{"paper_id":"fe205732-ea2f-4b17-a737-fe02bcdd9822","body_text":"Gynecological Endocrinology\nISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: www.tandfonline.com/journals/igye20\nEffects of various controlled ovarian\nhyperstimulation protocols and surgery\non pregnancy outcomes in women with\nendometriosis\nHan Zeng & Yanbin Wang\nTo cite this article: Han Zeng & Yanbin Wang (2024) Effects of various controlled\novarian hyperstimulation protocols and surgery on pregnancy outcomes in\nwomen with endometriosis, Gynecological Endocrinology, 40:1, 2381504, DOI:\n10.1080/09513590.2024.2381504\nTo link to this article:  https://doi.org/10.1080/09513590.2024.2381504\n© 2024 The Author(s). Published by Informa\nUK Limited, trading as Taylor & Francis\nGroup\nPublished online: 21 Jul 2024.\nSubmit your article to this journal \nArticle views: 1940\nView related articles \nView Crossmark data\nCiting articles: 1 View citing articles \nFull Terms & Conditions of access and use can be found at\nhttps://www.tandfonline.com/action/journalInformation?journalCode=igye20\n\nReview AR ticle\nGynecoloGical endocrinoloGy\n2024, Vol. 40, no . 1, 2381504\nEffects of various controlled ovarian hyperstimulation protocols and surgery on \npregnancy outcomes in women with endometriosis\nHan Zeng and Yanbin wang\nr eproductive Medical c enter, d epartment of obstetrics and Gynecology, Peking University People’s Hospital, Beijing, china\nABSTRACT\nendometriosis is a common gynecological condition in women of childbearing age that causes symptoms \nsuch as menstrual changes and dysmenorrhea, and is also a major cause of infertility. t herefore, women \nwith endometriosis usually need to use assisted reproductive technology (AR t ), such as in vitro fertilization \nor intracytoplasmic sperm injection, to increase their chances of conceiving. Numerous clinical observations \nand studies have indicated that endometriosis can affect the success of AR t, such that women with \nendometriosis who use AR t have a lower live-birth rate than those without endometriosis who use AR t. \nt herefore, this article reviews the impact of various controlled ovarian hyperstimulation protocols and \nsurgery on the pregnancy outcomes of women with endometriosis using AR t to explore the selection of \nindividualized treatment.\nBackground\nEndometriosis is an estrogen-dependent disease characterized by \nthe presence of endometrial tissue outside the uterine cavity [ 1]. \nIt is a major cause of infertility, with studies indicating that \napproximately 30–50% of women with endometriosis experience \ninfertility and 20–50% of women with infertility also have endo -\nmetriosis [ 2]. There are various treatments for infertility related \nto endometriosis, with the most effective being assisted reproduc -\ntive technology (ART), such as in vitro  fertilization – embryo \ntransfer (IVF–ET) [ 3]. Nonetheless, women with endometriosis \nhave a lower live-birth rate than those with infertility due to \nother causes, and this difference increases as the severity of endo -\nmetriosis increases [ 4]. Adverse pregnancy outcomes in women \nwith endometriosis may be related to impaired sperm function, \npoor ovarian reserve, a decreased number of retrieved oocytes, \nlow-quality oocytes and embryos, decreased uterine receptivity, \nand an inflammatory pelvic environment, especially in advanced \nstages of the disease [ 5, 6]. Therefore, a determination of the abil -\nity of various controlled ovarian hyperstimulation protocols and \nsurgery to improve pregnancy outcomes in women with endome -\ntriosis would not only assist clinicians to treat infertile women \nwith endometriosis but also assist such women to achieve fertility.\nMechanism by which endometriosis affects the \noutcome of IVF–ET\nThe effect of endometriosis on the fertility of women has been \nextensively examined in several references. Moreover, the rela -\ntionship between endometriosis and infertility is multifaceted, as \nit involves the disruption of the normal anatomical structures of \nthe fallopian tubes and ovaries; a decrease in oocyte and embryo \nquality due to inflammation and oxidative stress; and changes in \nthe receptivity of the endometrium [ 7, 8].\nEffect of endometriosis on the quality of oocytes and \nembryos\nThe quality of oocytes and embryos is an important factor that \naffects the success of in vitro  fertilization (IVF). However, the \nimpact of endometriosis on the quality of oocytes and embryo \ndevelopment remains debated. Current research indicates that \nendometriosis decreases the quality of oocytes and the potential \nfor embryo development via several pathological mechanisms, \nsuch as by increasing the production of reactive oxygen species \nand other free radicals, inducing immune-system imbalance, and \nimpairing extracellular matrix remodeling [ 9]. In addition, cell \nbiology research has shown that the general morphology, matu -\nration ability, and organelles of oocytes from women with infer -\ntility due to endometriosis differ from those of oocytes from \nwomen with infertility caused by other factors. For example, \nGoud et  al. evaluated immature oocytes from infertile women \nwith endometriosis and infertile women with other conditions. \nThey observed that compared with the latter group, the former \ngroup showed a greater loss of cortical granules