{"paper_id":"98fea519-7abe-40b7-8639-7bc5d5860b4c","body_text":"Abstract\nObjective\nTo compare the efficacy of different COH protocols on pregnancy outcomes in adenomyosis patients.\nStudy design\nA real-world retrospective cohort study analyzed 1486 IVF-ET cycles in adenomyosis patients who received COH regimens between 2018 and 2021. Pregnancy outcomes were compared among patients under different COH protocols.\nResults\nThe short-acting long protocol achieved the highest live birth (47.92%) and cumulative clinical pregnancy (68.84%) rates. The antagonist protocol showed lower fresh-cycle pregnancy (36.63% vs. 52.10%, p = 0.036), live birth (21.78% vs. 36.55%, p = 0.009), and cumulative clinical pregnancy rates (39.31% vs. 53.29%, p < 0.001) compared to the long/ultra-long protocol. Multivariable logistic regression confirmed that the COH protocol was an independent predictor of both clinical pregnancy (Wald χ² = 8.127, p = 0.043) and cumulative clinical pregnancy (Wald χ² = 40.344, p < 0.001). In patients <35 years with a normal ovarian reserve (anti-Müllerian hormone ≥ 1.2 ng/mL), live birth rates and cumulative clinical pregnancy rates were similar between the antagonist protocol and long/ultra-long protocols (27.59% vs. 44.94%, p = 0.098; 63.83% vs. 63.87%, p = 0.995), with significantly less gonadotropin used in the antagonist protocol.\nConclusions\nIn adenomyosis patients, the long/ultra-long provided better fresh-cycle outcomes. While the antagonist protocol had lower overall pregnancy rates, it preserved cumulative pregnancy rates in young patients with normal ovarian reserves and reduced gonadotropin exposure.\nIntroduction\nAdenomyosis, which is characterized by endometrial gland invasion into the uterine myometrium and subsequent hyperplasia and fibrosis development [Citation1,Citation2], affects 20%–30% of infertile women [Citation3,Citation4]. Although the causal relationship between adenomyosis and infertility remains incompletely defined, existing evidence shows that adenomyosis could compromise fertility potential in women of reproductive age [Citation5–7]. Assisted reproductive technology (ART) has been developed to treat women with infertility. However, compared to women with no adenomyosis, adenomyosis women have significantly reduced clinical pregnancy and live birth rates, as well as increased miscarriage risk, during in vitro fertilization-embryo transfer (IVF-ET) [Citation8,Citation9]. Pretreatment with gonadotropin-releasing hormone (GnRH) agonists or antagonists and the use of frozen embryo transfer might achieve pregnancy outcomes, but the optimal regimen remains unknown in adenomyosis patients [Citation10,Citation11].\nAt present, there are different protocols (such as the ultra-long, long, short, microstimulation, and antagonist protocols) for controlled ovarian hyperstimulation (COH) in women during IVF-ET. The ultra-long protocol can yield higher implantation and pregnancy outcomes, when compared to other protocols, but prolonged GnRH agonist pretreatment (over two months) might risk a low response or premature menopause in ovarian reserve-deficient adenomyosis patients [Citation12]. With the development of cryopreservation techniques, shorter protocols (e.g. antagonist) followed by frozen-thawed transfer have become a preferred choice. Furthermore, the GnRH antagonist protocol has been used with the potential advantages of short treatment duration, reduced gonadotropin requirements, and a significantly lower risk of ovarian hyperstimulation syndrome [Citation13]. However, it remains unknown whether the antagonist protocol without downregulation would impact the pregnancy and cumulative pregnancy rates in adenomyosis patients.\nTherefore, the investigators aimed to evaluate the ovarian response, embryonic characteristics, and clinical pregnancy outcomes associated with different COH protocols in adenomyosis patients across various age groups and ovarian reserve statuses. The present study aims to identify the most suitable COH protocol for adenomyosis patients under different clinical scenarios to offer evidence-based insights to optimize infertility treatment strategies in this population.