High-intensity focused ultrasound combined with hysteroscopic insertion of levonorgestrel-releasing intrauterine system for intrinsic adenomyosis: a retrospective observational study

Objective To retrospectively analyze the safety and efficacy of high-intensity focused ultrasound (HIFU) combined with hysteroscopic insertion of Levonorgestrel-Releasing Intrauterine System the treatment of intrinsic adenomyosis.

A total of 30 patients with intrinsic adenomyosis were enrolled. All patients initially underwent HIFU treatment, followed by hysteroscopic surgery to remove the remaining unabsorbed necrotic tissue and simultaneously insert the levonorgestrel-releasing intrauterine system (LNG-IUS) for long-term management of adenomyosis. The treatment results, adverse events, and 2-year follow-up data were analyzed statistically.

All 30 patients successfully completed the treatment without serious complications, and achieved remarkable symptom improvement. The VAS score of dysmenorrhea and MSF score of menorrhagia both decreased significantly (p < 0.05). Uterine volume decreased significantly after treatment (p < 0.05). The proportion of patients with dysmenorrhea and menorrhagia who experienced significant symptom relief was 86.7% and 93.3%, and the clinical efficacy rates were 93.3% and 96.7% respectively, with no recurrent cases. LNG-IUS was inserted during hysteroscopic surgery in 30 patients. Up to the time of submission, no significant symptom recurrence and the LNG-IUS displacement rate is 3.3%.

Combination of HIFU and hysteroscopic insertion of Levonorgestrel-Releasing Intrauterine System is an effective and recommended therapeutic strategy for treating intrinsic adenomyosis.

Adenomyosis is a benign gynecologic disease characterized by the nonmalignant invasion of endometrial tissue into the myometrium [Citation1]. Its symptoms include menorrhagia, dysmenorrhea and subfertility. Currently, hysterectomy is considered as the definitive therapy for uterine adenomyosis [Citation2]. However, even if both ovaries are preserved, hysterectomy may continue to exert adverse effects on women’s psychological and physiological well-being [Citation3]. Given the progress in society and the trend of delayed childbearing, conservative treatment options have become imperative for patients seeking fertility preservation and a high quality of life. High-intensity focused ultrasound (HIFU) ablation is a noninvasive thermoablative technique that has been successfully employed in the treatment of uterine fibroids, adenomyosis and other benign or malignant solid tumors. Although numerous studies have demonstrated the safety and short-term efficacy of HIFU in treating adenomyosis [Citation4–6], postoperative recurrence persists. Recent evidence strongly indicates that adenomyosis originates from the invagination of the basal layer of the endometrium into the myometrium [Citation7]. So, for patients without the requirement of fertility, clinical studies have demonstrated that ablation of the in situ endometrium can achieve superior therapeutic outcomes. However, this procedure may also lead to an increased incidence of postoperative vaginal discharge and vaginal bleeding [Citation8], which compromises patients’ satisfaction with long-term treatment. In addition, the presence of necrotic tissue may hinder direct contact between the LNG-IUS and the active tissue, thereby potentially compromising the therapeutic efficacy. In this study, we present a novel therapeutic approach for intrinsic adenomyosis: the combination of HIFU and hysteroscopic insertion of LNG-IUS. And analyze its feasibility and clinical value.

