1.13–6.36, p  = 0.02) [ 48 ]. A subsequent study by Rabbattu et al. investigated the role of ethanol sclerotherapy for endometriomas greater than 25 mm. 96 cycles from 67 patients were examined in which 46 cycles involved ethanol sclerotherapy prior to ovarian stimulation and 50 controls. The sclerotherapy group exhibited greater pregnancy and live birth rates compared to controls (OR, 2.9; 95 CI, 1.4—6.6 and OR 2.4; 95 CI, 1.1—5.4 respectively) [ 49 ]. While promising, larger controlled studies are needed before this technique will be used more widespread. In addition, future studies need to assess the long-term effect of sclerotherapy on ovarian reserve to gauge its overall usefulness. Prior to doing surgery for endometriomas, patients could consider oocyte/embryo cryopreservation. Henry et al. noted in their meta-analysis of 8 studies that the number need to treat for oocyte cryopreservation was 16 to achieve one additional live birth among patients with endometriomas [ 50 ]. A retrospective study of 485 women with endometriosis of various stages indicated that oocyte yield and cumulative live birth rate (CLBR) was noticeably higher in women that did not do surgery (ie. resection of endometriomas) prior to cryopreservation compared to those that did (vitrified oocytes = 8.6 ± 6.9 vs. 5.1 ± 4.8) and CLBR = 72.5% vs. 52.8%, respectively) [ 51 ]. In summary, surgery for endometriomas prior to IVF appears to consistently be detrimental to ovarian reserve. This is particularly evident in women with endometrioma(s) given the well-documented irreversible damage to the ovarian cortex where small pre-antral and antral follicles reside. Thus, it is recommended to avoid resection of endometriomas prior to an IVF cycle so as not to contribute to an accelerated loss of ovarian reserve. If resection is planned prior to attempting pregnancy than egg/embryo cryopreservation ought to be offered as an option prior to resection. Another modality used to improve IVF outcomes in endometriosis is the use of GnRH analogues (Fig.  1 ). The concept behind pretreatment with these agents, is to deprive a patient’s endometriosis of the stimulatory effects of estrogen [ 10 ]. Surrey et al. conducted a small randomized controlled trial of 25 patients undergoing pretreatment with a long-acting GnRH agonist for three months prior to IVF and compared them to 25 patients not undergoing pretreatment [ 50 ]. All patients underwent a standard GnRH agonist downregulation protocol. The study did exhibit higher ongoing pregnancy rates for the pretreatment group (80% vs 53.85%) compared to controls. However, the control group did have a significantly higher proportion of patients with Stage III-IV disease (11 versus 4%). This disparity in addition to the small sample size calls into question the stark difference in pregnancy rates. A subsequent Chinese study of 162 women with Stage III-IV disease noted a greater implantation rate in those treated with a GnRH agonist for two months prior to undergoing a standard GnRH agonist downregulation protocol compared to no pretreatment [ 52 ]. However, this study also noted that patients that underwent pre-treatment needed greater gonadotropin doses. In contrast to the differences seen in these prior studies, a single-blinded RCT of 200 total patients looking at GnRH agonist pre-treatment for 3-months did not observe any increase in pregnancy rate, implantation rate, and ongoing pregnancy rates in the pre-treatment group compared to controls [ 53 ]. Yet,this same study observed a higher cancellation rate and total gonadotropin dose in the pretreatment group in concordance with the aforementioned Chinese study. Kaponis et al. performed the largest RCT with 200 patients each in the GnRH agonist pre-treatment and control arms, spread over three centers. The agonist pre-treatment arm underwent three months of a depo-preparation of Leuprolide. All patients underwent a standard GnRH agonist down regulation protocol. While they noted lower follicular fluid cytokine levels and greater fertilization rates for the pretreatment group, they did not observe a difference in pregnancy and live birth rates [ 54 ]. A large meta-analysis of eight RCTs could not find any significant improvement in oocyte yield, clinical pregnancy rates, miscarriage rates, or live birth rates with pre-treatment with a GnRH agonist prior to IVF. However, the authors stated that the studies incorporated were single-blinded, hence significant bias remained a possible confounding factor. [ 55 ]. In summary, GnRH agonist pretreatment remains a readily available option for patients with endometriosis; however, the true efficacy of this approach remains to be clarified especially with other IVF protocols. Patients should be counseled that it remains unclear if IVF outcomes are truly improved with GnRH agonist pretreatment; however, higher gonadotropin doses and even cancellation rates