\nMaterials and methods\nStudy design and participant selection\nThe present retrospective cohort study was conducted with adenomyosis patients who underwent IVF-ET treatment at the First Affiliated Hospital, Sun Yat-sen University, China, between January 2018 and February 2021. The hospital institutional review board approved the present study (Approval no. [2023]500). The research was performed in accordance with the principles stated in the Declaration of Helsinki. The informed consent was waived because of the retrospective design of the study.\nAdenomyosis patients between 20 and 45 years old, who received IVF-ET, were selected. Adenomyosis was determined based on the transvaginal ultrasound (TVUS) examination results, which included heterogeneous myometrium, myometrial cysts, asymmetric wall thickening ≥12 mm, or junctional zone ≥8 mm [Citation3]. Patients with incomplete medical records were excluded.\nThe selection of COH protocols was based on patient characteristics and clinical judgment at the discretion of the treating physician. In general, the long/ultra-long protocol was preferred for patients with severe adenomyosis or those requiring downregulation, while the antagonist protocol was often chosen for patients with a normal ovarian reserve to reduce treatment duration and gonadotropin exposure. The short-acting long protocol was typically used for patients with satisfactory ovarian reserve who might benefit from a less intensive stimulation regimen.\nCOH protocols\nLong/Ultra-long protocol: mid-luteal or early-follicular GnRH agonist (0.375–3.750 mg) followed by gonadotropins (human menopausal gonadotropin/recombinant follicle-stimulating hormone 125–300 IU/day) after pituitary suppression (serum estradiol < 50 pg/mL).\nAntagonist protocol: gonadotropins (day 2–3) with the GnRH antagonist (0.25 mg/day ganirelix/cetrorelix) was initiated when the lead follicle reached ≥12 mm.\nShort-acting long protocol: mid-luteal GnRH agonist (0.10–0.05 mg) followed by gonadotropins.\nOther protocols: microstimulation, natural cycle, or gonadotropins-only cycle.\nThe trigger was completed by hCG 10,000 IU or Ovitrelle 250 μg when ≥2 follicles reached ≥18 mm.\nEmbryology and transfer\nFertilization, embryo grading (day 3: 6–8 cells, grade 1–2 = top-quality), and transfer (fresh: day 3/5; frozen embryo transfer following hormone replacement therapy, natural cycle therapy, or ovulation induction therapy) were performed based on the American Society of Reproductive Medicine guidelines.\nOutcomes\nThe primary outcomes included the clinical pregnancy and cumulative clinical pregnancy rates (gestational sac on TVUS). The secondary outcomes included miscarriage, oocyte yield, embryo quality, and gonadotropin dosage. All the information was retrieved from the medical record review.\nThe live birth rate is affected by abortion in the second and third trimesters of pregnancy, and there are many factors affecting abortion in the second and third trimesters, such as fetal malformation, intrauterine infection, etc., which are not necessarily related to the use of IVF or adenomyosis. Therefore, this study used the clinical pregnancy rate and cumulative clinical pregnancy rate as the primary outcomes.\nStatistical analysis\nAll analyses were conducted using SPSS 27.0 (IBM, USA). Continuous variables were tested for normality, presented as the mean ± standard deviation or median (interquartile range), and compared using analysis of variance (ANOVA) or the Kruskal‒Wallis test, when appropriate. Categorical variables are presented in frequencies with percentages and were compared by Chi-square or Fisher's exact test. Subgroup analyses by age (<35 or ≥35 years) and ovarian reserve status (anti-Müllerian hormone [AMH] < 1.2 or ≥1.2 ng/mL) were also conducted.\nIn order to control for potential confounding factors, multivariable logistic regression analyses were performed to identify independent predictors for clinical pregnancy and cumulative clinical pregnancy. The following covariates were included in the regression models: COH protocol (categorical, with the antagonist as the reference), female age, duration of infertility, infertility type (primary/secondary), basal follicle-stimulating hormone (FSH), antral follicle count (AFC), body mass index (BMI), and stage of embryo transfer. Model fit was assessed using the Hosmer‒Lemeshow goodness-of-fit test. The Nagelkerke R2 was calculated to estimate the proportion of variance explained by the models.\nA p-value of <0.05 was considered statistically significant.