Hormonal Therapies before in vitro fertilization in women with

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<p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>Available online 8 May 2024</p><p>1521-6934/© 2024 Elsevier Ltd. All rights reserved.</p><p>Hormonal Therapies before in vitro fertilization in women with</p><p>endometriosis: The Minotaur’s Labyrinth and the</p><p>Ariadne’s Thread</p><p>Antoine Naem a,b,*,1, Harald Krentel a,1, Gaby Moawad c,d, Joelle Naem e,</p><p>Renato Venezia f, Andrea Etrusco f, Sanja Terzic g, Antonio Simone Laganà f</p><p>a Department of Obstetrics, Gynecology, Gynecologic Oncology and Senology, Bethesda Hospital Duisburg, 47053 Duisburg, Germany</p><p>b Faculty of Mathematics and Computer Science, University of Bremen, 28359 Bremen, Germany</p><p>c Department of Obstetrics and Gynecology, George Washington University, Washington, DC 20037, USA</p><p>d The Center for Endometriosis and Advanced Pelvic Surgery, Washington, DC 22101, USA</p><p>e Faculty of Medicine of Damascus University, Damascus, Syria</p><p>f Unit of Obstetrics and Gynecology, “Paolo Giaccone” Hospital, Department of Health Promotion, Mother and Child Care, Internal Medicine and</p><p>Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy</p><p>g Department of Medicine, School of Medicine, Nazarbayev University, Zhanybek-Kerey Khans Street 5/1, Astana 010000, Kazakhstan</p><p>A R T I C L E I N F O</p><p>Keywords:</p><p>Endometriosis</p><p>Infertility</p><p>In vitro fertilization</p><p>GnRH agonists</p><p>Dienogest</p><p>Aromatase inhibitors</p><p>A B S T R A C T</p><p>Endometriosis-related infertility is one of the most debated topics in reproductive medicine. In</p><p>recent years, prolonged pre-cycle hormonal regimens gained attention as a mean of improving the</p><p>assisted reproduction technologies (ART) success rates in endometriosis patients. GnRH agonists,</p><p>dienogest, medroxyprogesterone acetate, and aromatase inhibitors are the most studied medi-</p><p>cations. Conflicting results and a high risk of bias exist in almost all of the conducted studies in</p><p>the field. However, current evidence suggests that pre-cycle treatment with GnRH agonists may</p><p>be beneficial for patients with stage III/IV endometriosis. Dienogest and medroxyprogesterone</p><p>acetate-based progestin-primed ovarian stimulation protocol was shown to be comparable to the</p><p>prolonged GnRH agonists protocol. Finally, aromatase inhibitors seem to be of limited benefit to</p><p>the assisted reproductive outcomes of endometriosis patients. Although it is challenging to draw</p><p>any clinical conclusions, pre-cycle hormonal treatments seem to be best indicated in endome-</p><p>triosis patients who had previously failed ART treatment.</p><p>1. Introduction</p><p>Endometriosis is defined by the presence of endometrial-like glands and/or stroma out of the uterus [1]. It is a debilitating chronic</p><p>inflammatory estrogen-dependent disease that affects women of all age groups [2]. However, its prevalence peaks in women of</p><p>reproductive age [3]. The estimated prevalence of endometriosis among women of childbearing age is estimated to be around 10% [4].</p><p>Accurate data regarding the incidence of endometriosis and its related risk factors is lacking. Nevertheless, the relative risk of</p><p>developing endometriosis in first-degree relatives of patients with advanced-stage endometriosis was estimated to be around 15% [5].</p><p>* Corresponding author.Max-von-Laue Street 5, 28359 Bremen, Germany</p><p>E-mail address: antoine.naem@gmail.com (A. Naem).</p><p>1 Both authors contributed equally to this paper.</p><p>Contents lists available at ScienceDirect</p><p>Best Practice & Research Clinical</p><p>Obstetrics & Gynaecology</p><p>journal homepage: www.elsevier.com/locate/bpobgyn</p><p>https://doi.org/10.1016/j.bpobgyn.2024.102500</p><p>Received 25 November 2023; Accepted 2 May 2024</p><p>mailto:antoine.naem@gmail.com</p><p>www.sciencedirect.com/science/journal/15216934</p><p>https://www.elsevier.com/locate/bpobgyn</p><p>https://doi.org/10.1016/j.bpobgyn.2024.102500</p><p>https://doi.org/10.1016/j.bpobgyn.2024.102500</p><p>http://crossmark.crossref.org/dialog/?doi=10.1016/j.bpobgyn.2024.102500&domain=pdf</p><p>https://doi.org/10.1016/j.bpobgyn.2024.102500</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>2</p><p>Additionally, it was reported that patients with a positive family history of endometriosis tend to have more severe forms of endo-</p><p>metriosis [6]. The exact pathogenesis mechanisms of endometriosis are merely understood. Although the retrograde menstruation</p><p>theory by Sampson was largely adopted [7], recent visions suggest that the origin of endometriosis extends beyond the regurgitated</p><p>menstrual flow to include environmental, genetic, and epigenetic predisposing factors [8]. Recent studies suggested that patients with</p><p>endometriosis express a higher burden of rare and damaging variants in endometriosis-related genes in comparison to healthy controls</p><p>[9]. Moreover, cancer-driving mutations were identified in the histologically benign endometriomas [10]. The endometriotic lesions</p><p>were also found to exhibit posttranscriptional miRNAs dysregulations related to regeneration, proliferation, and invasion [11].</p><p>Furthermore, patients with endometriosis were reported to have defective peritoneal hemoglobin-clearance capacity [12], immune</p><p>and hormonal dysregulations [13], and higher intraperitoneal oxidative stress levels [14]. This in turn reflects the complexity of the</p><p>endometriosis pathogenesis and its underlying etiologies. This could also suggest that different subtypes of endometriosis have their</p><p>proper genomic profile and epigenetic regulations that cause the observed variations in the phenotypes and symptomatology of</p><p>endometriosis [8,11,15].</p><p>The clinical manifestations of endometriosis could be broadly categorized into endometriosis-related pain and endometriosis-</p><p>related infertility. Chronic pelvic pain, dysmenorrhea, and dyspareunia are the most commonly reported symptoms [16]. However,</p><p>the symptoms may vary depending on the lesion’s location and the involvement of the pelvic neural structures [17–19]. It is note-</p><p>worthy that endometriosis could be asymptomatic as it was encountered in up to 43% of patients undergoing tubal ligation [4].</p><p>The association between endometriosis and infertility has been already established. Endometriosis is estimated to affect around</p><p>25–50% of patients with infertility [20]. Alternatively, 30–50% of endometriosis patients are infertile [20]. It was estimated that</p><p>couples with a female partner affected by endometriosis are three times less likely to achieve a conception per month in comparison to</p><p>their healthy counterpart [21].</p><p>The exact mechanisms by which endometriosis decreases the female fertility are under ongoing debate. Nonetheless,</p><p>endometriosis-associated fibrogenesis and adhesiogenesis are important factors that distort the pelvic anatomy and the tubo-ovarian</p><p>relationship [22]. Besides the mechanical effect, the harsh intraperitoneal inflammatory milieu associated with endometriosis is</p><p>thought to impair folliculogenesis and ovulation [23]. The peritoneal fluid of endometriosis patients was proved to have elevated</p><p>concentrations of pro-inflammatory cytokines, heme, and iron deposits [12,24]. Moreover, higher levels of Reactive Oxygen Species</p><p>(ROS) and inflammatory cytokines were identified in the follicular fluid of patients with endometriosis [25]. Those alterations are</p><p>suggested to decrease the oocytes’ quality and quantity [26,27]. Patients with ovarian endometriomas were found to have lower</p><p>follicular densities in the area surrounding the cyst [28,29]. A recent study demonstrated through single-cell RNA-sequencing tran-</p><p>scriptomic dysregulations in the oocytes of patients with endometriosis, suggesting a lower oocyte quality [30]. This conclusion gains</p><p>further justification from the observation that recipients of oocytes from donors with endometriosis achieved a lower pregnancy rate</p><p>than those receiving oocytes from healthy donors [31].