Effect of Hormonal Pre-treatment of Endometriosis on ICSI Outcome: A randomized Controlled trial

Effect of Hormonal Pre-treatment of Endometriosis on ICSI Outcome: A randomized Controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of Hormonal Pre-treatment of Endometriosis on ICSI Outcome: A randomized Controlled trial Mariam Ahmed Dawoud, Ahmed Alhalwagy¹, Rasha Omar Fathy, Mohamed Gamal, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-10691781/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Endometriosis-associated infertility may compromise oocyte competence, fertilization, embryo development, and implantation. Hormonal pretreatment with dienogest has been proposed to improve the reproductive environment before intracytoplasmic sperm injection (ICSI), although evidence remains inconsistent. Objective To evaluate the effect of dienogest pretreatment on embryological and pregnancy outcomes in women with endometriosis-associated infertility undergoing their first ICSI cycle. Methods This single-center, open-label, randomized controlled trial was conducted at Kasr Al-Ainy Hospital, Cairo University, between November 2023 and April 2025. It included 86 women aged 20–40 years with endometriosis-associated infertility. Participants were allocated equally to dienogest pretreatment for 3–6 months before ICSI or to direct ICSI without hormonal pretreatment. Both groups underwent the same long gonadotrophin-releasing hormone agonist stimulation protocol. Primary outcomes were the number of retrieved oocytes, fertilization rate, and number of good-quality embryos. Secondary outcomes were biochemical and clinical pregnancy rates. Results Forty-three women were analyzed in each group, with comparable baseline demographic, hormonal, ovarian-reserve, and infertility characteristics. The mean number of retrieved oocytes did not differ significantly between groups (10.91 ± 3.06 versus 10.72 ± 2.32; p = 0.752). Dienogest pretreatment was associated with higher numbers of metaphase-II oocytes (7.30 ± 2.16 versus 5.63 ± 1.50; p < 0.001), two-pronuclear oocytes (4.19 ± 1.44 versus 2.84 ± 1.07; p < 0.001), fertilization rates (56.88 ± 10.42% versus 49.35 ± 10.50%; p = 0.001), and good-quality embryos (1.98 ± 0.94 versus 1.47 ± 0.88; p = 0.011). Biochemical pregnancy (48.8% versus 27.9%; p = 0.046) and clinical pregnancy (46.5% versus 23.3%; p = 0.024) were also higher with dienogest. Conclusion Dienogest pretreatment improved oocyte maturation, fertilization, embryo quality, and early pregnancy outcomes in women without increasing total oocyte yield. Trial Registration Not applicable. Endometriosis Dienogest Intracytoplasmic sperm injection Infertility. Figures Figure 1 Introduction Endometriosis is a chronic, estrogen-dependent inflammatory disorder characterized by endometrium-like glands and stroma outside the uterine cavity, predominantly within the pelvis [ 1 , 2 ]. Endometriosis affects a substantial proportion of women of reproductive age, although its true prevalence remains uncertain because estimates vary according to the population studied, case definitions, data sources, and diagnostic methods, with undiagnosed disease likely contributing to underestimation [ 3 ]. Clinical manifestations include dysmenorrhea, chronic pelvic pain, dyspareunia, dyschezia and infertility, with substantial adverse effects on psychological, social and reproductive well-being [ 4 ]. Endometriosis-associated infertility is multifactorial and may result from pelvic adhesions, distorted tubo-ovarian anatomy, impaired tubal function, diminished ovarian reserve, chronic inflammation, oxidative stress and altered endometrial receptivity [ 5 , 6 ]. These mechanisms may adversely affect folliculogenesis, oocyte competence, fertilization, embryo development and implantation [ 6 ]. Management should therefore be individualized according to age, ovarian reserve, infertility duration, disease severity, tubal status, previous treatment and coexisting male-factor infertility [ 2 ]. Assisted reproductive technologies, particularly in-vitro fertilization and intracytoplasmic sperm injection (ICSI), are important when tubal function is compromised, previous treatment has failed or rapid conception is clinically indicated [ 2 , 5 ]. Nevertheless, IVF/ICSI outcomes in women with endometriosis remain inconsistent, with some studies reporting reduced oocyte yield, impaired embryo quality or lower implantation rates, whereas clinical-pregnancy and live-birth rates are not uniformly reduced [ 7 , 8 ]. Hormonal pretreatment before controlled ovarian stimulation has been proposed to suppress endometriotic activity and improve the ovarian or endometrial environment before ICSI [ 9 , 10 ]. However, randomized evidence has not established a consistent benefit for pregnancy or live-birth outcomes, and uncertainty remains regarding the optimal agent, duration and patient selection. Accordingly, this randomized controlled trial evaluates whether dienogest pretreatment before ICSI improves the numbers of retrieved and mature oocytes, fertilization rate, number of good-quality embryos, and biochemical and clinical pregnancy rates among women with endometriosis-associated infertility. Patients and Methods Study Design and Setting This single-center, two-arm, parallel-group randomized controlled clinical trial was conducted at the Assisted Reproductive Technology Unit, Department of Obstetrics and Gynecology, Kasr Al-Ainy Hospital, Cairo University, between November 2023 and April 2025. The trial compared dienogest pretreatment before ICSI with direct initiation of an ICSI cycle without hormonal pretreatment. Participants were allocated to the two study groups in a 1:1 ratio. The reporting of the trial was structured in accordance with the CONSORT 2025 recommendations for transparent reporting of randomized trials [ 11 , 12 ]. Study Population Women presenting to the ART unit with endometriosis-associated infertility and scheduled to undergo their first ICSI cycle were assessed for eligibility. Endometriosis was established either by transvaginal ultrasonographic evidence of an ovarian endometrioma or by documented visualization of endometriotic lesions during previous laparoscopic surgery. On ultrasonography, an endometrioma was defined as an ovarian cystic lesion with homogeneous low-level internal echoes and the characteristic “ground-glass” appearance. The use of imaging in the diagnostic assessment of endometriosis is consistent with current clinical recommendations, although negative imaging does not exclude superficial peritoneal disease [ 2 ]. Eligibility Criteria Women were eligible when they were 20–40 years of age, had endometriosis-associated infertility, had endometriosis diagnosed by ultrasound or previous laparoscopy, and were scheduled for their first IVF/ICSI treatment cycle. Women were excluded when they had an ovarian endometrioma measuring more than 3 cm in its largest diameter; evidence of poor ovarian reserve or a predicted poor ovarian response, defined as an antral follicle count below five or an anti-Müllerian hormone concentration below 0.5 ng/mL; previous uterine surgery; or a uterine abnormality that could adversely affect implantation or pregnancy. Uterine abnormalities, including endometrial polyps, submucous fibroids, intrauterine adhesions and congenital uterine anomalies, were excluded using hysterosalpingography and/or hysteroscopy when clinically indicated. Women were also excluded when their partners had severe male-factor infertility. Severe male-factor infertility should be defined using the exact semen concentration, motility or morphology thresholds applied by the study investigators. Semen samples were evaluated using standardized laboratory procedures, as standardized semen-analysis procedures improve the comparability and reproducibility of andrology assessments [ 13 ]. Recruitment and Eligibility Assessment Potentially eligible women presenting to the ART unit during the recruitment period were informed about the purpose of the trial, the study procedures, foreseeable risks and potential benefits, available alternative treatments, confidentiality arrangements and their right to withdraw without affecting their clinical care. Women who expressed an interest in participation underwent a formal eligibility assessment before providing written informed consent. The screening assessment included a detailed review of medical, surgical, obstetric, menstrual and infertility histories; clinical examination; transvaginal ultrasonography; assessment of ovarian reserve using antral follicle count and serum anti-Müllerian hormone; evaluation of the uterine cavity when indicated; review of previous laparoscopic findings; and semen analysis of the participant’s partner. Randomization and Allocation Concealment Following confirmation of eligibility and completion of baseline assessments, participants were randomly assigned in a 1:1 ratio to the dienogest pretreatment group or the control group. Eligible participants were randomly allocated in a 1:1 ratio to either the dienogest pretreatment group or the control group. An independent biostatistician who was not involved in participant recruitment, clinical management or outcome assessment generated the allocation sequence using a computer-based random-number generator. The allocation sequence was retained exclusively by the independent biostatistician and was inaccessible to the investigators responsible for screening and recruitment. Allocation concealment was maintained using sequentially numbered, opaque, sealed, and tamper-evident envelopes prepared according to the allocation sequence. After confirming eligibility and obtaining written informed consent, the recruiting investigator enrolled each participant. Envelopes were opened only after the participant’s identification details and enrolment date had been recorded on the envelope, thereby preventing foreknowledge of the forthcoming allocation. Blinding This was an open-label randomized controlled trial. Participants and treating clinicians were not blinded because the intervention involved 3–6 months of dienogest pretreatment, while the control group proceeded directly to ICSI without placebo treatment. No formal blinding procedures were documented for embryologists, ultrasonographers, or outcome assessors; therefore, their blinding status was considered unclear. Embryological outcomes were assessed using standardized laboratory procedures to minimize observer-related variation. Allocation was disclosed after randomization because knowledge of treatment assignment was necessary for implementation of the allocated intervention. Sample-Size Calculation The sample size was calculated using the number