may be higher. One serious shortcoming of the aforementioned studies is the lack of information about add-back therapy (e.g. daily Norethindrone acetate/NETA) to reduce vasomotor symptoms which are a serious side-effect of GnRH agonists which could affect patient compliance [ 56 , 57 ]. Future studies should seek to understand the role of a 2–3 months course of a GnRH agonist with NETA or another form of add-back therapy. One variation on GnRH agonist pretreatment is the addition of the aromatase-inhibitor, Letrozole. A prospective cohort study was performed by Piedimonte et al. in which 68 patients underwent GnRH agonist pre-treatment for two months with or without concomitant treatment with an aromatase inhibitor. This study noted improvements in clinical pregnancy and live birth rates in the GnRH agonist + aromatase inhibitor arm (24 [66.7%] vs. 13 [40.6%]), (22 [61.1%] vs 10 [31.3%], respectively) [ 58 ]. Cantor et al. did a retrospective analysis of 126 patients who underwent Depo-Leuprolide treatment with or without Letrozole 5 mg for 60 days. They noted lower gonadotropin dosages, greater oocyte yield and a greater number of 2PN embryos in the group that received Letrozole. In addition, the group that received Letrozole also experienced greater pregnancy and live birth rates (50% versus 22%, P  = 0.003 and 40% versus 17%, P  = 0.008, respectively) [ 59 ]. While adding Letrozole to GnRH pre-treatment may improve pregnancy and live birth rates, additional prospective studies are needed before a firm conclusion can be made. Recently, a new class of oral GnRH analogues have been developed, these are the GnRH antagonists which have shown efficacy in treating dysmenorrhea and non-menstrual pelvic pain in women with endometriosis [ 60 – 62 ]. The ability to take these medications orally offers an advantage to patients that wish to avoid intramuscular injections e.g. GnRH agonists. There is currently a Phase III, RCT looking to assess the effect of three months of pretreatment of patients with endometriosis with Elagolix prior to IVF [ 63 ]. While Relugolix has also been shown to reduce dysmenorrhea and non-menstrual pelvic pain in addition to being non-inferior to Leuprolide, no similar pre-IVF treatment trial is currently underway [ 64 ]. Once a patient has completed preparation for IVF with or without surgery or pre-treatment, the conduct of the IVF cycle is the next crucial step to reproductive success. To obtain the maximum number of good quality oocytes, an optimal protocol for controlled ovarian stimulation (COS) should be utilized. Historically, there has been a debate as to whether the older, GnRH agonist downregulation protocol is better than the GnRH antagonist protocol for endometriosis patients. In the general infertility population, the GnRH agonist protocol has been associated with slightly lower mean FSH dose (2186.9 ± 626, vs 2230 ± 636 IU) and greater pregnancy rates (RR 0.89, 95% CI 0.82–0.96). This is in addition to higher implantation (aOR] 1.36, CI 1.08 to 1.73) and live birth rates, (aOR 1.33, CI 1.07 to 1.66). However, the GnRH antagonist protocol was associated with a consistently lower ovarian hyperstimulation (OHSS) risk (RR 0.63, 95% CI 0.50–0.81) [ 65 , 66 ]. This lower OHSS risk is especially important for PCOS patients and other patients with a high ovarian reserve. For this high responder population, both the agonist and antagonist protocols are similar in efficacy, but safety is consistently greater with the antagonist protocol due to lower OHSS risk [ 65 , 67 ]. The two protocols have also been compared in terms of inflammation based upon serum and follicular cytokines. For pro-inflammatory cytokines such as IL-1β, IL-6, TNFα, no difference was seen in both the serum and follicular fluid. Basic fibroblast growth factor (bFGF) levels were lower in the antagonist group; however, the clinical significance of this is unclear [ 68 ]. Nonetheless, this cytokine assessment is relevant given the pro-inflammatory state produced by endometriotic lesions [ 1 ]. Therefore, it remains to be seen if this baseline, pro-inflammatory state could respond differently between the two protocols.. Now that the performance of these two protocols has been reviewed in the general infertility population, their performance in endometriosis patients can be assessed. One of the earliest attempts to address this question was a single-site RCT from Pabuccu et al. in which 246 patients were split into Stage I-II endometriosis, surgically-excised endometrioma, and endometrioma without surgical excision. The patients in each group were then randomized to undergo COS with a GnRH agonist or antagonist protocol. No significant difference was found in implantation (22.6 vs 15.9%) and clinical pregnancy rates (39% vs 27.5%). However, no power calculation was done and each group had a relatively small sample size calling into question the lack of differences