</p><p>The influence of endometriosis on the endometrial receptivity is suspected but largely debated. It was reported that the normal mid-</p><p>cycle surge in the expression of the Homebox A10 (HOXA10) gene</p><p>Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril 2001;75(1):1–10. https://doi.org/10.1016/s0015-0282(00)01630-7.</p><p>[47] Tamura H, Takasaki A, Nakamura Y, Numa F, Sugino N. A pilot study to search possible mechanisms of ultralong gonadotropin-releasing hormone agonist</p><p>therapy in IVF-ET patients with endometriosis. 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Naem et al.</p><p>https://doi.org/10.1080/09513590802627647</p><p>https://doi.org/10.1210/jcem.82.2.3783</p><p>https://doi.org/10.1093/humupd/4.5.752</p><p>https://doi.org/10.1095/biolreprod54.2.371</p><p>https://doi.org/10.1530/rep.0.1260559</p><p>https://doi.org/10.1016/j.ejogrb.2015.01.009</p><p>https://doi.org/10.1186/1477-7827-9-88</p><p>https://doi.org/10.1186/1477-7827-9-90</p><p>https://doi.org/10.1093/humrep/deh035</p><p>https://doi.org/10.1093/humrep/deh035</p><p>https://doi.org/10.1016/j.rbmo.2018.12.028</p><p>https://doi.org/10.1016/j.rbmo.2018.12.028</p><p>https://doi.org/10.1111/j.1600-0412.2011.01346.x</p><p>https://doi.org/10.1111/j.1600-0412.2011.01346.x</p><p>https://doi.org/10.1002/mrd.10107</p><p>https://doi.org/10.1080/09513590.2019.1650338</p><p>https://doi.org/10.1080/09513590.2019.1650338</p><p>https://doi.org/10.1093/humrep/der452</p><p>https://doi.org/10.1016/j.ejogrb.2009.02.001</p><p>https://doi.org/10.1007/s00404-010-1599-6</p><p>https://doi.org/10.1080/09513590.2018.1519790</p><p>https://doi.org/10.1111/1471-0528.12366</p><p>https://doi.org/10.1016/j.rbmo.2023.02.012</p><p>https://doi.org/10.1038/s41598-023-34045-7</p><p>https://doi.org/10.1186/s13048-022-01042-9</p><p>https://doi.org/10.1007/s00404-023-07036-2</p><p>https://doi.org/10.1093/humrep/deab216</p><p>https://doi.org/10.1055/s-0032-1333481</p><p>https://doi.org/10.1055/s-0032-1333481</p><p>https://doi.org/10.1111/ajo.13643</p><p>https://doi.org/10.1016/j.fertnstert.2020.07.050</p><p>https://doi.org/10.1023/a:1026586709554</p><p>https://doi.org/10.3389/fendo.2022.825934</p><p>https://doi.org/10.1002/14651858.CD008571.pub2</p><p>https://doi.org/10.1016/j.rbmo.2021.10.014</p><p>https://doi.org/10.1016/j.jogoh.2017.09.007</p><p>Hormonal Therapies before in vitro fertilization in women with endometriosis: The Minotaur’s Labyrinth and the Ariadne’s Thread</p><p>1 Introduction</p><p>2 The GnRH agonists and the endometriosis-related infertility</p><p>2.1 An Overview of the mechanism of action and side effects of the GnRH agonists</p><p>2.2 The ultralong GnRH agonist protocol and IVF-ET outcomes of patients with endometriosis</p><p>3 The role of progestins in the endometriosis-related infertility</p><p>3.1 The general characteristics and Indications of progestins in endometriosis</p><p>3.2 The prolonged administration of dienogest before IVF-ET cycles</p><p>3.3 Progestin-primed ovarian stimulation in patients with endometriosis</p><p>4 Aromatase inhibitors and endometriosis</p><p>4.1 General characteristics of aromatase inhibitors</p><p>4.2 The prolonged administration of aromatase inhibitors before IVF-ET in endometriosis patients</p><p>5 Discussion</p><p>5.1 The Dilemma of the effect of endometriosis on ART outcomes</p><p>5.2 Hormonal, surgical, or no treatment before ART: the Unanswered Question</p><p>6 Summary</p><p>Funding</p><p>7 Institutional review board statement</p><p>8 Data availability statement</p><p>10 Research Agenda</p><p>11 Practice points</p><p>CRediT authorship contribution statement</p><p>9 Declaration of generative AI in scientific writing</p><p>Declaration of Competing interest</p><p>Acknowledgments</p><p>Abbreviations</p><p>References</p><p>– an important regulator of the endometrial receptivity – is lost in</p><p>the eutopic endometrium of patients with endometriosis [32]. Moreover, loss of integrin expression was reported in 44% of patients</p><p>with endometriosis [33]. On the contrary, the gene signature of the endometrial receptivity did not differ significantly during the</p><p>implantation window of patients with and without endometriosis [34].</p><p>Infertile endometriosis patients are often referred to surgery, Assisted Reproduction Technologies (ART) treatment, or both with</p><p>the hopes of improving their fertility status. There is a notion that extracorporeal fertilization in the means of ART is supposed to avoid</p><p>the hostile intraperitoneal environment and at least decrease its impact on the oocytes, sperms, and the developing embryo. However,</p><p>patients with endometriosis were found to be 35% less likely to achieve a pregnancy after the In Vitro Fertilization and Embryo</p><p>Transfer (IVF-ET) cycles [35]. Furthermore, patients with stage III and IV endometriosis according to the revised classification of the</p><p>American Society of Reproductive Medicine (r-ASRM) were found to have poorer ART outcomes in comparison with patients diag-</p><p>nosed with stage I and II endometriosis [35,36]. In the meta-analysis of Horton et al. [37], stage I-II endometriosis seemed to have a</p><p>negative effect on the fertilization and implantation rates only, while stage III-IV endometriosis was also associated with a lower live</p><p>birth rate [37].</p><p>To improve the ART outcomes of patients with endometriosis, surgery and suppressive pre-cycle hormonal treatments were largely</p><p>implicated. Although surgical excision of deep pelvic endometriosis was found to significantly improve the IVF/Intracytoplasmic</p><p>Sperm Injection (ICSI) outcomes in terms of the clinical pregnancy and live birth rates [38], the surgery itself carries an increased risk</p><p>of damaging the ovarian reserve by injuring the ovarian vasculature and causing a thermal injury to the ovarian cortex [39]. The risks</p><p>of surgery on the patient’s fertility become of particular significance when considering the treatment of ovarian endometriomas. It was</p><p>reported that endometrioma cystectomy was associated with a significantly higher loss of ovarian follicles [40], and the amount of</p><p>resected healthy ovarian cortex correlated significantly with the size of the endometrioma [41]. Therefore, non-surgical approaches to</p><p>potentially improve ART outcomes should be considered. Hormonal suppressive treatments were proven to be effective in treating the</p><p>endometriosis-related pain [42,43]. Nonetheless, their effectiveness in improving ART outcomes has not been established yet. The</p><p>most commonly administered medications include the Gonadotropin-Releasing Hormone (GnRH) agonists, progestins, and to a lesser</p><p>extent, the aromatase inhibitors. In this review, we aim to summarize the current evidence concerning the effectiveness of the pro-</p><p>longed administration of each of the aforementioned drug groups and provide a thorough discussion of the benefits and drawbacks of</p><p>their use in patients with endometriosis undergoing ART treatment.