{"paper_id":"6973c8e3-7ad9-4ceb-ae23-82336ae2dc14","body_text":"R E S E A R C H A R T I C L E Open Access\nRole of suppression of endometriosis with\nprogestins before IVF-ET: a non-inferiority\nrandomized controlled trial\nEissa Khalifa 1, Hashem Mohammad 1, Ameer Abdullah 1, Mazen Abdel-Rasheed 2* , Mohammed Khairy 1 and\nMahmoud Hosni 1\nAbstract\nBackground: Endometriosis affects the responsiveness to ovarian stimulation. This study aimed to assess the role of\nDienogest pretreatment for endometriosis suppression as compared to Gonadotropin-releasing hormone agonist\n(GnRHa) in patients with endometriosis pursuing IVF treatment.\nMethods: In this randomized controlled trial, 134 women with endometriosis-related infertility were randomly\nallocated to group A ( n = 67) who had monthly depot GnRHa for 3 months before ovarian stimulation in IVF\ntreatment (Ultra-long protocol), and Group B ( n = 67) who had daily oral Dienogest 2 mg/d for 3 months before\nstarting standard long protocol for IVF. The primary outcome measure was the number of oocytes retrieved. The\nsecondary outcome measures included the number of mature oocytes, fertilization rate, quality of life assessed by\nFertiQoL scores, cost of treatment, and pregnancy outcomes.\nResults: Although there was no statistically significant difference between both groups regarding ovarian\nstimulation, response parameters, and pregnancy outcomes, the Dienogest group had a lower cost of treatment\n(2773 vs. 3664 EGP, P < 0.001), lower side effects (29.9% vs. 59.7%, P < 0.001), higher FertiQoL treatment scores (33.2\nvs. 25.1, P < 0.001) and higher tolerability scores (14.1 vs. 9.4, P < 0.001 < 0.001).\nConclusion: Our study indicates that Dienogest is a suitable and safe substitute for GnRHa pretreatment in\nendometriosis patients.\nTrial registration: NCT04500743 “Retrospectively registered on August 5, 2020 ”.\nKeywords: Endometriosis, IVF-ICSI, Dienogest, Progestins, GnRH-analogue\nBackground\nEndometriosis affects nearly 15% of patients with\ninfertility requiring assisted reproduction treatment. It is\nbelieved that endometriotic lesions in the pelvis create a\nhostile microenvironment for the fertilization of oocytes\nand the early development of an embryo in the fallopian\ntubes in vivo. Ovarian endometriosis also may affect the\novarian reserve and responsiveness to ovarian stimulation\nin IVF programs. These effects lead to lower fertilization\nand pregnancy rates in patients with endometriosis\npursuing IVF compared with other groups of patients [ 1].\nThis is probably related to an increased level of pro-\ninflammatory cytokines and abnormal oxidation damage\nto ovarian follicles, resulting in diminished oocyte quality\nregardless of endometriosis stage [2–4].\nContinuous GnRH agonist (GnRH-a) administration\ncauses a down-regulation of GnRH-a receptors on\npituitary gonadotropins and a severe hypo-estrogenic\n© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,\nwhich permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give\nappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if\nchanges were made. The images or other third party material in this article are included in the article's Creative Commons\nlicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons\nlicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain\npermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nThe Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the\ndata made available in this article, unless otherwise stated in a credit line to the data.\n* Correspondence: doctor_mazen@hotmail.com\n2Reproductive Health Research Department, National Research Centre, 33\nEl-Buhouth St, Dokki, Cairo 12622, Egypt\nFull list of author information is available at the end of the article\nKhalifa et al. BMC Pregnancy and Childbirth          (2021) 21:264 \nhttps://doi.org/10.1186/s12884-021-03736-2\n\nstate, causing suppression of endometriotic lesions. This\nhas led to the use of long-acting depot GnRH-a prepar-\nation for control of pelvic pain and other endometriosis-\nrelated symptoms [ 5]. Its use alone without adding back\nhormonal therapy should be to a maximum of 6 months\nas long-term use of GnRH-a is associated with hypo-\nestrogenic adverse effects, such as hot flushes, vaginal\ndryness, decreased libido, and decreased bone mineral\ndensity [ 6].