of oocytes retrieved as the outcome on which statistical power was based. The calculation used findings reported by Tamura et al. (2019) [ 14 ], in which the mean number of retrieved oocytes was 5.0 ± 3.6 among women receiving dienogest and 7.5 ± 4.2 among controls. Using a two-sided significance level of 5%, a statistical power of 80%, an equal allocation ratio and the anticipated difference between the two groups, a minimum of 39 participants was required in each group. The calculated sample was increased by approximately 10% to compensate for possible withdrawal or loss to follow-up. Accordingly, 43 participants were recruited into each group, producing a total planned sample of 86 women. Baseline Clinical Assessment A structured history was obtained from each participant. The collected information included age, type and duration of infertility, menstrual history, obstetric history, sexual history, previous medical and surgical conditions, previous laparoscopic treatment of endometriosis, current medication use, lifestyle factors and relevant family history. A general physical examination was undertaken, including measurement of height and weight for calculation of body mass index. Pelvic examination was performed to identify adnexal tenderness, adnexal masses, restricted pelvic organ mobility or palpable endometriotic nodules, particularly within the posterior vaginal fornix or pouch of Douglas. Transvaginal ultrasonography was used to document the presence, laterality and maximum diameter of endometriomas; determine the antral follicle count; assess the uterus and endometrium; and monitor follicular development during controlled ovarian stimulation. Ultrasound findings were recorded using a standardized study form. Study Interventions Dienogest Pretreatment Group Treatment adherence was evaluated at monthly follow-up visits through structured participant interviews and counts of returned tablets. Participants were considered adherent when they had taken at least 80% of the prescribed doses of Dienogest (Visanne 2 mg tablet ,Bayer Weimar Gmbh & Co) Control Group Participants allocated to the control group proceeded directly to controlled ovarian stimulation and ICSI without receiving hormonal pretreatment for endometriosis. Apart from the dienogest pretreatment, both groups underwent the same ovarian-stimulation, oocyte-retrieval, laboratory and embryo-transfer procedures. Controlled Ovarian Stimulation Both groups underwent controlled ovarian stimulation using a gonadotrophin-releasing hormone agonist long down-regulation protocol. Daily GnRH-agonist treatment with triptorelin acetate (Decapeptyl 0.1mg/1ml, prefilled syringe, Ferring Pharmaceuticals) was administered by subcutaneous injection initiated during the mid-luteal phase, approximately on day 21 of the preceding menstrual cycle. Pituitary down-regulation was assessed on the second day of the subsequent menstrual cycle. Adequate suppression was defined as an endometrial thickness below 6 mm on transvaginal ultrasonography and a serum estradiol concentration below 50 pg/mL. Following confirmation of suppression, ovarian stimulation was initiated using highly purified urofollitropin (Fostimon 75 or 150 IU, lyophilized powder for solution for intramuscular injection, IBSA Institute Biochimique SA) with a starting dose of 150 IU, then dose adjustment according to follicular development by serial transvaginal ultrasonography. Follicular development was monitored using serial transvaginal ultrasonography and serum estradiol measurements. When at least three follicles reached a mean diameter of 17 mm or greater, gonadotrophin and GnRH-agonist administration was discontinued, and final oocyte maturation was triggered using HCG ( Choriomon, 5000 IU, lyophilized powder for solution for intramuscular injection, IBSA Institute Biochimique SA) Oocyte Retrieval and ICSI Transvaginal ultrasound-guided oocyte retrieval was performed 34–36 hours after hCG administration under general anesthesia, and then retrieved cumulus–oocyte complexes were identified and processed according to the ART laboratory’s standard operating procedures. Oocyte maturity was assessed following denudation, and oocytes presenting with the first polar body were classified as metaphase-II oocytes. ICSI was performed on mature oocytes using prepared sperm from the participant’s partner. Fertilization was assessed approximately 16–18 hours after injection and was considered normal when two pronuclei were identified. Embryo Culture and Transfer Normally fertilized oocytes were cultured under standardized laboratory conditions. Embryo morphology was evaluated using Time-lapse incubation system according to cell number, blastomere symmetry, developmental stage, and degree of fragmentation. Embryos classified as grades A or B according to the unit’s grading system were considered good-quality embryos. The complete grading criteria should be reported because standardized embryo assessment is necessary for meaningful comparison of ART outcomes between treatment groups and centers [ 15 ]. Embryo transfer was undertaken on day 5 of embryo development, and the number of embryos transferred varies with participants' age and embryo quality, but in most cases 2 embryos were transferred under ultrasound guidance in lithotomy position using a soft embryo transfer catheter and the catheter tip positioned 1–2 cm below the uterine fundus. Luteal-phase support consisted of micronized progesterone (Prontogest, 200mg, vaginal suppository or pessary, Marcyrl Pharmaceuticals Industries) twice daily until 10 weeks of pregnancy. Outcome Measures Primary Outcomes The outcome used as the basis for sample-size estimation was the number of oocytes retrieved per participant. Additional prespecified embryological outcomes were the fertilization rate and number of good-quality embryos. The number of retrieved oocytes was defined as the total number of oocytes collected during transvaginal oocyte retrieval. The number of mature oocytes was defined as the number of metaphase-II oocytes available for ICSI. Fertilization rate was calculated as the number of normally fertilized two-pronuclear oocytes divided by the number of metaphase-II oocytes injected, multiplied by 100. The number of good-quality embryos was defined as the number of embryos classified as grade A or B on the prespecified day of morphological assessment. Secondary Outcomes The secondary outcomes were biochemical pregnancy rate and clinical pregnancy rate. Biochemical pregnancy was defined as a positive urine pregnancy test performed 14 days after embryo transfer. Clinical pregnancy was defined as ultrasonographic visualization of an intrauterine gestational sac containing a fetal pole at approximately seven weeks of gestation. Safety Monitoring Participants were monitored for adverse events associated with dienogest, controlled ovarian stimulation, oocyte retrieval, ICSI and embryo transfer. Potential dienogest-associated adverse effects included headache, nausea, mood changes and irregular uterine bleeding. Follicular development and serum estradiol concentrations were monitored during stimulation to identify an excessive ovarian response and reduce the risk of ovarian hyperstimulation syndrome. Participants were also monitored for complications related to oocyte retrieval, including bleeding, infection and injury to adjacent pelvic structures. Statistical Analysis Data were analyzed using SPSS version 26.0 (IBM Corp., Chicago, IL, USA). Quantitative variables were expressed as mean ± standard deviation or median (interquartile range) according to data distribution, while categorical variables were presented as frequencies and percentages. Normality was assessed using the Kolmogorov–Smirnov and Shapiro–Wilk tests. Comparisons were performed using the independent-samples t -test, Chi-square test, or Fisher's exact test, as appropriate. A two-sided P value < 0.05 was considered statistically significant. Results A total of 86 women with endometriosis-associated infertility were included and divided equally into two groups: the dienogest group (Group A, n = 43) and the control group (Group B, n = 43) ( Fig. 1 ) . There were no statistically significant differences between the dienogest and control groups regarding age, body mass index, or duration of infertility. The mean ages were 28.74 ± 3.82 and 29.37 ± 4.96 years, respectively ( p = 0.513). Mean BMI values were 25.56 ± 4.21 and 25.73 ± 3.78 kg/m² ( p = 0.844), while the mean durations of infertility were 3.97 ± 1.30 and 3.95 ± 1.53 years, respectively ( p = 0.970) ( Table 1 ) . Table 1 Baseline Demographic Characteristics of the Randomized Participants Characteristic Dienogest group (n = 43) Control group (n = 43) Age, years 28.74 ± 3.82 29.37 ± 4.96 BMI, kg/m² 25.56 ± 4.21 25.73 ± 3.78 Duration of infertility, years 3.97 ± 1.30 3.95 ± 1.53 Data are presented as mean ± SD. BMI, body mass index; SD, standard deviation. No statistically significant differences were observed between the two groups in the baseline hormonal profile. Mean AMH concentrations were 2.01 ± 0.58 ng/mL in the dienogest group and 2.01 ± 0.74 ng/mL in the control group ( p = 0.991). The groups were also comparable regarding AFC, FSH, LH, E2, PRL, and TSH, with all p values greater than 0.05 ( Table 2 ) . Table 2 Baseline Ovarian-Reserve and Hormonal Characteristics Characteristic Dienogest group (n = 43) Control group (n = 43) AMH, ng/mL 2.01 ± 0.58 2.01 ± 0.74 AFC, follicles 10.91 ± 2.29 10.88 ± 2.79 FSH, mIU/mL 7.90 ± 1.08 7.93 ± 1.74 LH, mIU/mL 6.79 ± 0.69 6.76 ± 0.92 E2, pg/mL 57.88 ± 7.99 58.02 ± 11.72 PRL† 9.21 ± 2.73 9.61 ± 2.15 TSH† 1.87 ± 0.49 1.89 ± 0.51 Data are presented as mean ± SD. †The measurement units for PRL and TSH were not specified in the supplied results and should be confirmed from the laboratory records. AFC, antral follicle count; AMH, anti-Müllerian hormone; E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; SD, standard deviation; TSH, thyroid-stimulating hormone. Primary infertility was present in 29 women (67.4%) in each group, while secondary infertility was present in 14 women (32.6%) in each group ( p = 1.000). Laparoscopic evidence of endometriosis was identified in 37 women (86.0%) in the dienogest group and 32 women (74.4%) in the control group ( p = 0.176). Ultrasonographic evidence of endometrioma was detected in 31 women (72.1%) and 35 women (81.4%), respectively ( p = 0.307). None of these differences was statistically significant ( Table 3 ) . Table 3 Baseline Infertility and Endometriosis Characteristics Characteristic Dienogest group (n = 43) Control group (n = 43) Type of infertility Primary infertility 29 (67.4%) 29 (67.4%) Secondary infertility 14 (32.6%) 