Effect of high-intensity focused ultrasound ablation on lesion stiffness and symptoms of adenomyosis

Objectives To investigate the relationship between lesion stiffness and symptoms of patients and to evaluate the effectiveness of high-intensity focused ultrasound ablation (HIFUa) against lesion stiffness and symptoms of patients with adenomyosis.

A total of 124 patients with adenomyosis treated with HIFUa were included. Baseline characteristics and adenomyotic lesion stiffness were collected to identify factors associated with stiffness. Data on the changes of uterine lesion stiffness (E value), the menstrual volume score (PBAC), and the dysmenorrhea numeric rating scale (NRS) score before and 1, 3, and 6 months after HIFUa treatment in 42 patients were collected to explore the effects of HIFUa on stiffness and symptom changes.

Before HIFUa, adenomyotic lesion stiffness was significantly greater than that of the normal myometrium. Adenomyotic lesion stiffness was significantly positively correlated with moderate to severe dysmenorrhea (r = 0.731), however, there was no significant linear correlation with hypermenorrhea (r = 0.153). Compared with that at pretreatment, stiffness at 3 and 6 months significantly decreased (that is, the elasticity increased) (p < 0.01). The NRS and PBAC scores at 1, 3, and 6 months were significantly lower than those at before HIFUa (p < 0.01), and the decrease in the NRS score was related to the decrease in stiffness.

For adenomyosis patients with moderate to severe dysmenorrhea, lesion stiffness has been proven to be an objective reflection of dysmenorrhea severity. Lesion stiffness can be used as an imaging index to evaluate dysmenorrhea severity. Dysmenorrhea relief after HIFUa is related to decreased lesion stiffness.

Adenomyosis (AM) is a complex benign gynecological disease often accompanied by dysmenorrhea, menorrhagia, chronic pelvic pain, irregular vaginal bleeding, and infertility, seriously affect the quality of life of patients [Citation1]. The disease was discovered more than 100 years [Citation2], but its pathogenesis remains unknown. In terms of pathophysiology, AM is characterized by the infiltration of ectopic endometrial glands and stroma into the myometrium. Microtrauma at the endometrium-uterine junction zone, inflammation, and fibrosis are all implicated in the development of this disease and its symptoms [Citation3–5]. The degree of fibrosis may be related to dysmenorrhea and excessive menstrual bleeding. The patients with more fibrosis in adenomyotic lesion had more severe symptoms of dysmenorrhea than patients with less fibrosis in adenomyotic lesion [Citation6,Citation7]. In a previous study, patients in the group of failed treatment with levonorgestrel release intrauterine system (LNG-IUS) had lower levers of estrogen-α and progesterone receptors in the stroma of adenomyotic lesions and more pronounced fibrosis [Citation8]. Therefore, fibrosis in adenomyotic lesion is not only related to symptoms in patients, but also affects therapeutic efficacy, so more effective treatment programs are needed. In recent years, high-intensity focused ultrasound ablation (HIFUa) has shown good therapeutic effects in the treatment of adenomyosis and this technique has been considered to potentially have a positive impact on infertility. However, the mechanism by which HIFUa alleviates the symptoms of adenomyosis is unclear. Histopathological diagnosis of tissue fibrosis requires samples of tissue, which are often difficult to obtain in vivo. However, the advent of ultrasound elastography has made noninvasive clinical assessment of tissue stiffness possible. Through this method, it has been demonstrated that there is a significant correlation between the degree of fibrosis in adenomyotic lesions and tissue stiffness, thereby improving the diagnostic imaging accuracy for adenomyosis [Citation9]. Strain elastography is the earliest diagnostic method used to evaluate the pathological and stiffness conditions of the uterus [Citation10]. Nevertheless, the semiquantitative nature of this method, coupled with its dependence on manual compression, limits its reliability for objective quantification of uterine stiffness or elasticity. In contrast, shear wave elastography (SWE), employing acoustic radiation force impulses or external mechanical vibrations to generate transverse wave propagation through tissues, has emerged as a technologically superior alternative. This advanced diagnostic approach enables direct quantification of tissue stiffness or elasticity through the precise measurement of shear wave velocity, which can be subsequently converted into stiffness parameters, thereby providing clinicians with a reliable, reproducible assessment tool for evaluating tissue stiffness or elasticity [Citation11]. Several studies have demonstrated that the stiffness of adenomyotic lesions is significantly greater than that of normal myometrium [Citation12,Citation13]. Nevertheless, the clinical correlation between lesion stiffness and symptom severity remains poorly understood. To address this scientific question, this study was organized into two integrated parts. The initial phase involved the use of shear wave elastography (SWE) to conduct real-time quantitative assessments of lesion stiffness in patients with adenomyosis. In this phase, the relationships between lesion stiffness and the clinical characteristics of patients with adenomyosis were evaluated to establish a crucial foundation for the second phase. The second phase is involved implementing a follow-up protocol, monitoring post-treatment outcomes, and modifying lesion stiffness to assess the effect of HIFUa treatment on stiffness and adenomyosis symptoms to provide preliminary insights into the potential mechanisms underlying HIFUa-mediated symptom alleviation in adenomyosis patients.