</p><p>A. Naem et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>3</p><p>2. The GnRH agonists and the endometriosis-related infertility</p><p>2.1. An Overview of the mechanism of action and side effects of the GnRH agonists</p><p>The GnRH agonists mainly function through suppressing the pituitary-ovarian axis and causing a subsequent hypogonadotropic</p><p>hypogonadism. Those agents tend to irreversibly bind to the GnRH receptors in the pituitary gland and eventually induce pituitary</p><p>desensitization. This in turn results in a decreased secretion of the Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH)</p><p>and a subsequent suppression of ovarian steroidogenesis and ovulation. This chain effect finally leads to menopausal-like hypo-</p><p>estrogenemia [44]. The medically-induced hypoestrogenic status is suggested to cause endometriosis remission and neutralize the</p><p>intraperitoneal inflammatory milieu [45,46]. In fact, the administration of buserelin for 3 months in patients with endometriosis was</p><p>found to significantly decrease the follicular fluid levels of Tumor Necrosis Factor-α (TNF-α) and 8-hydroxy-2’ deoxyguanosine</p><p>(8-OHdG), and increase the melatonin concentrations [47]. Melatonin is a free-radical scavenger and is suggested to protect the</p><p>oocytes from ROS [26,46]. The prolonged administration of GnRH agonists resulted also in increasing the proapoptotic molecules and</p><p>decreased the anti-apoptotic activities in the endometriotic lesions [48]. This leads eventually to the shrinkage of the endometriotic</p><p>nodules and decreases their vascularization [49]. The GnRH agonists administration and the subsequent medically-induced amen-</p><p>orrhea may also have a positive effect on the endometrial receptivity.</p><p>The exact mechanism by which the GnRH agonists improve the endometrial receptivity is merely understood. However, the</p><p>prolonged administration of GnRH agonists was reported to increase the endometrial pinopodes and restore the αvβ3 vitronectin</p><p>expression [50,51]. The hypoestrogenic status as provoked by the prolonged administration of the GnRH agonists may also inhibit the</p><p>P450 aromatase in the eutopic endometrium [52]. This is also linked to an optimized endometrial receptivity since the increased</p><p>expression of the P450 aromatase mRNA was found to have a detrimental effect on embryo implantation [53].</p><p>The prolonged administration of GnRH agonists is associated with some symptoms that may not be tolerable by all patients. The</p><p>most commonly reported side effects include hot flashes, vaginal dryness, decreased libido, and bone loss [54]. Those symptoms result</p><p>mainly from the menopause-like medically-induced hypoestrogenemia. Although less frequent, abnormal uterine bleeding may occur</p><p>during the administration of GnRH agonists [55]. It is noteworthy that almost all patterns of irregular vaginal bleeding were reported,</p><p>ranging from spotting to menstruation-like bleeding or even higher quantities. Spotting and menstruation-like bleeding are the most</p><p>common bleeding patterns, and those are more frequent during the first treatment cycle. The prevalence of spotting and</p><p>menstruation-like bleeding during the first treatment cycle was 18.5% and 10.3% respectively [55]. However, such bleeding disorders</p><p>were observed until the third treatment cycle, but in lesser frequencies [55].</p><p>2.2. The ultralong GnRH agonist protocol and IVF-ET outcomes of patients with endometriosis</p><p>To the best of our knowledge, the ultralong administration of GnRH agonists as indicated to improve the conception chances of</p><p>patients with endometriosis dates back to 1990. It was first described by Dale et al. [56] that administered buserelin for 4–6 months in</p><p>two patients with endometriosis-related infertility [56]. Since then, the effectiveness of the prolonged administration of the GnRH</p><p>agonists has been widely investigated. In 2006, Sallam et al. [57] published a systematic review investigating the potential benefits of</p><p>the ultralong GnRH agonists protocol in improving the fertility outcomes of patients with endometriosis undergoing IVF/ICSI treat-</p><p>ment. The authors concluded that administering the GnRH agonists for a period of 3–6 months could increase the clinical pregnancy</p><p>rate of patients with endometriosis by 4 folds and the live birth rate by 9 folds [57]. The major limitations of this meta-analysis are the</p><p>few number of included studies, and that the odds of obtaining a live birth were calculated based on one study only [58]. Years later,</p><p>Georgiou et al. [59] conducted a larger systematic review and meta-analysis of the data of 640 patients. Contrary to what was pre-</p><p>viously reported, the treated</p><p>endometriosis patients with the ultralong GnRH agonists protocol had a decreased live birth rate by 52%.</p><p>Moreover, the mean number of retrieved oocytes, the mean number of obtained embryos, and the clinical pregnancy rate were similar</p><p>to the control group [59]. The major discrepancy between these two reviews is worth questioning. By taking a closer look at the used</p><p>methodologies, it would be noted that the two reviews followed different strategies in dealing with missing data. The review of</p><p>Georgiou et al. [59] considered all the missing data as negative findings when examining the outcomes of the included studies.</p><p>Conversely, Sallam et al. [57] postulated that all the ongoing pregnancies reported by Dicker et al. [58] terminated in live births, and</p><p>drew their conclusion about the effect of the ultralong GnRH agonists protocol on live birth rates on that basis. It should be noted that</p><p>Georgiou et al. [59] excluded the study of Dicker et al. [58] from the live birth rate analysis as their data did not match the</p><p>Zegers-Hochschild definition of live birth [60]. It is also worth mentioning that Georgiou et al. [59] calculated the odds ratio of the live</p><p>birth rates based on the data of one study only, which was different to the one analyzed in the review of Sallam et al. [57]. The study of</p><p>Dicker et al. [58] consisted of patients with stage III/IV endometriosis treated with triptorelin for 6 months compared to patients</p><p>receiving the conventional ovarian stimulation protocol. The authors reported higher numbers of retrieved oocytes and embryos, with</p><p>higher clinical pregnancy rates per cycle and per transfer [58]. Conversely, the study by Rodríguez-Tárrega et al. [61] included</p><p>endometriosis patients with varying disease severity. The authors did not detect a significant impact of the ultralong protocol on the</p><p>IVF-ET outcomes of patients with endometriosis [61]. The same conclusion was drawn by another open-label randomized controlled</p><p>trial that included patients who were previously operated for endometriosis [62]. It should be noted that the extent and type of the</p><p>surgical intervention was not reported and the trial was terminated early [62]. Similar to the later studies, Kaponis et al. [63] con-</p><p>ducted a multicentric randomized controlled trial to investigate the effectiveness of the ultralong GnRH agonists protocol on patients</p><p>with mild to moderate endometriosis. Despite the reported higher fertilization rate in the ultralong GnRH agonists group, the live birth</p><p>rate did not differ significantly between patients receiving the ultralong GnRH agonists protocol and the control group [63]. In line</p><p>A. Naem et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>4</p><p>with the previous results, administering goserelin for 3 months in patients with peritoneal endometriosis did not result in significant</p><p>improvement in the IVF-ET outcomes [64]. However, Surrey et al. [65] reported that the 3-month administration of depot-leuprolide</p><p>resulted in a significantly higher rate of ongoing pregnancy in patients with endometriosis when compared to the conventional</p><p>stimulation protocol alone. In this study, the majority of patients in the endometriosis group were diagnosed with stage III-IV</p><p>endometriosis [65], unlike the aforementioned studies that were focused on patients with milder forms of endometriosis [63,64].