and a harder \nzona pellucida, which may interfere with fertilization, zona pel -\nlucida dissolution, embryo hatching, and implantation. \nAdditionally, they tested the ability of immature oocytes to \nundergo in vitro  maturation (IVM) to the metaphase II (MII) \nstage. They found that the number of germinal vesicles and \noocytes reaching the MII stage was significantly lower in the \nendometriosis group than in the control group, and during IVM, \n© 2024 The a uthor(s). Published by i nforma UK limited, trading as Taylor & Francis Group\nCONTACT yanbin Wang  iriswang0411@163.com   r eproductive Medical c enter, d epartment of obstetrics and Gynecology, Peking University People’s Hospital, \nBeijing, 100044, china\nhttps://doi.org/10.1080/09513590.2024.2381504\nThis is an o pen a ccess article distributed under the terms of the c reative c ommons a ttribution license ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distri -\nbution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the a ccepted Manuscript in \na repository by the author(s) or with their consent.\nARTICLE HISTORY\nr eceived 3 March 2024\nr evised 7 May 2024\na ccepted 12 July 2024\nPublished online 17 July \n2024\nKEYWORDS\nendometriosis; pregnancy \noutcome; ar T; controlled \novarian hyperstimulation; \nsurgery\n\n2 H. ZeNG AND Y. wANG\na higher proportion of abnormal spindle fibers were observed in \noocytes from women with endometriosis than in oocytes from \nwomen using ART as a treatment for male factor infertility \n(66.7% vs 16%, p < 0.05) [ 10]. Moreover, Xu et  al. employed \ntransmission electron microscopy to investigate 50 MII stage \noocytes from women diagnosed with stage I–II endometriosis \nand tubal or male factor infertility. They found that compared \nwith oocytes from the control group, those from the endometri -\nosis group had a higher proportion of abnormal mitochondria, \nsuch as small or swollen and blurry vesicles, and fewer mito -\nchondria. In addition, real-time quantitative polymerase chain \nreaction detected lower copy numbers of mitochondrial DNA in \nthe endometriosis group than in the control group [ 11].\nHowever, although the above-mentioned results of basic \nexperiments suggest that endometriosis affects the quality of \noocytes and embryos, the results of clinical assisted reproductive \ntreatments do not all support this. For example, an early study \non oocyte donation found that women with and without endo -\nmetriosis had the same implantation and pregnancy rates after \nthey had received oocytes from healthy donors, with these rates \ndecreasing after they had received oocytes from donors with \nendometriosis [ 12]. However, this study had a small sample size. \nIn 2022, Kamath et  al. published a study reporting the live birth \nrates of 758 women with endometriosis who had undergone \ncycles of IVF with donated oocytes and those of 12,856 women \nwith endometriosis who had undergone cycles of autologous IVF . \nAfter adjusting for confounding factors, they found that the live \nbirth rates of the women who had received donated oocytes for \nfresh and frozen embryo transfers were not significantly different \nfrom those of the women who had undergone autologous IVF . \nTherefore, they concluded that oocyte quality may have a limited \neffect on IVF outcomes in women with endometriosis [ 13]. \nHowever, they did not report the severity of the women’s endo -\nmetriosis or the number of oocytes that had been retrieved. It is \nalso unclear whether the donors had been screened for endome -\ntriosis or if some women with endometriosis had coexisting ade -\nnomyosis, both of which might have affected the results. A \nretrospective study published in the same year found that com -\npared with infertile women without endometriosis, infertile \nwomen with endometriosis had a significantly reduced ovarian \nreserve and response to stimulation but did not have signifi -\ncantly worse oocyte quality or clinical outcomes, such as the \nclinical pregnancy rate and cumulative live birth rate [ 14]. \nHowever, a retrospective study by Wu et  al. published in 2021 \nsuggested that endometriosis does have a negative impact on the \nquality and quantity of oocytes but not on overall pregnancy \noutcomes [ 15]. In addition, a retrospective analysis by Sanchez \net  al. found that endometriosis does not affect the fertilization \nrate, quality of cleavage-stage embryos, number of blastocysts, \nand blastocyst rate, but does decrease ongoing pregnancy rates \n[16]. The differences between the results of the above-described \nstudies demonstrate that further clinical research is needed to \nclarify how endometriosis affects oocyte and embryo quality.