Evaluation of the therapeutic efficacy of high-intensity focused ultrasound ablation combined with different drugs in the treatment of adenomyosis

Objectives To observe the therapeutic efficacy of high-intensity focused ultrasound (HIFU) combined with different pharmacological treatments for adenomyosis.

A total of 126 patients with adenomyosis who underwent HIFU combined with pharmacological treatment were retrospectively reviewed. Patients were treated with either dienogest (DNG) (Group A, N = 38) or GnRH-a (Group B, N = 88) for three months after HIFU, and received levonorgestrel-releasing intrauterine systems (LNG-IUS) at the end of the third month. Visual Analog Scale (VAS) and Pictorial Blood Loss Assessment Chart (PBAC) scores were used for evaluating symptom improvement.

After propensity score matching (1:2), 38 patients were included in Group A and 76 in Group B. All patients showed significant improvement in VAS and PBAC scores after HIFU, but the PBAC score of Group A was significantly higher than that of patients in Group B at 18 months [11.50 (1.00, 29.50) vs. 0.00 (0.00, 16.50), p < 0.01] and 24 months [4.00 (0.25, 27.75) vs. 0.00 (0.00, 12.75), p = 0.04] after HIFU. Furthermore, patients in Group B had a greater uterine volume reduction at 24 months after HIFU than that of patients in Group A [51.00 (27.00, 62.00) vs. 30.00 (17.00, 42.75, p = 0.02)]. However, the adverse effects in Group A were lower than those in Group B [7 (15.79) vs. 35 (46.05), p < 0.01]. No significant difference was observed in the recurrence rate between the two groups.

HIFU combined with DNG and LNG-IUS is a safe and effective treatment for patients with adenomyosis.

Adenomyosis is characterized by the active infiltration of endometrial tissue into the myometrium of the uterus, resulting in the formation of localized or diffused lesions, which in turn cause related clinical symptoms [Citation1]. The primary clinical presentations typically include progressive exacerbation of dysmenorrhea, increased menstrual volume, and infertility [Citation2]. It is a prevalent chronic gynecological disorder that poses substantial threats to women’s physical and mental well-being, thereby constituting a noteworthy burden on healthcare economics [Citation3]. According to reports, the prevalence of adenomyosis among reproductive age women ranges from 7 to 23% [Citation4]. In recent years, with the growing concern and demand for reproductive health, more and more patients with adenomyosis tend to accept conservative treatment. High-intensity focused ultrasound (HIFU) is a noninvasive technique that converts acoustic energy into thermal energy at a focal point. Currently, HIFU has been widely used in the treatment of adenomyosis and many studies have shown its safety and efficacy [Citation5–8]. To better maintain the efficacy of HIFU and reduce the long-term recurrence rate of adenomyosis, long-term management is often required [Citation9]. In clinical practice, nonsteroidal anti-inflammatory drugs (NSAIDs), combined oral contraceptives (COCs), dienogest (DNG), gonadotropin-releasing hormone agonists (GnRH-a), levonorgestrel-releasing intrauterine systems (LNG-IUS), traditional Chinese medicine, and other medications are often used for symptom improvement [Citation9]. Currently, there are no established guidelines, neither in China nor in other countries, for the long-term management of adenomyosis following HIFU treatment. However, clinical exploration into subsequent treatment modalities has been undertaken, with a predominant focus on dual or triple therapy involving HIFU, GnRH-a, and/or LNG-IUS. Several studies suggested that DNG exhibits comparable efficacy to GnRH-a in managing symptoms associated with adenomyosis [Citation10,Citation11], with a lower incidence of adverse effects. Nonetheless, there is limited documentation regarding the short- and long-term efficacy of HIFU combined with DNG and LNG-IUS in treating adenomyosis. This study aimed to utilize triple therapy comprising HIFU, GnRH-a, and LNG-IUS as a positive control, comparing its clinical efficacy with that of HIFU combined with DNG and LNG-IUS in the treatment of adenomyosis.