</p><p>In another study, Rickes et al. [66] stratified the endometriosis patients based on the disease severity. The results demonstrated that</p><p>patients with stages I and II endometriosis did not benefit from the ultralong GnRH agonists protocol, while patients with stages III and</p><p>IV endometriosis had a 2-fold higher pregnancy rate compared to the untreated control group [66]. In accordance with these results,</p><p>Marcus et al. [67] demonstrated a favorable effect of the prolonged administration of goserelin on the clinical pregnancy rate in</p><p>patients with severe endometriosis. Those results were further justified in a meta-analysis conducted by Cao et al. [68]. The authors</p><p>concluded that the ultralong protocol results in an approximately 2-fold increase in the clinical pregnancy rate of patients with stage</p><p>III-IV endometriosis in comparison with the long protocol alone [68]. More recently, another study conducted by Wang et al. [69]</p><p>demonstrated that the long-acting GnRH agonists long protocol results in a significantly higher number of high-quality embryos,</p><p>clinical pregnancy rate, and implantation rates compared to the short-acting GnRH agonists long protocol and the GnRH antagonists</p><p>protocol. Similarly, the superiority of the ultralong GnRH agonists protocol over the antagonists protocol was further demonstrated in</p><p>a propensity score-matched cohort study [70]. The antagonist group showed a significantly lower clinical pregnancy rate, implantation</p><p>rate, and live birth rate compared to the agonists protocol in the fresh cycles [70].</p><p>Therefore, it seems that prolonged down-regulation with GnRH agonists in patients with stages I and II endometriosis before the</p><p>controlled ovarian stimulation cycle may be considered meaningless and ineffective. Nevertheless, scattered pieces of evidence suggest</p><p>that prolonged pituitary down-regulation with the GnRH agonists in patients with severe endometriosis (i.e. stages III and IV) may</p><p>improve the IVF-ET success rates. Although this conclusion is supported by various studies and a meta-analysis, a definitive clinical</p><p>recommendation cannot be drawn due to the heterogeneity of the studies and included patients in both the cases and control groups.</p><p>Future randomized controlled trials, preferably multicentric, are heavily needed to justify any recommendation in this regard.</p><p>3. The role of progestins in the endometriosis-related infertility</p><p>3.1. The general characteristics and Indications of progestins in endometriosis</p><p>Progestins are synthetic progestogens that can be divided into three main classes: progesterone derivatives, testosterone de-</p><p>rivatives, and spironolactone derivatives [71]. Dienogest is a testosterone derivative that belongs to the estranes group. It is a</p><p>fourth-generation progestin that exhibits progestational characteristics with minimal anti-estrogenic and anti-angiogenic effects [72,</p><p>73]. Medroxyprogesterone Acetate (MPA) on the other hand is a 17-hydroxyprogesterone that has anti-androgenic and strong</p><p>anti-glucocorticoid effects [71]. As it is for all the progestogens, dienogest, and MPA act on the endometriotic implants through</p><p>systemic and local effects. These agents induce anovulation and hypoestrogenism, which leads to the decidualization of endometriosis</p><p>and eutopic endometrium [71].</p><p>This effect is achieved through decreasing the frequency but increasing the intensity of the GnRH pulses at the level of the hy-</p><p>pothalamus, which in turn reduces the secretion of FSH and LH. This eventually leads to the suppression of ovarian steroidogenesis and</p><p>ovulation [71]. In addition to the aforementioned systemic effects, dienogest possesses significant anti-inflammatory, anti-angiogenic,</p><p>and cytokine-inhibiting effects that could help neutralize the peritoneal milieu and ameliorate the hostile inflammatory environment</p><p>[74–76]. Dienogest was also reported to increase the progesterone concentration within the endometriotic implants leading to</p><p>decidual changes and subsequent shrinkage and atrophy of the endometriotic lesions [77,78]. Moreover, dienogest was also found to</p><p>exhibit a stronger cytoreductive effect on endometriosis when compared to the GnRH agonists [79,80]. Furthermore, progesterone</p><p>supplementation was found to restore the normal activity of matrix metalloproteinases and their tissue inhibitor in patients with</p><p>endometriosis [81]. From a clinical point of view, dienogest and MPA</p><p>were proven to be as effective as the GnRH agonists and more</p><p>effective than the placebo in controlling endometriosis-related pain [43,76,82]. Despite that progestins have an acceptable safety</p><p>profile, their tolerability is controversial. The most commonly reported adverse effects associated with the progestin administration are</p><p>breakthrough vaginal bleeding, depression, breast tenderness, headache, and weight gain [71,73]. Nonetheless, these effects become</p><p>quite overt in prolonged administration durations of 6 months or more.</p><p>Nonetheless, the use of progestins in ART is less studied, especially in patients with endometriosis. The application of progesterone-</p><p>primed ovarian stimulation protocols showed favorable IVF-ET outcomes in the general population [83]. On the one hand, these agents</p><p>were also suggested to suppress the premature LH surge by inhibiting the endogenous GnRH secretion [84]. Progestins were also found</p><p>to effectively reduce the risk of moderate to severe Ovarian Hyperstimulation Syndrome (OHSS) [85,86]. On the other hand, the</p><p>administration of progestins may have certain drawbacks on the developing follicles as it was suggested to suppress follicular growth,</p><p>induce follicular atresia, and inhibit the recruitment of primordial follicles [87–89].</p><p>3.2. The prolonged administration of dienogest before IVF-ET cycles</p><p>The prolonged suppression with progestins prior to ovarian stimulation has been investigated in recent years. Most studies focused</p><p>on the administration of progestins for a period between 2 and 6 months. In a randomized controlled trial, Tamura et al. [90] tested the</p><p>effects of administering oral dienogest for 3 months in endometriosis patients and compared them to untreated controls with the same</p><p>r-ASRM endometriosis classification. Patients who received dienogest had poorer ovarian response to stimulation demonstrated by</p><p>A. Naem et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>5</p><p>increased gonadotropin dosages and decreased antral follicular count and serum estradiol levels [90]. Consequently, the number of</p><p>retrieved oocytes, the fertilization rate, pregnancy rate, and live birth rates were significantly lower in patients who received</p><p>dienogest. However, the authors administered estrogen and progesterone prior to ovarian stimulation to induce withdrawal bleeding,</p><p>which is supposed to bias the study’s results [90]. On the contrary, another randomized controlled trial by Khalifa et al. [91] compared</p><p>the effectiveness of the prolonged administration of dienogest for 3 months to that of the 3-month ultralong protocol of</p><p>depot-leuprolide prior to ovarian stimulation. The study groups demonstrated comparable cycle outcomes in terms of the number of</p><p>mature oocytes, the number of transferred embryos, the fertilization rate, and the clinical pregnancy rate [91]. On the other hand, the</p><p>authors found that using dienogest is cheaper and more tolerable than the ultralong GnRH agonist protocol [91]. However, the dif-</p><p>ferences in the characteristics of the included patients in both trials should be considered when interpreting the results. Tamura et al.