\nEffect of endometriosis on endometrial receptivity\nEmbryo implantation requires both high-quality embryos and a \nwell-prepared uterine lining [ 17]. Endometriosis can affect the \nreceptivity of the uterine lining and is primarily associated with \nimbalances in steroid-hormone signaling (such as upregulation of \nestrogen function and resistance to progesterone), differential \ngene expression in the uterine lining, immune abnormalities, and \nabnormal expression of cell adhesion molecules [ 17–19]. \nMoreover, compared with women without endometriosis, those \nwith endometriosis have lower levels of expression of uterine \nendometrial hormone receptors and, in the mid-secretory phase \nof the endometrium, higher levels of expression of estrogen \nreceptor 1 [ 20]. Additionally, a comparative transcriptomic anal -\nysis of eutopic and ectopic endometria between women with and \nwithout endometriosis revealed that women with endometriosis \nexhibit dysregulation of selected genes related to implantation, \nwith decreased expression of homeobox A10 ( HOXA10) and \nHOXA11 in the luteal phase. This decreases the level of tran -\nscription of empty spiracles homeobox 2 and directly affects the \nproliferation and function of endometrial cells before and after \nimplantation, resulting in abnormal implantation [ 6].\nThe impact of the immune system on the endometrial micro -\nenvironment and implantation window is currently unclear. \nCompared with women without endometriosis, those with endo -\nmetriosis have significantly higher concentrations of \npro-inflammatory cytokines (interleukin [IL]-1α, IL-1β, and IL-6) \nin their endometrial microenvironment. In addition, unlike the \nformer group, the latter group has activated class I macrophages \n(which secrete pro-inflammatory factors) as the main cell popu -\nlation in the endometrium throughout the menstrual cycle. This \ndominance of a pro-inflammatory phenotype may affect embryo \nimplantation [7, 19].\nHowever, the extent to which the above-described genetic and \nimmunological factors affect the clinical outcomes of assisted \nreproduction in women with endometriosis remains debated. In \none example, it was reported that endometriosis negatively affects \nendometrial receptivity, leading to a decrease in implantation and \nongoing pregnancy rates [ 21]. Moreover, considering that hor -\nmone concentrations greater than normal physiological concen -\ntrations during conventional stimulation may impair endometrial \nreceptivity, regulated thawed embryo transfer is often employed \nto restore optimal receptivity in women with endometriosis and \nthus improve pregnancy rates. A large retrospective study found \nthat in women with advanced endometriosis, implantation rates, \nclinical pregnancy rates, and live birth rates were significantly \nhigher after frozen embryo transfer than after fresh embryo \ntransfer [ 22]. A retrospective matched-cohort study of 135 \nwomen with endometriosis who had undergone either fresh or \nfrozen embryo transfer revealed that the cumulative clinical \npregnancy rates and cumulative ongoing pregnancy rates were \nsignificantly higher in the frozen embryo transfer group than in \nthe fresh embryo transfer group [ 23]. In contrast, another retro -\nspective matched cohort study found that compared with women \nwith tubal factor infertility, women with endometriosis had lower \nclinical pregnancy rates and live birth rates ( p = 0.028 and \np = 0.008, respectively) in frozen–thawed embryo transfer cycles, \nleading to a decrease in cumulative live birth rates ( p = 0.001) \n[24]. Similarly, a retrospective analysis conducted by Peking \nUnion Medical College Hospital found no significant differences \nin clinical pregnancy, implantation, live birth, miscarriage, or \nmultiple pregnancy rates between women with endometriosis \nwho had received high-quality embryo transfer and women with \ntubal factor infertility who had received the same treatment, sug -\ngesting that endometriosis does not alter endometrial receptivity \n[25]. Moreover, Pirtea et  al. posited that reduced endometrial \nreceptivity may play a minimal or no role in ART failures [ 26]. \nTherefore, although the above-described studies have confirmed \nthat there are differences between the endometrial characteristics \nof women with endometriosis and those of women without \nendometriosis, there remains a need for more clinical data to \nvalidate the impact of changes in endometrial receptivity on \npregnancy outcomes.\n\nGYNecoloGic Al eNDocRiNoloGY 3\nEffect of various controlled ovarian hyperstimulation \nprotocols on the outcomes of IVF in women with \nendometriosis\nThe inflammatory reaction caused by endometriosis within the \npelvic cavity can disrupt the interaction between sperm and \noocytes, reducing the chances of fertilization. However, this \ninflammatory reaction does not affect IVF , which means that \nIVF is an excellent option for women with endometriosis-related \ninfertility [ 27]. Controlled ovarian hyperstimulation is imple -\nmented in an IVF cycle to obtain a sufficient number of oocytes \nto increase the cultivation and quality of embryos and thus opti -\nmize the chance of pregnancy [ 28]. Commonly used ovulation \nhyperstimulation protocols include ultralong, long, short, antago -\nnist, and progesterone protocols. Which of these protocols is best \nfor women with endometriosis-related infertility remains to be \ndetermined, as there is insufficient clinical research in this area. \nThe results of recent research are summarized in Table 1.\nGonadotropin-releasing hormone agonist protocols\nGonadotropin-releasing hormone agonists (GnRH-a) significantly \nreduce secretion of luteinizing hormone (LH) by blocking the \nproduction of the LH-β subunit, and maintain responsiveness to \nexogenous GnRH injections by increasing the production of the \nLH-α subunit. Furthermore, GnRH-a can prevent premature \nluteinization of follicles, alleviate inflammation, and improve the \nmicroenvironment of the pelvic cavity, thereby aiding the growth \nand development of follicles [ 29]. Consequently, GnRH-a are \nused to downregulate production of LH in women with \nendometriosis-related infertility and are typically employed in \nultralong, long, or short ovulation hyperstimulation protocols.