14 (32.6%) Evidence of endometriosis at laparoscopy Yes 37 (86.0%) 32 (74.4%) No 6 (14.0%) 11 (25.6%) Evidence of endometrioma on ultrasonography Yes 31 (72.1%) 35 (81.4%) No 12 (27.9%) 8 (18.6%) Data are presented as number (%). The mean number of retrieved oocytes was 10.91 ± 3.06 in the dienogest group and 10.72 ± 2.32 in the control group, with no statistically significant difference between the groups ( p = 0.752). The dienogest group had significantly higher mean numbers of metaphase-II oocytes (7.30 ± 2.16 versus 5.63 ± 1.50; p < 0.001) and normally fertilized two-pronuclear oocytes (4.19 ± 1.44 versus 2.84 ± 1.07; p < 0.001). The mean fertilization rate was also significantly higher in the dienogest group than in the control group (56.88 ± 10.42% versus 49.35 ± 10.50%; p = 0.001). Similarly, the mean number of good-quality embryos was significantly higher in the dienogest group (1.98 ± 0.94 versus 1.47 ± 0.88; p = 0.011) ( Table 4 ) . Table 4 Primary ICSI and Embryological Outcomes Outcome Dienogest group (n = 43), mean ± SD Control group (n = 43), mean ± SD Mean difference (95% CI)† p value Number of oocytes retrieved 10.91 ± 3.06 10.72 ± 2.32 0.19 (− 0.97 to 1.35) 0.752 Number of MII oocytes 7.30 ± 2.16 5.63 ± 1.50 1.67 (0.87 to 2.47) < 0.001 Number of normally fertilized 2PN oocytes 4.19 ± 1.44 2.84 ± 1.07 1.35 (0.81 to 1.89) < 0.001 Fertilization rate, % 56.88 ± 10.42 49.35 ± 10.50 7.53 (3.04 to 12.02) 0.001 Number of good-quality embryos 1.98 ± 0.94 1.47 ± 0.88 0.51 (0.12 to 0.90) 0.011 Mean differences were calculated as dienogest group minus control group. Between-group comparisons were performed using two-sided independent-samples t tests. †The 95% CIs were estimated from the reported means, SDs. 2PN, two pronuclei; CI, confidence interval; ICSI, intracytoplasmic sperm injection; MII, metaphase-II oocytes; SD, standard deviation. A positive pregnancy test 14 days after embryo transfer was recorded in 21 women (48.8%) in the dienogest group and 12 women (27.9%) in the control group, representing a statistically significant difference ( p = 0.046). Clinical pregnancy was achieved in 20 women (46.5%) in the dienogest group compared with 10 women (23.3%) in the control group, and this difference was also statistically significant ( p = 0.024) ( Table 5 ) . Table 5 Biochemical- and Clinical-Pregnancy Outcomes Outcome Dienogest group (n = 43) Control group (n = 43) Absolute risk difference, percentage points (95% CI)† p value Positive biochemical pregnancy test at 14 days 21 (48.8%) 12 (27.9%) 20.9 (0.4 to 39.2) 0.046 Clinical pregnancy 20 (46.5%) 10 (23.3%) 23.3 (3.1 to 41.0) 0.024 Data are presented as number (%). CI, confidence interval. Discussion This randomized controlled trial evaluated whether dienogest pretreatment before ICSI improved reproductive outcomes in women with endometriosis-associated infertility. The randomized groups were similar regarding the measured demographic, ovarian-reserve, hormonal, and infertility characteristics. Dienogest pretreatment did not increase the total number of oocytes retrieved; however, it was associated with higher numbers of metaphase-II oocytes, normally fertilized two-pronuclear oocytes and good-quality embryos, together with a higher fertilization rate. Positive 14-day pregnancy tests and clinical pregnancies were also more frequent in the dienogest group. These findings suggest that the observed benefit was related more to oocyte maturation, fertilization and subsequent embryo development than to the magnitude of ovarian recruitment. Nevertheless, these pregnancy findings represent early reproductive outcomes and cannot establish an improvement in live birth. The absence of a difference in the total number of retrieved oocytes is clinically relevant because prolonged hormonal suppression may affect ovarian responsiveness. The higher number of mature oocytes despite a similar total oocyte yield may indicate an improvement in the proportion of competent oocytes reaching metaphase II. The accompanying increases in two-pronuclear fertilization and good-quality embryos provide internal consistency, as the differences occurred at sequential stages of the laboratory pathway. However, the study did not report the proportion of mature oocytes, implantation rate or cumulative embryo-transfer outcomes and therefore cannot determine which stage contributed most strongly to the higher clinical-pregnancy rate. The present findings are partly consistent with Barra et al. (2020) [ 17 ], who reported higher cumulative implantation, clinical-pregnancy and live-birth rates after three months of dienogest in women with endometriosis who had failed a previous IVF cycle. Their study also found higher numbers of retrieved oocytes, two-pronuclear embryos and blastocysts among women with endometriomas measuring at least 4 cm. In contrast, the present trial included women undergoing their first ICSI cycle and excluded endometriomas larger than 3 cm. Differences in previous treatment failure, endometrioma size and study design may therefore account for the disagreement regarding total oocyte yield, while the improvement in two-pronuclear fertilization and embryo development was broadly concordant between the studies. Conversely, Tamura et al. (2019) [ 14 ] reported less favourable ovarian and reproductive outcomes following dienogest pretreatment, including fewer growing follicles, retrieved oocytes, fertilized oocytes and blastocysts, as well as lower cumulative pregnancy and live-birth rates. They also did not demonstrate a reduction in inflammatory cytokines or oxidative-stress markers within follicular fluid. These results contrast with the improved maturation, fertilization and pregnancy outcomes observed in the present trial. Variations in endometriosis severity, ovarian reserve, previous surgery, pretreatment duration and ovarian-stimulation protocols may contribute to this heterogeneity, but the available evidence does not permit a definitive explanation for the conflicting findings. Evidence comparing dienogest with other hormonal pretreatments also remains inconclusive. Khalifa et al. (2021) [ 18 ] randomized 134 women to three months of dienogest or a depot GnRH agonist before IVF and found no significant differences in ovarian response, mature oocytes, fertilization or pregnancy outcomes. Dienogest was, however, associated with lower treatment costs, fewer adverse effects and better treatment-tolerability scores. Because that trial compared dienogest with active GnRH-agonist suppression rather than with no pretreatment, it does not directly contradict the benefit observed against the untreated control group in the present study. The systematic review by Shao, Li and Wang (2023) [ 19 ], which included five studies and 568 women, found no overall difference between dienogest and non-dienogest strategies across the combined reproductive outcomes. Subgroup analyses nevertheless suggested higher clinical-pregnancy and live-birth rates when dienogest was compared specifically with no hormonal pretreatment, but lower rates when it was compared with long GnRH-agonist treatment. More recently, a network meta-analysis of 11 randomized trials involving 1,435 women found no clear improvement in clinical-pregnancy or live-birth rates with dienogest, GnRH-agonist or other pretreatment protocols compared with conventional treatment. A potential explanation is that dienogest suppresses estrogen-dependent endometriotic activity and may exert anti-inflammatory and anti-angiogenic effects. Such actions could theoretically improve the follicular microenvironment, oocyte competence or endometrial receptivity. The pattern observed in this trial unchanged total oocyte yield but improved maturation, fertilization and embryo quality is compatible with an effect on oocyte competence rather than follicle quantity. This remains a hypothesis because inflammatory markers, follicular-fluid characteristics and endometrial-receptivity measures were not assessed, while previous mechanistic research has not consistently demonstrated improvement in follicular inflammation or oxidative stress [ 20 ]. The results should also be considered in relation to current clinical guidance. The ESHRE guideline states that evidence is insufficient to recommend prolonged combined oral contraceptive or progestogen pretreatment before ART for the purpose of increasing live-birth rates. The present trial contributes randomized evidence suggesting improvement in intermediate embryological outcomes and early pregnancy; however, it does not address live birth and is therefore insufficient by itself to support routine dienogest pretreatment for all women with endometriosis undergoing ICSI. The study has several strengths, including its randomized parallel-group design, equal group sizes, restriction to first ICSI cycles and comparable measured baseline characteristics. Both groups underwent the same ovarian-stimulation approach, thereby reducing procedural variation. Important limitations remain. The study was conducted at a single center and included only 86 participants, limiting statistical precision and generalizability. The procedures used for random-sequence generation, allocation concealment and outcome-assessor blinding were not clearly documented. Dienogest exposure varied from three to six months without reported criteria for determining treatment duration, and outcomes were not analyzed according to endometriosis stage. The embryo-grading system was incompletely described, while live birth, miscarriage, cumulative pregnancy, treatment adherence and adverse events were not reported. Furthermore, several primary outcomes were tested without a stated adjustment for multiple comparisons, increasing the possibility of chance-positive findings. Conclusion Dienogest pretreatment before ICSI was associated with improved oocyte maturation, fertilization, embryo quality and early pregnancy outcomes but did not increase the total number of retrieved oocytes. The findings support further investigation rather than routine universal pretreatment. Larger multicentre randomized trials should use concealed allocation, blinded embryological assessment, a standardized dienogest duration and live birth as the primary outcome, together with systematic reporting of cumulative reproductive outcomes and treatment-related harms. Declarations Ethics Approval and Consent to Participate The study protocol was reviewed and approved by the Research Ethics Committee of the Faculty of Medicine, Cairo University, under approval code MD-70-2023, dated 10 August 2023. The study was conducted in accordance with the approved protocol and the ethical principles governing research involving human participants. Written informed consent was obtained from all participants before enrolment in the study. Consent for Publication Not applicable. Competing Interests The authors declare that they have no competing interests. Funding None. Author Contribution Dr Ahmed Halwagi: protocol and study designDr Rasha El Komy: statitsctical analysis, setting randimzation, patient selection according to inclusion and exclusion criteriaDr Mohamed Gamal: data collectionDr Mona Sdeiek: data collection and revsionDr mariam Dawoud: mauscript writing and final revision Availability of Data and Materials The data generated and analyzed during the study are available from the corresponding author upon reasonable request. References Zondervan KT, Becker CM, Missmer SA (2020) Endometriosis N Engl J Med 382(13):1244–1256 Becker CM et al (2022) ESHRE guideline: endometriosis. 