Endometrial Preparation Strategies for Frozen Embryo Transfer in Women with Adenomyosis: A Systematic Review of Hormone Replacement Therapy, Gonadotropin-Releasing Hormone Agonist, and Oxytocin Antagonists

Adenomyosis is associated with impaired reproductive outcomes, including reduced implantation potential, lower pregnancy rates, and increased miscarriage risk. Despite the widespread use of frozen embryo transfer (FET), the optimal endometrial preparation strategy for women with adenomyosis remains uncertain. Purpose: This systematic review aimed to evaluate the effectiveness of different endometrial preparation strategies, including hormone replacement therapy (HRT), gonadotropin-releasing hormone agonist (GnRHa)-based protocols, and oxytocin receptor antagonist therapy, in women with adenomyosis undergoing FET.

A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Cochrane, Oxford, Scopus, and Wiley databases were searched until November 2024. Randomized controlled trials and comparative observational studies evaluating endometrial preparation strategies in women with adenomyosis undergoing FET were included. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool for randomized controlled trials and ROBINS-I for observational studies.

Seven studies were included, consisting of one randomized controlled trial and six observational cohort studies. The randomized trial found no significant differences in clinical pregnancy, chemical pregnancy, miscarriage, or live birth rates between HRT with GnRHa pretreatment and HRT alone. In contrast, several observational studies suggested that long-term GnRHa down-regulation combined with HRT may improve implantation, clinical pregnancy, ongoing pregnancy, and live birth outcomes, particularly in selected patients with more severe adenomyosis characteristics. Oxytocin receptor antagonist administration was associated with a lower early miscarriage rate.

GnRHa-based endometrial preparation, particularly long-term down-regulation, may provide potential benefits for selected women with adenomyosis undergoing FET, although randomized evidence remains inconclusive. Oxytocin receptor antagonist therapy may reduce early miscarriage risk, but further studies are required. Additional randomized controlled trials are needed to establish optimal GnRHa duration, patient selection criteria, and standardized treatment strategies.

adenomyosis, HRT, GNRH agonist down-regulation, GNRH agonist, oxytocin antagonist

Adenomyosis is a benign gynecological disorder characterized by the presence of endometrial glands and stroma within the myometrium, accompanied by reactive hyperplasia of surrounding smooth muscle cells. With an estimated incidence of 20–35% in various populations, this disorder affects a large percentage of women, particularly those who are in their reproductive years. The incidence of adenomyosis was 28.9 per 10,000 woman-years, or 1.03% overall. Advances in transvaginal ultrasound and magnetic resonance imaging have improved the diagnosis of adenomyosis without requiring surgical confirmation.1–3 Adenomyosis has been associated with unfavorable reproductive outcomes, particularly among women undergoing assisted reproductive technology (ART). Previous studies have demonstrated reduced implantation and pregnancy rates, lower live birth rates, and increased miscarriage risk among women with adenomyosis undergoing in vitro fertilization (IVF). These adverse outcomes are thought to be related to chronic inflammation, estrogen-dependent activity, impaired endometrial receptivity, and abnormal uterine contractility.4 Frozen embryo transfer (FET) provides flexibility in embryo transfer timing and allows controlled preparation of the endometrium. Hormone replacement therapy (HRT) is commonly used for FET cycles, while gonadotropin-releasing hormone agonist (GnRHa) pretreatment has been proposed as an adjunctive strategy in women with adenomyosis. GnRHa may improve the uterine environment by suppressing estrogen activity, reducing inflammation, inhibiting angiogenesis, and modulating adenomyosis-associated changes that may impair implantation.5 However, the clinical benefit of adding GnRHa to HRT remains uncertain, particularly regarding the optimal duration and patient selection. The use of FET has increased rapidly, yet the most optimal endometrial preparation protocol remains a subject of ongoing debate.6 Although several endometrial preparation strategies, including HRT, GnRHa-based protocols, and oxytocin receptor antagonist therapy, have been investigated in women with adenomyosis undergoing FET, the optimal approach remains uncertain. Existing studies have reported conflicting results, particularly regarding the additional benefit of GnRHa pretreatment and the role of adjunctive therapies. Differences in adenomyosis characteristics, treatment duration, and clinical protocols further limit the interpretation of current evidence. Therefore, a systematic evaluation of available studies is needed to clarify the effectiveness of these strategies. The aim of this systematic review was to assess the impact of different endometrial preparation strategies, including HRT, GnRHa-based protocols, and oxytocin receptor antagonist administration, on reproductive outcomes in women with adenomyosis undergoing FET, with particular focus on implantation rate, clinical pregnancy rate, live birth rate, miscarriage rate, and other pregnancy-related outcomes.