\nA 2021 meta-analysis by Shuai Liu et  al. [ 30] examined the \neffect of ultralong protocols versus long protocols on the out -\ncomes of IVF/intracytoplasmic sperm injection – embryo trans -\nfer (IVF/ICSI-ET) in women with endometriosis-related infertility. \nThis meta-analysis included nine randomized controlled trials \n(RCTs) involving a total of 943 participants and found that com -\npared with a long protocol, an ultralong protocol with a 3-month \nsuppression period increased the clinical pregnancy rate and \nongoing pregnancy rate (relative risk RR = 1.90, 95% CI: 1.39–\n2.61, p < 0.0001) in infertile women with endometriosis. However, \nthere was no difference in the clinical pregnancy rate between \nthe ultralong and long protocols for women with various sub -\ntypes of endometriosis, nor between a 6-month suppression \nperiod and a 3-month suppression period. Furthermore, there \nwere no significant differences between the ultralong and long \nprotocols in terms of other reproductive outcomes (implantation \nrate, miscarriage rate, ectopic pregnancy rate, multiple pregnancy \nrate, live birth rate) and ovulation hyperstimulation outcomes \n(duration of ovarian stimulation, dosage of gonadotropins, num -\nber of retrieved mature oocytes, fertilization rate, number of \nobtained embryos, and number of transferred embryos). However, \nthis meta-analysis did not compare the protocols’ respective \neffects on the cumulative pregnancy rate and cumulative live \nbirth rate.\nAnother meta-analysis [ 31] that compared RCT studies and \nnon-RCT studies found that in non-RCT studies, ultralong pro -\ntocols typically improved implantation rates, while in RCT stud -\nies, the clinical pregnancy rate of women with stage III–IV \nendometriosis in ultralong protocol groups was significantly \nhigher than that of such women in long protocol groups. \nHowever, the RCT studies found that the ultralong and long \nprotocols resulted in no significant differences in the implanta -\ntion rate, fertilization rate, oocytes quantity, and clinical preg -\nnancy rate in women with stage I–II endometriosis. These \nfindings differ from the findings of the meta-analysis by Shuai \nLiu et  al. [ 30], i.e. there was no difference in efficacy between \nultralong and long protocols in women with different subtypes of \nendometriosis. This suggests that the use of an ultralong protocol \nin women with stage III–IV endometriosis is of unclear utility, \nperhaps as most published RCTs or non-RCT studies have been \nconducted in a small number of women. Therefore, more clinical \nresearch is needed to confirm the effectiveness of ultralong pro -\ntocols in women with different stages of endometriosis, and a \nsystematic analysis of RCTs is needed to obtain reliable results. \nNevertheless, it appears that compared with long protocols, \nultralong protocols result in higher pregnancy rates.\nThis meta-analysis [ 31] also compared the effectiveness of \nultralong and short protocols in treating endometriosis-related \nIVF-ET and included non-RCTs. The results showed that the fer -\ntilization rate, duration of controlled ovarian hyperstimulation \n(COH), and number of oocytes retrieved were significantly \nhigher in an ultralong protocol group than in a short protocol \ngroup. However, there were no significant differences between \nthe ultralong and short protocol groups in terms of the implan -\ntation rate, clinical pregnancy rates in women with different sub -\ntypes of endometriosis, baseline follicle-stimulating hormone \n(FSH) concentrations, and dosage of gonadotropins. Additionally, \nthis meta-analysis did not compare the ultralong and short pro -\ntocols in terms of their effects on cumulative pregnancy rates \nand cumulative live birth rates.\nGnRH-a and GnRH-antagonist protocols\nGnRH antagonists competitively bind to pituitary GnRH recep -\ntors and thus immediately suppress the secretion of gonado -\ntropins and prevent early peaks in LH concentrations during \novarian stimulation [ 32]. In 2007, Pabuccu et  al. [ 33] reported a \ncomparison of the effects of GnRH antagonists and GnRH-a in \nCOH followed by ICSI cycles in women with mild-to-moderate \nendometriosis and ovarian endometrioma. The women were \ndivided into groups comprising women with confirmed stage I–\nII endometriosis by laparoscopic examination, women with a his -\ntory of ovarian surgery and ovarian endometrioma, and women \nwith unilateral or bilateral ovarian endometrioma without a his -\ntory of ovarian surgery. They were randomly assigned to receive \neither a GnRH-a long protocol or a GnRH-antagonist protocol, \nand the resulting embryos were transferred in fresh cycles. The \nresults showed that the GnRH-a and GnRH-antagonist protocols \nled to similar pregnancy outcomes in women with stage I–II \nendometriosis, with no statistically significant differences in \nimplantation and clinical pregnancy rates. In women with a his -\ntory of ovarian surgery for endometrioma, the GnRH-antagonist \nprotocol resulted in a decrease in the number of MII