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BMJ 389:e081124 Organization WH (2021) WHO laboratory manual for the examination and processing of human semen 6th edition ; Available from: https://www.who.int/publications/i/item/9789240030787/ Tamura H et al (2019) The clinical outcome of Dienogest treatment followed by in vitro fertilization and embryo transfer in infertile women with endometriosis. J Ovarian Res 12(1):123 The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod, (2011) 26(6): pp. 1270-83 Zegers-Hochschild F et al (2017) The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod 32(9):1786–1801 Barra F et al (2020) Pretreatment with dienogest in women with endometriosis undergoing IVF after a previous failed cycle. Reprod Biomed Online 41(5):859–868 Khalifa E et al (2021) Role of suppression of endometriosis with progestins before IVF-ET: a non-inferiority randomized controlled trial. BMC Pregnancy Childbirth 21(1):264 Shao W, Li Y, Wang Y (2023) Impact of dienogest pretreatment on IVF-ET outcomes in patients with endometriosis: a systematic review and meta-analysis. J Ovarian Res 16(1):166 Li D et al (2026) Efficacy of different pretreatments in IVF outcomes in patients with endometriosis: A systematic review and network meta–analysis. Sci Rep, 16(1) Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-10691781","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":707973789,"identity":"df8b1d86-f7bd-4e7a-a572-e0db257e8b0d","order_by":0,"name":"Mariam Ahmed Dawoud","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABRUlEQVRIie2RMUvDQBTHHwRuOtv1SsH6BYQLgRAxxK+SIxCX6iIUQdGCULc6C8XP4JT5JNAsMVlPsjQUOlUsCKUu6iVUxMSgo2B+wzv43/3ee3AANTV/FTsrPCvIpHkyAZKf5BeKS9fJDwp8Kv6HApXK9uV9uki7FjSCUJ3iXqw1r2RinxqHlCt3CQbT6n9V9HBfI8xzoBV2NQ1HiU6ETOwxOaIcObsYXKeocBekogDlB157Y5CYIBAQGxF2y7HexuA7hcX0eKasmHcONH7MlMjsxGNlZb9mSnMplbeSIlzZ0POBinwK1ynPkkE+BUmFWyVlhgzmBbglnp7VUeRoqmxisCFh1z7SdkbUsYtK7CoPL97JZiN22WTes9QbuZhYLM/YMLhIxfzY2vv2TwBwOdrys0qB9ct3FXTWT6um1NTU1Pwb3gGiCHV41U0QxQAAAABJRU5ErkJggg==","orcid":"","institution":"Cairo University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mariam","middleName":"Ahmed","lastName":"Dawoud","suffix":""},{"id":707973790,"identity":"a1435599-0828-4dc6-8bfe-1608b2e35613","order_by":1,"name":"Ahmed Alhalwagy¹","email":"","orcid":"","institution":"Cairo University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Alhalwagy¹","suffix":""},{"id":707973791,"identity":"56745c9d-d777-4fa0-acf0-f04665fc1088","order_by":2,"name":"Rasha Omar Fathy","email":"","orcid":"","institution":"Cairo University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rasha","middleName":"Omar","lastName":"Fathy","suffix":""},{"id":707973792,"identity":"11fa5d39-1699-44e5-b67a-10a91bf9ba18","order_by":3,"name":"Mohamed Gamal","email":"","orcid":"","institution":"Cairo University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"Gamal","suffix":""},{"id":707973793,"identity":"dc7ebc40-5d45-4cba-ba11-8bf6ba038bd3","order_by":4,"name":"Mona sediek¹","email":"","orcid":"","institution":"Cairo University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mona","middleName":"","lastName":"sediek¹","suffix":""}],"badges":[],"createdAt":"2026-08-13 13:53:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-10691781/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-10691781/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":119347869,"identity":"3aa2940b-ba5c-47c1-8d17-c4309b1bbfb0","added_by":"auto","created_at":"2026-09-06 10:30:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":370552,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT flowchart.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-10691781/v1/aee5b51171f3f8813e10eddb.png"},{"id":119348058,"identity":"fa780a65-978f-4de4-9a1d-b716139aee25","added_by":"auto","created_at":"2026-09-06 10:35:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":563805,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-10691781/v1/ef21b457-81ca-4a28-80b1-63d0cf773ac3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Hormonal Pre-treatment of Endometriosis on ICSI Outcome: A randomized Controlled trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a chronic, estrogen-dependent inflammatory disorder characterized by endometrium-like glands and stroma outside the uterine cavity, predominantly within the pelvis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Endometriosis affects a substantial proportion of women of reproductive age, although its true prevalence remains uncertain because estimates vary according to the population studied, case definitions, data sources, and diagnostic methods, with undiagnosed disease likely contributing to underestimation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Clinical manifestations include dysmenorrhea, chronic pelvic pain, dyspareunia, dyschezia and infertility, with substantial adverse effects on psychological, social and reproductive well-being [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEndometriosis-associated infertility is multifactorial and may result from pelvic adhesions, distorted tubo-ovarian anatomy, impaired tubal function, diminished ovarian reserve, chronic inflammation, oxidative stress and altered endometrial receptivity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These mechanisms may adversely affect folliculogenesis, oocyte competence, fertilization, embryo development and implantation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Management should therefore be individualized according to age, ovarian reserve, infertility duration, disease severity, tubal status, previous treatment and coexisting male-factor infertility [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAssisted reproductive technologies, particularly in-vitro fertilization and intracytoplasmic sperm injection (ICSI), are important when tubal function is compromised, previous treatment has failed or rapid conception is clinically indicated [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Nevertheless, IVF/ICSI outcomes in women with endometriosis remain inconsistent, with some studies reporting reduced oocyte yield, impaired embryo quality or lower implantation rates, whereas clinical-pregnancy and live-birth rates are not uniformly reduced [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHormonal pretreatment before controlled ovarian stimulation has been proposed to suppress endometriotic activity and improve the ovarian or endometrial environment before ICSI [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, randomized evidence has not established a consistent benefit for pregnancy or live-birth outcomes, and uncertainty remains regarding the optimal agent, duration and patient selection.\u003c/p\u003e \u003cp\u003eAccordingly, this randomized controlled trial evaluates whether dienogest pretreatment before ICSI improves the numbers of retrieved and mature oocytes, fertilization rate, number of good-quality embryos, and biochemical and clinical pregnancy rates among women with endometriosis-associated infertility.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003eThis single-center, two-arm, parallel-group randomized controlled clinical trial was conducted at the Assisted Reproductive Technology Unit, Department of Obstetrics and Gynecology, Kasr Al-Ainy Hospital, Cairo University, between November 2023 and April 2025. The trial compared dienogest pretreatment before ICSI with direct initiation of an ICSI cycle without hormonal pretreatment. Participants were allocated to the two study groups in a 1:1 ratio. The reporting of the trial was structured in accordance with the CONSORT 2025 recommendations for transparent reporting of randomized trials [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population\u003c/h3\u003e\n\u003cp\u003eWomen presenting to the ART unit with endometriosis-associated infertility and scheduled to undergo their first ICSI cycle were assessed for eligibility. Endometriosis was established either by transvaginal ultrasonographic evidence of an ovarian endometrioma or by documented visualization of endometriotic lesions during previous laparoscopic surgery. On ultrasonography, an endometrioma was defined as an ovarian cystic lesion with homogeneous low-level internal echoes and the characteristic \u0026ldquo;ground-glass\u0026rdquo; appearance. The use of imaging in the diagnostic assessment of endometriosis is consistent with current clinical recommendations, although negative imaging does not exclude superficial peritoneal disease [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eWomen were eligible when they were 20\u0026ndash;40 years of age, had endometriosis-associated infertility, had endometriosis diagnosed by ultrasound or previous laparoscopy, and were scheduled for their first IVF/ICSI treatment cycle.\u003c/p\u003e \u003cp\u003eWomen were excluded when they had an ovarian endometrioma measuring more than 3 cm in its largest diameter; evidence of poor ovarian reserve or a predicted poor ovarian response, defined as an antral follicle count below five or an anti-M\u0026uuml;llerian hormone concentration below 0.5 ng/mL; previous uterine surgery; or a uterine abnormality that could adversely affect implantation or pregnancy. Uterine abnormalities, including endometrial polyps, submucous fibroids, intrauterine adhesions and congenital uterine anomalies, were excluded using hysterosalpingography and/or hysteroscopy when clinically indicated. Women were also excluded when their partners had severe male-factor infertility. Severe male-factor infertility should be defined using the exact semen concentration, motility or morphology thresholds applied by the study investigators. Semen samples were evaluated using standardized laboratory procedures, as standardized semen-analysis procedures improve the comparability and reproducibility of andrology assessments [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eRecruitment and Eligibility Assessment\u003c/h3\u003e\n\u003cp\u003e Potentially eligible women presenting to the ART unit during the recruitment period were informed about the purpose of the trial, the study procedures, foreseeable risks and potential benefits, available alternative treatments, confidentiality arrangements and their right to withdraw without affecting their clinical care. Women who expressed an interest in participation underwent a formal eligibility assessment before providing written informed consent. The screening assessment included a detailed review of medical, surgical, obstetric, menstrual and infertility histories; clinical examination; transvaginal ultrasonography; assessment of ovarian reserve using antral follicle count and serum anti-M\u0026uuml;llerian hormone; evaluation of the uterine cavity when indicated; review of previous laparoscopic findings; and semen analysis of the participant\u0026rsquo;s partner.