\nResults\nParticipant characteristics\nA total of 1486 in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles in adenomyosis patients were analyzed for the present study. The baseline characteristics significantly varied across protocols (p < 0.001, ). Patients who received the short-acting long protocol were the youngest, with the highest AMH (3.67 ± 2.16 ng/mL) and AFC (11.99 ± 4.95) values. Patients who underwent other protocols were the oldest, with the poorest ovarian reserve (AMH 0.85 ± 1.77 ng/mL, AFC 3.56 ± 2.90).\nClinical outcomes\nThe short-acting long protocol yielded the highest usable embryos (5.12 ± 3.39), live birth rate (47.9%), and cumulative pregnancy rate (68.8%). The antagonist protocol yielded lower fresh-cycle clinical pregnancy rates (36.63% vs. 52.10%, p = 0.036), live birth rates (21.8% vs. 36.6%, p = 0.009), and cumulative clinical pregnancy rates (39.31% vs. 53.29%, p < 0.001), when compared to the long/ultra-long protocol ().\nSubgroup analysis\nSubgroup analyses were further performed for patients in different age and AMH level groups.\nFor patients <35 years old, with AMH ≥ 1.2 ng/mL (n = 332), the cumulative clinical pregnancy rates were similar between the antagonist (63.83%) and long/ultra-long (63.87%) COH protocols (p = 0.995), with lower gonadotropin use in the antagonist protocol (2,228.72 ± 839.52 vs. 2,923.11 ± 795.16 IU in the antagonist and long/ultra-long protocol, respectively, p < 0.001) ().\nFor patients ≥35 years old, with AMH ≥ 1.2 ng/mL (n = 159), the cumulative pregnancy rates favored the long/ultra-long protocol (47.17% vs. 23.53%, p = 0.006) ().\nFor patients with AMH < 1.2 ng/mL, the live birth and cumulative pregnancy rates were comparable across protocols, regardless of age ().\nInfluence of different GnRH agonist doses on pregnancy outcomes\nThe patient outcomes were analyzed based on different GnRH agonist doses (Supplementary Table 1). The highest clinical pregnancy rates and live birth rates were observed in patients who were administered the middle-range dose of 1.3–1.8 mg GnRHa, with similar cumulative clinical pregnancy rates. However, either too low or too high dose of GnRHa led to decreased live birth and cumulative clinical pregnancy rates. (Supplementary Table 1).\nMultivariable logistic regression analysis\nMultivariable logistic regression analysis identified the COH protocol as an independent predictor of both clinical pregnancy (Wald χ² = 8.127, p = 0.043) and cumulative clinical pregnancy (Wald χ² = 40.344, p < 0.001), with both models showing good fit. Compared to the antagonist protocol, the long/ultra-long protocol showed significantly higher odds of clinical pregnancy (OR: 1.888, 95% CI: 1.157–3.082, p = 0.011) and cumulative clinical pregnancy (OR: 1.495, 95% CI: 1.140–1.961, p = 0.004). The short-acting long protocol also demonstrated higher odds for cumulative clinical pregnancy (OR: 2.227, 95% CI: 1.418–3.498, p = 0.001). Female age (OR: 0.939, p = 0.031) and basal FSH (OR: 0.912, p = 0.042) were negatively associated with clinical pregnancy, while age (OR: 0.899, p < 0.001), infertility duration (OR: 0.933, p = 0.005), basal FSH (OR: 0.919, p < 0.001), and AFC (OR: 1.054, p < 0.001) were independent predictors of cumulative clinical pregnancy (Supplementary Tables 2 and 3).\nDiscussion\nAdenomyosis significantly impaired fertility potential. The present study expanded the present understanding by evaluating the COH protocol outcomes, not only across standard clinical characteristics, but also stratified by age and ovarian reserve status in adenomyosis patients. The present results indicated that the long/ultra-long regimen was the most commonly used COH protocol in the present adenomyosis patients. The antagonist protocol yielded the lowest live birth and cumulative clinical pregnancy rates in the overall patients analyzed, but preserved the cumulative pregnancy rate in young adenomyosis patients with a normal ovarian reserve, while reducing gonadotropin exposure.\nAdenomyosis refers to a uterine disorder with ectopic endometrial tissue within the myometrium, leading to impaired endometrial receptivity, altered hormone signaling, and increased inflammation. All of these can cause reduced embryo implantation, high pregnancy failure, low live birth, and frequent miscarriage in affected women undergoing ART treatments [Citation14]. Various COH protocols have been reported to improve successful pregnancy in these patients, with the best pretreatment regimen before ART is still under investigation.