seen [ 69 ]. Kolanska et al. performed a single-site retrospective cohort study of 284 patients, 165 that underwent a GnRH agonist protocol and 119 that underwent a GnRH antagonist protocol. They observed greater pregnancy and live birth rates for the GnRH agonist group (25% vs. 18%, p  = 0.02 and 18% vs 8%, p  < 0.04, respectively) when a per-cycle analysis was done. A significant difference in live birth rates was also observed in their per-transfer analysis. However, this difference in live birth rate was only for fresh embryo transfers; no difference was seen for frozen embryo transfers. Interestingly, no differences was observed in pregnancy or live birth rates when a subgroup analysis was done comparing the lower stage patients to those with endometriomas [ 70 ]. A later retrospective cohort study of 386 patients was done looking at early stage (I-II) and moderate/advanced stage (III-IV) endometriosis patients and comparing those undergoing a GnRH agonist protocol versus an antagonist protocol. Greater, but non-significant, rates of positive hCG, clinical pregnancy, and live birth rates were seen in the GnRH agonist group in women with lower stage endometriosis. However, no differences were observed for more advanced stage (rASRM III and IV) patients [ 71 ]. A subsequent retrospective cohort study of 639 patients noted improved clinical pregnancy rates in women undergoing a GnRH agonist stimulation protocol, but this was only for fresh embryo transfers. No difference was found with frozen embryo transfers in both cumulative clinical pregnancy and cumulative live birth rates between a GnRH agonist or antagonist protocol [ 72 ]. This correlates with the per-transfer analysis done by Kolanska et al. indicating that outcomes are similar for subsequent frozen embryo transfers regardless of protocol type. Overall, the GnRH agonist protocol may have somewhat better IVF outcomes; especially in the setting of fresh embryos transfers. However, numerous studies indicate that this difference may dissipate for advanced stage endometriosis and in the setting of frozen embryos transfers. Furthermore, these differences, especially for lower stage endometriosis, must be balanced by the increased risk of OHSS in high responders. An alternative stimulation protocol has increasingly been studied for the better part of this past decade. Progestin-primed ovarian stimulation (PPOS) protocols have been increasingly used in both the general infertility population and in patients with endometriosis. A prospective cohort study with 108 patients compared outcomes in fertility preservation cycles for PPOS cycles and antagonist cycles. No difference was seen in terms of oocytes retrieved. Additionally, a substantially lower cost was observed for the PPOS group [ 73 ]. Calero et al. subsequently performed a small multicenter retrospective cohort that showed non-inferiority of a PPOS using Dienogest compared to a GnRH agonist and an antagonist protocol. In 201 treatment cycles, they did not observe any difference in mature oocyte numbers or ovarian stimulation parameters [ 74 ]. The PPOS protocol appears to offer comparable performance, in terms of oocyte yield, at a significantly lower cost. However, additional studies need to be done with frozen embryo transfers since a fresh transfer is not possible with a PPOS cycle as it predictably disrupts normal endometrial receptivity [ 75 ]. Expanding on the data from several of the previously mentioned studies, much research has been done to determine if fresh or frozen thaw embryo transfer (FET) is better for endometriosis patients. Moderate quality data indicates that such patients may benefit from an FET with improved endometrial receptivity because the endometrium is exposed to physiological levels of estrogen in contrast to an endometrium exposed to the supraphysiological levels of estrogen present in a fresh embryo transfer following an egg retrieval. Han et al. performed a meta-analysis of 11 studies to address this question. This group noted greater clinical pregnancy rates (OR: 1.25; 95% CI: 1.11, 1.40), live birth rates (OR: 1.31; 95% CI: 1.15, 1.49), and implantation rates (OR: 1.27; 95% CI: 1.05, 1.54) for frozen embryo transfers compared to fresh embryo transfers [ 76 ]. However, this study was limited by significant heterogeneity in the demographics of included patients and in how they distinguished patients with endometriosis, adenomyosis or both. Given this data, we recommend encouraging patients to consider opting for a frozen thaw embryo transfer in preference to a fresh embryo transfer. In performing a frozen thaw embryos transfer, numerous approaches for endometrial preparation are available. Historically, this has been done via a “programmed” cycle using exogenous estradiol to increase the uterine lining thickness and then using intramuscular (IM) progesterone alone or combined with vaginal