</p><p>[90] included patients with severe endometriosis only, while Khalifa et al. [91] included all stages of endometriosis. Therefore, any</p><p>beneficial or harmful effect of dienogest on patients with mild or severe disease may have been masked by the inclusion of different</p><p>stages of the disease. In addition, both studies did not adjust for the coexistence of adenomyosis. Another two prospective cohort</p><p>studies favored the prolonged administration of dienogest before ovarian stimulation. In the study of Muller et al. [92], the authors</p><p>compared the administration of dienogest for 6 months to the administration of triptorelin and to an untreated control group. All</p><p>groups included patients who had surgical removal of ovarian endometriosis and were scheduled for fertility treatment [92]. The</p><p>patients who were not treated at all had significantly lower antral follicular count compared to patients who were treated with</p><p>dienogest. Regarding the clinical pregnancy and live birth rates, those were significantly 2.5 and 3 times higher in patients who were</p><p>treated with dienogest compared to the untreated controls, respectively. On the other hand, there were no significant differences</p><p>between patients pretreated with dienogest and patients pretreated with triptorelin in terms of ovarian responsiveness, number of</p><p>high-quality embryos, clinical pregnancy, and live birth rates [92].</p><p>In another study, Barra et al. [93] investigated the effects of the 3-month dienogest pretreatment on patients with unoperated</p><p>ovarian endometriomas. The stimulation duration, gonadotropin dosages, and the number of retrieved oocytes were comparable</p><p>between the two groups. However, the authors reported significantly higher cumulative implantation rates, clinical pregnancy rates,</p><p>and live birth rates in patients who received dienogest pretreatment [93]. Moreover, the authors noted a reduction in the endome-</p><p>trioma’s size and maximal diameter in patients who were treated with dienogest. It is noteworthy that patients who had ovarian</p><p>endometriomas ≥4 cm in size exhibited higher numbers of antral follicles, MII oocytes, blastocysts, and transferrable embryos in</p><p>comparison to untreated patients with similar endometriomas size [93]. A recent systematic review compared the ART outcomes of</p><p>patients who were treated with dienogest and those who received other hormonal and non-hormonal treatments [94]. It is noteworthy</p><p>that the non-dienogest group consisted also of patients who received no pretreatment at all. The authors found comparable outcomes</p><p>between both groups [94]. In a subgroup analysis, the authors reported that the dienogest pretreatment resulted in a significantly</p><p>lower pregnancy rate in comparison with the GnRH agonists pretreatment. This meta-analysis also suggested that dienogest may carry</p><p>a beneficial impact on endometrial receptivity and embryonic implantation in fresh-ET cycles. This was reflected by the higher im-</p><p>plantation rate, clinical pregnancy rate, and live birth rate in patients pretreated with dienogest in comparison to the non-dienogest</p><p>pretreatment. On the other hand, the results of frozen-Thawed Embryo Transfer (FET) cycles were comparable between the dienogest</p><p>and non-dienogest groups, suggesting that this impact is subject to a wash-out effect [94].</p><p>3.3. Progestin-primed ovarian stimulation in patients with endometriosis</p><p>Research focusing on the effects of the pre-cycle prolonged administration of MPA is lacking. Through our search, we could identify</p><p>only one study that investigated the effects of MPA on IVF-ET cycles in patients with endometriosis [95]. The studied cycles were</p><p>unstimulated and the MPA administration duration was 2 months. Despite the small sample size and the weak study design, the authors</p><p>reported a beneficial effect of MPA on ART outcomes [95]. On the other hand, MPA has an essential role in the progestin-primed</p><p>ovarian stimulation protocols in the general population and the endometriosis patients as well.</p><p>Progestin-primed ovarian stimulation could be considered a new stimulation protocol as it was introduced in 2015 by Yanping</p><p>Kuang’s group [84]. This protocol mainly consists of the co-administration of MPA and Human Menopausal Gonadotropins (HMG)</p><p>starting from the 3rd day of the menstrual cycle. Follicular monitoring usually starts between the 9th and 11th days of the menstrual</p><p>cycle. When at least 3 growing follicles reach the diameter of 18 mm, ovulation triggering with Human Chorionic Gonadotropin (hCG)</p><p>takes place [86]. Although MPA seems to be the most commonly used progestin in progestin-primed ovarian stimulation protocols, an</p><p>open-label</p><p>randomized trial compared three different progestins for progestin-primed ovarian stimulation, namely MPA, dydroges-</p><p>terone, and progesterone [96]. The study demonstrated comparable fertilization, implantation, clinical pregnancy, and live birth rates</p><p>among all three study groups. However, patients treated with MPA had significantly deeper suppression of LH and higher numbers of</p><p>retrieved oocytes and mature oocytes [96].</p><p>In 2017, Guo et al. [86] published a retrospective study comparing the ART outcomes of patients with endometriosis who received</p><p>the progestin-primed ovarian stimulation protocol to those who received the conventional GnRH agonists short protocol. On trigger</p><p>day, patients treated with MPA and HMG were found to have a deeper suppression of LH and lower progesterone serum levels. On the</p><p>other hand, the estrogen levels increased gradually during the stimulation, reflecting an acceptable ovarian responsiveness [86]. There</p><p>was no premature ovulation or moderate to severe OHSS in patients treated with the progestin-primed ovarian stimulation protocol.</p><p>Although the number of retrieved oocytes was comparable between the two study groups, patients who received the progestin-primed</p><p>ovarian stimulation protocol had significantly higher mature oocytes and high-quality embryo rates. Nonetheless, both study groups</p><p>had comparable fertilization rates, cleavage rates, and clinical pregnancy rates. The cancellation rate was slightly but insignificantly</p><p>higher in patients treated with MPA and HMG [86]. It should be kept in mind that those results are subject to bias and several</p><p>A. Naem et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>6</p><p>confounders. Firstly, the patients who were treated with the progestin-primed ovarian stimulation protocol also had surgical removal</p><p>of ovarian endometriosis, unlike the control group that had unoperated ovaries. Secondly, this study included without stratification</p><p>results of fresh and FET cycles. FET was suggested to have inherent beneficial outcomes on ART regardless of the used stimulation</p><p>protocol [97], which may have a confounding effect on the study’s outcomes. Lastly, the control group of this study consisted mainly of</p><p>patients with severe endometriosis. As previously mentioned, the short GnRH agonists protocol was proven to be ineffective when</p><p>applied in patients with stage III/IV endometriosis [58,68]. In another prospective study, the same investigators focused on the effects</p><p>of progestin-primed ovarian stimulation protocol on the ART outcomes of patients with stage III/IV endometriosis and surgically</p><p>removed ovarian endometriomas [98]. The control group consisted of patients with tubal factor infertility who received the same</p><p>progestin-primed ovarian stimulation protocol. Both study groups had comparable numbers of retrieved oocytes, mature oocytes,</p><p>fertilization rate, clinical pregnancy rate, and live birth rate [98]. In a recent randomized trial, Guo et al. [99] compared the ART</p><p>outcomes between patients receiving the MPA-based progestin-primed