This retrospective study was approved by the Ethics Committee of Shenzhen Maternity and Child Healthcare Hospital, Guangdong, China (SFYLS[2021]017) and the requirement for informed consent was waived. Patients One hundred and twenty-six patients with adenomyosis who underwent HIFU treatment at our hospital between December 2019 and December 2020 were retrospectively reviewed. According to the treatment regimen, all patients were divided into Group A (HIFU + DNG + LNG-IUS) with 38 cases and Group B (HIFU + GnRH-a + LNG-IUS) with 88 cases. The inclusion criteria were as follows: (1) female patients aged between 18 and 50 years old, (2) the diagnosis of adenomyosis was suspected by medical history and confirmed by ultrasound and magnetic resonance imaging (MRI), (3) voluntarily choosing HIFU treatment, (4) no further fertility requirements. The exclusion criteria were as follows: (1) patients previously had other treatments before HIFU therapy, (2) patients combined with uterine fibroids, and (3) failure to complete 24-month follow-up. HIFU treatment Equipment The JC-200D focused ultrasound tumor therapeutic system (Chongqing Haifu Medical Technology Co. Ltd., Chongqing, P.R. China) was utilized for ultrasound-guided HIFU treatment. Treatment energy was generated by a transducer with a 20 cm diameter and 15 cm focal length. Real-time ultrasound monitoring during HIFU treatment was conducted using an ultrasound imaging probe (My-Lab70, Esaote, Italy), positioned at the center of the transducer. The transducer was housed within a barrel filled with degassed water below HIFU table, with its movement controlled by a computer system. Research methods All patients underwent HIFU treatment, during which treatment-related parameters were recorded. Subsequently, long-term medication management was conducted according to the following protocols: Group A (DNG + LNG-IUS): One week after HIFU treatment, patients started taking DNG (Imported Drug JX20170016, Specification: 2 mg/tablet) orally, at a dosage of one tablet per day for three consecutive months (calculated as one month per 28 days). At the end of the third treatment cycle, gynecological ultrasonography was performed, and LNG-IUS (Registration No.: H20140237, Bayer, Germany; Specification: 52 mg/item, 20 ug/24 h) was inserted. Group B (GnRH-a + LNG-IUS): One week after HIFU treatment, patients received their first subcutaneous injection of GnRH-a (Leuprorelin Acetate Sustained-Release Microspheres for Injection, Beijing Borna, National Drug Approval No.: H20093809, Specification: 3.75 mg/syringe). Subsequently, injections were administered every 28 days as one treatment cycle, continued for three consecutive cycles. At the end of the third treatment cycle, gynecological ultrasonography was performed, and LNG-IUS was inserted.