and method Patients This observational retrospective study included 30 patients with intrinsic adenomyosis who underwent HIFU combined with hysteroscopic insertion of LNG-IUS at our institution from January 2020 to December 2022. Inclusion criteria were: (1) Premenopausal women with no fertility requirement, (2) With symptoms of dysmenorrhea and/or heavy menstruation, (3) MRI examination revealed an enlarged uterus, thickening of the uterine subendometrial layer without involving the outermost myometrium (). (4) Patients could communicate with the nurse or physician during the procedure of HIFU. The exclusion criteria were as follows: (1) Combined with other diseases that may cause abnormal menstruation or dysmenorrhea, such as uterine fibroids, endometrial diseases, hematological diseases, pelvic endometriosis. (2) Incomplete treatment or follow-up information. This study was approved by ethics committee of the Women and Children’s Hospital, Qingdao University (No.QFELL-YJ-202353). And the patient’s informed consent was obtained. Surgical procedures In addition to routine preoperative examinations, patients with irregular vaginal bleeding needs to undergo diagnostic curettage or endometrial biopsy to rule out endometrial diseases. Intestinal preparation should start three days before HIFU. The patients were instructed to consume a semiliquid diet for 2 consecutive days, followed by the intake of liquid nutrition for 1 day. They were then required to fast for 12 h and undergo an enema prior to undergoing HIFU treatment. Routine skin preparation included removing hair from the skin between umbilicus and the superior border of the symphysis pubis, degreasing and degassing with 70% ethanol and degassed water. The catheter is indwelled preoperatively for bladder perfusion during the operation. The HIFU procedure conformed to the guidelines of Focused Ultrasound Tumor Therapeutic System (Model-JC200D1, Chongqing Haifu Medical Technology Co., Ltd., Chongqing, China), which is equipped with an ultrasound imaging probe (MyLab 90, Esaote, Genova, Italy) used for real-time monitoring during treatment. Sedation and analgesia were administered by anesthesiologist during the operation. The patient assumed a prone position on the treatment table, and the treated area was immersed in degassed water up to the midaxillary line. A degassed water balloon was positioned between the abdominal wall and the transducer to facilitate the establishment of a secure acoustic pathway. During the course of HIFU treatment, sagittal view of the ultrasound scanning mode was selected to achieve a real-time ultrasonic monitoring. The point scanning was selected, with sonication power 400 W. During the surgery, oxytocin is administered intravenously to reduce uterine blood flow and minimize heat loss. The power and treatment intensity can be flexibly adjusted according to the patient’s response and the gray-scale changes of target tissue observed on ultrasound. After the treatment, the skin of abdomen was immersed in low-temperature degassing water for 10–30 min. Bladder infusion with 4 °C normal saline should be done to assist in cooling the treatment zone. Give symptomatic support treatments such as pain relief and fluid rehydration. If necessary, antibiotics could be given to prevent postoperative infections. HIFU termination criteria:(1) Loss of blood flow signal of target lesions with the gray-scale changed; (2) Contrast-enhanced ultrasound examination indicated a satisfactory ablation range. (3) Recuring symptoms of skin burning or nerve irritation with no improvement after adjustment. Because adenomyosis has unclear boundaries, the uterine volume was measured by transvaginal ultrasonography, while the volume of adenomyosis and nonperfused volume (NPV) were measured and calculated according to MRI images, V = 0.5233*A*B*C (A = length, B = width, C = thickness). The NPV ratio was calculated as the volume of nonperfused area after HIFU/the volume of adenomyotic lesion before HIFU × 100%. After HIFU treatment, the uterine body shrinks as necrotic tissue is absorbed. When the volume of the uterus shrinks to less than that of an 8-week pregnancy, it can be regarded as an appropriate time for hysteroscopic surgery [Citation9]. Hysteroscopic surgery was performed under general anesthesia, and 1 mg carboprost methylate suppositorites for vagina was used to soften the uterus cervix. After cervical dilation, the hysteroscopic electrotomy system was inserted into the uterine cavity. The flow rate of dilating fluid was set at 400–500 ml/min, and pressure 100–120 mmHg (1 mmHg= 0.133 kPa). The necrotic tissue was removed by electrotomy or suction curettage, and endometriectomy should be performed simultaneously if necessary. Whether to simultaneously place LNG-IUS based on the size of the uterine cavity. Assessment of effect After hysteroscopy, the patients were followed up at 1, 6, 12, 18 and 24 months to assess relief of symptoms. Dysmenorrhea visual analog scale (VAS) scores: the severity of dysmenorrhea was evaluated by measuring VAS scores on a scale of 0–10, with 0 meaning there was no pain and 10 meaning the worst possible pain, and the patient was asked to choose a number based on his individual perception of pain. The menstrual blood volume is scored using a 5-point scale (1= ‘not at all’, 2 = ‘a little’, 3 = ‘more’, 4 = ‘very much’, 5 = ‘extremely large amount’), and subjectively evaluated by the patient [Citation10]. The degree of symptom relief was assessed based on the following criteria: (1) partial relief, defined as a relief ratio below 50%; (2) significant relief, characterized by a relief ratio exceeding 50%; (3) complete relief, indicating full resolution of symptoms; (4) clinically ineffective, where post-HIFU scores were equal to or higher than pre-HIFU scores. Clinical relief encompassed partial relief, significant relief, and complete relief [Citation11]. Our primary outcome was relief of symptoms at 24 months after treatment. In addition, we monitored the uterine volume, the position of the LNG-IUS and the recurrence status of patients after treatment. A recurrent postoperative case is defined as the reappearance of symptoms following a substantial or complete remission, with the severity reverting to the pretreatment level [Citation12]. Statistics Statistical analysis was performed using SPSS 19.0 software. Continuous data were expressed as ±, and count data were expressed as numbers and percentages. Paired samples Wilcoxon test was used for comparision of pre-and-post treatment efficacy. A p-value < 0.05 was considered to indicate statistical significance.