\nIn the same vein, it has been proposed that long-term\nGnRH-a pretreatment for 3 months should be used in\npatients with endometriosis before IVF treatment to\nsuppress any endometriotic lesions [ 7]. This so-called\nultra-long protocol has been suggested to improve the\npregnancy rates in endometriosis patients after IVF\ncompared with other protocols for pituitary down-\nregulation. However, systematic reviews have shown\nconflicting evidence [ 8–10]. The relatively long period of\nhypo-estrogenic side effects associated with an ultra-\nlong protocol with a potential need for higher doses of\ngonadotropins and recent evidence from Cochrane\nreview showing inconclusive evidence of benefit has\nled to research into better alternatives for control of\nendometriosis before IVF [ 9].\nDienogest (DNG) is a fourth-generation selective\nprogestin (highly selective for binding to progesterone\nreceptors in endometrial tissue). It has a potent oral\nprogesterone activity, a little androgenic or estrogenic\nactivity. It reduces the activity of endometriotic lesions\nby creating a local dominant progesterone effect while\nsuppressing the estrogen effect moderately, and it is\nthought to have anti-angiogenic and anti-inflammatory\neffects [ 11, 12]. The incidence of hypo-estrogenic side\neffects with Dienogest is not prominent. This has led to\nthe use of Dienogest for control of pelvic pain due to\nendometriosis with beneficial and comparable effect to\ndepot GnRHa [11, 13–15]. However, its role in suppressing\nthe endometriotic lesions before IVF treatment and its\nimpact on IVF outcome is still unclear [16, 17].\nThe study aimed to compare the impact of pretreatment\nwith Dienogest for 3 months in women diagnosed with\nendometriosis and attending for IVF with pretreatment\nwith GnRH-a similar patients group regarding ovarian\nresponse, pregnancy outcomes, and quality of life.\nMethods\nStudy design and participants\nThis was a parallel-group open-label randomized controlled\nclinical trial conducted at Minia Infertility Research Unit\n(MIRU) in Egypt during the period from 8/2018 until 10/\n2019. All consecutive patients attending for IVF at MIRU\nwere assessed for eligibility for inclusion in the study.\nWomen were deemed eligible for inclusion if they had a\nconfirmed diagnosis of endometriosis by laparoscopy in the\nlast 2 years, their age at the s tart of treatment < 40 years,\nand their body mass index < 35 Kg/m2. Women were\nexcluded if they have been al ready on long-term down-\nregulation of the pituitary gland with GnRHa for control of\nendometriosis or if they have liver or kidney disease pre-\ncluding the use of Dienogest or have evidence of dimin-\nished ovarian reserve (e.g., high FSH level > 12 IU/L, low\nAMH level < 1.1 ng/ml or low antral follicle number < 7).\nAll patients were allowed to pa rticipate once in the trial\nwith no second entry after a failed IVF cycle.\nThe study was ethically approved by the institutional\nreview board of the Faculty of Medicine, Minia University,\nand was registered at an international clinical trial registry\n(NCT04500743). All eligible women were given verbal\nand written information about the trial, and written\ninformed consents were obtained before enrollment.\nRandomization was done using computer-generated ran-\ndom sequence numbers generated by the clinical research\nunit at the Faculty of Medicine, Minia University, with\nconcealment of allocation by sealed opaque envelopes.\nDue to the nature of the intervention and its design, it was\nimpossible to blind participants or clinicians. However,\nphysicians who performed the oocyte retrieval and the\nembryo transfer were blinded to the group type to\nminimize bias. All participants were followed by the\nclinical research team at MIRU till 12 weeks pregnant.