assessment The severity of symptoms, as indicated by VAS scores, PBAC scores, and the reduction rate in uterine volume, was compared between Groups A and B at 1, 6, 12, 18, and 24 months post-treatment. Visual analog scale (VAS) A 10 cm line was utilized, with ‘0’ indicating ‘no pain’ at one end and ‘10’ indicating ‘most severe pain’ at the other end. If the VAS score decreased by ≥2 points compared to before treatment, it was considered effective in relieving dysmenorrhea; otherwise, it was considered ineffective. Pictorial blood loss assessment chart (PBAC) The PBAC method was used to assess menstrual blood loss. Scores of 1, 5, or 20 were assigned based on the proportion of the blood-stained area on sanitary pads (≤1/3, 1/3–3/5, 1). Additionally, the presence and size of blood clots were evaluated, with areas smaller than a one-yuan coin scored as 1 and areas equal to or larger than a one-yuan coin scored as 5. Reduction rate in uterine volume The formula for calculating uterine volume (V1) was V1 = 0.5233 × the maximum length × the maximum anteroposterior diameter × the maximum transverse diameter of the uterus. The reduction rate in uterine volume was calculated as: (uterine volume before HIFU treatment − uterine volume after HIFU treatment)/uterine volume before HIFU treatment × 100%. Follow-up Patients’ degree of dysmenorrhea, changes in menstrual blood loss, changes in uterine volume, adverse drug reactions, and any subsequent interventions were recorded through outpatient visits or telephone follow-ups. HIFU treatment parameters and efficacy evaluation indicators: Parameters: Sonication time, sonication intensity, average power, total sonication dose, and Energy Equivalent Factor (EEF), where EEF = η × P × t/V (J/mm3), with η representing the focusing coefficient of the HIFU transducer (set to η = 0.7), P representing the source power of HIFU (W), t representing the sonication time (s), and V representing the total volume of the lesion (target volume) (mm3). Non-perfused volume ratio (also known as ablation rate): On the first day after HIFU treatment, MRI was performed and the maximum length, maximum anteroposterior diameter, and maximum transverse diameter of the non-perfused area in the target area were measured on contrast-enhanced images of MRI, denoted as a, b, and c, respectively. The non-perfused volume (NPV) was calculated as NPV = 0.5233 × a × b × c, and the non-perfused volume ratio (NPVR) was calculated as NPVR = NPV/V. Besides, hospital stay and hospitalization costs were also assessed. Statistical analysis SPSS software (version 26.0; IBM, New York, NY, USA) was used for statistical analysis. Normally distributed continuous data were expressed as mean ± standard deviation, while non-normally distributed data were represented by the median (M) and interquartile range (P25, P75). Categorical data were described using proportions or percentages. Comparisons between the two groups were conducted using the Pearson chi-square test or Fisher’s exact test. For continuous data meeting the assumptions of normality and homogeneity of variance, comparisons between two independent groups were performed using the independent samples t-tests. For skewed data or data with unequal variances, the Friedman test was used for within-group comparisons, and the Mann–Whitney U test was used for between-group comparisons. Multiple group comparisons were conducted using ANOVA or Kruskal–Wallis one-way ANOVA. Propensity score matching was implemented using Matchlt and Tableone packages in R 4.2.3. Near neighbor matching was applied in a 1:2 ratio to match baseline characteristics between groups.