stage \noocytes, number of available embryos, and fertilization rate com -\npared with the GnRH-a protocol. However, there was no statis -\ntically significant difference between the implantation rates and \nclinical pregnancy rates resulting from the two protocols. In \nwomen with no history of surgery for endometrioma, the use of \na GnRH-antagonist protocol significantly reduced human chori -\nonic gonadotropin-day estradiol concentrations, the number of \nfollicles larger than 17 mm, the total number of retrieved oocytes, \nand the number of MII stage oocytes compared with the use of \na GnRH-a protocol. However, there was no statistically signifi -\ncant difference between the implantation and clinical pregnancy \n\n4 H. ZeNG AND Y. wANG\nTable 1. e ffect of various controlled ovarian hyperstimulation protocols on the outcomes of iVF in women with endometriosis.\na rticle Type Subgroup\nexperimental \ngroup c ontrol group r etrieved oocytes Fertilization rate implantation rate clinical pregnancy rate live birth rate\nliu et  al. \n[30]\nMeta-analysis / Ultralong \nprotocol\nl ong protocol Md = 0.70,95%ci: (-0.67–\n2.07), p = 0.31\nrr = 0.97,95%ci: \n[0.93, 1.01], \np = 0.19\nrr = 1.37,95%ci:(0.78–\n2.38), p = 0.27\nrr = 1.33,95%ci:(1.13–\n1.56), p = 0.002\nrr = \n2.07,95%ci:[1.00,4.27], \np = 0.05\nc ao et  al. \n[31]\nMeta-analysis rc Ts Ultralong \nprotocol\nl ong protocol Md=-0.2,95%ci:(−0.50–0.10), \np > 0.05\nrr = \n0.97,95%ci:(0.93–\n1.01), p > 0.05\nrr = 1.37,95%ci:(0.78–\n2.38), p > 0.05\nrr = 1.44,95%ci:(1.21–\n1.72), p < 0.05\nstages i–ii rr = \n0.99,95%ci:(0.64–1.55), \np > 0.05\nstages iii–iV rr = \n2.04,95%ci:(1.37–3.04), \np < 0.05\n/\nnon-rc Ts Ultralong \nprotocol\nl ong protocol Md=-0.09,95%ci :(−0.39–0.22), \np > 0.05\nrr = \n1.02,95%ci:(0.85–\n1.22), p > 0.05\nrr = 1.18,95%ci:(0.78–\n2.38), p > 0.05\nrr = 1.05,95%ci:(0.93–\n1.20), p > 0.05\nstages i–iirr= \n1.05,95%ci:(0.80–1.37), \np > 0.05\nstages iii–iVrr= \n1.16,95%ci:(0.93–1.44), \np > 0.05\n/\nnon-rc Ts Ultralong \nprotocol\nShort \nprotocol\nMd = 0.50,95%ci:(0.27–0.74), \np < 0.05\nrr = \n1.19,95%ci:(1.01–\n1.40), p < 0.05\nrr = 1.85,95%ci:(0.58–\n5.90), p > 0.05\nrr = 1.78,95%ci:(1.07–\n2.97), p < 0.05\nstages i–ii rr = \n1.21,95%ci:(0.58–2.53), \np > 0.05\nstages iii–iV rr = \n2.28,95%ci:(0.88–5.91), \np > 0.05\n/\nPabuccu [ 33] rc T Stages of i–ii \nendometriosis\nGnrH \nantagonist\nl ong protocol / / 15.4% vs 18.2%, p = 0.90 30% vs 31.2%, p = 1.00 /\nHistory of ovarian \nsurgery for \nendometrioma\nGnrH \nantagonist\nlong\nprotocol\n4.3 ± 2.6 vs. 8.8 ± 4.6, p = \n0.0001\n/ 15.9% vs 22.6%, p = 0.60 27.5% vs 39%, p = 0.38 /\nendometrioma \nand no history \nof ovarian \nsurgery\nGnrH \nantagonist\nl ong protocol 6.7 ± 2.6 vs 8.2 ± 5.5, p = \n0.002\n/ 12.5% vs 14.8%, p = 0.70 20.5% vs 24.2%, p = 0.90 /\nKolanska \net  al. [ 34]\nr etrospective \nanalysis\nFresh e T GnrH-a GnrH \nantagonist\n/ / / 25% vs 13%, p = 0.02 18% vs 8%, p = 0.04\nFeT GnrH-a GnrH \nantagonist\n/ / / 5% vs 7%, p = 0.70 2% vs 7%, p = 0.09\nFresh e T+FeT GnrH-a GnrH \nantagonist\n/ / / 29% vs 18%, p = 0.06 21% vs 14%, p = 0.2,\ndrakopoulos \net  al. [ 36]\nr etrospective \ncohort \nstudy\nendometriosis \nstages i–ii\nGnrH-a GnrH \nantagonist\nMedian(iQr) 9 (6–13) vs 7 \n(5–12), p = 0.09\n/ / 50% vs 36%; p = 0.14 42.8% vs 26.7%, p = 0.07\nendometriosis \nstages iii–iV\nGnrH-a GnrH \nantagonist\nMedian(iQr) 8 (5–11) vs 7 \n(5–11), p = 0.33\n/ / 34.3% vs 32.5%; p = 0.70 27.3% vs 23.8%,\np = 0.50\nGuo et  al. \n[41]\nrc T / MPa + HMG Ultralong \nprotocol\nMean ± Sd:9.30 ± 5.73 vs \n9.33 ± 5.36 p = 0.959\n65.23% (910/1395) vs \n65.35% \n(915/1400), \np = 0.945\nMPa + HMG-FeT vs \nultralong-eT vs \nultralong-FeT: 34.27% \n(98/286) vs 33.85% \n(65/192) vs 39.67% \n(48/121), p = 0.517\nMPa + HMG-FeT vs \nultralong-eT vs \nultralong-FeT: 50.31% \n(79/157) vs 55 \n%(55/100) vs 48.53% \n(33/68), p = 0.67\nMPa + HMG-FeT vs \nultralong-eT vs \nultralong-FeT:43.95 \n%(69/157) vs 49.00 \n%(49/100) vs39.71% \n(27/68), p = 0.48\n(Continued)\n\nGYNecoloGic Al eNDocRiNoloGY 5\nrates resulting from the two protocols. In summary, in women \nwith stage I–II endometriosis, the outcomes of IVF using \nGnRH-a and GnRH-antagonist protocols are similar. However, in \nwomen with endometrioma, a GnRH-a protocol can yield more \nMII oocytes and viable embryos than a GnRH-antagonist proto -\ncol, and thus, the cumulative pregnancy rate subsequent to a \nGnRH-a protocol may be higher than that subsequent to a \nGnRH-antagonist protocol.\nA recent retrospective analysis by Kolanska et  al. [ 34] com -\npared the pregnancy outcomes of infertile women with endome -\ntriosis who used a GnRH-a protocol and those whose used a \nGnRH-antagonist protocol for COH. The results showed that \nsubsequent to fresh embryo transfer, the GnRH-a group had \nhigher pregnancy rates and live birth rates than the GnRH \nantagonist group. However, subsequent to frozen embryo transfer \nusing the same artificial cycle protocol, there was no statistically \nsignificant difference between the groups in terms of clinical \npregnancy rates and live birth rates. This finding was similar to \nthat of Chen et  al. [ 35] who retrospectively analyzed 639 infertile \nwomen with endometriosis, some of whom were treated with a \nGnRH-a protocol and others were treated with a GnRH-antagonist \nprotocol for ovulation