\nStudy protocol\nAll patients had workup before starting IVF treatment,\nincluding pelvic ultrasound assessment of the antral\nfollicle count (AFC), measurements of Anti-Mullerian\nHormone (AMH), and Follicle-Stimulating Hormone\n(FSH), and basic semen analysis. All eligible patients\nwere randomly assigned at the point of enrollment into\ntwo groups;\n(1) Group A included patients who had pretreatment\nwith GnRH-a in the form of depot leuprorelin\nacetate (LEUCRAN, ABVIA, EGYPT) 3.75 mg SC\nmonthly injections for 3 months before starting\novarian stimulation after the third dose of depot\nGnRH-a., and\n(2) Group B included women who had pretreatment\nwith Dienogest 2 mg tablet orally daily for 3\nmonths. In the last 3 weeks of the pretreatment\nperiod, short-acting GnRH-a was started in a dose\nof 0.5 mg SC daily followed by ovarian stimulation\nwhen Dienogest was stopped, as shown in Fig. 1.\nThe ovarian stimulation was started in both groups\nwith a flexible dose of Human menopausal gonadotropin\n(HMG, Fostimon® or Merional®, IBSA, EGYPT) modified\naccording to the patients ’ age, FSH level, total antral fol-\nlicle count at the start of ovarian stimulation, polycystic\nKhalifa et al. BMC Pregnancy and Childbirth          (2021) 21:264 Page 2 of 8\n\novary status, and previous ovarian response. In brief, pa-\ntients under 35 years were given 150 IU/day, and patients\n35–40 years were given 225 IU/day. The ovarian stimula-\ntion dose was increased by 75 IU/day for corresponding\nage groups if they had a suboptimal ovarian response in\na previous cycle of (4 –7) oocytes or have BMI > 30 Kg/\nm2. Patients were monitored for the ovarian response\nwith serial transvaginal ultrasound scans starting from\nday 8 of ovarian stimulation until there were at least\nthree follicles > 17 mm in average diameter when Human\nChorionic Gonadotropin (HCG) was administered in a\ndose of 10,000 IU IM (Profasi/Pregnyl). After that, patients\nwere booked for transvaginal oocyte retrieval under\ngeneral anesthesia 36 h later. During monitoring, further\nstep-down or step-up of the dose was done according to\nthe patient’sr e s p o n s e .\nFertilization was achieved by either conventional IVF\nor ICSI, depending mainly on the sperm parameters on\nthe day of oocyte retrieval, duration of subfertility, and\nprevious IVF performance. Embryo transfer was done\nunder ultrasound guidance on day 3 or 5, depending on\nthe number and quality of the developing cohort of em-\nbryos. Patients were given progesterone vaginal supposi-\ntories (Uterogestan or Cyclogest 400 mg PV BD) starting\non the oocyte retrieval day and continued for 16 days\nuntil the day of the urinary pregnancy test. All patients\nenrolled in the study were planned to have a fresh embryo\ntransfer with no frozen/thawed embryo transfer included\nin the analysis, and all patients were only allowed to have\n1 cycle of treatment.\nData on the participants ’ baseline characteristics, their\novarian response, and the pregnancy outcomes were\ncollected prospectively in a dedicated register. At the\nstart of enrollment of the study, patients were given the\nArabic version of the FertiQoL questionnaire and asked\nto answer the questions in the first (core) part of the\nquestionnaire regarding their overall satisfaction and\nquality of life and the domains on emotional, mind/body,\nrelational and social functioning. At the consultation to\nconfirm pituitary down-regulation before starting\novarian stimulation, patients were asked to answer the\nquestions regarding the treatment part to assess their\nexperience during the pretreatment period. Answers to\nthese questions in the FertiQoL were scored according\nto the scoring scheme suggested by the Cardiff Univer-\nsity group [ 18]. Patients were also asked verbally about\nany side effects that they have experienced during the\nsame period.