Comparison analysis of baseline characteristics Comparison of baseline characteristics between Groups A and B revealed no significant differences in age, BMI, CA125 levels, gravidity, or number of cesarean sections. The only significant difference observed was in parity, with patients in Group B having a higher parity than patients in Group A (p < 0.05). Therefore, propensity score matching (PSM) was utilized to balance the differences between the two groups. Variables including age, BMI, and parity were included, and propensity score matching was conducted to balance the baseline differences between the two groups. Ultimately, 114 patients were selected in a 1:2 ratio, with 38 cases in Group A and 76 cases in Group B. Post-matching analysis revealed notably diminished discrepancies in baseline characteristics between the two groups, thus confirming their comparability (). Disease characteristics We compared the uterine characteristics, the types, and characteristics of adenomyosis lesions between the two groups after matching. However, the results indicated that there were no statistically significant differences in uterine position, uterine volume, lesion type, main lesion site, compression of endometrium, and volume of localized lesions between group A and group B (p > 0.05) (). HIFU treatment parameters There was no significant difference in NPV, NPVR, sonication time, sonication power, treatment duration, sonication intensity, total dose, EEF, length of hospital stay, and hospital expenses between the two groups (p > 0.05), indicating that the difficulty and efficacy of HIFU treatment were comparable between the two groups (). Additionally, adverse reactions during HIFU treatment in both groups were analyzed. There was no significant difference in the incidence of limb radiation pain, sacrococcygeal pain, skin burning sensation, and inguinal area pain between the two groups (p > 0.05). Only a statistical significance of the incidence of pain in the treated area was observed (p < 0.05), with a higher proportion in Group B (52.63%) compared to Group A (26.32%) (). Follow-up outcomes Dysmenorrhea severity score (VAS) Dysmenorrhea severity in patients of groups A and B was evaluated using VAS (). There was no significant difference in VAS between the two groups before and at 1, 6, 12, 18, and 24 months after HIFU treatment (p > 0.05). However, dysmenorrhea was significantly relieved after HIFU treatment, with a gradual decrease in severity observed over time with extended drug management. Uterine bleeding assessment The PBAC method was used to compare the menstrual blood loss between the two groups before and after HIFU treatment, as well as at various time points during long-term management (). The results indicated no statistical difference in uterine bleeding between the two groups before treatment. Following HIFU therapy, menstrual blood volume significantly decreased compared to baseline, and PBAC scores gradually decreased with extended drug management. Comparison between the groups revealed no significant differences in PBAC scores before treatment and at 1, 6, and 12 months after treatment (p > 0.05). However, at 18 and 24 months after treatment, group A exhibited higher PBAC scores than group B (p < 0.05). Uterine volume reduction rate At 6, 12, and 24 months after HIFU treatment, ultrasound examinations were conducted to evaluate the uterine volume of patients, and calculations were performed using the formula described in the section of Materials and methods. There were no significant differences in the reduction rate of uterine volume between the two groups at 6 and 12 months after treatment (p > 0.05). However, at 24 months after treatment, the uterine volume of patients in group B was higher than that of group A (p < 0.05) (). Adverse reactions We conducted a statistical analysis of adverse reactions following HIFU combined with different drugs in the two groups (). The results revealed no significant differences in the occurrence of constipation, breast discomfort, and LNG-IUS displacement between the two groups (p > 0.05). Patients in both groups experienced mild constipation, with the longest defecation interval of three days, which could be improved through dietary adjustments. Breast discomfort was characterized by mild, intermittent tingling or distending pain in both breasts. Ultrasound examinations revealed no abnormalities. However, the patients in group B exhibited a noteworthy occurrence of hot flushes and sweating, with 22 cases reported, whereas no similar cases were observed in group A (p < 0.01). Night sweats are mainly presented as transient, generalized sweating at rest, which slightly affects sleep. This condition can be relieved with symptomatic treatment using oral traditional Chinese medicine. Additionally, LNG-IUS displacement was observed in two cases in group A, occurring at 6 months after placing LNG-IUS (one case) and 12 months after placing LNG-IUS (one case), whereas six cases were reported in group B, occurring at 6 months after placing LNG-IUS (three cases) and 12 months after placing LNG-IUS (three cases). In three patients with LNG-IUS displacement, the intrauterine device was replaced, while the remaining patients were treated with a combination of medications. Notably, the overall incidence of adverse events in group A (15.79%) was significantly lower than that in group B (46.05%). Throughout the follow-up period, no severe complications were noted in either cohort. Recurrence rate The determination of adenomyosis recurrence typically relies on the recurrence of symptoms. In this study, the recurrence of dysmenorrhea and excessive menstrual bleeding was based on the recurrence of symptoms at 24 months after HIFU treatment. The recurrence rate for dysmenorrhea was 7.89% in group A and 5.26% in group B. Among them, three cases in Group A recurred at 9, 15, and 24 months after HIFU treatment, and four cases in Group B recurred at 8, 12, and 20 months after HIFU treatment; while those for excessive menstrual bleeding were 5.26% in group A and 3.95% in group B. No statistically significant differences were observed between the two groups (p > 0.05) (). Among the recurrence cases, four patients underwent hysteroscopic lesion resection, while the remaining cases were managed with LNG-IUS combined with long-term drug therapy, including DNG, oral contraceptives, and traditional Chinese medicine.