This retrospective study was approved by the Ethics Committee of Guizhou Provincial People’s Hospital, Guizhou, China (No. 2021-83) and the requirement for informed consent was waived. Patients A total of 124 patients with adenomyosis who underwent HIFU treatment at our hospital between April 2023 and March 2024 were enrolled. The inclusion criteria were as follows: (1) premenopausal women with moderate to severe dysmenorrhea, with or without menorrhagia, (2) the diagnosis of adenomyosis was made by transvaginal ultrasound and magnetic resonance imaging (MRI), (3) patients with adenomyosis who didn’t take other medication or had surgery within 3 months before treatment and provided voluntary consent for HIFUa treatment, (4) body mass index <28 kg/m2, (5) had pretreatment elastography assessment of adenomyosis lesions with all HIFUa procedures successfully administered to ensure eligibility for part I of this study. (6) Participants who underwent lesion elastography tests and whose symptoms were followed up before and after treatment were included in part II of the study. The inclusion criteria for the part II of the study were identical to those in the first part. Subjects from the initial part who had undergone at least one postoperative stiffness measurement were recruited for the second part of the study. Due to the retrospective nature of the study, postoperative elastography was not available for all enrolled patients. To mitigate potential selection bias, we consecutively included all eligible cases rather than only those with complete postoperative data. Patients were excluded if the met any of the following criteria: (1) had ovarian endometrioma, pelvic endometriosis, or uterine fibroid; or (2) had any other medical condition deemed ineligible by the principal investigators. Premenopausal patients without myometrial lesions were included in the control group, encompassing three conditions: ovarian cyst, cervical intraepithelial neoplasia, or endometrial polyps; no history of dysmenorrhea or menorrhagia, and no abnormalities in the myometrium on ultrasound (). Imaging diagnosis of adenomyosis The diagnostic criteria for adenomyosis on ultrasound are based on the Consensus on Revised Definitions of Morphological Uterus Sonographic Assessment (MUSA) [Citation14]. All the ultrasound examinations were performed by ultrasound physicians with more than 5 years’ experience in gynecological ultrasound. A GE Voluson E6 diagnostic ultrasound system (GE Healthcare, Austria, Innsbruck) with a transvaginal IC5-9-D probe was used. All patients underwent standard pelvic magnetic resonance imaging (MRI) examinations with a 1.5T Siemens Aera scanner (Siemens Healthineers, Shenzhen, China) before HIFUa. The imaging protocol consisted of T1-weighted imaging (T1WI) in the axial, sagittal, and coronal planes, complemented by dynamic contrast-enhanced sequences to obtain detailed morphological and vascular information. The diagnostic criteria for adenomyosis on MRI based on MRI diagnostic standards outlined in the European Society of Urogenital Radiology (ESUR) guidelines [Citation15]. MRI T2-weighted imaging (T2WI) classification was performed according to the spatial relationship between lesions and endometrial/myometrial boundaries, categorizing adenomyosis into four distinct types: Subtype I (intrinsic), Subtype II (extrinsic), Subtype III (intramural), and type IV (mix/indeterminate) [Citation16]. Signal intensity assessment was conducted using normal myometrium and the endometrial cavity as reference standards: hypointense (lesion signal intensity lower than the normal myometrium), isointense (lesion signal intensity equal to the normal myometrium), hyperintense (lesion signal intensity higher than the normal myometrium but lower than the endometrial cavity) [Citation17], and heterogeneous (mixed signal characteristics with interspersed areas of hypointensity). Two-dimensional shear wave elastography (2D-SWE) The Siemens ACUSON Sequoia ultrasonic diagnostic system (Siemens ACUSON Sequoia, Siemens Healthineers, Issaquah, America), which uses a 5C1 transducer with a frequency range of 1.0–5.7 MHz and incorporates shear wave