\nStudy outcomes\nThe primary outcome measure of this study was the\nnumber of retrieved oocytes, as the main concern was\nthe effect of either GnRHa or Dienogest on ovarian\nresponsiveness. The secondary outcome measures were\nthe fertilization rate (defined as the number of zygotes\nwith two pronuclei divided by the number of oocytes),\nFig. 1 Flowchart of ovarian stimulation in both groups\nKhalifa et al. BMC Pregnancy and Childbirth          (2021) 21:264 Page 3 of 8\n\nthe number of transferrable embryos (defined as the\nnumber of embryos suitable for transfer in the stimu-\nlated cycle or cryopreservation), the cost of the treat-\nment in Egyptian pounds including cost of pretreatment\nand ovarian stimulation drugs, the pregnancy rate per\ncycle started (defined as patients with positive urinary or\nserum pregnancy test divided by the number of patients\nstarting the treatment), the clinical pregnancy rate per\ncycle started (defined as the number of patients with at\nleast one intrauterine gestational sac with identifiable\nfetal heart pulsations over the total number of patients\nstarting the treatment), and the miscarriage rate (defined\nas patients with identified intrauterine gestational sac\nwithout a fetal pole, or a fetal pole with no heart pulsa-\ntions with no other viable fetuses over the number of\npatients with positive pregnancy test). Other secondary\noutcomes were the patient ’s quality of life during the\npretreatment period as assessed by the FertiQoL ques-\ntionnaire and side effects documentation.\nStatistical analysis\nThis study was powered to assess the difference in the\nmean number of retrieved oocytes of 2 with a standard\ndeviation of 1.5 (allowing for uncertainty regarding the\nmean number of retrieved oocytes (range from 5 to 11)\nand variance (range of standard deviation from 1 to 3) in\na parallel independent cohort design with 1:1 ratio of\nrandomization and allowing for type I error of 5%\n(significance level < 0.05) and type II error of 20% (power\nof 80%). An estimated sample size of 120 (60 patients in\neach arm) was deemed suitable, and to allow for a drop-\nout rate of 10%, we aimed to recruit 132 patients.\nThe groups ’ baseline characteristics were tabulated as\nmeans ± standard deviation or frequency/percentages.\nDifferences in baseline characteristics and outcomes be-\ntween groups were evaluated by independent t-test when\nnormally distributed and by Mann-Whitney test when\nnon-normally distributed for continuous variables and\nchi-square test for categorical ones. A P-value < 0.05 was\nconsidered significant. All analyses were carried out with\nSPSS software for Windows version 19.0 (SPSS Inc.\nChicago, IL.)\nResults\nFollowing the CONSORT guidelines, 200 patients were\nassessed for enrollment eligibility in the trial, and 66\npatients were excluded, as 45 patients did not meet the\neligibility criteria, and 21 patients declined to participate.\nPatients that were eligible and consented to participate\nwere enrolled in the study, and all patients enrolled\ncompleted the trial period with no dropouts, as shown\nin Fig. 2. The participants ’ baseline characteristics (age,\nbody mass index, duration of subfertility, causes of\nsubfertility, grades of endometriosis, baseline FSH, and\nanti-Mullerian hormone) did not differ significantly be-\ntween the two intervention groups, as shown in Table 1.\nThere was also no difference regarding the severity of\nendometriosis between the two groups. There was also\nno statistically significant difference between both\ngroups regarding ovarian stimulation and response pa-\nrameters (total dose of FSH injections required, number\nof oocytes retrieved, number of metaphase II oocytes,\nfertilization rate), and pregnancy outcomes (pregnancy\nrate, clinical pregnancy rate, miscarriage rate). However,\nthere was a statistically significant difference between\nthe mean combined cost of pretreatment with GnRH\nagonist and ovarian stimulation (3664 LE), and the mean\ncombined cost of Dienogest pretreatment and ovarian\nstimulation (2773 LE) with p-value < 0.001 (Table 2).\nThe quality of life of patients was assessed by the\nFertiQoL questionnaire (Table 3), which was adminis-\ntered before the pretreatment period (core part) and be-\nfore the start of the ovarian stimulation (treatment part).\nNeither the overall rating of the quality of life nor the\ncore FertiQoL score with its four subsets of emotional,\nmind/body, relational nor social domains differs signifi-\ncantly at the start of treatment between the two groups.