In this study, 38 patients with adenomyosis were treated with HIFU combined with DNG and LNG-IUS, and 76 patients were treated with HIFU followed by GnRH-a and LNG-IUS. Our results showed that both patients treated with HIFU followed by DNG and LNG-IUS and patients treated with HIFU followed by GnRH-a and LNG-IUS had significant symptom relief. The findings revealed no significant difference in the efficacy between the two treatment strategies within the 12-month follow-up period. An extended 24-month follow-up indicated that both strategies were equally effective in alleviating dysmenorrhea symptoms. However, the HIFU combined with GnRH-a and LNG-IUS strategy demonstrated a marginal advantage in terms of reducing menstrual bleeding and uterine size. However, HIFU combined with DNG and LNG-IUS treatment had a lower incidence of adverse reactions and was more favorably received by patients. LNG-IUS is a special type of intrauterine device loaded with synthetic progestogens. The levonorgestrel can be autonomously released at a rate of 20 μg per day within the uterus, increasing the concentration of progestogens and exerting an antagonistic effect on endometrial proliferation [Citation12]. LNG-IUS can be used to effectively inhibit the activity of ectopic endometrium and control the progression of adenomyosis, thus being designated as a first-line drug for long-term management of adenomyosis [Citation13]. A study showed that after 12 months of LNG-IUS treatment of patients with adenomyosis, the median VAS score of dysmenorrhea decreased from 46.5 (13.0, 68.0) before treatment to 1.0 (0.0, 13.0) [Citation14]. A meta-analysis of 1861 participants showed that HIFU combined with LNG-IUS was superior to HIFU alone in relieving symptoms and reducing uterine volume [Citation15]. However, LNG-IUS has limitations due to its single model and lack of adjustability, resulting in a tendency for displacement and expulsion in patients with a larger uterine cavity. The reported rates of displacement or expulsion of LNG-IUS ranged from 9.1 to 37.5% [Citation16]. Therefore, the long-term management of adenomyosis using LNG-IUS often requires combining with other treatment strategies to overcome its defects and improve treatment efficacy. GnRH-a stands as the ‘gold standard’ medication for treating adenomyosis, exhibiting significant efficacy in relieving dysmenorrhea, reducing menstrual flow, and shrinking uterine volume [Citation17,Citation18]. A study of HIFU combined with GnRH-a and LNG-IUS involving 142 patients with adenomyosis showed that the uterine volume decreased significantly after the use of the combined treatment strategy, and the recurrence rates of dysmenorrhea and menorrhagia were lower than that of patients without using this strategy (5.68 and 7.91%, respectively) [Citation19]. However, according to the ESHRE (European Society of Human Reproduction and Embryology) guidelines, long-term use of GnRH-a may lead to certain side effects, such as hypoestrogenic symptoms, bone loss, and cardiovascular symptoms [Citation20]. Additionally, a retrospective cohort study found that although all subjective symptoms disappeared in patients with adenomyosis after receiving GnRH-a treatment for 6 months, almost all symptoms returned in 6 months after withdrawal of this medication, including excessive menstrual bleeding (63.6%) and dysmenorrhea (80.0%), while uterine volume significantly increased to 282.3 cm3 at 12 months (p = 0.003) [Citation21]. This indicated that GnRH-a is only suitable as a short-term treatment for adenomyosis. DNG is a novel type of progestin, combining the pharmacological properties of progesterone and 19-deoxyprogesterone derivatives, which can effectively inhibit the endometrium and improve adenomyosis-related pain symptoms, and is effective in the long term [Citation22,Citation23]. DNG received approval for market release in China in 2018 and was initially used for the treatment of endometriosis. Given the similarity in drug use between adenomyosis and endometriosis, researchers have explored the potential of DNG in the management of adenomyosis. Results from a study suggested that DNG can achieve similar therapeutic effects to GnRH-a in reducing pelvic pain, with a similar onset time and relief effects [Citation24]. Furthermore, dinoprostone has a dual mechanism of action in the central and peripheral systems, which can reduce side effects without affecting the treatment efficacy. Although it reduces estrogen levels, it remains within the treatment window. It can effectively inhibit the endometrium without increasing the risk of estrogen deficiency or bone loss, making it a popular choice in the long-term management of adenomyosis [Citation25]. At present, there is limited research on the sequential use of DNG in the treatment of adenomyosis after HIFU treatment. This study innovatively evaluated and compared the efficacy of using HIFU in combination with different drug management strategies for treating adenomyosis. The results showed that the VAS of Groups A and B at each postoperative follow-up time point were significantly lower than baseline, and the degree of pain continued to decrease with the extension of treatment time, confirming the exact short-term and long-term efficacy of the two treatment strategies. These findings suggested that both long-term drug management strategies were effectively controlled dysmenorrhea severity, and the effects were comparable. Additionally, comparisons between the two groups showed no statistical difference in VAS at each follow-up time point, indicating comparable efficacy in dysmenorrhea control between the two treatment strategies. Regarding menstrual volume, this study compared changes in uterine bleeding volume in the two groups of patients using the quantitative indicator PBAC score. According to the statistics, the bleeding volume of