The baseline clinical data of the 30 patients were summarized in . All patients completed HIFU ablation for adenomyotic lesions in one session. The detailed treatment statistics are presented in , while the adverse effects are summarized in . Intraoperative adverse effects commonly included radiating pain, treated area pain, sacrococcygeal pain, and skin burning sensation. Of these, the incidence of treated area pain is the highest. When the VAS score exceeds 4 points, pharmacological analgesic treatment is initiated, and the pain is typically alleviated within 24 h. Patients with a skin burning sensation were given cold compression for 2 h. The common adverse reactions after surgery primarily include increased vaginal discharge and vaginal spotting, and observation or short-term symptomatic drug treatment is provided. All adverse events were CTCAE Grade ≤ 2 (CTCAE v.5.0). Postoperative enhanced MRI revealed nonperfused areas in the lesion which involved the endometrium, indicating partial endometrial ablation). The ablation (nonperfused volume) ratio is 65.3 ± 6.8%. The hysteroscopic surgery was performed on all 30 patients, with a median time interval of 6 months after HIFU. Pre-hysteroscopic MRI showed a clear area within the myometrial tissue, extending partially into the uterine cavity, suggesting the presence of unabsorbed necrotic tissue (). Hysteroscopy revealed the presence of grayish yellow brittle tissue within the myometrium, partially protruding into the uterine cavity (). Due to the mud-like texture of necrotic tissue (), suction curettage can significantly enhance removal efficiency (). LNG-IUS was simultaneously placed in the 30 patients. The average duration of hysteroscopic operation was 45.8 ± 16.7 min, with an intraoperative blood loss of 23.0 ± 11.5 ml. We conducted a 2-year postoperative follow-up on the patients. As shown in , after HIFU treatment, the pain and menstruation volume score both significantly decreased (p < 0.05), and the uterine volume has decreased significantly (p < 0.05). After 24-months follow up, the incidence of LNG-IUS abnormal position is 3.3%. The proportion of patients with dysmenorrhea and menorrhagia who experienced significant symptom relief was 86.7% and 93.3%, and the clinical efficacy rates were 93.3% and 96.7% respectively (), with no recurrent cases.