\nHowever, there was a statistically significant difference\nbetween the two groups, with the overall FertiQoL treat-\nment and tolerability scores favoring the Dienogest\ntreatment. There were no major or life-threatening side\neffects reported in either group requiring stop or\nwithdrawal from both treatment groups. There were 40\npatients (59.7%) in the GnRHa group reporting side\neffects of hot flushes ( n = 11), body aches( n = 6), sleep\ndisturbances ( n = 8), low mood ( n = 8), vaginal dryness\n(n = 7) and in the Dienogest group a total of 20 patients\n(29.9%) reporting side effects of headache ( n = 13), breast\npain ( n = 7). The difference in the number of patients\nreporting these minor side effects was statistically signifi-\ncant, favoring lower side effects profile in the Dienogest\ngroup.\nDiscussion\nFor the last two decades, the ultra-long protocol of\npituitary down-regulation using GnRH agonist has been\npromoted as the recommended treatment protocol for\npatients with endometriosis undergoing ART. The pre-\nsumed benefits of the ultra-long protocol are maintained\nsuppression of endometriotic implants with improve-\nment in clinical and ongoing pregnancy rates [ 7, 19].\nThis has recently been proposed also to improve the\npregnancy rate in patients with associated adenomyosis\n[11]. The disadvantages of the ultra-long protocol com-\npared to the standard long protocol are the longer\nperiod of pituitary/ovarian suppression with a higher\nreported rate of hypo-estrogenic side effects and lower\novarian responsiveness. It should be noted that a recent\nKhalifa et al. BMC Pregnancy and Childbirth          (2021) 21:264 Page 4 of 8\n\nsystematic review has not shown a significant benefit of\nthe ultralong protocol on live birth outcomes for patients\nwith endometriosis undergoing IVF [ 9]. This, however,\ncontradicts another systematic review demonstrating a\nbeneficial effect of the ultralong protocol over long/antag-\nonist protocols in the same group of patients [ 8].\nDienogest, a synthetic progestin, has been extensively\nstudied recently to manage pelvic pain in endometriosis.\nIn a recent systematic review of 9 randomized controlled\ntrials, Dienogest in a dose of 2 mg/day for periods\nranging from 3 to 12 months was more effective than\nplacebo and was comparable to GnRH agonist in\ncontrolling endometriosis symptoms [ 11]. However, like\nother medical treatments for suppressing endometriosis,\nDienogest is not suitable for patients trying naturally for\npregnancy because of its central effect of pituitary\nsuppression. With its endometriotic suppressive effect,\nthis latter effect places it as an ideal substitute for the\nuse of GnRHa as a pretreatment before ART treatment.\nMoreover, the side effects profile of Dienogest reported\nfrom RCTs was also minimal.\nThis study has shown that suppressing endometriosis\nbefore ovarian stimulation in ART with the progestin\n(Dienogest) is a suitable substitute for GnRHa. Our\nfindings have demonstrated a non-inferiority of the\nDienogest in terms of ovarian response and pregnancy\noutcomes. Dienogest was better tolerated than GnRHa\nwith a better tolerability score as assessed by FertiQoL\nscore and a lower reported side effects rate. Furthermore,\nbased on the two medications ’ cost by the Egyptian\npharmaceutical authority, the combined Dienogest\npretreatment and ovarian stimulation regimen were\nsignificantly less expensive than the ultra-long protocol\nindicating better cost-effectiveness.\nOur study was mainly powered to detect a difference\nin ovarian response in terms of the number of retrieved\noocytes. In this respect, we could not detect any signifi-\ncant difference between the two intervention groups in\nFig. 2 Flowchart of participants in the trial comparing GnRH agonist versus Dienogest pretreatment in endometriosis patients before ART\nKhalifa et al. BMC Pregnancy and Childbirth          (2021) 21:264 Page 5 of 8\n\nboth the quantitative as well as surrogate parameters of\noocyte quality, i.e., the number of mature oocytes, the\nfertilization rate, and the number of transferrable\nembryos. Although our study was underpowered to\ndetect a minimally significant difference in the clinical\npregnancy rate, reassuringly, we could not detect any\nsignificant difference between the two intervention\ngroups in pregnancy rates. This was the main limitation\nof the study. Therefore, it is considered mainly as a\nproof-of-concept study and a primer for further larger\nstudies.