elastography (SWE) technology, was used in this study. Shear wave elastography (SWE) examinations were independently performed by two gynecologists, each with over 5 years of experience in ultrasonographic diagnosis and therapy of gynecological diseases, as well as experience in SWE. The procedure was conducted as follows. Initially, the sagittal plane was selected, and the surrounding intestinal structures were gently displaced. In accordance with the MRI findings, the 2D mode was employed to clearly visualize the adenomyotic lesion. During imaging, the operator’s elbow was stabilized against the patient’s leg to maintain probe stability. The system was subsequently switched to two-dimensional shear wave elastography mode. Upon achieving stable imaging, each patient was instructed to hold her breath to minimize respiratory motion artifacts. Shear waves were then emitted to generate elastography images. Quantitative measurements, including shear wave velocity (Vs) and tissue stiffness (E-value), were obtained after satisfactory image quality was confirmed. Each physician took at least three stiffness measurements per lesion, with the final E-value calculated as the average of the median values. The tissue elasticity values were calculated using the formula E = 3ρCs2 [Citation18], where E represents the tissue stiffness or elasticity, ρ denotes the tissue density, and Cs indicates the shear wave velocity. Higher E values correspond to greater tissue stiffness and reduced elasticity. All measured E values within the region of interest (ROI) were collected, with a minimum requirement of three measurements. The software automatically calculates the median E value. This procedure was repeated in the transverse plane to obtain corresponding E values, enabling comprehensive assessment of lesion stiffness through multiplanar evaluation. HIFU ablation An Focused Ultrasound Tumor Therapeutic System (Model-JC200D, Chongqing Haifu Medical Technology Co., Ltd., Chongqing, China) was used for ultrasound ablation treatment. The procedure HIFUa was performed by gynecologists who were certified in this technique and had a minimum of three years of hands-on experience. The therapeutic ultrasound parameters included a focal length of 170 mm, focal region dimensions of 3 mm (width) × 8 mm (length), and an operating frequency of 1.0 MHz. The patient was maintained in the prone position throughout the procedure. A water-filled balloon catheter was employed to displace the bowel to create an optimal acoustic pathway for treatment. Intraoperative conscious sedation was achieved through intravenous administration of sufentanil citrate (1 μg per dose) at 30-min intervals, ensuring adequate patient comfort and treatment efficacy. The target lesion was systematically divided into 5-mm thick treatment layers. Treatment parameters, including location and intensity, were dynamically adjusted on the basis of real-time patient responses and grayscale changes observed during sonography. The therapeutic focal points were maintained at a safety margin of ∼15 mm from both the endometrial and serosal layers. Immediately following treatment completion, contrast-enhanced ultrasound using sulfur hexafluoride microbubbles was performed to evaluate the immediate treatment efficacy. The adenomyotic volume was calculated as follows: Uterine/lesion/nonperfused volume (V) = 0.5233*D1 × D2 × D3, where D1 is the long diameter, D2 is the left–right diameter, and D3 is the anteroposterior diameter. The non-perfused volume (NPV) ratio = NPV/primary lesion volume*100%. Symptom assessment The intensity of dysmenorrhea was measured utilizing the numeric rating scale (NRS) score, a tool that spans from 0 to 10, with ‘0’ denoting ‘absence of pain’ and ‘10’ indicating ‘the most severe pain conceivable’ [Citation19]. Based on the NRS classification, pain was graded as none (0), mild (1–3), moderate (4–6), or severe (7–10). Clinical evaluation was performed by two experienced attending gynecologists using Pictorial Blood Loss Assessment Chart (PBAC) score to assess menstrual blood loss. The PBAC score is determined based on the degree of sanitary pad soiling and the size of blood