ovarian stimulation protocol to those undergoing an approx-</p><p>imately 1-month suppression with triptorelin. This trial did not demonstrate any significant difference between the two groups in terms</p><p>of ovarian responsiveness and the embryo’s quality. Moreover, the implantation rates, fertilization rate, miscarriage rate, clinical</p><p>pregnancy, and live birth rates were comparable between the two patient groups [99]. In contrast, Yang et al. [100] conducted a</p><p>retrospective study comparing the ART outcomes between patients receiving the MPA-based progestin-primed ovarian stimulation</p><p>protocol, patients undergoing a 1-month suppression with triptorelin, and patients receiving the conventional GnRH antagonists</p><p>protocol. In this study, the number of oocytes retrieved was significantly lower in the progestin-primed ovarian stimulation group</p><p>compared to the GnRH agonists group, but comparable to the antagonists group [100]. Furthermore, the number of viable embryos in</p><p>the progestin-primed ovarian stimulation group was significantly lower than those in the GnRH agonists and antagonists’ groups. The</p><p>implantation rate, biochemical pregnancy rate, clinical pregnancy, and ongoing pregnancy rates were significantly lower in the</p><p>progestin-primed ovarian stimulation group when compared to the GnRH agonists group [100]. Nonetheless, the results should be</p><p>interpreted with caution, since the patients who received the progestin-primed ovarian stimulation protocol had significantly lower</p><p>Anti-Müllerian Hormone (AMH) levels than patients undergoing the suppression with triptorelin. On this basis, progestin-primed</p><p>ovarian stimulation protocols could be a good option for endometriosis patients. However, current results are obtained from the</p><p>same working group, which poses challenges to their generalizability. More research on different ethnicities and endometriosis se-</p><p>verities is substantial to define the exact role of progestin-primed ovarian stimulation in the ART treatment of endometriosis patients.</p><p>4. Aromatase inhibitors and endometriosis</p><p>4.1. General characteristics of aromatase inhibitors</p><p>Anastrozole and Letrozole belong to the third generation of aromatase inhibitors. These agents are effective with an excellent</p><p>bioavailability of 99.9% when administered orally. The effects of aromatase inhibitors are reversible owing to their short half-life [101,</p><p>102]. Aromatase inhibitors can lower the estrogen levels by suppressing its biosynthesis in the ovarian and extra-ovarian locations. The</p><p>mechanism of action of aromatase inhibitors mainly relies on the direct suppression of P450 aromatase; an enzyme expressed in the</p><p>adrenal glands, fatty tissue, skin, and ovarian granulosa. P450 aromatase produces estrogen through the catalytic conversion of</p><p>circulating androgens namely testosterone and androstenedione [103]. In fact, aromatase inhibitors were found to decrease the</p><p>circulating estrogen levels by 97% [101,102]. In addition, aromatase inhibitors also have a direct effect on endometriosis and the</p><p>endometrial receptivity, since aromatase was found to be aberrantly expressed in the endometriotic implants and eutopic endome-</p><p>trium of patients with endometriosis [104,105]. The biosynthesis of estrogen on the level of the endometriotic implants is maintained</p><p>by a positive feedback loop mediated by P450 aromatase and Cyclooxygenase-2 (COX-2). Aromatase produces estrogen through the</p><p>conversion of adrenal and cutaneous androgens. The produced estrogen stimulates COX-2 to synthesize Prostaglandin (PG) E2. PGE2</p><p>in turn stimulates the P450 aromatase to produce estrogen and thus, the loop continues. This results in the continuous maintenance of</p><p>the local hyperestrogenic milieu in endometriosis [103,106]. In addition to stimulating aromatase, PGE2 induces the local production</p><p>of oxytocin and increases the expression of its receptor [107]. Oxytocin in turn stimulates the production of PGF2-α [108]. Indeed,</p><p>PGE2 and PGF2-α are two substantial elements in the endometriosis-related pain pathophysiology [109]. It is noteworthy that a similar</p><p>feedback loop is thought to be harvested in the eutopic endometrium of patients with endometriosis [107]. Therefore, the inhibition of</p><p>aromatase would result in the deactivation of a complex and interwoven feedback loops which are deemed crucial for the endome-</p><p>triosis activity. In line with these speculations, the suppression of the aromatase activity of the endometriotic cells in vitro resulted in a</p><p>significant decrease in their proliferation [110]. Besides the in vitro observations, the administration of letrozole and triptorelin to</p><p>patients with rectovaginal endometriosis resulted in a significant reduction in the nodule size</p><p>and the endometriosis-associated</p><p>symptoms [111]. Furthermore, letrozole was found to decrease the size of endometriotic lesions in postmenopausal patients and</p><p>reduce the symptomatology as well with an acceptable safety profile [112]. Additionally, the co-administration of anastrozole and</p><p>goserelin for 6 months postoperatively is suggested to minimize the recurrence rates of endometriosis in comparison to the sole</p><p>administration of goserelin [113]. Moreover, patients who received anastrozole and goserelin did not have a deteriorated post-</p><p>menopausal quality of life when compared to patients who received goserelin only [113]. On the other hand, letrozole and anastrozole</p><p>have limited effects on ovarian steroidogenesis [114]. Therefore, when administered alone, those medications were found to stimulate</p><p>ovulation. It is noteworthy that letrozole was reported to be as effective as clomiphene citrate in inducing ovarian superovulation</p><p>[115]. It should be noted that letrozole was also found to induce an early formation of the antral cavity in vitro [116]. Therefore, the</p><p>ovulation triggering should occur when the dominant follicle reaches at least 19 mm in diameter [117]. In addition to its endocrine</p><p>effects, letrozole was suggested to restore the normal expression of integrin in around 66% of patients with integrin deficiency.</p><p>A. Naem et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>7</p><p>Letrozole was also suggested to improve the reproductive outcomes of endometriosis patients with integrin type 2 deficiency [118]. In</p><p>contrast, another study suggested that adding letrozole to the ovarian stimulation protocol did not have significant benefits on the</p><p>IVF-ET outcomes of patients with endometriosis [119].</p><p>4.2. The prolonged administration of aromatase inhibitors before IVF-ET in endometriosis patients</p><p>To the best of our knowledge, only two observational studies and one randomized trial investigated the effectiveness of the aro-</p><p>matase inhibitors pretreatment on the ART outcomes of patients with endometriosis. In a multicentric retrospective cohort study,</p><p>Cantor et al. [114] investigated the benefits of letrozole administration with depot-leuprolide acetate for 2 months in patients with</p><p>radiologically diagnosed ovarian endometrioma and a previously failed IVF-ET cycle in comparison with administering</p><p>depot-leuprolide acetate alone. Patients who received letrozole with depot-leuprolide acetate had significantly higher numbers of</p><p>retrieved oocytes, mature oocytes, and 2-pronuclei embryos. Accordingly, the clinical pregnancy and live birth rates were significantly</p><p>higher in patients receiving depot-leuprolide acetate with letrozole compared to patients who received depot-leuprolide acetate alone.