Study Design This systematic review was conducted to evaluate the effectiveness of different endometrial preparation strategies, including HRT, GnRHa-based protocols, and oxytocin receptor antagonist administration in women with adenomyosis undergoing FET. Search Strategy This systematic review was carried out based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) standards. Literature was searched from PubMed, Cochrane, Oxford, Scopus, and Wiley with the keywords “Hormone Replacement Therapy” OR “HRT” AND “Gnrh Agonist” OR “Gnrha” AND “Adenomyosis” as well as related MeSH synonyms until November 28, 2024. The search results and selection process are illustrated in Figure 1. | Figure 1 PRISMA flow diagram of study selection process. | Study Selection Process The selection of studies for this systematic review was conducted using strict inclusion and exclusion criteria. The inclusion criteria consisted of randomized controlled trials and comparative observational studies (prospective or retrospective cohort studies) involving women with adenomyosis undergoing FET. Eligible studies evaluated endometrial preparation strategies, including HRT, GnRHa pretreatment or down-regulation, and oxytocin receptor antagonist administration. Studies were required to report reproductive outcomes, including implantation rate, clinical pregnancy rate, live birth rate, miscarriage rate, or other pregnancy-related outcomes. Three independent reviewers screened titles and abstracts after removing duplicates. Full texts were assessed independently according to predefined eligibility criteria. Any disagreement was resolved through discussion with a fourth reviewer. Quality Assessment Risk of bias assessment was performed according to the study design. The Cochrane Risk of Bias 2 (RoB 2) tool was used to evaluate randomized controlled trials, assessing five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. For observational cohort studies, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool was applied. Furthermore, to incorporate the assessment of the certainty of evidence, we performed an evaluation using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The evaluation considered five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Data Analysis Data extraction was performed using a standardized data extraction form developed specifically for this systematic review. The extracted data included study characteristics, participant characteristics, intervention and comparator characteristics, and reproductive outcomes. For study characteristics, the following information was extracted: first author, country of study, and study design. Participant characteristics included sample size, adenomyosis diagnosis or eligibility criteria, baseline patient characteristics, and relevant clinical characteristics. Intervention-related data included the type of endometrial preparation strategy, including HRT, GnRHa pretreatment or down-regulation, and oxytocin receptor antagonist administration. Comparator groups, FET protocols, and treatment duration or GnRHa regimen details were also extracted when available. For reproductive outcomes, extracted data included clinical pregnancy rate, implantation rate, live birth rate, miscarriage rate, biochemical pregnancy rate, ongoing pregnancy rate, and other reported pregnancy or neonatal outcomes. Adjusted effect estimates, including odds ratios (ORs) and confidence intervals (CIs), were extracted when available. The extracted information was organized into evidence tables (Table 1 and Table 2) to facilitate qualitative synthesis and comparison across included studies. Due to heterogeneity among studies regarding participant characteristics, adenomyosis severity, endometrial preparation protocols, and reported outcomes, the extracted data were synthesized narratively rather than pooled quantitatively. | Table 1 Characteristics of Studies Included | | Table 2 Reproductive Outcomes of Included Studies |

The literature search identified 35 records. After screening and eligibility assessment, seven studies were included in the final systematic review, consisting of one randomized controlled trial and six observational cohort studies. The study characteristics and results of the studies can be seen in Table 1 and Table 2, respectively. Risk of bias assessment was performed separately according to study design. The randomized controlled trial was assessed using the Cochrane RoB 2 tool, whereas observational studies were assessed using ROBINS-I. The results of the risk of bias assessment are presented in Figure 2 (for RCT) and Figure 3 (for observational studies). Furthermore, the results of the certainty of evidence assessment using the GRADE approach have been incorporated and presented in Table 3 | Table 3 GRADE Assessment of Included Studies |

