Symptom improvement in adenomyosis patients after ultrasound guided microwave ablation or uterine artery embolization, A randomized controlled pilot study

Adenomyosis is a benign condition causing symptoms such as heavy menstrual bleeding (HMB), anemia, dysmenorrhea, chronic pelvic pain, and impaired fertility [ 1 , 2 ]. About 2/3 of patients with adenomyosis have symptoms that negatively impact their quality of life and lead to absence from work [ 3 , 4 ]. The pathogenesis of adenomyosis results in endometrial deposits within the myometrium leading to either focal or diffuse adenomyotic lesions [ 5 , 6 ]. Adenomyosis is considered diffuse when endometrial glands and stroma are spread in the myometrium and focal when they are isolated in one part of the myometrium [ 7 , 8 ]. Earlier reports of the prevalence of adenomyosis were based on hysterectomy specimens, which may not be accurate to describe the true burden of the disease [ 1 , 2 , 9 ]. With better awareness about adenomyosis and more consensus in diagnostic criteria on ultrasound and magnetic resonance imaging (MRI), the diagnosis can now be made by noninvasive methods [ 10 – 13 ]. Among women seeking care for symptoms such as menorrhagia and dysmenorrhea, the reported prevalence on transvaginal ultrasound has been between 21% to 34% [ 10 ]. When medical treatment fails, hysterectomy has often been the recommended treatment, which is curative for bleedings but might not reduce the need of pain medication [ 14 ]. For patients that want to preserve their uterus and to avoid risks of major surgery, accessibility of alternative treatment options varies. As for uterine fibroids, minimally invasive treatment options for adenomyosis are receiving increased attention and ablative techniques are developing rapidly. Uterine artery embolization (UAE) is a well-established non-invasive treatment option for fibroids and adenomyosis [ 15 ]. A meta-analysis has shown that UAE improved clinical symptoms of patients with isolated adenomyosis in 89% of cases in the short term follow up (during the first 12 months after treatment) and 74% of cases in the long term follow up (12-65 months after treatment) [ 15 ]. Ablative techniques like Radio Frequency ablation (RF), High-intensity focused ultrasound (HIFU) and Microwave Ablation (MWA) have been studied as treatment of adenomyosis, with similar effect on symptoms and few adverse events, and with shorter ablation time for MWA [ 16 – 18 ]. Also, MWA treatment of adenomyosis has not shown any effect on ovarian reserve [ 19 ]. A review article from 2021 including 13 published studies and 736 patients showed symptom reduction and few mild complications after MWA of adenomyosis [ 20 ]. Uterine volume decreased by 55-65%, dysmenorrhea by 50-82%, SSS by 21-60% and anemia by 56-79% at follow up after 3 to 12 months. To our knowledge, no previous RCT between MWA and UAE for adenomyosis has been performed, and patient’s acceptability of MWA treatment for adenomyosis has not been reported. The effect of MWA treatment of adenomyosis have previously been monitored by Ca-125 [ 21 ] and prolactin [ 22 ] levels in blood, as greater uterine size has been correlated with higher Ca-125 levels [ 23 ]. Our earlier studies on MWA for uterine fibroids [ 24 – 26 ] have recently led to implementation of this treatment into clinical praxis at Danderyd Hospital. The aim of this study was to evaluate the potential of efficacy and acceptability of MWA and UAE on symptomatic adenomyosis in a randomized controlled pilot trial.