clots. All scores recorded throughout the entire menstrual cycle were summed to obtain a total PBAC score for each patient. The scores exceeding 100 points are diagnostic of menorrhagia [Citation20]. Evaluation of clinical symptom after HIFUa treatment The criterion for dysmenorrhea and menstrual volume relief was defined as follows: (1) obvious relief: the difference is over 2 points; (2) partial relief: the difference is 1 point; (3) complete relief: symptoms are completely relieved; (4) aggravation: post-operative scores increase. The clinical overall symptom relief included obvious relief, partial relief, and complete relief [Citation21]. Statistical analysis SPSS software (version 23.0; IBM, New York, NY, USA) was used for the statistical analysis. Normally distributed continuous data were expressed as the means ± standard deviations, whereas skewed distributed data were presented as medians (Q1, Q3). A generalized linear regression model was used to assess the relationships between the NRS score, PBAC and lesion stiffness, MRI classification, MRI-T2 signal, gravidity, parity, uterine volume, and lesion volume. The strength of the associations between symptoms and the aforementioned variables was analyzed using Spearman’s correlation method. For intergroup comparisons, the t-test was applied for normally distributed data, whereas the Mann–Whitney U test was used for skewed distributed data. The chi-square test was used to compare proportions. Changes in E values and symptoms before and after treatment, along with their relationships, were analyzed using linear mixed-effects models.

Baseline characteristics and patients with adenomyosis Data, including tissue stiffness E values (11.73 ± 5.24 kPa), dysmenorrhea pain scores assessed by means of the NRS score (6.21 ± 1.53), menstrual blood loss scores evaluated by PBAC (191.51 ± 122.2), and relevant clinical characteristics (), were collected from 124 patients before HIFU therapy. The uterine volume and stiffness in the adenomyosis group were significantly greater than those in the control group (p < 0.01) (). A significant difference in lesion stiffness was observed between patients with moderate and severe dysmenorrhea (p < 0.01) (). Correlation analysis of dysmenorrhea with tissue stiffness and clinical characteristics The degree of dysmenorrhea as measured with the NRS, showed a significant positive linear correlation with lesion stiffness (, p 0.05, Spearman’s coefficient r = 0.153). Furthermore, no significant associations were found between dysmenorrhea or menorrhagia symptoms and gravidity, parity, adenomyosis MRI classification, MRI-T2 signal, or lesion volume ( and ). Changes in lesion stiffness and symptoms after HIFU treatment In total, 124 patients were enrolled before treatment. Following HIFU therapy, the overall symptom relief rate for dysmenorrhea at 1, 3, and 6 months post-treatment were 83.47% (96/115), 89.22% (91/102), and 86.67% (78/90), respectively. The overall symptom rate for menorrhagia, respectively at 1, 3, and 6 months post-treatment were 65.22% (75/115), 79.41% (81/102), and 76.67% (69/90). Among these patients, 42 underwent at least one follow-up assessment for lesion stiffness and symptom changes (designated Group A). To evaluate the representativeness of Group A, baseline characteristics and treatment parameters were compared with those of the 82 patients who did not undergo stiffness follow-up (designated Group B). No significant differences between the two groups (p > 0.05) were observed, as detailed in . In Group A, consisting of 42 patients, at least one follow-up was completed at 1, 3, and 6 months posttreatment, with follow-up rates of 95.3% (40/42), 83.3% (35/42), and 76.2% (32/42), respectively. Compared with that at baseline, lesion stiffness at 1 month was not significantly different (p > 0.05). However, the posttreatment E values at 3 and 6 months were significantly lower than the pretreatment ones (p < 0.01) (). Compared with those at baseline, the NRS and PBAC scores at 1, 3, and 6 months were significantly reduced (all p < 0.01) ( and ). Reduction in the NRS score correlating with a decrease in lesion stiffness (p < 0.01) ().