General Overview of Adenomyosis Adenomyosis is a benign condition characterized by the presence of basal endometrial glands and stroma in the myometrium, as well as reactive hyperplasia of the smooth muscle myometrial cells. Traditionally, the diagnosis was made through a histopathological study. With the advancement of magnetic resonance imaging (MRI) and high-quality transvaginal ultrasound (TVUS), the diagnosis can now be done with an accuracy of 80%-90% without requiring excisional surgery. Adenomyosis is related with an enlarged uterus, pelvic pain, heavy vaginal bleeding, and a lower quality of life. It has also been associated with worse obstetrical outcomes. A matched case-control research found that women with adenomyosis had a higher risk of preterm delivery and premature membrane rupture.4 Pathophysiology of Adenomyosis In women during their reproductive years, an imbalance between progesterone and estrogen signaling promotes adenomyosis. Because aromatase is highly expressed in adenomyotic lesions, there is a high local synthesis of estrogen and normal peripheral levels of estradiol. In fact, women with adenomyosis have also been found to have elevated levels of estradiol in their menstrual blood when compared to normal serum levels. Additionally, the eutopic endometrium of patients with adenomyosis has been revealed to have the aromatase cytochrome P450 gene polymorphism, which is linked to a high level of local estrogen production. Increased ER-beta expression in the myometrium of adenomyotic uteri is associated with polymorphisms of the estrogen receptor alpha (ERα) gene, which also contributes to myometrial hyperplasia. Additionally, because mRNA and 17bHSD2 activity are four to six times higher in adenomyosis, the modulation of 17b-hydroxysteroid dehydrogenase type 2 (an enzyme necessary for the deactivation of estradiol to estrone) in the eutopic endometrium of women with adenomyosis differs from that of women without the condition.13 It is possible that the enhanced anti-apoptotic activity of the basalis, which promotes the invagination process and the “spreading” of adenomyosis into the myometrium, is connected to the increased estrogen activity, which boosts the proliferative response and alters the expression of numerous other genes. The TIAR mechanism is stimulated by altered contractions, which leads to increased synthesis of estradiol. This creates a loop that causes the endometrial basalis to invade the myometrium and generate an adenomyotic lesion. The evidence that stromal cells of the functionalis and basalis endometrium of women with adenomyosis exhibit decreased immunoreactivity for isoform B of progesterone receptor (PR-B), resulting in a loss of progesterone effects, suggests that a decrease in progesterone activity is also responsible for the imbalance between estrogens and progesterone signaling. Because progesterone is unable to adequately counteract the proliferative effects of estrogen on the endometrium during the secretory phase of the cycle, aberrant endometrial development is strengthened.13 Mechanism of Action of HRT, GnRH Agonist, GnRH Agonist Down-Regulation, and Oxytocin Antagonist Hormone replacement therapy (HRT) is commonly used for endometrial preparation in frozen embryo transfer (FET) cycles by providing exogenous estrogen and progesterone to establish adequate endometrial proliferation and synchronization with embryo development. In women with adenomyosis, HRT may help overcome impaired endogenous hormonal regulation and allow controlled timing of embryo transfer; however, HRT alone does not directly suppress the inflammatory and estrogen-dependent abnormalities associated with adenomyotic lesions.6 GnRH agonists (GnRHa) act through initial stimulation followed by desensitization and down-regulation of pituitary GnRH receptors, resulting in suppression of gonadotropin secretion (FSH and LH) and subsequent reduction of ovarian estradiol production. This hypoestrogenic state may reduce adenomyosis-associated inflammatory activity, angiogenesis, and estrogen-dependent proliferation within adenomyotic tissue. Additionally, GnRHa pretreatment has been proposed to improve endometrial receptivity by modifying the abnormal uterine environment associated with adenomyosis.14 GnRH agonist (GnRHa) down-regulation works through continuous stimulation of pituitary GnRH receptors, followed by receptor desensitization and suppression of gonadotropin secretion. This process reduces circulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH), leading to a hypoestrogenic state. In adenomyosis, estrogen suppression may reduce estrogen-dependent proliferation, inflammation, angiogenesis, and abnormal myometrial remodeling. Prolonged GnRHa exposure may also promote regression of adenomyotic lesions, decrease uterine volume, and improve endometrial receptivity by reducing inflammatory mediators and restoring a more favorable uterine environment for implantation.15,16 Oxytocin receptor antagonists represent a different therapeutic approach by targeting abnormal uterine contractility associated with adenomyosis. Adenomyotic uteri demonstrate increased oxytocin receptor expression, which may contribute to excessive myometrial contractions, abnormal uterine peristalsis, and disruption of the endometrial–myometrial