Postoperative Outcomes on Endometriosis-related Pain Following Laparoscopic Adenomyomectomy: A Retrospective Cohort Study

Adenomyosis is considered another common spectrum of endometriosis defined by the presence of endometrial glands and stroma within the hypertrophic myometrium.[ 1 ] Despite growing evidence of endometriosis, specific studies focusing on adenomyosis are still lacking. Numbers of theories have been investigated and the invagination of the basalis endometrium through the junctional zone is widely accepted.[ 2 ] After the disruption of endometrial–myometrial interface occurs, the ectopic endometrium recruits macrophages and fibroblasts that produce inflammatory cytokines and angiogenic factors causing repeated tissue injury and repair. Common presenting symptoms are pelvic pain, heavy menstrual bleeding, and infertility.[ 3 ] Even with the use of assisted reproductive treatment (ART), adenomyosis also harms clinical pregnancy after in vitro fertilization (IVF).[ 4 ] Several methods of treatment were investigated. Based on the pathogenic mechanism that is mostly shared with endometriosis, the rationale of medical treatment is to regulate the sex steroid-dependent endometrial proliferation.[ 5 ] Progestin promotes decidualization and then atrophic change of endometrial tissue causing significant pain and bleeding reduction. Hormonal therapy is the main conservative treatment of adenomyosis to control pain and bleeding symptoms, but it limits the chance of conceiving during treatment. However, histologic studies in adenomyosis patients showed lower estrogen and progesterone receptor expression in ectopic endometrium compared to the functionalis layer. Owing to the repeated inflammatory process, the surrounding myometrium becomes fibrosis. The response to medical treatment might be suboptimal. Surgical treatment of adenomyosis aims to relieve pain symptoms together with promoting fertility. Because of the aforementioned fibrotic lesion, the procedure becomes more challenging, especially the diffuse type. Optimal uterine incisions aim to remove the lesion with sufficient residual tissue to be approximated tightly. The creation of the flap providing multilayer closure has been reported. Moreover, the uterine defect should be sutured meticulously without leaving any dead space. The triple flap method is a well-known technique that was first demonstrated using the laparotomic approach to remove affected tissue with a 1 cm margin below the serosal surface and another 1 cm beneath the endometrial cavity. Afterward, the endometrial lining was approximated; then, a part of the bisected uterus was closed from the anteroposterior, the another was brought over the closed seromuscular suture line.[ 6 ] Laparoscopic adenomyomectomy was first performed using the flap between upper and lower serosal layers and the results showed favorable pain and bleeding.[ 7 8 ] The postoperative pregnancy rate is between 29% and 72.7%, but it is largely confounded by a number of factors, such as age, male factor infertility, and the use of ART.[ 9 10 ] Some obstetric complications were lower in patients who underwent adenomyomectomy, such as preeclampsia and fetal growth restriction[ 11 ] Lately, the novel four-petal method was demonstrated. It resects adenomyotic lesion at 5 mm depth from the tip of each petal toward the lateral border. A subsequent incision at 10 mm superficial to the endometrium was created parallelly. After the removal of adenomyosis, closure by suturing between the serosal flap and subendometrial layer was performed.[ 12 ] However, the drawback of adenomyomectomy is the inadequate removal of adenomyosis resulting in recurrent pain following surgery with a 3-year recurrent rate of 34.8%.[ 13 ] This article aims to evaluate the remission of endometriosis-related pain after laparoscopic adenomyomectomy and the risk of recurrence following the operation.

