Uterine fibroids are the most prevalent benign tumors among reproductive-aged women, affecting 70%–80% of this population. Uterine fibroids can cause symptoms such as heavy menstrual bleeding, pelvic pain, and infertility, making them the primary indication for hysterectomy [1, 2]. The conventional management of uterine fibroids involves pharmacological interventions (gonadotropin-releasing hormone agonists and selective progesterone receptor modulators) and surgical approaches encompassing minimally invasive techniques and laparotomy. Primary surgical options consist of total hysterectomy, which results in permanent fertility loss, and myomectomy requiring postoperative contraception for $\ge$6 months [3, 4, 5]. Recent advancements have introduced non-invasive modalities such as uterine artery embolization (UAE) and high-intensity focused ultrasound (HIFU) [6, 7]. Notably, HIFU was approved by the U.S. Food and Drug Administration (FDA) in 2004, and achieves thermal ablation of fibroids through focused ultrasound energy, offering advantages including shortened recovery periods, enhanced patient tolerance, and fertility preservation (recommended contraceptive duration: 3 months) [2, 8]. However, limitations remain in the clinical implementation of HIFU, including the anatomical positioning of fibroids, magnetic resonance imaging (MRI)-guidance costs, and interference from subcutaneous adipose tissue, which may prolong treatment duration and affect HIFU compliance [8, 9]. Thus, current investigations are exploring the pharmacological enhancement of HIFU efficacy, with the drug oxytocin demonstrating potential to improve thermal ablation efficiency by reducing perfusion [6, 10]. While a research report has shown that administering appropriate doses of oxytocin enhances the precision of ablation and reduces treatment duration, others have highlighted the potential risks of systemic adverse reactions associated with administering this medication [11]. Therefore, the therapeutic efficacy of oxytocin remains controversial, with inconsistent evidence regarding the reduction in fibroid volume and symptom alleviation [12]. Hence, this systematic review and meta-analysis aim to provide a comprehensive evaluation of the safety profile and therapeutic efficacy of oxytocin in HIFU procedures, to clarify the clinical utility of oxytocin, identify risk parameters, and inform evidence-based practice. Ultimately, resolving these uncertainties may significantly optimize treatment paradigms for uterine fibroids.

In HIFU treatment, the therapeutic efficacy is commonly quantified using the NPV%, which corresponds to the volume of tissue effectively ablated. NPV% denotes the ratio of the non-perfused volume after HIFU treatment relative to the original fibroid volume. This quantitative metric serves as a critical imaging biomarker for assessing the success of uterine fibroid ablation therapy [20, 21]. The meta-analysis showed a pooled MD of 13.31 in the NPV% between the oxytocin and control groups, with a 95% CI of 9.17–17.44. This result, combined with a low heterogeneity value (I² = 26.00%), indicates a consistent effect of oxytocin across the studies. The statistically significant improvement in NPV% underscores the enhanced thermal ablation efficiency associated with oxytocin administration. A higher NPV% correlates with increased tissue necrosis, improved clinical outcomes, and potential symptom relief, establishing this metric as a critical marker of treatment success in HIFU therapy [6, 15, 16]. Funaki et al. [22] noted that the efficacy of HIFU treatment for uterine fibroids is influenced by the vascularization and blood flow within the fibroids. Oxytocin enhances thermal efficiency by reducing blood perfusion, which is achieved through uterine smooth muscle contraction, ultimately decreasing vascular supply and mitigating the cooling effect of high blood flow [18, 22, 23]. This reduction in perfusion facilitates more effective energy deposition, as evidenced by the increased NPV% and reduced energy requirements observed in the analyzed studies. These physiological effects not only boost HIFU efficacy but also address a significant limitation related to outcome variability caused by fibroid vascularization [16].

Oxytocin not only increases the NPV% but also significantly shortens treatment duration and reduces procedural interruptions. These subsequent shorter treatment times improve patient comfort and facilitate greater efficiency in the utilization of MRI-guided HIFU systems, potentially reducing the overall cost of the procedure [15]. Studies consistently reported fewer instances of treatment discontinuation in the oxytocin group, likely due to decreased discomfort and improved ablation efficiency. However, there was notably no clear consensus in the studies on the timing and dosage of oxytocin use, which is related to the habits of clinical workers.

The safety profile of uterine stimulants used in HIFU treatments is well-established. Temporary side effects, such as mild nausea or dizziness, are typically self-limiting and easily managed [9]. Moreover, no severe or long-term adverse effects have been reported. These benefits make uterine stimulants a practical and effective adjunct to HIFU therapy, enhancing both efficacy and usability. Furthermore, the implementation of personalized treatment protocols based on factors such as fibroid vascularity—classified by the Funaki system [24]—has further improved treatment effectiveness, especially for challenging cases such as Funaki type 3 fibroids [9, 17]. These advancements highlight the importance of tailoring HIFU treatments to individual patient characteristics for optimal results.

In addition, advanced imaging techniques, especially a 3-Tesla (3T) MRI scanning system, markedly aid in the use of uterotonic agents, such as oxytocin, in magnetic resonance (MR)-guided HIFU treatment of uterine fibroids [6]. High-resolution imaging allows for detailed vascular analysis and accurate patient selection for uterotonic-enhanced MR-HIFU treatment [6, 25]. Dynamic contrast-enhanced MRI has also emerged as a robust predictor of treatment outcomes, evidenced by an improved NPV ratio with the use of uterotonic agents [9, 26]. These advancements underscore the critical role of imaging in maximizing the efficacy and safety of oxytocin-enhanced MR-HIFU for the treatment of uterine fibroids.