\nAnother important asp ect of the assessment of\ninterventions is safety and tolerability and its impact\non patients ’ quality of life (QoL). We have, therefore,\nTable 1 Baseline characteristics (mean/SD) of the two groups of endometriotic patients having GnRH agonist or Dienogest as a\npretreatment before ART\nGnRH agonist Dienogest P-value\nAge (years)a 35.6 ± 3.5 36.1 ± 2.7 0.24\nBMI (Kg/m2)a 22.5 ± 1.6 22.3 ± 1.9 0.18\nDuration of subfertility a 6.6 ± 1.5 7.2 ± 1.7 0.1\nPrevious ART (%) b 20/67 (29.85%) 17/67 (25.37%) 0.56\nPrevious live birth (%) b 10/67 (14.93%) 10/67 (14.93%) 1\nCause of infertility (%) b\nMale 25 (37.31%) 27 (40.3%) –\nAnovulation 27 (40.3%) 30 (44.78%)\nTubal 32 (47.76%) 32 (47.76%)\nuterine 23 (34.33%) 30 (44.78%)\nStage of Endometriosis b\nMinimal 5/67 (7.46%) 8/67 (11.94%) 0.69\nMild 13/67 (19.4%) 12/67 (17.91%)\nModerate 27/67 (40.3%) 22/67 (32.84%)\nSevere 22/67 (32.84%) 25/67 (37.31%)\nFSH (IU/L)a 5.4 ± 1.7 4.3 ± 1.8 0.22\nAMH (ng/ml)a 3.5 ± 1.3 2.8 ± 1.8 0.07\nAFCa 12 ± 3.2 11.8 ± 2.3 0.08\nFSH Follicle-stimulating Hormone, AMH Anti-Mullerian Hormone, AFC Antral Follicle Count\naValues are expressed as means ± standard deviations\nbValues expressed as percentages\nTable 2 Outcomes of assisted reproduction treatment cycles after pretreatment with either GnRH agonist or Dienogest\nOutcome GnRH agonist Dienogest P-value\nTotal dose of FSH (IU) a 2047 ± 67.7 2180 ± 57.4 0.65\nNo. of oocyte a 11.4 ± 1.2 11.1 ± 1.4 0.78\nNo. of mature oocytes a 6.6 ± 1.3 6 ± 1.8 0.71\nFertilization rate (%) b 40.3% 47.67% 0.38\nNo. of transferrable embryos a 4.5 ± 1.8 5.1 ± 2.1 0.63\nTransferred embryo b\nCleavage stage 37 (55.22%) 42 (62.69%) 0.37\nBlastocyst stage 30 (44.78%) 25 (37.31%)\nPregnancy rate (%) b 15/67 (22.39%) 1 7/67 (25.37%) 0.69\nClinical pregnancy rate (%) b 12/67 (17.91%) 17/67 (25.37%) 0.29\nMiscarriage rate (%) b 2/15 (13.3%) 0 –\nCost of pretreatment /ovarian stimulation (EGP) a 3664 ± 45.1 2773 ± 38.1 < 0.001\nEGP Egyptian Pounds, GnRHa Gonadotropin-releasing hormone agonist, FSH Follicle-stimulating Hormone\naValues are expressed as means ± standard deviations\nbValues expressed as numbers and percentages\nKhalifa et al. BMC Pregnancy and Childbirth          (2021) 21:264 Page 6 of 8\n\ncompared the ultra-long protocol with the Dienogest\npretreatment for QoL outcomes. This has shown no\ndifference in the patients in the two groups in their\nbaseline QoL domains as assessed by the FertiQoL\ninternational (Arabic version) available from the Cardiff\nUniversity website. This is a validated tool, which has been\nsupported by professional organizations such as the\nEuropean Society of Human Reproduction and Embryology\n(ESHRE) and the American Society of Reproductive Medi-\ncine (ASRM) for use in clinical practice and research. On\nassessing the treatment part of FertiQoL, Our study showed\nthat the treatment tolerability scores for Dienogest are sig-\nnificantly better than the Gn RHa group. This may not be\nsurprising given the known hypo-estrogenic side effects of\nthe GnRHa, which may substantially disrupt the patients ’\nQoL. This was further confirmed by the higher rate of side\neffects reported in the GnRHa group. This latter observa-\ntion with the significantly higher cost of the ultra-long\nprotocol may be essential factors that may lead to prefer-\nence of the Dienogest over GnRHa if similar effects on\novarian response and pregnancy rates are further confirmed\nin future studies.\nRecently, another RCT had shown that Dienogest\npretreatment for patients with endometriosis before IVF\nwas associated with a significantly lower number of\noocytes retrieved and worse pregnancy outcomes [ 16].