Sixty-eight patients who underwent laparoscopic adenomyomectomy were enrolled. After exclusion, 3 patients with age more than 45 years old, 14 patients with incompatible pathologic diagnosis, 9 with coexisting ovarian endometrioma, 8 without preoperative pain, 1 with chronic lumbar radiculopathy, 2 with Mullerian duct anomaly, and 4 losses follow-up, 26 were included in the final analysis. The baseline characteristics including preoperative and intraoperative data are revealed separately in Tables 1 and 2 , respectively. The mean age of patients was 38.0 ± 3.40 years. The mean VAS score for endometriosis-related pain symptoms was 6.1 ± 0.9. 53.8% of patients are nulliparous and 78.5% of these patients need fertility within 1 year. About 76.9% had been underwent abdominal surgeries, mostly endometriosis-related surgeries. The average uterine diameter was 10.2 ± 2.17 cm and the largest diameter of the adenomyoma was 4.8 ± 2.01 cm. Baseline preoperative characteristics BMI: Body mass index, IQR: Interquartile range, VAS: Visual Analog Scale, SD: Standard deviation Intraoperative characteristics BMI: Body mass index, IQR: Interquartile range, 3D: Three-dimensional, rAFS: Revised american fertility society Intraoperative findings showed that the majority, 64.3% of cases, were classified as severe according to the American Society of Reproductive Medicine, and excision of deep endometriosis was also performed. Urologic reconstruction was performed in two cases; both were intended for ureteroureterostomy by urologists. The mean operative time was 276.2 ± 105.31 min. Intraoperative blood loss of more than 500 mL was in 30.8% of patients and 87.5% of them received blood transfusion. Postoperative outcomes in Table 3 shows that all patients reported remission of pain in the 6 th week, 84.6% complete remission, 11.5% significant remission, and 3.9% partial remission. There are 2 patients with recurrent symptoms existed. At 12 th and 24 th week postoperative, 96.2% and 96.0% were in remission. Hormonal treatment was prescribed for 86.4%, 68%, and 60% of patients in 6 th , 12 th , and 24 th week, respectively. The lower rate of hormonal use was due to the need to try conception of the patients. Six patients visited the infertility unit to undergo infertility treatment; three patients to IVF and 3 to transfer the frozen embryos. Postoperative outcomes There are 2 recurrent cases. The first patient had increasing dysmenorrhea at the 8 th week postoperative and she decided to undergo hysterectomy. Another case had a recurrence in the 22 nd week with mild symptoms. Fortunately, her dysmenorrhea was relieved using combined oral contraceptive pills. No recurrence of heavy menstrual bleeding was reported. Univariate analysis on recurrence of pain symptoms is shown in Table 4 . All of the recurrent cases had larger size of adenomyoma than 4 cm. However, severe endometriosis, excision of deep endometriosis, and postoperative hormonal treatment, either GnRH agonist or hormonal treatment, had no different impact on pain recurrence. Adjusted by postoperative hormonal uses, remission of pain, and heavy menstrual bleeding were also not different. Two patients with recurrent pain symptoms are in the hormonal treatment group and no recurrent heavy menstrual bleeding in our study. Univariate analysis on factors associated with the recurrence of pain symptoms DE: Deep endometriosis Four patients were hormone-free throughout the postoperative period and they were analyzed separately shown in Table 5 . No significant symptomatic recurrence, both pain and heavy bleeding, compared with those who received postoperative hormonal treatment. Subgroup analysis on recurrent rate adjusted by hormonal treatment

Laparoscopic adenomyomectomy is the option of treatment with dramatically improved endometriosis-related pain symptoms, even in patients with severe endometriosis. Conceptualization, C. L. Lee and P. Maneerat; Methodology, P. Maneerat; Investigation, P. Maneerat and W. L. Lin; Resources, C. L. Lee and W. L. Lin; Writing - Original Draft Preparation, P. Maneerat and W. L. Lin; Writing - Review & Editing, C. L. Lee and P. Maneerat; Visualization, P. Maneerat; Supervision, C. L. Lee; Project Administration, C. L. Lee; Funding Acquisition, C. L. Lee. All authors have read and agreed to the final version of the manuscript. The datasets generated during and/or analyzed during the current study are publicly available. Prof. Chyi-Long Lee, the Editori-in-Chief at Gynecology and Minimally Invasive Therapy , had no role in the peer review process of or decision to publish this article. All authors declared no conflicts of interest in writing this paper.