\u003c/p\u003e\n\u003ch3\u003eRandomization and Allocation Concealment\u003c/h3\u003e\n\u003cp\u003eFollowing confirmation of eligibility and completion of baseline assessments, participants were randomly assigned in a 1:1 ratio to the dienogest pretreatment group or the control group.\u003c/p\u003e \u003cp\u003eEligible participants were randomly allocated in a 1:1 ratio to either the dienogest pretreatment group or the control group. An independent biostatistician who was not involved in participant recruitment, clinical management or outcome assessment generated the allocation sequence using a computer-based random-number generator. The allocation sequence was retained exclusively by the independent biostatistician and was inaccessible to the investigators responsible for screening and recruitment. Allocation concealment was maintained using sequentially numbered, opaque, sealed, and tamper-evident envelopes prepared according to the allocation sequence. After confirming eligibility and obtaining written informed consent, the recruiting investigator enrolled each participant. Envelopes were opened only after the participant\u0026rsquo;s identification details and enrolment date had been recorded on the envelope, thereby preventing foreknowledge of the forthcoming allocation.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBlinding\u003c/h2\u003e \u003cp\u003eThis was an open-label randomized controlled trial. Participants and treating clinicians were not blinded because the intervention involved 3\u0026ndash;6 months of dienogest pretreatment, while the control group proceeded directly to ICSI without placebo treatment. No formal blinding procedures were documented for embryologists, ultrasonographers, or outcome assessors; therefore, their blinding status was considered unclear. Embryological outcomes were assessed using standardized laboratory procedures to minimize observer-related variation. Allocation was disclosed after randomization because knowledge of treatment assignment was necessary for implementation of the allocated intervention.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSample-Size Calculation\u003c/h3\u003e\n\u003cp\u003eThe sample size was calculated using the number of oocytes retrieved as the outcome on which statistical power was based. The calculation used findings reported by Tamura \u003cem\u003eet al.\u003c/em\u003e (2019) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], in which the mean number of retrieved oocytes was 5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 among women receiving dienogest and 7.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 among controls. Using a two-sided significance level of 5%, a statistical power of 80%, an equal allocation ratio and the anticipated difference between the two groups, a minimum of 39 participants was required in each group. The calculated sample was increased by approximately 10% to compensate for possible withdrawal or loss to follow-up. Accordingly, 43 participants were recruited into each group, producing a total planned sample of 86 women.\u003c/p\u003e\n\u003ch3\u003eBaseline Clinical Assessment\u003c/h3\u003e\n\u003cp\u003eA structured history was obtained from each participant. The collected information included age, type and duration of infertility, menstrual history, obstetric history, sexual history, previous medical and surgical conditions, previous laparoscopic treatment of endometriosis, current medication use, lifestyle factors and relevant family history.\u003c/p\u003e \u003cp\u003eA general physical examination was undertaken, including measurement of height and weight for calculation of body mass index. Pelvic examination was performed to identify adnexal tenderness, adnexal masses, restricted pelvic organ mobility or palpable endometriotic nodules, particularly within the posterior vaginal fornix or pouch of Douglas.\u003c/p\u003e \u003cp\u003eTransvaginal ultrasonography was used to document the presence, laterality and maximum diameter of endometriomas; determine the antral follicle count; assess the uterus and endometrium; and monitor follicular development during controlled ovarian stimulation. Ultrasound findings were recorded using a standardized study form.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy Interventions\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eDienogest Pretreatment Group\u003c/h2\u003e \u003cp\u003eTreatment adherence was evaluated at monthly follow-up visits through structured participant interviews and counts of returned tablets. Participants were considered adherent when they had taken at least 80% of the prescribed doses of Dienogest (Visanne 2 mg tablet ,Bayer Weimar Gmbh \u0026amp; Co)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eControl Group\u003c/h2\u003e \u003cp\u003eParticipants allocated to the control group proceeded directly to controlled ovarian stimulation and ICSI without receiving hormonal pretreatment for endometriosis. Apart from the dienogest pretreatment, both groups underwent the same ovarian-stimulation, oocyte-retrieval, laboratory and embryo-transfer procedures.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eControlled Ovarian Stimulation\u003c/h2\u003e \u003cp\u003eBoth groups underwent controlled ovarian stimulation using a gonadotrophin-releasing hormone agonist long down-regulation protocol. Daily GnRH-agonist treatment with triptorelin acetate (Decapeptyl 0.1mg/1ml, prefilled syringe, Ferring Pharmaceuticals) was administered by subcutaneous injection initiated during the mid-luteal phase, approximately on day 21 of the preceding menstrual cycle.\u003c/p\u003e \u003cp\u003ePituitary down-regulation was assessed on the second day of the subsequent menstrual cycle. Adequate suppression was defined as an endometrial thickness below 6 mm on transvaginal ultrasonography and a serum estradiol concentration below 50 pg/mL. Following confirmation of suppression, ovarian stimulation was initiated using highly purified urofollitropin (Fostimon 75 or 150 IU, lyophilized powder for solution for intramuscular injection, IBSA Institute Biochimique SA) with a starting dose of 150 IU, then dose adjustment according to follicular development by serial transvaginal ultrasonography.\u003c/p\u003e \u003cp\u003eFollicular development was monitored using serial transvaginal ultrasonography and serum estradiol measurements. When at least three follicles reached a mean diameter of 17 mm or greater, gonadotrophin and GnRH-agonist administration was discontinued, and final oocyte maturation was triggered using HCG ( Choriomon, 5000 IU, lyophilized powder for solution for intramuscular injection, IBSA Institute Biochimique SA)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eOocyte Retrieval and ICSI\u003c/h2\u003e \u003cp\u003eTransvaginal ultrasound-guided oocyte retrieval was performed 34\u0026ndash;36 hours after hCG administration under general anesthesia, and then retrieved cumulus\u0026ndash;oocyte complexes were identified and processed according to the ART laboratory\u0026rsquo;s standard operating procedures. Oocyte maturity was assessed following denudation, and oocytes presenting with the first polar body were classified as metaphase-II oocytes. ICSI was performed on mature oocytes using prepared sperm from the participant\u0026rsquo;s partner. Fertilization was assessed approximately 16\u0026ndash;18 hours after injection and was considered normal when two pronuclei were identified.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eEmbryo Culture and Transfer\u003c/h2\u003e \u003cp\u003eNormally fertilized oocytes were cultured under standardized laboratory conditions. Embryo morphology was evaluated using Time-lapse incubation system according to cell number, blastomere symmetry, developmental stage, and degree of fragmentation. Embryos classified as grades A or B according to the unit\u0026rsquo;s grading system were considered good-quality embryos. The complete grading criteria should be reported because standardized embryo assessment is necessary for meaningful comparison of ART outcomes between treatment groups and centers [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEmbryo transfer was undertaken on day 5 of embryo development, and the number of embryos transferred varies with participants' age and embryo quality, but in most cases 2 embryos were transferred under ultrasound guidance in lithotomy position using a soft embryo transfer catheter and the catheter tip positioned 1\u0026ndash;2 cm below the uterine fundus. Luteal-phase support consisted of micronized progesterone (Prontogest, 200mg, vaginal suppository or pessary, Marcyrl Pharmaceuticals Industries) twice daily until 10 weeks of pregnancy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measures\u003c/h2\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003ePrimary Outcomes\u003c/h2\u003e \u003cp\u003eThe outcome used as the basis for sample-size estimation was the number of oocytes retrieved per participant. Additional prespecified embryological outcomes were the fertilization rate and number of good-quality embryos.\u003c/p\u003e \u003cp\u003eThe number of retrieved oocytes was defined as the total number of oocytes collected during transvaginal oocyte retrieval. The number of mature oocytes was defined as the number of metaphase-II oocytes available for ICSI. Fertilization rate was calculated as the number of normally fertilized two-pronuclear oocytes divided by the number of metaphase-II oocytes injected, multiplied by 100. The number of good-quality embryos was defined as the number of embryos classified as grade A or B on the prespecified day of morphological assessment.