\nDespite similarities in desig n, there are important differ-\nences between this trial and our study. First, the trial by\nTamura et al. recruited patients with stage III-IV endomet-\nriosis, whereas our study was not restricted to a particular\nstage of endometriosis. It is known that patients with\nadvanced-stage endometriosis, particularly with previous\novarian surgery, would have markedly compromised\novarian reserve. Second, in the trial by Tamura et al.,\npatients were given a combined estrogen and progesterone\ntreatment following the Dienogest suppression; the inclu-\nsion of estrogen could have counteracted the treatment\neffect of Dienogest. Furthermore, in that trial, GnRHa in\nthe treatment arm was used in a flare protocol, which could\nalso be counteracting the effect of Dienogest, whereas\nprevious trials have shown that ultra-long protocol is more\nbeneficial due to suppression of endometriosis.\nConclusion\nThe findings of our study should be corroborated with\nlarger adequately powered studies to confirm or refute a\ncomparable effect of Dienogest to the ultra-long proto-\ncol on pregnancy outcomes, particularly impact on the\nlive birth rate in endometriosis patients having ART. If\nconfirmed, these findings would represent a major step\ntowards the facilitation of endometriosis suppression\nbefore ART.\nAcknowledgments\nThe authors are quite grateful to the entire medical, laboratory, and nursing\nstaff of Minia Infertility Research Unit for their kind help and cooperation\nthroughout the research work.\nAuthors’ contributions\nEK, HM, MK, AA and MH designed, conducted, and supervised the study. MA\nanalyzed the data. All authors have read and approved the manuscript.\nFunding\nThere is no specific grant from any funding agency.\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study available from\nthe corresponding author on reasonable request.\nTable 3 Quality of life assessed by the FertiQoL questionnaire and side effects of GnRHa and Dienogest pretreatment protocols\nbefore ART for endometriotic patients\nGnRH agonist Dienogest P-value\nTotal FertiQoL score a 94.2 ± 11.5 105 ± 12.6 0.04\nOverall quality of life a 2.9 ± 1.1 3.1 ± 0.7 0.78\nOverall physical health satisfaction a 3.2 ± 0.6 3.1 ± 0.3 0.82\nFertiQoL Core score a 71.8 ± 12.5 72.1 ± 13.5 0.67\nEmotional score 18.6 ± 8.3 18.2 ± 7.9 0.54\nMind/Body score 17.4 ± 8.2 19.4 ± 8.8 0.77\nRelational score 18.9 ± 7.6 18.4 ± 7.3 0.67\nSocial score 17.1 ± 6.2 17.5 ± 5.2 0.80\nFertiQoL Treatment score a 25.1 ± 7.8 33.2 ± 6.2 < 0.001\nTolerability 9.4 ± 2.3 14.1 ± 3.1 < 0.001\nEnvironment 16.6 ± 4.4 18.2 ± 3.7 0.15\nSide effects b 40/67 (59.7%) 20/67 (29.9%) < 0.001\nSide effects in the GnRH agonist included; hot flushes ( n = 11), body aches ( n = 6), sleep disturbances ( n = 8), low mood ( n = 8) and vaginal dryness ( n =7 )\nSide effects in the Dienogest included; headache ( n = 13) and Breast pain ( n =7 )\naValues are expressed as means ± standard deviations\nbValues expressed as numbers and percentages\nKhalifa et al. BMC Pregnancy and Childbirth          (2021) 21:264 Page 7 of 8\n\nDeclarations\nEthics approval and consent to participate\nThe study was approved by the local ethical research committee of Minia\nMaternity and Children University Hospital, Egypt. All participants were\ninformed about the study, and written consent was taken from each of\nthem.\nConsent for publication\nNot Applicable.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthor details\n1Obstetrics and Gynecology Department, Faculty of Medicine, Minia\nUniversity, Minia, Egypt. 2Reproductive Health Research Department, National\nResearch Centre, 33 El-Buhouth St, Dokki, Cairo 12622, Egypt.\nReceived: 13 January 2021 Accepted: 18 March 2021\nReferences\n1. Harb H, Gallos I, Chu J, Harb M, Coomarasamy A. The effect of\nendometriosis on in vitro fertilisation outcome: a systematic review and\nmeta-analysis. BJOG Int J Obstet Gynaecol. 2013;120(11):1308 –20. https://doi.\norg/10.1111/1471-0528.12366.\n2. Sanchez AM, Vanni VS, Bartiromo L, Papaleo E, Zilberberg E, Candiani M,\net al. Is the oocyte quality affected by endometriosis? A review of the\nliterature. J Ovarian Res. 2017;10:1 –11.