interface. By blocking oxytocin signaling, oxytocin antagonists such as atosiban may reduce uterine hypercontractility, improve embryo implantation conditions, and potentially decrease early pregnancy loss.14,17 Effectiveness of HRT, GnRH Agonist, and GnRH Agonist Down-Regulation The effectiveness of adding GnRHa to HRT remains controversial. The randomized controlled trial conducted by Moayed et al evaluated women with adenomyosis undergoing FET and compared HRT combined with GnRHa pretreatment versus HRT alone. The study found no significant differences between groups in clinical pregnancy rate, chemical pregnancy rate, miscarriage rate, or live birth rate, suggesting that GnRHa pretreatment may not provide additional reproductive benefits for all patients with adenomyosis. These findings indicate that routine administration of GnRHa before HRT should be interpreted cautiously, particularly in patients without severe adenomyosis-related abnormalities.5 Similarly, Li et al reported that GnRHa pretreatment before artificial FET cycles did not significantly improve clinical pregnancy rate or live birth rate compared with HRT alone. Clinical pregnancy rates and live birth rates were comparable between groups, indicating that the benefit of GnRHa may not be universal across all adenomyosis populations.7 In contrast, several observational studies have suggested that prolonged GnRHa suppression may provide additional benefits, particularly in patients with more advanced adenomyosis characteristics. Niu et al demonstrated that long-term pituitary down-regulation combined with HRT significantly improved clinical pregnancy, implantation, and ongoing pregnancy rates compared with HRT alone. In this study, the down-regulation plus HRT group achieved clinical pregnancy, implantation, and ongoing pregnancy rates of 51.35%, 32.56%, and 48.91%, respectively, compared with 24.83%, 16.07%, and 21.38% in the HRT-only group.12 Supporting these findings, Guo et al evaluated pregnancy and neonatal outcomes after pituitary down-regulation in adenomyosis patients undergoing IVF/ICSI followed by FET. Their retrospective cohort study investigated whether GnRH agonist treatment before frozen-thawed embryo transfer could improve reproductive outcomes in women with adenomyosis. The study reported favorable pregnancy outcomes among patients receiving pituitary down-regulation, supporting the potential role of prolonged GnRH agonist suppression in modifying the adenomyosis-associated uterine environment before embryo transfer.11 Wu et al further supported the potential benefit of long-term GnRHa administration by demonstrating improved implantation, clinical pregnancy, and live birth outcomes following long-term GnRHa pretreatment before FET.8 Zhang et al also reported that GnRHa pretreatment was associated with reduced miscarriage rates and increased live birth rates in adenomyosis patients with uterine volume between 56 and 100 cm3, although clinical pregnancy rates were not significantly improved.9 The discrepancy between randomized and observational evidence may be explained by differences in patient selection, adenomyosis severity, uterine volume, and GnRHa treatment duration. Patients with more severe disease may benefit more from prolonged suppression because GnRHa may reduce local inflammation, estrogen-dependent activity, abnormal angiogenesis, and uterine hypercontractility. Therefore, GnRHa-based preparation should likely be considered as an individualized strategy rather than a universal approach for all women with adenomyosis undergoing FET. The Role of Oxytocin Receptor Antagonist in Reducing Miscarriage Risk Adenomyosis is associated with impaired uterine function, including increased myometrial contractility and abnormal uterine peristalsis, which may interfere with embryo implantation and early pregnancy maintenance. Oxytocin receptor antagonists, such as atosiban, have been investigated as an adjunctive therapy aimed at reducing uterine contractions during the peri-implantation period. Among the included studies, only Lin et al evaluated the effect of atosiban administration in women with adenomyosis undergoing FET. In this propensity score-matched cohort study, atosiban administration was associated with a significantly lower early miscarriage rate compared with the control group (8.1% vs 21.5%, p = 0.015). Multivariate analysis further demonstrated that atosiban use was independently associated with reduced early miscarriage risk (adjusted OR 0.32; 95% CI 0.11–0.95).10 Interestingly, atosiban did not significantly improve overall clinical pregnancy, ongoing pregnancy, or live birth rates in the general population. However, subgroup analyses suggested potential benefits among specific patient groups, including women aged ≥37 years, those with secondary infertility, day-3 embryo transfer cycles, and patients with diffuse adenomyosis. These findings indicate that atosiban may primarily influence pregnancy maintenance rather than embryo implantation itself by reducing excessive uterine contractility during early gestation.10 Heterogeneity of GnRH Agonist Protocols and Optimal Duration The included studies demonstrated substantial heterogeneity in GnRHa protocols, particularly regarding treatment duration, timing before FET, and