\nDuring IVF-ET, COH protocols use exogenous gonadotropin hormone to stimulate the ovaries to develop many follicles, thereby increasing the number of oocytes for retrieval and fertilization. This is a critical step to maximize embryos available for improved overall pregnancy outcomes. In COH, long- or short-acting GnRH agonist or antagonist protocols are applied to prevent premature ovulation or trigger final oocyte maturation. Several recent studies have suggested that long and ultra-long GnRH agonist regimens can achieve improved live birth rates and cumulative clinical pregnancy rates when compared with other regimens in adenomyosis patients [Citation10,15–17]. A recent systematic review and meta-analysis conducted by Latif et al. revealed that prolonged downregulation with GnRHa treatment in adenomyosis women undergoing IVF/ICSI is associated with improved clinical outcomes [Citation12]. Similarly, the systematic review and meta-analysis conducted by Ge et al. revealed that the ultra-long protocol is superior to the antagonist protocol in adenomyosis women undergoing IVF/ICSI [Citation18]. These findings are consistent with the present results, showing better IVF outcomes with the long/ultra-long protocol in the overall population.\nIn the present study, most of the adenomyosis patients (44.95%) received the long/ultra-long agonist COH protocol, which is consistent with previous reports [Citation15–18]. However, the long/ultra-long regimen typically involves GnRH administration for up to four months to reduce adenomyosis-related inflammation before ovarian stimulation. The long period of medication injection can certainly increase medical expenses and the risk of low patient compliance, and cause excessive anxiety. Meanwhile, a successful COH protocol with an improved pregnancy rate can reduce further IVF-ET cycles to achieve live birth, potentially offsetting high expenses with the prolonged COH regimen administration. Furthermore, the present study revealed that the antagonist protocol required a lower total dose of gonadotropin, when compared to the long/ultra-long protocol, implying a lower total expense for infertility treatment. However, there is no prior cost-effectiveness study that has directly compared different COH protocols in patients with adenomyosis. Thus, further research is required to clarify whether the improved outcomes with the long/ultra-long COH protocol can justify the potential increase in costs and longer treatment duration.\nVarious outcomes have been applied to evaluate the successful performance of COH and IVF-ET protocols [Citation19]. Historically, the cumulative clinical pregnancy rate has been commonly used for primary outcome evaluations in IVF-ET research. However, using the live birth rate has become an increasing trend, since live birth is the ultimate goal of IVF, and the outcome of greatest importance to patients [Citation20,Citation21]. Clinical pregnancy does not guarantee a live birth, since it does not account for pregnancy losses after detecting a fetal heartbeat. The present study used both live birth rates and cumulative clinical pregnancy rates as the primary outcomes to evaluate different COH protocols. The present analyses revealed that the short-acting long COH protocol achieved the highest live birth rate (47.9%) and cumulative clinical pregnancy rate (68.8%).\nThe short-acting long COH protocol administers the GnRH agonist in the middle luteal phase to cause an initial flare-up of endogenous gonadotropins, with subsequent pituitary suppression, which is followed by gonadotropin stimulation to drive follicular growth. Compared with the long protocol, the short-acting long COH protocol takes to daily flare-up effects, with relatively mild suppression of the pituitary gland by daily injection. However, it has been reported that the short-acting long COH protocol can yield fewer oocytes and lower successful pregnancy rates, when compared with the long protocol [Citation22,Citation23]. In the present study, it was found that both the highest live birth rate and the highest cumulative clinical pregnancy rate were observed in adenomyosis patients under the short-acting long-protocol treatment. This finding might indicate that adenomyosis patients can benefit better with a less intensive COH protocol, such as the short-acting long regimen. Alternatively, the possible influences of other