progesterone. However, a programmed cycle results in ovulation suppression and thus preventing the formation of a corpus luteum. Over the past decade, natural cycle approaches that allow for ovulation and preserve the formation of a corpus luteum have become common and are generally preferred for women with regular periods as well as for greater patient comfort [ 77 ]. In addition, natural cycle approaches are associated with less maternal complications (hypertension, preeclampsia) and neonatal complications (large for gestational age, macrosomia, preterm birth) compared to programmed cycles as the vasoactive factors secreted by the corpus luteum which include VEGF and relaxin influence normal placentation [ 78 , 79 ]. For patients with endometriosis, the goal is to maximize the chance of conception while minimizing the risk of disease proliferation. This goal can be achieved by using an aromatase inhibitor and keeping estradiol levels generally lower than the threshold for endometriosis proliferation while promoting an optimal endometrial lining and formation of a corpus luteum through ovulation (Fig.  2 ) [ 10 ]. Tatsumi et al. did a large retrospective cohort study of 110, 722 single embryo FET cycles in which they noted greater clinical pregnancy rates in the Letrozole-stimulated compared to the natural cycle and programmed cycle groups, 1.48 (95% CI: 1.41–1.55) and 1.62 (95% CI: 1.54–1.70), respectively [ 80 ]. However, this study was limited by lack of information on the justification for using each frozen embryo transfer protocol and on embryo quality. In a subsequent retrospective cohort study of 2849 patients from a single center in China, Letrozole-stimulated cycles exhibited greater clinical pregnancy and live birth rates compared to both natural and programmed cycles. While this study seems to support the results from Tatsumi et al., it must be noted that the patients in the Letrozole group were also supplemented with human menopausal gonadotropin until the follicle size reached 18−20 mm which was not the case in the Japanese study[ 81 ]. Godiwala et al. also noted a significantly greater ongoing pregnancy rate/live birth rate (OPR/LBR) with Letrozole-stimulated FET cycles compared to programmed cycles in their retrospective study of 3148 patients, (aRR 1.11, 95% CI: 1.02–1.21) [ 82 ]. Comparable OPR/LBR was noted between Letrozole-stimulated cycle and natural cycles. In summary, a Letrozole-stimulated protocol likely provides enhanced embryo transfer outcomes compared to programmed cycle protocols. Yet there does not appear to be any advantage over natural cycle protocols. While these studies did not specifically focus on endometriosis patients and did not have subgroup analysis for this patient group, the use of Letrozole stimulation holds high potential as the optimal approach for frozen embryo transfer for patients with endometriosis. Fig. 2 Letrozole cycle frozen thaw embryo transfer (for ovulatory cycles) Letrozole cycle frozen thaw embryo transfer (for ovulatory cycles) A lingering question remains concerning the role of GnRH agonist suppression prior to a frozen embryo transfer in endometriosis patients. In a single-center, retrospective study Yang et al. compared frozen embryo transfer outcomes in 2048 cycles. They comprised 859 natural cycles, 42 ovulation induction cycle with Clomiphene or Letrozole, 696 programmed cycles, and 459 programmed cycles with GnRH agonist pre-treatment. No difference were found in clinical pregnancy or miscarriages rates. Unfortunately, this study was substantially undermined by the limited duration of GnRH agonist treatment ranging for 1–2 months [ 83 ]. Another single-center retrospective cohort study assessed 1413 frozen embryo transfer cycles in women with endometriosis. These cycles encompassed 74 natural cycles, 950 programmed cycles, and 389 programmed cycle with GnRH agonist pre-treatment. As with the Yang et al., no differences were seen in any embryo transfer outcomes or in perinatal outcomes. This study was also marked by significant heterogeneity in the inconsistent combinations of oral, intramuscular, and vaginal formulation of progesterone that were used. Furthermore, GnRH agonist use was limited to 2 months of pretreatment. In light of these studies, it remains unclear if GnRH agonists provide any benefit prior to frozen embryo transfers. Future studies need to assess a 3-month duration of pretreatment as was done in studies involving pretreatment prior to IVF. Additionally, future studies should further investigate the use of GnRH agonist pretreatment prior to stimulated cycles (e.g. Letrozole) since pituitary function should recover sufficiently to be responsive to Letrozole once a GnRH agonist has been stopped. Numerous crucial mechanisms have been discovered in the pathogenesis of endometriosis. These mechanisms are now considered possible new targets for future therapy to improve