down-regulation strategies. Although GnRHa is proposed to improve reproductive outcomes by suppressing adenomyosis-associated inflammation, estrogen activity, and abnormal uterine contractility, the optimal protocol and duration remain unclear. The randomized controlled trial by Moayed et al evaluated three-month GnRHa pretreatment combined with HRT and found no significant improvement in clinical pregnancy, chemical pregnancy, miscarriage, or live birth rates compared with HRT alone.5 In contrast, observational studies suggested potential benefits of prolonged GnRHa suppression. Niu et al reported higher clinical pregnancy, implantation, and ongoing pregnancy rates with long-term GnRHa down-regulation combined with HRT compared with HRT alone.12 Similarly, Guo et al and Wu et al demonstrated favorable pregnancy outcomes following pituitary down-regulation or long-term GnRHa pretreatment before FET.8,11 However, differences in adenomyosis severity, uterine characteristics, and patient selection may contribute to the inconsistent findings. Zhang et al suggested that GnRHa pretreatment may be more beneficial in specific populations, such as women with enlarged uterine volume, by reducing miscarriage risk and improving live birth outcomes.9 Therefore, current evidence does not support a universal GnRHa protocol, and prolonged suppression should be considered as an individualized strategy based on disease characteristics and previous reproductive outcomes. Advantages and Disadvantages This systematic review has several strengths. First, this review provides a comprehensive evaluation of different endometrial preparation strategies, including HRT, GnRH agonist pretreatment/down-regulation, and oxytocin receptor antagonist administration in women with adenomyosis undergoing FET. By including both randomized controlled trial and observational studies, this review provides a broader assessment of intervention effectiveness while considering different levels of evidence. Second, the included studies specifically focused on women with adenomyosis undergoing FET, reducing heterogeneity associated with mixed infertility populations. The review also evaluated clinically relevant reproductive outcomes, including implantation rate, clinical pregnancy rate, live birth rate, and miscarriage rate, which are important indicators of treatment effectiveness. Third, the inclusion of a randomized controlled trial assessed using the Cochrane RoB 2 tool alongside observational studies assessed using ROBINS-I allowed a more comprehensive evaluation of evidence quality according to study design. However, several limitations should be considered. First, although one randomized controlled trial was included, most available evidence was derived from observational cohort studies, which remain susceptible to selection bias, confounding factors, and limitations in establishing causal relationships. Differences in baseline patient characteristics, adenomyosis severity, uterine volume, embryo quality, and ART protocols may have influenced the reported outcomes. Second, substantial clinical heterogeneity existed among GnRH agonist protocols, particularly regarding treatment duration, dosage, and timing before FET. Variations between short-term pretreatment, long-term suppression, and pituitary down-regulation strategies limited direct comparison between studies and prevented determination of the optimal GnRHa regimen. Third, the diagnostic criteria and severity classification of adenomyosis varied among studies, including differences in uterine volume, disease distribution, and concomitant gynecological conditions, which may affect treatment response and limit generalizability. Finally, evidence regarding oxytocin receptor antagonist therapy remains limited because only one included study evaluated atosiban administration. Although atosiban was associated with reduced early miscarriage rates, further prospective studies are required to confirm its effectiveness and identify the patient populations most likely to benefit. In addition, most included studies originated from China, which may limit the external validity of findings across different populations.

GnRH agonist-based endometrial preparation, particularly long-term down-regulation combined with HRT, may provide potential benefits for selected women with adenomyosis undergoing frozen embryo transfer. However, randomized evidence has not demonstrated a consistent improvement in reproductive outcomes compared with HRT alone. Oxytocin receptor antagonist therapy may reduce early miscarriage risk, although current evidence remains limited. Further well-designed randomized controlled trials are needed to determine the optimal GnRHa protocol, treatment duration, and patient selection criteria.

This publication charge was funded by Universitas Padjadjaran through the Indonesian Endowment Fund for Education (LPDP) on behalf of the Indonesian Ministry of Higher Education, Science, and Technology and managed under the EQUITY Program (Contract No. 4030/B3/DT.03.08/2025 and 3927/UN6.RKT/HK.07.00/2025). Author Contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Funding There is no funding to report. Disclosure The author(s) report no conflicts of interest in this work.

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