factors cannot be ruled out. For example, patients who received the short-acting long protocol were the youngest with the highest AMH (3.67 ± 2.16 ng/mL) and AFC (11.99 ± 4.95) values, which could certainly contribute to their best live birth and pregnancy outcomes. Given the significant baseline differences between the protocol groups, with patients in the short-acting long protocol being younger and having better ovarian reserve, the observed superior outcomes in this group might reflect patient selection rather than a true treatment effect. Therefore, these findings should be interpreted with caution. The conclusion that the short-acting long protocol yielded the best outcomes might be confounded by these baseline differences. Further prospective clinical trials may better compare these different long COH protocols in adenomyosis patients.\nPrevious studies have reported inconsistent results when comparing between COH antagonist and long agonist protocols during IVF-ET. A recent Cochrane review conducted by Siristatidis et al. examined the GnRH agonist protocols for pituitary suppression in assisted reproduction and revealed that the long protocol might improve clinical pregnancy rates, when compared to the antagonist protocol [Citation24]. In addition, the meta-analysis conducted by Liu C et al. suggested that the GnRH-ant protocol is comparable with the long GnRH-a protocol, when considering live birth as the primary outcome [Citation25]. However, other studies have favored the antagonist protocol, with less ovarian hyperstimulation syndrome, shorter and less burdensome medication administration, and comparable pregnancy outcomes with a long protocol [Citation26,Citation27].\nA recent retrospective study conducted by Li X et al. suggested that the long GnRH agonist protocol is associated with higher pregnancy rates, when compared to the non-GnRHa pre-treatment protocol in adenomyosis patients [Citation10]. This finding is consistent with the present findings, showing inferior outcomes with the antagonist protocol in the overall adenomyosis population. The low pregnancy outcomes in the antagonist group might have stemmed from the compromised endometrial receptivity associated with antagonist regimens, as evidenced by the endometriosis-related inflammation models [Citation15,Citation28]. The investigators did not find any previous study that directly compared pregnancy outcomes with the antagonist protocol vs. long agonist protocol, specifically in adenomyosis patients. Future studies are needed to examine the pregnancy efficacy and safety profiles between two distinct protocols in the adenomyosis patient population.\nIn women undergoing COH protocols during IVF-ET, age can determine both the oocyte quantity and quality and is a strong predictor of live birth [Citation29]. The serum AMH level is the most direct biomarker for the ovarian reserve and can predict the number of oocytes retrieved and response to stimulation [Citation30]. The present study performed subgroup analyses and compared the pregnancy outcomes among different COH protocols in adenomyosis patients in different age and AMH groups. It was found that the live birth rate was similar between the antagonist and long/ultra-long COH protocols across different age and AMH groups, while the cumulative clinical pregnancy rate was better in the long/ultra-long protocol, when compared to the antagonist protocol in adenomyosis patients ≥35 years old, with AMH ≥ 1.2 ng/mL. This finding also supports the general recommendation that the COH protocol is not a one-size-fits-all approach. That is, this should be selected based on patient characteristics, which include ovarian reserve, age, and potential side effects, including ovarian hyperstimulation syndrome, especially in advanced-aged patients with diminished ovarian reserve [Citation31,Citation32]. For adenomyosis patients, a freeze-all strategy with a subsequent frozen embryo transfer can be an optimal strategy [Citation18]. This finding is consistent with the present observation of the investigators on inferior fresh-cycle outcomes in non-ultra-long protocols.