reproductive outcomes. Various studies have identified altered lipid metabolism and steroidogenesis in oocytes from patients with endometriosis. [ 84 , 85 ]. Steroidogenesis is altered at the level of the endometrium and in endometriotic lesions, particularly those involved in producing estradiol and in inactivating progesterone such as 17β-hydroxysteroid dehydrogenase, aromatase, and aldo-ketoreductase family enzymes, respectively [ 86 – 88 ]. Increased oxidative stress is also another avenue in which could be explored in the future. As oxidative stress increases, the risk of DNA damage, lipid peroxidation, and protein oxidation increases especially in oocytes [ 89 ]. As with steroidogenesis, genes involved in oxidative stress are upregulated in oocytes from patients with endometriosis compared to controls [ 85 ]. Increased oxidative stress has also been noted in granulosa cells from patient with endometriosis [ 90 ] which may in part be due to higher levels of reactive oxygen species, nitric oxide, superoxide dismutase, among others [ 90 , 91 ]. Any of these agents could negatively impact the oocyte meiotic spindle thereby compromising oocyte quality in patients with endometriosis [ 92 ]. Within this steroidogenic, oxidatively stressed milieu, a greater level of chronic inflammation is present. Patients with endometriosis are known to have increased levels of peritoneal macrophages and higher level of peritoneal and follicular fluid cytokines and chemokines [ 51 , 93 , 94 ]. In addition to IL-6, IL-8, and TNFα, vascular endothelial growth factor (VEGF) is also increased in both the peritoneal and follicular fluid of patients with endometriosis [ 95 ]. The release VEGF may be related to ovarian steroidogenesis and higher levels of VEGF in follicular fluid may be implicated in reducing embryo quality and pregnancy [ 96 ]. Numerous agents have been developed which can address the detrimental effects of these aforementioned pathogenic mechanisms. The majority of the research in this capacity has focused on agents directed at reducing the inflammation seen in endometriosis. These include pentoxyfilline and anti-TNFα antibodies, both of which have shown promise in improving pregnancy rates in patients with infertility and endometriosis [ 97 , 98 ]. None unfortunately have been tested in patients undergoing IVF. Many other anti-inflammatory medications have been assessed in both animal and human studies to treat endometriosis, but not in the setting of infertility [ 99 ]. Hence, exploring novel agents that target these mechanisms remains a rich area for future research.

The optimal treatment of patients with endometriosis who are undergoing IVF remains a challenging prospect. Individualized treatment prior to IVF should take into account a multitude of patient considerations. These include age, the severity/stage of the endometriosis, ovarian reserve, history of prior response to ovarian stimulation, patients’ priorities regarding timetable for pregnancy and financial burden. In regards to excisional surgery prior to IVF especially for endometriomas, there does not appear to be a benefit in IVF outcomes, but there is clear risk of decreasing a patient’s ovarian reserve. Serious consideration should be given to oocyte/embryo cryopreservation prior to ovarian surgery for endometriomas as ovarian reserve is most likely to diminish from baseline after endometrioma(s) are resected. Prior to ovarian stimulation for IVF, it is worthwhile considering a 3-month pre-treatment with a GnRH analogue to potentially lower the disease burden and inflammatory impact of endometriotic lesions. When ovarian stimulation is initiated, progestin priming can lower costs, and it is beneficial to intentionally plan a “freeze all” embryo cycle. This is then later followed by a planned FET using Letrozole stimulation to optimize endometrial receptivity. Using these strategic approaches can maximize oocyte yield and pregnancy outcomes for patients with endometriosis particularly those with lower stage disease. With further research into treating oxidative stress and inflammation arising from this systemic disease, new therapeutics will likely become available in the future to further improve upon IVF outcomes in this patient group.