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcomes\u003c/h2\u003e \u003cp\u003eThe secondary outcomes were biochemical pregnancy rate and clinical pregnancy rate. Biochemical pregnancy was defined as a positive urine pregnancy test performed 14 days after embryo transfer. Clinical pregnancy was defined as ultrasonographic visualization of an intrauterine gestational sac containing a fetal pole at approximately seven weeks of gestation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSafety Monitoring\u003c/h2\u003e \u003cp\u003eParticipants were monitored for adverse events associated with dienogest, controlled ovarian stimulation, oocyte retrieval, ICSI and embryo transfer. Potential dienogest-associated adverse effects included headache, nausea, mood changes and irregular uterine bleeding.\u003c/p\u003e \u003cp\u003eFollicular development and serum estradiol concentrations were monitored during stimulation to identify an excessive ovarian response and reduce the risk of ovarian hyperstimulation syndrome. Participants were also monitored for complications related to oocyte retrieval, including bleeding, infection and injury to adjacent pelvic structures.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using SPSS version 26.0 (IBM Corp., Chicago, IL, USA). Quantitative variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range) according to data distribution, while categorical variables were presented as frequencies and percentages. Normality was assessed using the Kolmogorov\u0026ndash;Smirnov and Shapiro\u0026ndash;Wilk tests. Comparisons were performed using the independent-samples \u003cem\u003et\u003c/em\u003e-test, Chi-square test, or Fisher's exact test, as appropriate. A two-sided \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 86 women with endometriosis-associated infertility were included and divided equally into two groups: the dienogest group (Group A, n\u0026thinsp;=\u0026thinsp;43) and the control group (Group B, n\u0026thinsp;=\u0026thinsp;43) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere were no statistically significant differences between the dienogest and control groups regarding age, body mass index, or duration of infertility. The mean ages were 28.74\u0026thinsp;\u0026plusmn;\u0026thinsp;3.82 and 29.37\u0026thinsp;\u0026plusmn;\u0026thinsp;4.96 years, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.513). Mean BMI values were 25.56\u0026thinsp;\u0026plusmn;\u0026thinsp;4.21 and 25.73\u0026thinsp;\u0026plusmn;\u0026thinsp;3.78 kg/m\u0026sup2; (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.844), while the mean durations of infertility were 3.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30 and 3.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53 years, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.970) \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Demographic Characteristics of the Randomized Participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDienogest group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e28.74\u0026thinsp;\u0026plusmn;\u0026thinsp;3.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e29.37\u0026thinsp;\u0026plusmn;\u0026thinsp;4.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e25.56\u0026thinsp;\u0026plusmn;\u0026thinsp;4.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e25.73\u0026thinsp;\u0026plusmn;\u0026thinsp;3.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of infertility, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. BMI, body mass index; SD, standard deviation.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNo statistically significant differences were observed between the two groups in the baseline hormonal profile. Mean AMH concentrations were 2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58 ng/mL in the dienogest group and 2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74 ng/mL in the control group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.991). The groups were also comparable regarding AFC, FSH, LH, E2, PRL, and TSH, with all \u003cem\u003ep\u003c/em\u003e values greater than 0.05 \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Ovarian-Reserve and Hormonal Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDienogest group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFC, follicles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.91\u0026thinsp;\u0026plusmn;\u0026thinsp;2.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.88\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFSH, mIU/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e7.93\u0026thinsp;\u0026plusmn;\u0026thinsp;1.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLH, mIU/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e6.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e6.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE2, pg/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e57.88\u0026thinsp;\u0026plusmn;\u0026thinsp;7.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e58.02\u0026thinsp;\u0026plusmn;\u0026thinsp;11.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePRL\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.21\u0026thinsp;\u0026plusmn;\u0026thinsp;2.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. \u0026dagger;The measurement units for PRL and TSH were not specified in the supplied results and should be confirmed from the laboratory records. AFC, antral follicle count; AMH, anti-M\u0026uuml;llerian hormone; E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; SD, standard deviation; TSH, thyroid-stimulating hormone.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePrimary infertility was present in 29 women (67.4%) in each group, while secondary infertility was present in 14 women (32.6%) in each group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000). Laparoscopic evidence of endometriosis was identified in 37 women (86.0%) in the dienogest group and 32 women (74.4%) in the control group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.176). Ultrasonographic evidence of endometrioma was detected in 31 women (72.1%) and 35 women (81.4%), respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.307). None of these differences was statistically significant \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Infertility and Endometriosis Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDienogest group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29 (67.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29 (67.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (32.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (32.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvidence of endometriosis at laparoscopy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37 (86.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32 (74.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (14.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (25.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvidence of endometrioma on ultrasonography\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31 (72.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35 (81.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (27.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (18.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eData are presented as number (%).\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe mean number of retrieved oocytes was 10.91\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06 in the dienogest group and 10.72\u0026thinsp;\u0026plusmn;\u0026thinsp;2.32 in the control group, with no statistically significant difference between the groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.752). The dienogest group had significantly higher mean numbers of metaphase-II oocytes (7.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.16 versus 5.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and normally fertilized two-pronuclear oocytes (4.19\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44 versus 2.84\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The mean fertilization rate was also significantly higher in the dienogest group than in the control group (56.88\u0026thinsp;\u0026plusmn;\u0026thinsp;10.42% versus 49.35\u0026thinsp;\u0026plusmn;\u0026thinsp;10.50%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Similarly, the mean number of good-quality embryos was significantly higher in the dienogest group (1.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.94 versus 1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrimary ICSI and Embryological Outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDienogest group (n\u0026thinsp;=\u0026thinsp;43), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group (n\u0026thinsp;=\u0026thinsp;43), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean difference (95% CI)\u0026dagger;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of oocytes retrieved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.91\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.72\u0026thinsp;\u0026plusmn;\u0026thinsp;2.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19 (\u0026minus;\u0026thinsp;0.97 to 1.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.752\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of MII oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.67 (0.87 to 2.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of normally fertilized 2PN oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4.19\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.84\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.35 (0.81 to 1.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFertilization rate, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e56.88\u0026thinsp;\u0026plusmn;\u0026thinsp;10.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e49.35\u0026thinsp;\u0026plusmn;\u0026thinsp;10.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.53 (3.04 to 12.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of good-quality embryos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.51 (0.12 to 0.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eMean differences were calculated as dienogest group minus control group. Between-group comparisons were performed using two-sided independent-samples t tests.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003e\u0026dagger;The 95% CIs were estimated from the reported means, SDs. 2PN, two pronuclei; CI, confidence interval; ICSI, intracytoplasmic sperm injection; MII, metaphase-II oocytes; SD, standard deviation.