patients in both groups significantly decreased after HIFU treatment, and no statistically significant differences were found between the two groups at 1, 6, and 12 months postoperatively. However, with prolonged treatment time, the uterine bleeding volume of Group A was higher than that of Group B at 18 and 24 months postoperatively, but the median bleeding volume of both groups still did not reach the standard of menorrhagia. Based on the issue of differential bleeding volume in DNG treatment for adenomyosis, reports have suggested that this may be related to progesterone resistance in adenomyosis [Citation26,Citation27]. For example, Satoshi et al. found that KRAS gene mutations may weaken the efficacy of DNG by downregulating progesterone receptors in adenomyotic lesions [Citation28]. This may suggest a correlation with the effective concentration of progesterone under different dosing modes, but high-quality evidence from large samples is still lacking. In terms of uterine volume, this study evaluated changes in uterine volume before and after treatment in both groups of patients. The results indicated that the uterine volume of both groups significantly decreased after treatment, and both strategies were significantly effective. Comparisons between the two groups showed that the degree of uterine volume reduction was similar at 6 and 12 months after HIFU treatment. At 24 months postoperatively, the rate of uterine volume reduction in Group A was lower than that in Group B, indicating that the long-term efficacy of HIFU combined with GnRH-a + LNG-IUS in reducing uterine volume was superior to that of HIFU combined with DNG + LNG-IUS. The safety, feasibility, and acceptability of treatment are equally important aspects of long-term management of adenomyosis. A previous study has shown that the overall incidence of severe adverse reactions and complications after HIFU treatment is rare [Citation29]. Regarding adverse reactions to long-term drug management, our study showed that the incidence of hot flashes and sweating in Group B was significantly higher than that in Group A. Overall statistics suggest that the incidence of adverse reactions in Group B (46.05%) was significantly higher than that in Group A (15.79%). It is essential to ablate as much adenomyotic lesion as possible while maintaining the integrity of the serosal layer and the endometrium because residual lesions may develop over time. The main symptoms of recurrence after HIFU are dysmenorrhea and increased menstrual volume. Haiyan et al. found that the recurrence rates of dysmenorrhea and menorrhagia after 2 years of treatment with HIFU combined with GnRH-a and LNG-IUS were 3.55 and 5.24%, respectively [Citation20]. In this study, at 24 months after HIFU treatment, the recurrence rates of dysmenorrhea and menorrhagia in Groups A and B were 7.89 and 5.26%, and 5.26 and 3.95%, respectively. There was no significant difference in the overall recurrence rates between Groups A and B, indicating similar recurrence risks of HIFU combined with DNG and HIFU combined with GnRH-a for long-term management of adenomyosis, with low recurrence rates within 24 months. This study demonstrated that the combination of HIFU with DNG + LNG-IUS and HIFU combined with GnRH-a + LNG-IUS strategies have achieved favorable efficacy in the treatment and long-term management of adenomyosis. In terms of alleviating dysmenorrhea, reducing menstrual volume, and shrinking uterine volume, both strategies showed comparable short-term effects. However, HIFU combined with DNG + LNS-IUS treatment for adenomyosis is effective with fewer adverse reactions compared to the HIFU combined with GnRH-a + LNS-IUS. The limitations of this study are as follows: (1) The small sample size may not adequately represent the overall population, potentially leading to biased results. Since DNG was introduced as a new drug in 2019 and our study began in November 2019, the sample size was limited during this initial phase of exploring the drug’s efficacy. We plan to increase the sample size in future studies to enhance reliability. (2) Retrospective studies, which are usually conducted after events have occurred, pose challenges in controlling potential confounding factors, thereby reducing external validity. To address this, we performed data matching to ensure no statistical differences in baseline characteristics between the two groups, thus maintaining good comparability. We intend to design prospective studies in the future to improve accuracy. (3) Furthermore, conducting the study in one hospital within a single geographic area limits the generalizability of the results. When our study began, DNG was not yet widely used across many regions in the country, making multi-center studies difficult. We now plan to conduct multi-center studies across multiple cities nationwide to ensure the accuracy and broad applicability of our findings.

In summary, HIFU combined with DNG + LNS-IUS treatment for adenomyosis is effective with fewer adverse reactions and shows similar short- and long-term efficacy in relieving dysmenorrhea compared to the HIFU combined with GnRH-a + LNS-IUS. These two strategies have their own advantages from different perspectives, providing preferred options for patients with different demands. This study provides a scientific evidence for exploring more personalized, diversified, and feasible treatment options for adenomyosis. Disclosure statement No potential conflict of interest was reported by the author(s). Data availability statement The data that support the findings of this study are available upon request from the corresponding author, PJ. The data are not publicly available because they contain information that can compromise the privacy of the research participants. Additional information Funding

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