hyperstimulation. They found that the \nclinical pregnancy rate, implantation rate, and live birth rate were \nsignificantly lower in the GnRH-antagonist group than in the \nGnRH-a group (all p < 0.05) in fresh cycles, but that there was no \nsignificant between-group difference in pregnancy outcomes in \nsubsequent frozen cycles with the same number of retrieved \noocytes. Moreover, the cumulative clinical pregnancy rate (42.71% \nvs 55.2%, p = 0.083) and cumulative live birth rate (36.46% vs \n47.92%, p = 0.108) were similar between the GnRH antagonist \nand GnRH-a protocols. These results may be attributable to the \nfact that GnRH-a reduce the synthesis and release of nitric oxide \nin the endometrium, restore the normal expression of integrin in \nthe endometrium, and improve the receptivity of the endome -\ntrium. In contrast, GnRH antagonists alter the level of expression \nof HOXA10 protein in the endometrial stromal cells during \novarian stimulation treatment, thereby affecting the receptivity of \nthe endometrium.\nIn 2018, Drakopoulos et  al. [ 36] reported a retrospective \ncohort analysis that compared the effect of a long GnRH-a pro -\ntocol and an antagonist protocol on the live birth rate of women \nwith endometriosis undergoing IVF/ICSI treatment with fresh or \nfrozen embryo transfer. The results showed that in women with \nstage I and stage II endometriosis, the use of GnRH-a was asso -\nciated an increase in live birth rates and the quantity of frozen \nembryos, but this increase was not statistically significant. In \n2020, Zhao et  al. [ 37] reported a retrospective analysis of 342 \nwomen whose ovarian reserve function had declined after lapa -\nroscopic excision of endometriomas. The women were divided \ninto three groups: an ultralong GnRH-a protocol group ( n = 113), \nan GnRH-antagonist protocol group ( n = 121), and a long \nGnRH-a protocol group ( n = 108), and no statistically significant \nbetween-group differences were found in pregnancy, live birth, \nand abortion rates.\nProgestin protocols\nProgestin protocols are used to suppress pelvic inflammation and \nthus alleviate pelvic pain associated with endometriosis, as pro -\ngestins create a low-estrogen-concentration environment that \nslows the growth of endometrial tissue outside the uterus. \nProgestins protocols are also effective for preventing early LH \nsurges in women undergoing ovulation hyperstimulation [ 38, 39]. \na rticle Type Subgroup\nexperimental \ngroup c ontrol group r etrieved oocytes Fertilization rate implantation rate clinical pregnancy rate live birth rate\nGuo et  al. \n[40]\nrc T / / / Mean ± Sd:MPa + hMG vs \ndihydrogesterone + hMG \nvs progesterone + hMG \n:9.30 ± 5.7 vs 8.00 ± 4.5 vs \n7.60 ± 5.2, p = 0.021\n/ MPa + hMG vs \ndihydrogesterone + hMG \nvs progesterone + hMG \n:33.8% vs 34.2% vs \n38.9%, p > 0.05\nMPa + hMG vs \ndihydrogesterone + hMG \nvs progesterone + hMG \n:49.6% vs 57.9% vs \n56.2%, p > 0.05\n/\nZhao et  al. \n[37]\nr etrospective \nstudy\n/ / / / / Ultralong protocol vs GnrH \nantagonist vs long \nprotocol :25.16% vs \n18.01% vs 17.16% \np > 0.05\nUltralong protocol vs GnrH \nantagonist vs long \nprotocol :45.24% vs \n33.33% vs 28.99% \np > 0.05\nUltralong protocol vs \nGnrH antagonist vs \nlong protocol :32.14% \nvs 19.54% vs 24.64% \np > 0.05\nchen et  al. \n[35]\nr etrospective \nstudy\nFresh e T GnrH \nantagonist\nGnrH-a Mean ± Sd:6.17 ± 4.49 vs \n6.99 ± 4.86 p = 0.213\n77.87% (461/592) vs \n81.22% (545/671) \np = 0.140\n18.87% (20/106) vs 35.90% \n(56/156) p = 0.003\n28.57% (18/63) vs 50.57% \n(44/87) p = 0.007\n19.05%(12/63) vs \n41.38%(36/87) \np = 0.004\nFeT GnrH \nantagonist\nGnrH-a Mean ± Sd:6.17 ± 4.49 vs \n6.99 ± 4.86 p = 0.213\n77.87% (461/592) vs \n81.22% (545/671) \np = 0.140\n33.75% (27/80) vs 28.57% \n(14/49) p = 0.540\n47.27% (26/55) vs 37.5% \n(12/32) p = 0.375\n41.82%(23/55)vs 34.38% \n(11/32) p = 0.493\nNote. MPa = medroxyprogesterone acetate; hMG = human menopausal gonadotropin; GnrH-a = gonadotropin-releasing hormone agonist; Fe T = frozen–thawed embryo transfer; e T = embryo transfer.\nMd = mean difference; ci = confidence interval; rr = risk ratio; iQr = interquartile range; Sd = standard deviation.\nTable 1. c ontinued.\n\n6 H. ZeNG AND Y. wANG\nHowever, there has been little research on whether progestin \nprotocols can effectively improve oocyte quality, embryo quality, \nand pregnancy outcomes. It also remains unknown whether pro -\ngestin protocols can be used as an alternative protocol for women \nwith severe endometriosis who wish to receive IVF/ICSI treat -\nment. In 2020, Guo et  al. [ 40] reported the results of an RCT of \nthree progestin protocols in 450 women with severe endometri -\nosis who were undergoing IVF/ICSI and had normal ovarian \nfunction. The women were divided into three groups: a medroxy -\nprogesterone acetate + human menopausal gonadotropin (hMG) \ngroup, a dydrogesterone + hMG group, and a progesterone + hMG \ngroup. The embryos obtained were thawed and transferred. No \nsignificant between-group differences were found in fertilization \nand pregnancy outcomes, which suggests that these three proges -\ntin protocols achieve the same pregnancy outcomes in women \nwith late-stage endometriosis. However, this finding applies only \nto women with severe endometriosis and normal ovarian func -\ntion; further research is needed to determine if it can be gener -\nalized to women with decreased ovarian reserve. Additionally, \nthe RCT did not compare the effectiveness of GnRH-a with that \nof GnRH antagonists.