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA positive pregnancy test 14 days after embryo transfer was recorded in 21 women (48.8%) in the dienogest group and 12 women (27.9%) in the control group, representing a statistically significant difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046). Clinical pregnancy was achieved in 20 women (46.5%) in the dienogest group compared with 10 women (23.3%) in the control group, and this difference was also statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBiochemical- and Clinical-Pregnancy Outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDienogest group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbsolute risk difference, percentage points (95% CI)\u0026dagger;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive biochemical pregnancy test at 14 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21 (48.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (27.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.9 (0.4 to 39.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (46.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (23.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.3 (3.1 to 41.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eData are presented as number (%). CI, confidence interval.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis randomized controlled trial evaluated whether dienogest pretreatment before ICSI improved reproductive outcomes in women with endometriosis-associated infertility. The randomized groups were similar regarding the measured demographic, ovarian-reserve, hormonal, and infertility characteristics. Dienogest pretreatment did not increase the total number of oocytes retrieved; however, it was associated with higher numbers of metaphase-II oocytes, normally fertilized two-pronuclear oocytes and good-quality embryos, together with a higher fertilization rate. Positive 14-day pregnancy tests and clinical pregnancies were also more frequent in the dienogest group. These findings suggest that the observed benefit was related more to oocyte maturation, fertilization and subsequent embryo development than to the magnitude of ovarian recruitment. Nevertheless, these pregnancy findings represent early reproductive outcomes and cannot establish an improvement in live birth.\u003c/p\u003e \u003cp\u003eThe absence of a difference in the total number of retrieved oocytes is clinically relevant because prolonged hormonal suppression may affect ovarian responsiveness. The higher number of mature oocytes despite a similar total oocyte yield may indicate an improvement in the proportion of competent oocytes reaching metaphase II. The accompanying increases in two-pronuclear fertilization and good-quality embryos provide internal consistency, as the differences occurred at sequential stages of the laboratory pathway. However, the study did not report the proportion of mature oocytes, implantation rate or cumulative embryo-transfer outcomes and therefore cannot determine which stage contributed most strongly to the higher clinical-pregnancy rate.\u003c/p\u003e \u003cp\u003eThe present findings are partly consistent with Barra \u003cem\u003eet al.\u003c/em\u003e (2020) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], who reported higher cumulative implantation, clinical-pregnancy and live-birth rates after three months of dienogest in women with endometriosis who had failed a previous IVF cycle. Their study also found higher numbers of retrieved oocytes, two-pronuclear embryos and blastocysts among women with endometriomas measuring at least 4 cm. In contrast, the present trial included women undergoing their first ICSI cycle and excluded endometriomas larger than 3 cm. Differences in previous treatment failure, endometrioma size and study design may therefore account for the disagreement regarding total oocyte yield, while the improvement in two-pronuclear fertilization and embryo development was broadly concordant between the studies.\u003c/p\u003e \u003cp\u003eConversely, Tamura \u003cem\u003eet al.\u003c/em\u003e (2019) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] reported less favourable ovarian and reproductive outcomes following dienogest pretreatment, including fewer growing follicles, retrieved oocytes, fertilized oocytes and blastocysts, as well as lower cumulative pregnancy and live-birth rates. They also did not demonstrate a reduction in inflammatory cytokines or oxidative-stress markers within follicular fluid. These results contrast with the improved maturation, fertilization and pregnancy outcomes observed in the present trial. Variations in endometriosis severity, ovarian reserve, previous surgery, pretreatment duration and ovarian-stimulation protocols may contribute to this heterogeneity, but the available evidence does not permit a definitive explanation for the conflicting findings.\u003c/p\u003e \u003cp\u003eEvidence comparing dienogest with other hormonal pretreatments also remains inconclusive. Khalifa \u003cem\u003eet al.\u003c/em\u003e (2021) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] randomized 134 women to three months of dienogest or a depot GnRH agonist before IVF and found no significant differences in ovarian response, mature oocytes, fertilization or pregnancy outcomes. Dienogest was, however, associated with lower treatment costs, fewer adverse effects and better treatment-tolerability scores. Because that trial compared dienogest with active GnRH-agonist suppression rather than with no pretreatment, it does not directly contradict the benefit observed against the untreated control group in the present study.\u003c/p\u003e \u003cp\u003eThe systematic review by Shao, Li and Wang (2023) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], which included five studies and 568 women, found no overall difference between dienogest and non-dienogest strategies across the combined reproductive outcomes. Subgroup analyses nevertheless suggested higher clinical-pregnancy and live-birth rates when dienogest was compared specifically with no hormonal pretreatment, but lower rates when it was compared with long GnRH-agonist treatment. More recently, a network meta-analysis of 11 randomized trials involving 1,435 women found no clear improvement in clinical-pregnancy or live-birth rates with dienogest, GnRH-agonist or other pretreatment protocols compared with conventional treatment.\u003c/p\u003e \u003cp\u003eA potential explanation is that dienogest suppresses estrogen-dependent endometriotic activity and may exert anti-inflammatory and anti-angiogenic effects. Such actions could theoretically improve the follicular microenvironment, oocyte competence or endometrial receptivity. The pattern observed in this trial unchanged total oocyte yield but improved maturation, fertilization and embryo quality is compatible with an effect on oocyte competence rather than follicle quantity. This remains a hypothesis because inflammatory markers, follicular-fluid characteristics and endometrial-receptivity measures were not assessed, while previous mechanistic research has not consistently demonstrated improvement in follicular inflammation or oxidative stress [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe results should also be considered in relation to current clinical guidance. The ESHRE guideline states that evidence is insufficient to recommend prolonged combined oral contraceptive or progestogen pretreatment before ART for the purpose of increasing live-birth rates. The present trial contributes randomized evidence suggesting improvement in intermediate embryological outcomes and early pregnancy; however, it does not address live birth and is therefore insufficient by itself to support routine dienogest pretreatment for all women with endometriosis undergoing ICSI.\u003c/p\u003e \u003cp\u003eThe study has several strengths, including its randomized parallel-group design, equal group sizes, restriction to first ICSI cycles and comparable measured baseline characteristics. Both groups underwent the same ovarian-stimulation approach, thereby reducing procedural variation. Important limitations remain. The study was conducted at a single center and included only 86 participants, limiting statistical precision and generalizability. The procedures used for random-sequence generation, allocation concealment and outcome-assessor blinding were not clearly documented. Dienogest exposure varied from three to six months without reported criteria for determining treatment duration, and outcomes were not analyzed according to endometriosis stage. The embryo-grading system was incompletely described, while live birth, miscarriage, cumulative pregnancy, treatment adherence and adverse events were not reported. Furthermore, several primary outcomes were tested without a stated adjustment for multiple comparisons, increasing the possibility of chance-positive findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDienogest pretreatment before ICSI was associated with improved oocyte maturation, fertilization, embryo quality and early pregnancy outcomes but did not increase the total number of retrieved oocytes. The findings support further investigation rather than routine universal pretreatment. Larger multicentre randomized trials should use concealed allocation, blinded embryological assessment, a standardized dienogest duration and live birth as the primary outcome, together with systematic reporting of cumulative reproductive outcomes and treatment-related harms.