\n3. Fan Y-Y, Chen H-Y, Chen W, Liu Y-N, Fu Y, Wang L-N. Expression of\ninflammatory cytokines in serum and peritoneal fluid from patients with\ndifferent stages of endometriosis. Gynecol Endocrinol. 2018;34(6):507 –12.\nhttps://doi.org/10.1080/09513590.2017.1409717.\n4. Xu B, Guo N, Zhang X, Shi W, Tong X, Iqbal F, et al. Oocyte quality is\ndecreased in women with minimal or mild endometriosis. Sci Rep. 2015;\n5(1):10779. https://doi.org/10.1038/srep10779.\n5. Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues for\npain associated with endometriosis. Cochrane Database Syst Rev. 2010;\n2010(12):CD008475. https://doi.org/10.1002/14651858.CD008475.pub2.\n6. Della Corte L, Barra F, Mercorio A, Evangelisti G, Rapisarda AMC, Ferrero S,\net al. Tolerability considerations for gonadotropin-releasing hormone\nanalogues for endometriosis. Expert Opin Drug Metab Toxicol. 2020;16(9):\n759–68. https://doi.org/10.1080/17425255.2020.1789591.\n7. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged\ngonadotropin-releasing hormone agonist therapy on the outcome of\nin vitro fertilization-embryo transfer in patients with endometriosis. Fertil\nSteril. 2002;78(4):699–704. https://doi.org/10.1016/S0015-0282(02)03373-3.\n8. Cao X, Chang H, Xu J, Zheng Y, Xiang Y, Xiao B, et al. The effectiveness of\ndifferent down-regulating protocols on in vitro fertilization-embryo transfer\nin endometriosis: a meta-analysis. Reprod Biol Endocrinol. 2020;18:1 –12.\n9. Georgiou EX, Melo P, Baker PE, Sallam HN, Arici A, Garcia-Velasco JA, et al.\nLong-term GnRH agonist therapy before in vitro fertilisation (IVF) for\nimproving fertility outcomes in women with endometriosis. Cochrane\nDatabase Syst Rev. 2019. https://doi.org/10.1002/14651858.CD013240.pub2.\n10. Sallam HN, Garcia-Velasco JA, Dias S, Arici A, Abou-Setta AM. Long-term\npituitary down-regulation before in vitro fertilization (IVF) for women with\nendometriosis. Cochrane Database Syst Rev. 2006;(1):CD004635. https://doi.\norg/10.1002/14651858.CD004635.pub2.\n11. de Paula AM, Lopes LA, Baracat EC, Podgaec S. Dienogest in the treatment\nof endometriosis: systematic review. Arch Gynecol Obstet. 2015;292:523 –9.\n12. McCormack PL. Dienogest. Drugs. 2010;70(16):2073 –88. https://doi.org/10.21\n65/11206320-000000000-00000.\n13. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is as\neffective as leuprolide acetate in treating the painful symptoms of\nendometriosis: a 24-week, randomized, multicentre, open-label trial. Hum\nReprod. 2010;25(3):633 –41. https://doi.org/10.1093/humrep/dep469.\n14. Bedaiwy MA, Allaire C, Alfaraj S. Long-term medical management of\nendometriosis with dienogest and with a gonadotropin-releasing hormone\nagonist and add-back hormone therapy. Fertil Steril. 2017;107(3):537 –48.\nhttps://doi.org/10.1016/j.fertnstert.2016.12.024.\n15. Vercellini P, Buggio L, Frattaruolo MP, Borghi A, Dridi D, Somigliana E.\nMedical treatment of endometriosis-related pain. Best Pract Res Clin Obstet\nGynaecol. 2018;51:68 –91. https://doi.org/10.1016/j.bpobgyn.2018.01.015.\n16. Tamura H, Yoshida H, Kikuchi H, Josaki M, Mihara Y, Shirafuta Y, et al. The\nclinical outcome of Dienogest treatment followed by in vitro fertilization\nand embryo transfer in infertile women with endometriosis. J Ovarian Res.\n2019;12(1):123. https://doi.org/10.1186/s13048-019-0597-y.\n17. Barra F, Laganà AS, Scala C, Garzon S, Ghezzi F, Ferrero S. Pretreatment with\ndienogest in women with endometriosis undergoing IVF after a previous\nfailed cycle. Reprod BioMed Online. 2020;41(5):859 –68. https://doi.org/10.101\n6/j.rbmo.2020.07.022.\n18. Boivin J, Takefman J, Braverman A. The fertility quality of life (FertiQoL) tool:\ndevelopment and general psychometric properties. Hum Reprod. 2011;\n26(8):2084–91. https://doi.org/10.1093/humrep/der171.\n19. Rickes D, Nickel I, Kropf S, Kleinstein J. Increased pregnancy rates after\nultralong postoperative therapy with gonadotropin-releasing hormone\nanalogs in patients with endometriosis. Fertil Steril. 2002;78(4):757 –62.\nhttps://doi.org/10.1016/S0015-0282(02)03338-1.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional affiliations.\nKhalifa et al. 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