Endometriosis is one of the most insidious causes of chronic pelvic pain and remains one of the toughest issues for patients struggling with infertility [ 1 ]. It is characterized by ectopic endometrium composed of benign glands and stroma found outside the uterine cavity. Histologically there are endometrial glands and stroma often accompanied by the presence of hemosiderin-laden macrophages. The definitive diagnosis is surgical requiring confirmation by biopsy but often is made visually during laparoscopy. The severity of the disease is defined as minimal (Stage 1), mild (Stage 2), moderate (Stage 3) or severe (Stage 4) according to the revised American Society of Reproductive Medicine (rASRM) staging system [ 2 ]. Advanced stages 3 and 4 are associated with greater frequency of infertility and poorer fertility treatment outcomes than Stages 1 and 2 [ 3 ]. While the exact pathogenesis of endometriosis is unknown, there are several theorized suspected causes. The most accepted theory is that of retrograde menstruation or Sampson’s theory [ 4 ]. This is supported by data showing that most women experience retrograde menstruation and have an increased in prevalence of endometriosis occurring with outflow tract abnormalities [ 5 ]. There is also evidence of vascular or lymphatic dissemination of endometrial cells leading to endometrial lesions [ 6 ]. In addition, there is the theory of coelomic metaplasia [ 7 ]. The ability of mesenchymal tissue to convert into endometriotic lesions may explain the presence of such lesions in the thoracic cavity as well as in men [ 8 , 9 ]. Regardless of the genesis of these lesions, once established, endometriotic lesions proliferate by stimulation of estrogen [ 10 ]. The direct exacerbation of this disease by estrogen is a compelling reason why endometriosis affects approximately 5–10% of women of reproductive age [ 1 ]. For many women, endometriosis may be debilitating presenting clinically with chronic pelvic pain, dysmenorrhea, dyspareunia, and/or dyschezia. Each of these symptoms, individually or in combination, can have a profound effect on a woman’s quality of life and a substantial economic impact [ 10 ]. In addition to the physical manifestations of endometriosis, there is a strong association with infertility in these patients. Patients with endometriosis have a lower live birth rate compared to controls in both natural and assisted reproductive technology (ART)-assisted cycles [ 11 – 13 ]. Approximately 30–50% of women with infertility have been found to have endometriosis [ 14 , 15 ]. Numerous prospective studies have observed an association with diminished ovarian reserve accompanied by lower antral follicle and lower serum AMH levels in women with endometriosis compared to controls and thereby resulting in poor reproductive outcomes [ 16 – 19 ]. However, this association is most obvious in advanced staged endometriosis involving the ovary (Stage 3 or 4) versus peritoneal endometriosis (Stage 1 or 2) [ 18 ]. The mechanisms behind endometriosis-related infertility include increased chronic inflammation affecting oocyte quality, compromised endometrial receptivity, diminished ovarian reserve affecting oocyte quantity/quality as well as adhesive disease affecting the fallopian tubes [ 20 , 21 ]. These mechanisms, especially those affecting the ovary and the endometrium, can have a substantial impact on the success these patients have with in-vitro fertilization (IVF). A plethora of observational studies have noted lower oocyte retrieval yields, lower pregnancy, and live birth rates in women with endometriosis (especially in women with advanced Stage III-IV disease) [ 22 – 25 ]. Ovarian endometriomas pose a particular challenge because they can both encumber follicular growth and oocyte quality (via impaired maturation and fertilization capacity) [ 26 – 28 ]. Implantation rates have been noted to be lower with donor eggs obtained from patients with endometriomas compared to controls [ 29 ]. Additionally, endometriomas can make oocyte retrieval much more mechanically difficult and, if punctured, can lead to increased risk of post-retrieval ovarian abscess [ 30 , 31 ]. Retrospective cohort studies have also noted lower oocyte retrieval rates and higher cancellation rates in women with endometriomas [ 32 ]. Hence, performing IVF in patients with endometriosis particularly with endometriomas presents a unique set of challenges. However, despite these very real challenges IVF remains the bedrock and a most effective treatment for infertile women with this disease. In the last decade the general time sequence and approach of IVF for the treatment of infertility associated with endometriosis has evolved from utilizing IVF as a post-surgical treatment following initial laparoscopic treatment/staging of disease to preceding surgery. While at the same time, the approach to IVF itself has shifted away from fresh embryo transfer toward frozen thaw embryo transfer in part due to the realization of improved endometrial receptivity in a more physiologic, unstimulated cycle. These changes in the preparation and objective of the IVF cycle have further evolved to maximize successful treatment outcomes in women with endometriosis. Thus, it is the intention of this narrative review to discuss the most contemporary clinical approaches that may optimize IVF treatment outcomes for patients with endometriosis. These approaches will encompass the preparation for IVF including any forms of pretreatment, excisional surgery, IVF stimulation, and the method of frozen embryo transfer.