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e \u003cp\u003e The study protocol was reviewed and approved by the Research Ethics Committee of the Faculty of Medicine, Cairo University, under approval code MD-70-2023, dated 10 August 2023. The study was conducted in accordance with the approved protocol and the ethical principles governing research involving human participants. Written informed consent was obtained from all participants before enrolment in the study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for Publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDr Ahmed Halwagi: protocol and study designDr Rasha El Komy: statitsctical analysis, setting randimzation, patient selection according to inclusion and exclusion criteriaDr Mohamed Gamal: data collectionDr Mona Sdeiek: data collection and revsionDr mariam Dawoud: mauscript writing and final revision\u003c/p\u003e\u003ch2\u003eAvailability of Data and Materials\u003c/h2\u003e \u003cp\u003eThe data generated and analyzed during the study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZondervan KT, Becker CM, Missmer SA (2020) Endometriosis N Engl J Med 382(13):1244\u0026ndash;1256\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBecker CM et al (2022) ESHRE guideline: endometriosis. Hum Reprod Open 2022(2):hoac009\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarder C et al (2024) Assessing the true prevalence of endometriosis: A narrative review of literature data. Int J Gynaecol Obstet 167(3):883\u0026ndash;900\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSzypłowska M, Tarkowski R, Kułak K (2023) The impact of endometriosis on depressive and anxiety symptoms and quality of life: a systematic review. Front Public Health 11:1230303\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee D et al (2020) Management of endometriosis-related infertility: Considerations and treatment options. Clin Exp Reprod Med 47(1):1\u0026ndash;11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimopoulou M et al (2021) Getting to Know Endometriosis-Related Infertility Better: A Review on How Endometriosis Affects Oocyte Quality and Embryo Development. Biomedicines, 9(3)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQu H et al (2022) The effect of endometriosis on IVF/ICSI and perinatal outcome: A systematic review and meta-analysis. J Gynecol Obstet Hum Reprod 51(9):102446\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMappa I et al (2024) The Effect of Endometriosis on In Vitro Fertilization Outcomes: A Systematic Review and Meta-Analysis. Healthc (Basel), 12(23).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeorgiou EX et al (2019) Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis. Cochrane Database Syst Rev, 2019(11).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiemma G et al (2025) Efficacy of hormone pre-treatment before ART to improve reproductive outcomes in infertile women with endometriosis: Network meta-analysis of randomized controlled trials. Int J Gynaecol Obstet 170(3):1001\u0026ndash;1013\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHopewell S et al (2025) CONSORT 2025 statement: updated guideline for reporting randomised trials. BMJ 389:e081123\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHopewell S et al (2025) CONSORT 2025 explanation and elaboration: updated guideline for reporting randomised trials. BMJ 389:e081124\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrganization WH (2021) \u003cem\u003eWHO laboratory manual for the examination and processing of human semen 6th edition\u003c/em\u003e ; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/publications/i/item/9789240030787/\u003c/span\u003e\u003cspan address=\"https://www.who.int/publications/i/item/9789240030787/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTamura H et al (2019) The clinical outcome of Dienogest treatment followed by in vitro fertilization and embryo transfer in infertile women with endometriosis. J Ovarian Res 12(1):123\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u003cem\u003eThe Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting.\u003c/em\u003e Hum Reprod, (2011) 26(6): pp. 1270-83\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZegers-Hochschild F et al (2017) The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod 32(9):1786\u0026ndash;1801\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarra F et al (2020) Pretreatment with dienogest in women with endometriosis undergoing IVF after a previous failed cycle. Reprod Biomed Online 41(5):859\u0026ndash;868\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhalifa E et al (2021) Role of suppression of endometriosis with progestins before IVF-ET: a non-inferiority randomized controlled trial. BMC Pregnancy Childbirth 21(1):264\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShao W, Li Y, Wang Y (2023) Impact of dienogest pretreatment on IVF-ET outcomes in patients with endometriosis: a systematic review and meta-analysis. J Ovarian Res 16(1):166\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi D et al (2026) Efficacy of different pretreatments in IVF outcomes in patients with endometriosis: A systematic review and network meta\u0026ndash;analysis. Sci Rep, 16(1)\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"middle-east-fertility-society-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mefj","sideBox":"Learn more about [High Temperature Corrosion of Materials](https://www.springer.com/journal/43043)","snPcode":"43043","submissionUrl":"https://submission.nature.com/new-submission/43043/3","title":"Middle East Fertility Society Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Endometriosis, Dienogest, Intracytoplasmic sperm injection, Infertility.","lastPublishedDoi":"10.21203/rs.3.rs-10691781/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-10691781/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEndometriosis-associated infertility may compromise oocyte competence, fertilization, embryo development, and implantation. Hormonal pretreatment with dienogest has been proposed to improve the reproductive environment before intracytoplasmic sperm injection (ICSI), although evidence remains inconsistent.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo evaluate the effect of dienogest pretreatment on embryological and pregnancy outcomes in women with endometriosis-associated infertility undergoing their first ICSI cycle.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis single-center, open-label, randomized controlled trial was conducted at Kasr Al-Ainy Hospital, Cairo University, between November 2023 and April 2025. It included 86 women aged 20\u0026ndash;40 years with endometriosis-associated infertility. Participants were allocated equally to dienogest pretreatment for 3\u0026ndash;6 months before ICSI or to direct ICSI without hormonal pretreatment. Both groups underwent the same long gonadotrophin-releasing hormone agonist stimulation protocol. Primary outcomes were the number of retrieved oocytes, fertilization rate, and number of good-quality embryos. Secondary outcomes were biochemical and clinical pregnancy rates.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eForty-three women were analyzed in each group, with comparable baseline demographic, hormonal, ovarian-reserve, and infertility characteristics. The mean number of retrieved oocytes did not differ significantly between groups (10.91\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06 versus 10.72\u0026thinsp;\u0026plusmn;\u0026thinsp;2.32; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.752). Dienogest pretreatment was associated with higher numbers of metaphase-II oocytes (7.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.16 versus 5.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), two-pronuclear oocytes (4.19\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44 versus 2.84\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), fertilization rates (56.88\u0026thinsp;\u0026plusmn;\u0026thinsp;10.42% versus 49.35\u0026thinsp;\u0026plusmn;\u0026thinsp;10.50%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and good-quality embryos (1.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.94 versus 1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011). Biochemical pregnancy (48.8% versus 27.9%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046) and clinical pregnancy (46.5% versus 23.3%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) were also higher with dienogest.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eDienogest pretreatment improved oocyte maturation, fertilization, embryo quality, and early pregnancy outcomes in women without increasing total oocyte yield.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e","manuscriptTitle":"Effect of Hormonal Pre-treatment of Endometriosis on ICSI Outcome: A randomized Controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-09-06 10:30:03","doi":"10.21203/rs.3.rs-10691781/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-08-31T13:32:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"154583734065838595639085046602750797941","date":"2026-08-31T09:14:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-08-30T10:36:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102185014207593892903068746222167489158","date":"2026-08-30T10:35:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-08-30T06:07:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"148405229084575338562487806488641192099","date":"2026-08-30T05:39:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-08-29T05:18:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192008496094817826092290950347247708250","date":"2026-08-28T10:31:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-08-28T08:51:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-08-22T09:06:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-08-14T12:30:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Middle East Fertility Society Journal","date":"2026-08-13T13:37:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"middle-east-fertility-society-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mefj","sideBox":"Learn more about [High Temperature Corrosion of Materials](https://www.springer.com/journal/43043)","snPcode":"43043","submissionUrl":"https://submission.nature.com/new-submission/43043/3","title":"Middle East Fertility Society Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2e27d80b-adaa-4dd6-aa36-3f46d8ac347c","owner":[],"postedDate":"September 6th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-08-31T13:32:04+00:00","index":18,"fulltext":""},{"type":"reviewerAgreed","content":"154583734065838595639085046602750797941","date":"2026-08-31T09:14:45+00:00","index":17,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-08-30T10:36:38+00:00","index":16,"fulltext":""},{"type":"reviewerAgreed","content":"102185014207593892903068746222167489158","date":"2026-08-30T10:35:44+00:00","index":15,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-08-30T06:07:23+00:00","index":14,"fulltext":""},{"type":"reviewerAgreed","content":"148405229084575338562487806488641192099","date":"2026-08-30T05:39:25+00:00","index":13,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-08-29T05:18:31+00:00","index":12,"fulltext":""},{"type":"reviewerAgreed","content":"192008496094817826092290950347247708250","date":"2026-08-28T10:31:54+00:00","index":11,"fulltext":""},{"type":"reviewersInvited","content":"5","date":"2026-08-28T08:51:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-08-22T09:06:21+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-09-06T10:30:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-09-06 10:30:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-10691781","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-10691781","identity":"rs-10691781","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}