\nThe impacts of GnRH doses on the outcomes of COH protocols with IVF-ET were also examined. It was found that too low or too high doses of GnRH led to diminished live birth and cumulative clinical pregnancy, when compared to moderate doses of GnRH. This finding is consistent with the reports of previous studies, suggesting that excessive small doses of GnRH can cause insufficient pituitary suppression, leading to impaired oocyte recovery and cycle cancellation, while high GnRH doses can reduce endometrial receptivity and the embryo implantation rate, with a low rate of successful pregnancy outcomes [Citation24,Citation33]. For patients with advanced adenomyosis, the dose of GnRH should be optimized to improve endometrial receptivity through morphological and biochemical modulation for satisfactory pregnancy outcomes. Unfortunately, owing to the small sample size and unadjusted confounders (e.g. adenomyosis severity and age) in the present retrospective study, the investigators were not able to examine and identify the optimal dose for adenomyosis patients with different characteristics and different COH protocols.\nThe key strengths of the present study include the large cohort size and comprehensive age/ovarian reserve stratification. The limitations include the retrospective study design, single-center research absence of CA125 levels, the lack of standardized uterine volume/junctional zone measurements, and heterogeneous adenomyosis subtyping (diffuse vs. focal). All these factors can be potential confounders that might introduce bias to the present analysis. In addition, the database used for the present study did not include systematic symptomatology assessment (such as dysmenorrhea severity or menorrhagia scores), which might be relevant to disease severity and treatment outcomes. Furthermore, the single-center nature of the present study could have limited the generalizability of the present research results, warranting future multi-center validation studies to confirm the present findings in diverse clinical settings. Moreover, cost-effectiveness analyses or time-to-pregnancy assessments were not performed, which would have been valuable during the clinical decision-making.\nConclusions\nIn adenomyosis patients, the short-acting long COH protocol can yield the highest live birth and cumulative clinical pregnancy rates. The long/ultra-long regimen was the most commonly used COH protocol with better fresh-cycle outcomes, when compared to the antagonist protocol. Although the antagonist protocol demonstrated the lowest live birth and cumulative clinical pregnancy rates in the overall analysis, this preserved the cumulative pregnancy rate in young adenomyosis patients with a normal ovarian reserve while reducing gonadotropin exposure during IVF-ET.\nEthics approval and consent to participate\nThe institutional ethical board of the First Affiliated Hospital of Sun Yat-sen University approved the study. The informed consent was waived due to the study retrospective design.\nAbbreviations\n| AFC | = | antral follicle count |\n| ART | = | assisted reproductive technology |\n| COH | = | controlled ovarian hyperstimulation |\n| GnRH | = | gonadotropin-releasing hormone |\n| ICSI | = | intracytoplasmic sperm injection |\n| IVF-ET | = | in vitro fertilization-embryo transfer |\nSupplemental material\nSupplementary_materials.docx\nDownload MS Word (23 KB)Supplementary_materials.docxSTROBE guidelines.docx\nDownload MS Word (19.1 KB)STROBE guidelines.docxAcknowledgements\nNone.\nZengyan Wang analyzed the data and drafted the manuscript. Jingdi Yang and Chuan Huang collected the data. Yanwen Xu proposed the research idea and revised the manuscript. All authors approved the final version of the manuscript.\nDisclosure statement\nNo potential conflict of interest was reported by the author(s).\nFunding\nNo funding was received for this work.\nData availability statement\nThe data underlying this article can be shared upon reasonable request to the first author.\nSupplemental Material\nSupplemental data for this article can be accessed at https://doi.org/10.1080/09513590.2026.2668866.\nReferences\n- Becker CM, Bokor A, Heikinheimo O, et al. ESHRE endometriosis guideline group. Eshre guideline: endometriosis. Hum Reprod Open. 2022 Feb 26;2022(2):hoac009. doi: 10.1093/hropen/hoac009\n- Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. Brit Med J. 2022 Nov 14;379:e070750. doi: 10.1136/bmj-2022-070750\n- Alson S, Jokubkiene L, Henic E, et al. Prevalence of adenomyosis features in women scheduled for assisted reproductive treatment, using the morphological uterus sonographic assessment group definitions. 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