This systematic review and meta-analysis demonstrate that oxytocin significantly enhances the efficacy of HIFU treatment for uterine fibroids. Moreover, by improving the NPV%, reducing procedural duration, and decreasing treatment discontinuation rates, administering oxytocin serves as a valuable adjunctive approach to optimize this non-invasive therapy [19].

Furthermore, misoprostol, a uterotonic agent, has likewise been investigated as a treatment for uterine fibroids using MR-HIFU; Łoziński et al. [6, 10] highlighted distinct effects of misoprostol/diclofenac and oxytocin in enhancing MR-HIFU outcomes. The findings by Łoziński et al. [6, 10] showed that the misoprostol/diclofenac combination achieved a higher immediate NPV than the oxytocin group, reduced sonication time, and improved procedural efficiency. However, the misoprostol/diclofenac combination was associated with the lowest reduction in fibroid volume six months post-treatment. In contrast, oxytocin, although slightly less effective in achieving immediate NPV, resulted in the greater long-term reduction in fibroid volume, likely due to the sustained uterotonic effects of oxytocin. These findings suggest that misoprostol/diclofenac may optimize immediate procedural outcomes, whereas oxytocin may improve support for long-term fibroid regression. However, due to the limited number of studies on the application of misoprostol in MR-HIFU, the safety and efficacy of misoprostol require further clinical data for validation. Therefore, tailored pharmacological strategies could play a critical role in maximizing the efficacy of MR-HIFU treatment.

Despite the promising findings, the safety evaluation of uterotonics in HIFU therapy warrants cautious interpretation due to limitations in the current evidence. Most studies have primarily focused on short-term side effects, reporting mild and transient adverse events such as nausea or dizziness, which were self-limiting and manageable [9, 15]. However, the heterogeneity in adverse event reporting, including follow-up durations, limits a comprehensive risk assessment. Additionally, small sample sizes and limited patient diversity likely underestimate rare or delayed adverse events. Future research should standardize adverse event monitoring, include larger and more diverse cohorts, and extend follow-up periods to improve characterization of both acute and long-term safety profiles of uterotonics in HIFU therapy [9].

To our knowledge, this represents the first systematic review and meta-analysis to evaluate the safety and efficacy of oxytocin in HIFU therapy for uterine fibroids. By synthesizing existing evidence, this study highlights the potential of oxytocin to improve therapeutic outcomes, including enhanced thermal efficiency and NPV%. Nevertheless, several limitations must be acknowledged. The scarcity of available studies limits the analysis, as evidenced by the lack of randomized controlled trials (RCTs) and the reliance on retrospective or small-scale research. Heterogeneity in dosing, patient selection, and treatment protocols further limits the generalizability of the findings. There are no clear standards regarding the timing, mode, and dose of oxytocin administration. These gaps highlight the need for robust, prospective studies to confirm these results.

Future investigations should focus on optimizing the dosage and timing of oxytocin administration, as well as evaluating its effectiveness in specific patient subgroups, particularly those with highly vascularized fibroids. Advanced imaging techniques, such as perfusion-weighted MRI, can provide critical insights into real-time changes in fibroid vascularity during HIFU, paving the way for more personalized treatments [6]. Moreover, large-scale randomized trials with prolonged follow-ups are crucial for validating these findings and establishing robust clinical guidelines. Similarly, further trials are needed to assess the efficacy and safety of misoprostol in MR-HIFU, particularly its potential to enhance immediate procedural efficiency and support long-term fibroid regression.

Oxytocin significantly improves the efficacy of HIFU treatment for uterine fibroids by increasing NPV%, improving procedural efficiency, and maintaining a favorable safety profile. These findings provide a solid foundation for clinical application while underscoring the need for further research to optimize the use of HIFU and confirm its long-term benefits. Future studies should focus on determining the optimal dosage and administration protocols, as well as identifying specific patient subgroups that may derive the greatest benefit from this adjunctive treatment.

HIFU, high-intensity focused ultrasound; NPV%, non-perfused volume percentage; UAE, uterine artery embolization; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCTs, randomized controlled trials; MeSH, Medical Subject Headings; NOS, Newcastle-Ottawa scale; MD, mean difference; MRgFUS, Magnetic Resonance-guided Focused Ultrasound; n, number of samples; FDA, Food and Drug Administration; MRI, magnetic resonance imaging; 3T, 3-Tesla.

The data underlying this study are available in a public, open-access repository. Data can also be made available upon reasonable request. All relevant data have been included in the article or uploaded as supplementary information.

Study design: QQ, MC, YC. Literature search: QQ, MC, YW, LH. Statistical analysis: QQ, YW, AZ. All authors contributed to critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

We would like to express our gratitude to all those who helped us during the writing of this manuscript.

This research received no external funding.

The authors declare no conflict of interest.

During the preparation of this manuscript, the authors utilized ChatGPT-3.5 solely for grammar and language polishing. The authors thoroughly reviewed, edited, and revised the manuscript and take full responsibility for its content.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/CEOG40247.