Adenomyosis can result in menorrhagia, prolonged menstruation, dysmenorrhea, subfertility, and uterine enlargement. However, there is significant heterogeneity in the symptoms, which may be attributed to the different types of adenomyosis lesions. In 2012, Kishi et al. proposed an MRI classification system for adenomyosis: (i) subtype I or intrinsic adenomyosis is characterized by direct endometrial invasion involving the inner-mid myometrium without affecting outer structures; (ii) subtype II or extrinsic adenomyosis refers to adenomyotic lesions occurring in the outer uterine layer without affecting inner structures; (iii) subtype III or intramural type represents solitary occurrence of adenomyotic lesions unrelated to structural components; and (iv) subtype IV or indeterminate type includes cases that do not meet other criteria [Citation13]. Among these subtypes, subtype I and subtype II accounted for 38.8% and 33.6%, respectively. Previous literature reports and clinical observations have indicated that intrinsic adenomyosis is more likely to cause heavy menstrual bleeding and anemia [Citation14]. Currently, the radical treatment for adenomyosis still remains limited to hysterectomy. However, many patients prefer uterine preservation for their quality of life or future fertility plans. The preferred initial treatment for intrinsic adenomyosis is drug therapy, particularly when the lesion is limited or the thickness of the endometrium-myometrium junction has not yet reached 3 cm. Medications include non-steroidal anti-Inflammatory drugs, combined oral contraceptives, progestins, GnRH-a, LNG‑IUS, traditional Chinese medicine, and so on. Unfortunately, medicinal therapy often only provides temporary relief from symptoms, with symptom recurrence occurring after treatment cessation. The prolonged use of certain medications may result in noticeable adverse reactions, such as vasomotor syndrome, osteoporosis, and mood instability, thereby compromising treatment adherence. When patients who are intolerant to adverse drug reactions or fail to respond to drug therapy, surgical management can be considered. Currently, there is no optimal approach for preserving the uterus in cases of intrinsic adenomyosis. Adenomyosis leads to myometrial stiffening, resulting in abnormal opening of vessels within the lesion and subsequent uterine bleeding. This explains why the removal of endometrium cannot effectively improve excessive menstrual bleeding associated with adenomyosis. The hysteroscopic surgery is limited to the removal of focal adenomyosis lesions located in the superficial muscle layer adjacent to the endometrium. And due to lack of a distinct cleavage between the normal myometrial tissue and lesion make the procedure quite challenging [Citation15]. In addition, it carries a risk of intrauterine adhesion after the surgery. The combination of hysteroscopic surgery and LNG-IUS has been demonstrated in multiple studies to have a certain efficacy in improving abnormal uterine bleeding caused by adenomyosis [Citation16,Citation17]. However, its primary drawback is the high expulsion rates (ranging from 9.1% to 37.5%) [Citation18,Citation19]. Our experience has demonstrated that the LNG-IUS is prone to expulsion when the uterine depth exceeds 9 cm. Furthermore, in cases where there is a significant thickening of the endometrium-muscular junction area, effective drug concentration may not be achieved for lesions located away from the uterine cavity, potentially compromising disease control. Although the symptoms can be promptly alleviated following uterine-sparing adenomyomectomy, the procedure is associated with significant trauma and a high likelihood of blood transfusion. Moreover, due to the diffuse growth and invasive characteristics of adenomyosis, the recurrence rate remains high in the absence of long-term medication management. The non-surgical approach of focused ultrasound ablation system (HIFU) delivers energy through tissue to rapidly elevate temperature, inducing instant coagulative necrosis of target lesions. Operating under imaging guidance can avoid damage to nearby structures. Subsequently, immune phagocytosis gradually absorbs the necrotic lesions, effectively reducing menstrual volume and alleviating dysmenorrhea. However, in the case of intrinsic adenomyosis, the endometrium becomes thinner and susceptible to be ablated due to injury at the Junctional Zone endometrium [Citation20]. Therefore, it is challenging to expand the ablation rate while preserving the integrity of the endometrium, especially for lesions located in the posterior wall of the uterus. Recent evidence strongly indicates that ablation of the in situ endometrium can achieve superior therapeutic outcomes [Citation8]. In this study, HIFU may cause partial ablation of the endometrium. This type of damage creates a ‘window’ for subsequent hysteroscopic removal of lesions, as it exposes the necrotic tissue within the uterine cavity. But, such ablation could potentially impact fertility. Therefore, patients with fertility requirements were excluded from the study. If patients with fertility requirements are