</p><p>Additionally, the authors reported a significant reduction in the endometriomas diameters in patients receiving the combined treat-</p><p>ment [114]. In 2009, Lossl et al. [119] reported the IVF-ET outcomes of 20 patients with ovarian endometriomas who received</p><p>goserelin and anastrozole for 69 days. This study did not include a control group and the results were generally unfavorable. However,</p><p>the authors reported that 75% of patients had a reduction in the cyst’s size with a mean decrease of 29%. Furthermore, only one patient</p><p>had a flare-up phenomenon accompanied by ovarian cyst formation [119]. Finally, Alborzi et al. [120] conducted a randomized</p><p>controlled trial on endometriosis patients who were treated laparoscopically and were scheduled to have ART treatments. The trial</p><p>consisted of three groups, one group received letrozole, another group received triptorelin, and the control group consisted of patients</p><p>who did not receive any hormonal treatment before ART. The authors failed to detect any significant difference in the cycle outcomes</p><p>and pregnancy rates between all three study groups. However, this clinical trial included a relatively small sample size and it is subject</p><p>to selection and detection biases [120]. Finally, one study reported that a 2-month pretreatment with letrozole and depot-leuprolide</p><p>acetate in patients with recurrent abortions resulted in a significant increase in the number of mature oocytes, blastocysts, day-3</p><p>embryos, and higher pregnancy rates [121]. However, the results of this study are not robust since endometriosis was not investi-</p><p>gated and diagnosed systematically in the included sample.</p><p>Based on what was previously discussed, it is too early to draw conclusions regarding the usefulness of the pretreatment with</p><p>aromatase inhibitors in improving the ART outcomes of patients with endometriosis owing to the limited external validity of the</p><p>available studies. In addition, the conflicting results make it questionable whether it is worth it to conduct a large or multicentric</p><p>clinical trial to investigate precisely the benefits of the aromatase inhibitors on the ART cycle outcomes since the available results</p><p>indicate that this effect may be modest, if any.</p><p>5. Discussion</p><p>5.1. The Dilemma of the effect of endometriosis on ART outcomes</p><p>The association between endometriosis and infertility has been widely investigated and already established. However, the effect of</p><p>endometriosis on extracorporeal fertilization is still a matter of debate. In the meta-analysis of Horton et al. [37], endometriosis was</p><p>reported to reduce the clinical pregnancy rate by 15% with no significant effect on the live birth rate. In a subgroup analysis, the</p><p>authors reported a significantly reduced live birth rate in patients with stage III/IV endometriosis, while this reduction was not</p><p>observed in patients with stage I/II endometriosis [37]. In contrast, another meta-analysis suggested that the clinical pregnancy and</p><p>live birth rates of endometriosis patients undergoing IVF-ET are comparable to those of the controls [122]. Nonetheless, both</p><p>meta-analyses suggested that patients with severe endometriosis (i.e., r-ASRM stages III and IV) have a significantly reduced clinical</p><p>pregnancy rate [37,122]. The live birth rate also tended to be lower in patients with severe endometriosis, without statistical sig-</p><p>nificance [122]. Similarly, more recent observational studies have found that endometriosis does not affect the ART outcomes,</p><p>especially when the AMH levels are within the normal ranges, or at least comparable to the control groups. In the study of Zim-</p><p>mermann et al. [123], the cumulative live birth rates per cycle and per woman were found to be comparable between patients with and</p><p>without endometriosis. In another series, the clinical pregnancy and live birth rates were also comparable between patients with</p><p>endometriosis and controls [124]. In the same study, the authors reported that the patient group with coexisting adenomyosis and</p><p>endometriosis had significantly lower clinical pregnancy and live birth rates than the controls [124]. Furthermore, patients with</p><p>adenomyosis only had significantly lower clinical pregnancy and live birth rates. This also lines with the observation that the presence</p><p>of ovarian endometriomas results in a lower number of oocytes retrieved and mature oocytes, but the clinical pregnancy and live birth</p><p>rates would remain comparable to controls in fresh ET cycles [125,126]. In FET cycles, Zeng et al. [125] suggested that the clinical</p><p>pregnancy rate is lower in patients with ovarian endometriomas, while Chang et al. [126] suggested that the live birth rate is the</p><p>affected ART outcomes in patients with endometriosis. This may suggest a slight impact of ovarian endometriomas on the outcomes of</p><p>FET cycles, if any. Furthermore, several registry analyses indicated that patients with endometriosis have the same chances of</p><p>conceiving as patients without endometriosis in the means of ART [127,128], suggesting that the</p><p>endometrial receptivity at least in the</p><p>majority of patients with endometriosis is unaffected [129]. Another debate is the effect of endometriosis on the oocytes’ and embryos’</p><p>quality. In a recent study applying preimplantation genetic testing for aneuploidy, the aneuploidy rate of the blastocysts of patients</p><p>with endometriosis was comparable to those of patients with male factor infertility [130]. Moreover, Khamsi et al. [131] reported that</p><p>the direct exposure of oocytes to the endometrioma content during oocyte retrieval has no impact on the oocyte quality. These results</p><p>A. Naem et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>8</p><p>suggest that overall, endometriosis has no major consequences on the ART outcomes in terms of the quality of the retrieved oocytes,</p><p>obtained embryos, pregnancy, and live birth rates. On the other hand, a recent study by Shi et al. [132] identified different genetic</p><p>expression levels in the granulosa of ovaries with endometrioma that correlated negatively with the ART outcomes. It is not clear</p><p>whether such dysregulations are present in all the granulosa cells of ovaries affected with ovarian endometriosis, or those are present in</p><p>the subgroup of patients which is more prone to have negative outcomes of ART. Those results are perfectly in line with the novel</p><p>broader vision of endometriosis as subsets that share the same phenotype (i.e., endometrial-like tissue outside the uterus) with</p><p>different genetic and epigenetic regulations, which eventually lead to different symptomatology and consequences of the disease [8,</p><p>11]. In other words, it seems that a specific subtype of endometriosis affects the fertility potential and ART outcomes of the patients.</p><p>This subtype of endometriosis, if truly exists, should have its own genetic and epigenetic regulation.