Study flow is shown in the consort flow chart ( Fig 3 ). Of the 20 randomized patients, 10 were randomized to MWA and 10 to UAE. During the study period eight patients were treated with MWA and seven with UAE. The MWA treatment was performed by abdominal approach in 6/8 cases and vaginally in 2/8 cases. Baseline characteristics are presented in Table 1 . There was no difference between the groups regarding preoperative SSS, PBAC score, HR-QoL score, age, BMI, parity, hemoglobin, prolactin, AMH, or dysmenorrhea. Despite randomization, the MWA group had significantly higher Ca-125 at baseline. Presented as median, interquartile range and min-max values. P -value calculated by Mann Whitney U-test. MWA: microwave ablation; UAE: uterine artery embolization; BMI: body mass index; AMH: anti müllerian hormone; PBAC: pictorial bleeding assessment cart score; SSS: symptom severity score of the UFS-QoL questionnaire; QoL: quality of life score of the UFS-QoL questionnaire. P value < 0.05 was considered significant (bold value). Primary and secondary outcomes are presented in Table 2 . The MWA group had a significant decrease in SSS of 36%, median 69 to 44 (p=0.007), while the UAE group decreased in median SSS by 47% from 88 to 47 (p=0.067). The decrease in SSS between the two groups was not significant. Quality of life score increased significantly in the MWA group (p=0.002) and in the UAE group (p=0.013) at follow up compared to baseline, with no significant difference between the groups. Presented as median, interquartile range and min-max values. P-value calculated by Mann-Whitney U-test. MWA: microwave ablation; UAE: uterine artery embolization; SSS: symptom severity score of the UFS-QoL questionnaire; QoL: quality of life score of the UFS-QoL questionnaire; PBAC: pictorial bleeding assessment cart score; AMH: Anti-Müllerian hormone. P value < 0.05 was considered significant (bold values). 95% CI: 95% confidence intervals of the median of the difference. Bleeding during menstruation decreased in both groups. The median PBAC score in the MWA group decreased from 563 to 122 and in the UAE group from 877 to 197. There was no significant difference between the groups. Therewere no significant differences between the groups regarding the levels of Hemoglobin, AMH, or Prolactin after treatment. Ca-125 levels decreased significantly in the UAE group and when comparing the groups in favor of UAE (p=0.035). Uterine volume (measured on MRI before and after treatment) decreased in both treatment groups but without significant differences between the groups. Dysmenorrhea defined as NRS maximum during menstruation (on a scale from 0-10), extracted from the PBAC questionnaire, was analyzed. Both groups had a significant difference in reduction of dysmenorrhea six months after treatment. In the MWA group, the median of maximum pain reduced from NRS 6 to 1 (p=0.008) and in the UAE from 9 to 4 (p=0.02). There was no significant difference between the groups regarding treatment effect of dysmenorrhea. Regarding postoperative outcomes, there was a significant difference between the groups in favor of MWA treatment: hospitalization was shorter (median 0 days compared to 3 days in the UAE group, p=0,004) and shorter time of postoperative pain medication (median 3 days compared to 10 days in the UAE group, p=0,029). Regarding exploratory outcomes, there was no significant difference between the groups in reported postoperative pain level (NRS), however a significantly quicker return to daily activities was seen in the MWA group (median 3 days for MWA and 14 days for UAE, p=0.005) ( Fig 4 ). Both treatments led to reduction of symptoms, but there were no significant differensces between the two groups. There was no difference in acceptability, measured as recommendation of the treatment to a friend (score from 1-7), on day of treatment nor at follow up. All study participants could strongly recommend the treatment (score 6-7) two hours post treatment except for one participant who did not have sufficient anesthesia during UAE due to failure of epidural anesthesia (score 1). In the MWA group, one patient would not recommend the treatment to a friend (score 1-3) at follow up, compared to two patients in the UAE group. One patient in the MWA group and two in the UAE group would neither recommend nor discourage the treatment to a friend (score 4-5) at follow up. Acceptability results were analyzed by Chi 2 test due to non-numerical values, and thus not presented in Table 2 . There was one severe incident with a patient in the UAE group. Due to intense postoperative pain three days postoperatively, a computed tomography was performed, showing suspected colon diverticulum perforation. The condition was treated conservatively with antibiotics and the patient was discharged on postoperative day six. The diverticulosis was later confirmed by colonoscopy. It was considered unlikely that this condition was related to the UAE treatment, however this made evaluation of post-operative pain difficult, and she was excluded from the analyses of postoperative pain, use of analgesics and admission to hospital. One patient in the UAE group was diagnosed with and treated for cystitis postoperatively.