included, the ablation rate of lesions may need to be reduced to prioritize the protection of the endometrium, which could consequently lower the effectiveness rate. The ablation of endometrium may lead to post-operative irregular vaginal bleeding and abnormal vaginal discharge. In this study, 40% of the patients (12/30) experienced an increase in vaginal discharge, and 23.3% of the patients (7/30) complained about vaginal spotting following HIFU treatment, which diminished patients’ quality of life. As the necrotic tissue is gradually absorbed and the surrounding muscle layer retracts, it protrudes toward the uterine cavity. The presence of necrotic tissue in the uterine cavity may lead to an elevation in vaginal discharge. It is widely recognized that LNG-IUS plays a crucial role in long-term postoperative management of adenomyosis [Citation21]. The high local drug exposure of LNG-IUS in the uterine cavity creates a strong concentration gradient from the endometrium to the myometrium (>100 times) [Citation22]. However, in post-HIFU patients with intrinsic adenomyosis, residual necrotic tissue hinders the LNG-IUS from effectively contacting the active lesion, potentially compromising its therapeutic efficacy. In this study, we conducted hysteroscopic surgery to excise necrotic tissue caused by HIFU, and placed LNG-IUS simultaneously to ensure a proper placement. There is a clear boundary between necrotic tissue and myometrium and no blood flow within the necrotic tissue, which facilitates the removal of the lesion. In addition, because necrotic tissue is crumbly and soft, suction curettage can improve the efficiency of surgery. elucidates the treatment scheme. The 30 patients included in this study did not use GnRH-a. However, due to the long interval between HIFU and hysteroscopic surgery (median time interval is 6 months), there is a theoretical possibility of new lesion formation. Therefore, it is recommended to administer GnRH-a during the interval between HIFU and hysteroscopic surgery to prevent new lesion formation. When the uterus has shrunk to the size of an 8-week pregnant uterus [Citation9], hysteroscopic surgery should be considered. For patients whose uterine cavity depth is less than 9 cm after removing necrotic tissue during hysteroscopy, the probability of LNG-IUS expulsion is estimated to be relatively low. Currently, studies on HIFU treatment, as well as its combination with GnRH-a or LNG-IUS for uterine adenomyosis, have shown efficacy in symptom improvement [Citation23,Citation24]. Nevertheless, this study represents the first attempt to integrate HIFU with hysteroscopy-guided placement of LNG-IUS. In this study, the incidence of displacement of LNG-IUS within 2 years was 3.3%, which was significantly lower than the 9.1 − 37.5% reported in previous studies [Citation18,Citation19,Citation25], even when using GnRH-a pretreatment [Citation26]. Previous studies have shown that after 2 years of HIFU treatment, the rate of relief for dysmenorrhea was 82.3%, and the rate of relief for menorrhagia was 78.9% [Citation24]. Our two-year results show that the relief rates are 86.7% and 93.3%, respectively. Since this study exclusively focused on cases of intrinsic uterine adenomyosis and the majority of previous studies did not incorporate subtype classification, it is challenging to establish direct and objective comparisons of therapeutic efficacy. Since this is a single-arm retrospective study, it remains challenging to precisely quantify the individual contributions of HIFU, hysteroscopy, and LNG-IUS to symptom improvement and long-term disease management. The limited number of cases in this report also has imposed certain limitations on the research conclusions. In subsequent studies, we will strive to increase the sample size and add control groups, conduct prospective studies, and carry out long-term efficacy follow-ups to further verify the relevant research results. Furthermore, 30 patients who underwent HIFU treatment and successfully placed LNG-IUS under hysteroscopy were selected. Patients with extremely large uteruses were excluded from the study statistics as they were deemed unsuitable for contraceptive device placement after assessment. There was a certain selection bias. Therefore, the application value of this treatment method in patients with extremely large uterine adenomyosis requires further research. Pretreatment with GnRH-a before HIFU may increase the efficiency. Further research is needed in the future.

HIFU combined with hysteroscopic insertion of LNG-IUS is a recommended and effective therapeutic strategy for treating intrinsic adenomyosis. However, the existing studies are limited in the number of cases, and further clinical validation is essential to ascertain its prospective application value. 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 from the corresponding author, [S. P. Zhao], upon reasonable request. This study is a retrospective analysis and received ethical approval from the institutional medical ethics committee (No. QFELL-YJ-202353). Additional information Funding

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