</p><p>5.2. Hormonal, surgical, or no treatment before ART: the Unanswered Question</p><p>Based on the aforementioned discussion, endometriosis seems to affect fertility in a specific subgroup of patients, which is yet to be</p><p>identified. Current research indicates that, in the presence of normal AMH levels, the extracorporeal fertilization and pregnancy</p><p>outcomes remain almost the same in patients with and without endometriosis [123,125]. Furthermore, the advanced stages of</p><p>endometriosis seem to have a deleterious impact on ART [37,122]. In addition, the coexistence of adenomyosis and endometriosis</p><p>seems to have the major impact on IVF/ICSI-ET outcomes [124]. Until those arguments are solved and robust evidence is established, it</p><p>will remain challenging to recommend any sort of treatment for any patient population in light of current knowledge. Although a</p><p>recent meta-analysis reported better IVF-ET outcomes in patients operated for deep infiltrating endometriosis [38], recent studies</p><p>demonstrated that surgical removal of ovarian endometriomas has no significant positive impact on the ART outcomes [125,133]. The</p><p>same studies did not report whether those patients had previous excisional surgery for endometriosis or the patients had coexisting</p><p>adenomyosis. The same limitations extend to include almost all studies that investigated the effectiveness of hormonal pretreatment on</p><p>the IVF/ICSI-ET cycles. It is hard to draw a conclusion about the generalizability of current results in the presence of so many con-</p><p>founders and bias sources. In addition, the effect size and cost-effectiveness of such interventions has not been investigated thoroughly</p><p>yet. To the best of our knowledge, one study only found that the mean costs of the dienogest pretreatment were significantly lower than</p><p>that of the GnRH agonist prior to ovarian stimulation with comparable ART outcomes [91]. Moreover, no studies to date compared</p><p>hormonal to surgical treatment before ovarian stimulation in patients with endometriosis. Therefore, prolonged suppressive hormonal</p><p>treatments may be indicated in patients who had already a previously failed IVF/ICSI-ET cycles who were or were not operated, since</p><p>this is so far the only potential indicator of patients whom ART outcomes are affected by endometriosis. In addition, a 3-month</p><p>suppression with the GnRH agonists ultralong protocol may be indicated in endometriosis patients with coexisting adenomyosis,</p><p>since it was reported to have favorable impact on the ART outcomes of patients with adenomyosis [134]. On the other hand, several</p><p>reports demonstrated poorer ART outcomes when GnRH antagonists are used for ovarian stimulation in patients with endometriosis</p><p>[70,135]. Although the progestin-primed ovarian stimulation protocol with MPA demonstrated a preliminary positive impact, it re-</p><p>mains unclear whether this protocol is effective in advanced stages of endometriosis and in patients with coexisting adenomyosis and</p><p>endometriosis. Another drawback of the available studies comparing progestin-primed ovarian stimulation protocol to the GnRH</p><p>agonists prolonged protocol is that the authors compared the progestin-primed ovarian stimulation protocol to a 1-month suppression</p><p>with GnRH agonists [99]. Lastly, current knowledge encourages the usage of dienogest as a pretreatment in patients with endome-</p><p>triosis who are scheduled for fresh ET, as it was suggested to have a potential beneficial impact on the endometrial receptivity [94].</p><p>Although higher pregnancy and live birth rats were observed with the prolonged administration of dienogest, it remains challenging to</p><p>recommend this therapy before fresh and FET cycles unless this effect would become proved with larger series.</p><p>6. Summary</p><p>The impact of endometriosis on ART outcomes is becoming more debated. Current data suggests that a subgroup of patients</p><p>actually suffers from deteriorated ART outcomes due to endometriosis, but this subgroup is yet to be defined. Until this group of</p><p>patients is identified, recommending prolonged suppressive treatments before ART will remain controversial. However, prolonged</p><p>treatment with GnRH agonists for a duration of at least 3 months seems to be the most effective protocol, especially in the presence of</p><p>coexisting adenomyosis. Prolonged suppression with dienogest should be avoided when FET is planned. More research is required to</p><p>define the role of progestin-primed ovarian stimulation protocols in patients with different stages of endometriosis. Although it was not</p><p>investigated in an evidence-based manner, patients with a previously failed ART cycle could be the best candidates for prolonged</p><p>hormonal suppression before the next cycle of ovarian stimulation.</p><p>Funding</p><p>This research did not receive external funding.</p><p>7. Institutional review board statement</p><p>Not applicable.</p><p>A. Naem et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 95 (2024) 102500</p><p>9</p><p>8. Data availability statement</p><p>Not applicable.</p><p>10. Research Agenda</p><p>•The main issue that should be addressed is the effect of endometriosis on assisted reproduction technologies treatment. Patients</p><p>should be stratified by the r-ASRM stage and the location of the deep endometriotic lesions. The affected patients should be</p><p>identified based on the underlying genetic and epigenetic mechanisms of the endometriosis-related infertility.</p><p>•Future randomized controlled trials or high-quality prospective cohort studies should focus on the implantation rates, clinical</p><p>pregnancy rates, and live birth rates of stage III/IV endometriosis when treated with the ultralong GnRH agonists protocol.</p><p>•If indicated, the optimal administration duration of the ultralong GnRH agonists protocol should be precisely determined.</p><p>•Prospective</p><p>high-quality cohort studies should investigate the effect of dienogest on the implantation rate in fresh embryo transfer</p><p>cycles. The secondary endpoints could optimally be the clinical pregnancy and live birth rates. The optimal comparator for</p><p>dienogest in patients with stage I/II endometriosis would be the conventional long GnRH agonist protocol.</p><p>•The effects of the progestin-primed ovarian stimulation protocols should be investigated in multicentric studies including different</p><p>ethnicities and different endometriosis stages. The superiority or at least non-inferiority of the progestin-primed ovarian stimu-</p><p>lation protocols along with its cost-effectiveness should be investigated.</p><p>11. Practice points</p><p>•Utilizing the prolonged GnRH-a protocol could enhance the outcomes of in vitro fertilization in cases of severe endometriosis.</p><p>•In fresh cycles, the use of dienogest could enhance in vitro fertilization outcomes for individuals with endometriosis.</p><p>•It is recommended to refrain from using GnRH antagonists for endometriosis-associated infertility.</p><p>•The efficacy of progestin-primed ovarian stimulation remains uncertain in cases of endometriosis.</p><p>CRediT authorship contribution statement</p><p>Antoine Naem: Conceptualization, Writing – original draft, Writing – review & editing, Resources. Harald Krentel: Conceptu-</p><p>alization, Writing – original draft. Gaby Moawad: Supervision, Writing – review & editing. Joelle Naem: Writing – original draft.</p><p>Renato Venezia: Writing – original draft. Andrea Etrusco: Writing – original draft. Sanja Terzic: Writing – original draft, Writing –</p><p>review & editing. Antonio Simone Laganà: Conceptualization, Supervision, Writing – review & editing.</p><p>9. Declaration of generative AI in scientific writing</p><p>The authors declare that no generative AI assistance was applied in the conduct and writing of this review.</p><p>Declaration of Competing interest</p><p>The authors declare that they have no known competing financial interests or personal relationships that could have appeared to</p><p>influence the work reported in this paper.</p><p>Acknowledgments</p><p>None.</p><p>Abbreviations</p><p>ART Assisted Reproduction Technologies</p><p>IVF In Vitro Fertilization</p><p>ICSI Intracytoplasmic Sperm Injection</p><p>ROS Reactive Oxygen Species</p><p>HOXA 10 Homebox A10</p><p>ET Embryo Transfer</p><p>r-ASRM Revised Classification of the American Society of Reproductive Medicine</p><p>GnRH Gonadotropin-Releasing Hormone</p><p>FSH Follicular Stimulating Hormone</p><p>LH Luteinizing Hormone</p><p>TNF-α Tumor Necrosis Factor-α</p><p>8-OHdG 8-hydroxy-2′ deoxyguanosine</p><p>MPA Medroxyprogesterone Acetate</p><p>A. 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