\nIn 2022, Guo et  al. reported the results of an RCT [ 41] that \ninvestigated the effectiveness and safety of an MPA + hMG proto-\ncol vs a GnRH-a ultralong protocol during IVF in women with \nsevere endometriosis and normal ovarian reserve. They enrolled \n300 women with late-stage endometriosis and who were under -\ngoing IVF and divided them into two groups: an MPA + HMG \ngroup and an ultralong protocol group. The MPA + HMG group \nunderwent frozen embryo transfer, while the ultralong protocol \ngroup had fresh embryo transfer as the preferred option. There \nwere no significant differences between the two groups in terms \nof the numbers of retrieved oocytes, mature oocytes, high-quality \nembryos, and viable embryos. However, there were a larger num -\nber of follicles with a diameter greater than 10 mm or 14 mm in \nthe ultralong protocol group than in the MPA + HMG group, and \nthe fertilization rate with ICSI was higher in the MPA + HMG \ngroup than in the ultralong protocol group. Nevertheless, both \ngroups had similar implantation rates in terms of pregnancy out -\ncomes, as well as similar clinical pregnancy miscarriage, multiple \npregnancy, ongoing pregnancy, cumulative pregnancy, and live \nbirth rates. Furthermore, there were no statistically significant \ndifferences between the two groups in terms of pregnancy com -\nplications, postpartum complications, and the birth defect rate. \nTherefore, in women with late-stage endometriosis undergoing \nIVF/ICSI, the administration of MPA during COH may result in \na similar number of oocytes and pregnancy and live birth out -\ncomes as the administration of an ultralong protocol. This sug -\ngests that the use of MPA in COH could be a new alternative to \nthe standard protocol for women with endometriosis.\nEffect of surgery on the outcomes of IVF in women \nwith endometriosis\nSurgical treatment is another way to treat endometriosis, the \nbenefit of surgery on pain and quality of life is well known, but \nthe benefit on fertility remains controversial [ 42]. A few studies \nshow that surgery can improve the fertility rate in DIE patients \nfor both spontaneous pregnancy and IVF , but there are studies \nhave also confirmed that surgery can damage ovarian tissue, \nreduce ovarian reserve, and thus lower pregnancy rates [ 43, 44]. \nCurrent researches on the effect of surgery on endometriosis \nmostly relies on retrospective studies with low levels of evidence, \nwith only a few ongoing RCT studies being identified [ 45]. Some \nstudies suggest that surgery for endometriosis can be beneficial \nfor reproductive outcomes. For example, a retrospective review \nby Ekine et  al. in 2020 [ 46] examined the fertility performance \nof women after combined hysterolaparoscopic surgical manage -\nment of endometriosis have shown that the combined hystero -\nlaparoscopy treatment significantly improves reproductive \nperformance and is even more effective when combined with \nART, the pregnancy rate improved considerably after the surgery, \nand they have also found that the different stages of endometri -\nosis do not affect fertility. Another retrospective comparative \ncohort study by Ferrier et  al. [ 47] compared first-line surgery \nwith first-line assisted reproductive techniques (ART) in infertile \nwomen with deep infiltrating endometriosis (DIE) without col -\norectal involvement. Their results support that in patients with \nDIE without colorectal involvement, the first-line surgery offer \nhigher pregnancy rates, cumulative pregnancy rates, live birth \nrates, and cumulative live birth rates, with statistical differences \ncompared to first-line ART. This difference was observed even in \nwomen aged >35, AMH <2, and with concomitant adenomyosis, \nthey also found that in the surgery group, 17 cases of sponta -\nneous pregnancy could be observed, while no spontaneous preg -\nnancies were found in the ART group.\nCertainly, the opposite conclusion also exists. A retrospec -\ntive analysis by Maignien et  al. [ 48] examined the impact of \nprevious surgery for endometriosis on ART cumulative \nlive-birth rates in DIE patients, their study suggests that in a \npopulation of DIE patients, previous surgery for any type of \nendometriosis may be associated with less favorable ART out -\ncomes, patients with a history of surgical treatment for endo -\nmetriosis have significantly lower clinical pregnancy rates, live \nbirth rates, and cumulative live birth rates, all of which are \nstatistically significant. While the cumulative live birth rates are \nsatisfactory in bowel endometriosis patients undergoing \nfirst-line ART, with a low risk of complications. Study by \nFrangež et  al. [ 49] showed that for women with endometriosis \nwho need to undergo ART treatment, surgery may lead to \nimpaired ovarian reserve, reducing fertility chances. However, \npregnancy rates, implantation rates, fertilization rates, and live \nbirth rates remain unaffected.