Both MWA and UAE have potential as safe and acceptable treatments for adenomyosis, leading to decreased symptoms and increased quality of life, however no difference between the groups was seen regarding primary outcome. Patients in the MWA group seem to have more favorable postoperative outcome. Since this was a small pilot study; further research is needed to confirm these results and to analyze the long-term effect. Both MWA and UAE treatments of symptomatic adenomyosis patients resulted in symptom reduction and increased quality of life. The MWA group had more favorable postoperative recovery and no adverse events occurred.

The study was approved by the Swedish Ethical Review Authority with application number 2019-04262 and registered on clinicaltrials.gov with identifier NCT04209127 . Patients were recruited at Danderyd Hospital in Stockholm, a tertiary teaching hospital affiliated to Karolinska Institutet. From June 8, 2020, to February 28, 2023, a total of 20 patients were included in the study. The small study size was chosen due to absent previous clinical experience at our hospital of MWA or UAE as treatments for isolated adenomyosis. No power calculation was made. Follow-up visits were scheduled two- and six-months post treatment. The inclusion criteria’s were: premenopausal status 30-55 years of age, symptoms of adenomyosis and having at least two ultrasound criteria of adenomyosis. The exclusion criteria’s were: current or future pregnancy wish, Body Mass Index (BMI) ≥ 35, treatment with anticoagulant or having a bleeding disorder, verified or suspected endometriosis on ultrasound or MRI, contraindication to UAE or general anesthesia, fibroids >3 cm, and hormonal treatment three months prior to treatment. All patients were examined by a specialist in gynecological ultrasound. The ultrasound criteria used to identify adenomyosis were the following: a globular uterus or asymmetric uterine walls, fan shaped shadowing, heterogenous myometrium, ill-defined junctional zone, increased vertical/translesional vascularization and suspected adenomyosis cysts, as defined by the MUSA criteria described by Harmsen et al. [ 12 ]. Patients with focal and/or diffuse adenomyosis were included. If patients met the inclusion criteria and lacked exclusion criteria, they underwent an MRI as secondary imaging modality after signing informed consent. If adenomyosis was confirmed on MRI, the patients were included in the study and randomized 1:1 to either MWA or UAE by consecutive opening of numbered opaque sealed envelopes containing the allocation. The envelopes were prepared by staff not involved in the study following a computer-generated randomization list ( www.sealedenvelope.com ). The result of the randomization was not deemed possible to blind to the patients nor the providers. The length, anterio-posterior (AP) and width of the uterus were measured on MRI prior to the study and at the six-month follow-up ( Figs 1 and 2 ), to calculate uterine volume according to a defined formula (in centimeters: length x AP x width x 0.5233) [ 27 ]. Before treatment and at six-months follow-up all patients completed a validated questionnaire about symptoms and quality of life (Uterine fibroid symptom and health-related quality of life questionnaire, UFS-QoL) [ 28 ] and the validated Pictorial Blood loss Assessment Chart (PBAC) [ 29 ] to assess the menstrual blood loss. UFS-QoL generates two scores, a symptom severity score (SSS) where high scores indicate more severe symptoms, and a score on health-related quality of life (HR-QoL) where high scores indicate a higher quality of life. PBAC generates a score based on numbers of pads and tampons used, the degree of soaking of pads and tampons, clots passed and days of bleeding during a menstrual period. We also included numeric rating scale (NRS) [ 30 ] of maximum daily pain during menstruation (on a scale from 0-10) as a proxy for dysmenorrhea before treatment and at six-months follow-up. Patients also evaluated their maximum pain on NRS postoperatively and daily for the first 7 days at home after treatment. The hemoglobin count, Ca-125, prolactin and AMH were evaluated before treatment and at six months follow-up. A follow up MRI was performed six months after treatment ( Figs 1 and 2 ). At the two-month follow-up length of hospitalization was registered and patients were asked about time to return to daily activities and postoperative pain medication. On