Our study demonstrates that adenomyotic lesions are significantly stiffer than the normal myometrium (p < 0.01). Furthermore, adenomyotic lesion stiffness significantly positively correlation with moderate-to-severe dysmenorrhea (p < 0.01), suggesting a pivotal role of tissue fibrosis in the pathogenesis of the disease. Following HIFUa treatment, a significant clinical improvement was observed, concomitant with a gradual reduction in lesion stiffness. The stiffness significantly decreased at 3 (11.47 ± 1.19 vs. 8.60 ± 0.65, p < 0.05) and 6 months (11.47 ± 1.19 vs. 7.66 ± 0.59, p < 0.01) after HIFUa. The alleviation of dysmenorrhea was associated with the decrease in stiffness, indicating that the ablation of fibrotic tissue may be one of the underlying mechanisms of HIFUa for adenomyosis. Adenomyosis significantly affects the quality of life and reproductive health of patients, with a reported infertility incidence of 29.7% [Citation22]. Although the precise pathogenesis of adenomyosis remains unclear, accumulative evidence indicates that fibrosis plays a pivotal role in the initiation and progression of the disease [Citation3,Citation23]. The extent of fibrosis is considered a hallmark of advanced adenomyosis and elastographic imaging could be used to help choose the best treatment modality for deep endometriosis or adenomyosis [Citation9]. In this initial phase of the study, our results showed a significant correlation between lesion stiffness, measured by shear wave elastography, and dysmenorrhea of patients. This confirmed the pivotal role of fibrosis in symptom generation. As patients with mild pain often do not seek specialized care or have already received pharmacological management in outpatient clinics, those presenting to our center typically have moderate to severe pain; thus, lesion stiffness in patients with mild pain remains unclear. Owing to frequent diagnostic delays, adenomyosis is often characterized by a protracted clinical course and pronounced local fibrosis. This not only exacerbates clinical manifestations such as dysmenorrhea and heavy menstrual bleeding but also contributes to therapeutic resistance and reduced treatment efficacy [Citation24–29]. Furthermore, severe fibrosis is associated with an increased risk of LNG-IUS treatment failure [Citation8]. Consequently, there is a critical need to develop effective strategies for the assessment and targeted management of fibrosis in adenomyosis. The advent of elastography has provided a novel, noninvasive, and reproducible diagnostic tool in clinical practice. Currently, the clinical imaging diagnostic methods predominantly include strain elastography (SE), transient elastography (TE), acoustic radiation force impulse (ARFI) imaging, and shear wave elastography (SWE) [Citation30]. TE is limited by its inability to display two-dimensional grayscale images simultaneously and by its susceptibility to interference from factors such as obesity and ascites. On the other hand, ARFI and SE, which are stress-dependent methods, are limited by the nonquantifiable nature of manually applied pressure, necessitating operator expertise and stringent control to ensure reproducibility [Citation31]. In contrast, SWE quantitatively and qualitatively assesses tissue stiffness by generating and measuring shear waves within the tissue, with results expressed as shear wave velocity or converted into E values [Citation11]. While studies utilizing SWE to evaluate adenomyotic lesion stiffness have yielded heterogeneous results with some reporting reduced stiffness in lesions compared with the surrounding myometrium, the majority of evidence indicates elevated lesion stiffness relative to adjacent myometrial tissue [Citation32–34]. This increased stiffness has been postulated to be correlated with the severity of dysmenorrhea [Citation35]. In this study, shear wave elastography (SWE) was employed to evaluate adenomyotic lesions, revealing significantly greater stiffness in the lesions than that in the normal myometrium. The stiffness (E value) of the lesions was positively correlated with the severity of dysmenorrhea, further supporting the association between lesion stiffness and pain intensity, and indirectly indicating the degree of fibrotic changes within the lesions. Therefore, we speculated that tissue fibrosis is the basis of HIFU treatment for adenomyosis. As such, quantifying tissue stiffness presents a promising noninvasive method for evaluating disease severity and prognosis, potentially aiding in treatment selection. In recent years, HIFUa has emerged as a minimally invasive treatment modality widely applied in the management of benign uterine diseases, demonstrating efficacy and safety in the treatment of adenomyosis. However, the changes in lesion stiffness following HIFUa treatment for adenomyosis remain poorly understood, posing clinical uncertainties. This study aimed to address this question by comparatively analyzing changes in lesion stiffness before and after HIFUa treatment. Although stiffness measurements before and after treatment were available for only 42 of the 124 patients who underwent HIFU therapy, the NPV and overall symptom relief rate observed in this study aligns with previously reported results [Citation21]. Additionally, comparisons of clinical characteristics, HIFUa treatment