\nIn systematic reviews and meta-analyses with higher levels of \nevidence, most studies demonstrate that surgical treatment for \nendometriosis does not improve the outcomes of IVF . A \nmeta-analysis by Hamdan et  al. in 2015 [ 50] showed that com -\npared to patients with endometrioma who did not undergo sur -\ngical intervention, surgical treatment for endometrioma does \nnot alter the results of IVF/ICSI treatment. Two groups of live \nbirth rates, clinical pregnancy rates, miscarriage rates, mean \nnumber of oocytes retrieved, and cancellation rates of cycles \nwere similar, however, patients undergoing surgical treatment for \nendometrioma had lower AFC, required higher doses of FSH. \nDaniilidis et  al. [ 51] showed that there is no evidence to suggest \nthe surgical removal of deep endometriosis prior to ART in \ninfertile women with endometriosis to improve reproductive \noutcomes. Another meta-analysis by Bourdon et  al. in 2023 [ 52] \ncompared ongoing pregnancy rates and live birth rates in \npatients who underwent endometriosis surgery before ART in \ncomparison with patients who underwent first-line ART, the \nstudy showed that no statistically significant differences in live \nbirth rates, ongoing pregnancy rates, and early pregnancy loss \nrate per cycle were found when comparing patients who under -\nwent endometriosis surgery before IVF/ICSI and those who did \nnot. After the exclusion of the studies with high risks of bias, \nthe live birth rates per cycle was significantly reduced in the \ncase of surgical treatment before IVF/ICSI. Therefore, surgical \n\nGYNecoloGic Al eNDocRiNoloGY 7\nmanagement of endometriosis should not be routinely per -\nformed before ART.\nDiscussion\nEndometriosis is a common cause of infertility, and ART is widely \nused to treat infertility in women with endometriosis [ 3]. \nAccording to current research, the use of GnRH-a and \nGnRH-antagonist protocols for IVF treatment of infertile women \nwith endometriosis results in similar clinical pregnancy and live \nbirth rates. However, multiple studies have shown that the preg -\nnancy outcomes of ultralong protocols are better than those of \nother protocols, although some data did not reach statistical sig -\nnificance. GnRH-a protocols have been used for the longest time \nin the clinic because of their ability to precisely downregulate, \nwhich may help to enhance the pelvic microenvironment and \nendometrial receptivity. After binding to the corresponding recep -\ntors, GnRH-a causes desensitization of the pituitary receptors, \nleading to the inhibition of endogenous LH surge [ 53]. However, \nprolonged suppression of the pituitary gland and low concentra -\ntions of endogenous FSH may lead to a decrease in the number \nand size of follicles. This could potentially increase the concentra -\ntions of gonadotropins required and decrease the number of \nretrieved oocytes, thereby increasing the difficulty of oocyte \nretrieval, especially from women with diminished ovarian reserve \nwho have undergone ovarian surgery [ 54]. Compared with \nGnRH-a, GnRH antagonists have several advantages, such as a \nflexible timing of initiation, a lower average dosage, a shorter \nduration of treatment, a lower cost, and a lower risk of causing \novarian hyperstimulation syndrome. This improves patient com -\npliance and has resulted in the increasing use of GnRH antago -\nnists in clinical practice [ 55, 56]. GnRH antagonists also can be \ncombined with embryo cryopreservation protocols to achieve \ncumulative clinical pregnancy and cumulative live birth rates sim -\nilar to those of ultralong protocols, thereby avoiding the longer \npretreatment time required with the use of GnRH-a in ultralong \nprotocols [35]. Therefore, in clinical practice, ovulation hyperstim -\nulation protocols can be selected to suit the needs of the patient.\nOverall, there have been few studies on ovulation hyperstim -\nulation protocols for infertility related to endometriosis, and \nmost have been small-sample studies and retrospective analyses. \nTherefore, more RCT studies are needed to comprehensively \ncompare the efficacies of various ovulation hyperstimulation \nprotocols.\nAs for surgery treatment, according to the current research, \nfor patients with evident pain symptoms and complications such \nas hydronephrosis, pyelonephritis, intestinal obstruction, and pel -\nvic abscess, surgery is recommended firstly [ 57]. However, for \nasymptomatic patients, current data is insufficient to recommend \nsurgical intervention as a first-line treatment. The choice of treat -\nment between IVF and surgery as a first-line treatment remains \nquestionable, more RCTs are needed to compare the differences \nbetween surgery and IVF . Therefore, individualized treatment \nshould be considered for endometriosis patients before IVF/ICSI.\nDisclosure statement\nThe authors have no conflict of interest to declare.\nFunding\nThe author(s) reported there is no funding associated with the work featured \nin this article.\nData availability statement\nThe data in this paper is available.\nReferences\n [ 1] Horne AW , Missmer SA. Pathophysiology, diagnosis, and management \nof endometriosis. BMJ. 2022;379:e070750. doi: 10.1136/bmj-2022-\n070750.\n [ 2] Macer ML, Taylor HS. Endometriosis and infertility: a review of the \npathogenesis and treatment of endometriosis-associated infertility. \nObstet Gynecol Clin North Am. 2012;39(4):535–549. doi: 10.1016/j.\nogc.2012.10.002.\n [ 3] Filip L, Duică F , Prădatu A, et  al. 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