treatment day and at six months-follow up patients were asked if they would recommend the treatment to a friend using a Likert scale from 1 (very unlikely) to 7 (very likely) to assess acceptability. A score from 1-3 was considered as “would not recommend”, score 4-5 as “would neither recommend nor discourage” and score 6-7 as “would strongly recommend”. An Emprint TM Ablation Generator with Thermosphere TM Technology (Medtronic, Minneapolis, USA) with a 13-gauge antenna was used for MWA. The generator operates at a frequency of 2.45 GHz ± 50 MHz with an output power range of 5–100 Watts. The MWA was performed transabdominally or vaginally in the operation room under general anesthesia in supine position with the presence of a gynecologist and an interventional radiologist. Ultrasound (LOGIQ TM 10, GE Healthcare) was used for imaging and needle guidance. Contrast enhanced ultrasound was used to assess size and vascularization of the adenomyosis, with the administration of 2.4 ml of SonoVue ® medium (Bracco, Milan, Italy) before and immediately after MWA. The microwave effect in watts used was 50–100 Watts and the total time of ablation per patient was between 5 and 31 minutes. The effect of the MWA on the adenomyosis was monitored by real-time ultrasound and the ablation was stopped when the microbubbles, that roughly represent the ablation zone, covered the adenomyosis affected area. A standardized protocol was used for perioperative pain management for all MWA patients, they were given pre-operative medication of 1.5 g paracetamol, 400 mg celecoxib, and 5 mg oxycodone. Post-operative pain was managed with intravenous morphine if needed. The UAE was performed by an interventional radiologist at Danderyd Hospital under epidural anesthesia using sufentanil and ropivacaine according to hospital routine. UAE was carried out under fluoroscopic guidance (Alphenix TM , INFX-8000V, Canon Medical System Corporation, Askim, Sweden). A unilateral groin approach was used for bilateral, selective embolization of the uterine artery. Through a microcatheter (Embocath ® Plus, Merit Medical, Stockholm Sweden) tris-acryl polymer microspheres 500–700 mm (Embosphere ® , Merit Medical, Stockholm, Sweden) were injected until flow in the artery ceased in one side and then the other side. All patients had urinary catheter to avoid urinary retention related to the epidural. Postoperative pain management was by a standardized protocol as follows: the day after UAE patients received 400 mg celecoxib, 1g paracetamol and 10 mg oxycodone, after which the epidural was turned off. If the pain was not tolerated by the patient, the epidural was turned on again using only ropivacaine. The procedure was repeated daily until the patient could leave the hospital with per oral analgesia. Primary outcome was difference in symptoms six months after treatment, measured by the symptom severity score (SSS). Secondary outcomes were changes in quality of life, amount of menstrual bleeding/PBAC, dysmenorrhea on NRS, uterine volume, levels of Hb, Ca-125, prolactin and AMH, hospitalization, use of postoperative pain medication and acceptability. As exploratory outcomes, we evaluated postoperative pain and return to daily activities after treatment. Data generated or analyzed during the study are available from the corresponding author on request. Statistical Package for Social Sciences (SPSS) version 29 (IBM corporation, Armonk, New York, US) was used for statistical analysis. For baseline characteristics, comparison between the groups for continuous variables, and for analysis of differences between the groups for variables that were measured before and after treatment we used the Mann Whitney U-test. Statistical significance was assumed at a p-value <0.05. Median of the difference in outcomes between the groups and 95% Confidence intervals were calculated by custom tables. To compare the difference between variables that were measured before and after treatment within each group we used Paired T test and descriptive statistics. Acceptability of treatment was categorized into three groups “would recommend” (6–7), “would neither recommend nor discourage ” (4–5) and “would not recommend” (12–3). Differences between groups were analyzed by Chi2 test. We tried to apply multiple linear regression analysis on baseline variables, but the model lacked sufficient explanatory power.

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