parameters, and pretreatment stiffness between the group with stiffness follow-up and the group without stiffness revealed no significant differences, indicating that the 42 cases are representative. The fundamental principle of HIFUa treatment is based on the induction of coagulative necrosis within the target lesion tissue. Although coagulative necrosis is typically expected to result in increased tissue stiffness, our findings demonstrated no significant elevation in lesion stiffness at one month post-HIFUa intervention. This discrepancy may be explained by the delayed timing of the initial assessment, as the tissue repair and remodeling processes could have already modulated the mechanical properties of the lesion at this time point. Notably, despite the absence of a substantial reduction in lesion stiffness at one month posttreatment, patients exhibited marked alleviation of dysmenorrhea symptoms. This symptomatic improvement is likely attributable to the necrosis of both the lesion and surrounding nerve fibers induced by HIFUa, which may disrupt nociceptive pathways and contribute to pain relief. By utilizing elastography technology for dynamic monitoring of posttreatment lesion stiffness, we observed a significant temporal reduction in lesion stiffness, which may be attributable to the progressive softening and absorption of necrotic tissue. Concurrently, a corresponding decrease in numerical rating scale (NRS) scores, demonstrating a strong correlation with a decrease in lesion stiffness was noted. These findings suggested that the reduction in stiffness may represent one of the key mechanisms through which HIFUa treatment further alleviates dysmenorrhea symptoms in adenomyosis patients. Given that the regeneration rate of peripheral nerve fibers is 1–2 mm/day [Citation36], the necrosis of nerve fibers alone is unlikely to account for the long-term relief of dysmenorrhea. Therefore, the sustained reduction in lesion stiffness may serve as the critical pathophysiological basis for the persistent alleviation of dysmenorrhea symptoms following HIFUa treatment. Concurrently, the reduction in lesion stiffness suggests an improvement in uterine elasticity, which may facilitate the restoration of normal uterine function, including its role in supporting pregnancy. The disease is also associated with an increased risk of pregnancy-related complications, including preterm delivery, small-for-gestational-age infants, preeclampsia, and gestational hypertension [,Citation37]. Moreover, adenomyosis negatively impacts the outcomes of IVF/ICSI and increases the risk of early pregnancy loss [Citation38]. Several studies have indicated that HIFU may enhance reproductive outcomes in patients with adenomyosis. Compared with laparoscopic lesion resection, HIFU has been associated with higher rates of pregnancy and natural conception [Citation39]. Adenomyosis is known to significantly impact pregnancy outcomes, and our findings demonstrate a decrease in uterine stiffness and localized fibrosis following HIFUa treatment. We hypothesized that the observed increase in pregnancy rates among adenomyosis patients after HIFUa may be attributable to the reduction in stiffness and the corresponding improvement in uterine elasticity. The results of this study not only reaffirmed the correlation between lesion stiffness and the severity of dysmenorrhea in patients with adenomyosis, but also demonstrated for the first time that the reduction of lesion stiffness is closely associated with the relief of dysmenorrhea. These findings provided dual evidence supporting the significant relationship between lesion stiffness and dysmenorrhea in adenomyosis. In addition, this study demonstrated for the first time that the degree of stiffness in the lesions gradually decreases over time after HIFUa treatment, indicating a gradual improvement in uterine elasticity. This study is limited because of the sample size was relatively small and the absence of patients with mild pain, which may limit the generalizability of the findings. Secondly, the follow-up duration was insufficient to evaluate long-term outcomes. At last, the incomplete postoperative elastography data, which is inherent to its retrospective design and reflects real-world clinical follow-up challenges. However, a comparative analysis showed no significant differences in baseline characteristics between patients with and without postoperative data, suggesting that the missing data were random. Therefore, prospective, multicenter and prospective studies are needed to validate these results in the future.

A positive correlation was observed between uterine lesion stiffness and the severity of dysmenorrhea in patients with moderate to severe adenomyosis, and thus can serve as a reliable imaging biomarker for assessing the degree of dysmenorrhea in this patient population. The alleviation of dysmenorrhea symptoms following HIFUa is closely associated with a reduction in lesion stiffness, suggesting that the decline in stiffness may be one of the key mechanisms underlying the symptomatic relief observed in patients with 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 on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the privacy of research participants. Additional information Funding

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