Laparoscopic adenomyomectomy has been considered the option for surgical treatment in women suffering from adenomyosis who wish to preserve the uterus with favorable outcomes even in patients with severe endometriosis. The study showed a 96.2% rate of remission during the first 12 weeks postoperation. Compared with the other studies, that underwent both laparotomic and laparoscopic adenomyomectomy, 92.3%–100% of patients were completely in remission.[ 17 18 ] Another study also reported the mean VAS score was decreased from severe to mild degree.[ 6 ] The duration of follow-up varies up to 2 years. Even with the variation of surgical techniques and outcomes, adenomyomectomy was shown to relieve pain symptoms effectively.[ 19 ] Remission of bleeding was 96.2% and 100% in the 6 th and 24 th week, respectively. This was comparable with other studies. Other uterine-sparing modalities, such as uterine artery embolization (UAE) and high-frequency ultrasound (HIFU), have been reported to have benefits on adenomyosis-related pain by providing necrosis of adenomyotic tissue. UAE relieves symptoms in 83.1% of patients, especially in patients with higher vascularized adenomyosis and HIFU also improves the symptom severity score up to 65%. However, further pregnancy outcomes are the major concern after the necrosed uterus that impairs vascularization.[ 19 20 21 ] Hormonal treatment is another modality of endometriosis treatment in both pain and bleeding aspects. Thus, the outcomes of this study are considered to be confounded. However, subgroup analysis on symptomatic recurrence in the 24 th week was not different. Even in a small group of patients who were hormone-naïve, almost 40% of patients stopped using hormonal treatment within 24 th weeks without any recurrence. This finding warrants the favorable short-term outcomes following surgery that add value for patients who need to get pregnant. Infertility specialists should be consulted to promote ART for them. Similar to endometriosis, symptomatic recurrence without hormonal treatment has been reported up to 40% after 6 years.[ 16 ] Without fertility needs, all patients with adenomyosis should continue to use postoperative hormonal treatment. Hormonal treatment was the cointervention that could confound the surgical results. According to the European Society of Human Reproduction and Embryology recommendations,[ 22 ] postoperative hormonal treatment as an adjunctive treatment, defined as the short-term prescription of hormones <24 weeks, has been investigated and reported the benefit of GnRH agonists in postoperative pain reduction. Four patients in our study received GnRH agonists without additional benefit on symptom control. Strict inclusion criteria were the strength of this study. We aimed to avoid the coexisting endometrioma and preoperative medications to specify that the pain score was related directly to adenomyosis. However, coexisting deep endometriosis is common in adenomyosis and is usually undiagnosed preoperatively by pelvic ultrasonography. Most of the patients were severe cases that reflected the real-life encounters of adenomyosis patients who wished to preserve the uterus. Moreover, all of the patients underwent surgery by a single surgeon with expertise in deep endometriosis, so the surgeries were optimized equally for all patients. Detailed surgical data were also accessible from electronic medical records. Even though the pathologic results were all reported, the size of the excised lesion was not completely recorded. The analysis of the size of excised pathology was limited. Due to the surgical complexities, laparoscopic adenomyomectomy was not routinely performed. A retrospective study was conducted and some confounding factors could not be controlled. Prospective trials in a larger population would provide a higher power of study. Furthermore, fertility and pregnancy outcomes should be explored with longer follow-up duration.

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Medical Foundation (IRB No. 202400687B0). Informed consent was waived by the IRB. All patients who underwent adenomyomectomy from January 2019 to July 2023 were retrospectively reviewed using the electronic medical record. Preoperative baseline characteristics, intraoperative findings, and 24 th -week postoperative follow-up data were recorded. The inclusion criteria were as follows: (1) Age 20–45 years old; (2) Moderate degree of endometriosis-related pain; (3) Ultrasound findings revealed an enlarged uterus with the largest diameter of more than 8 cm with uterine wall thickening; (4) No coexisting ovarian endometrioma; and (5) Underwent laparoscopic adenomyomectomy. The exclusion criteria were listed as follows: (1) Coexisting ovarian endometrioma during intraoperative; (2) Conversion to laparotomy/hysterectomy; (3) Underlying Mullerian duct anomalies; (4) Final pathologic diagnosis is not adenomyosis; (5) Exposure to GnRH agonist or hormonal treatment within 6 months preoperative; (6) Incomplete follow-up data until 24 th week postoperative; (7) Patients with other conditions that affect pelvic pain, such as lumbar spondylosis, urinary tract calculi, and poor control diabetes; and (8) Patients with limited cognition to inform pain symptoms, such as mental disability and psychiatric disorders. The surgical procedures were performed under general anesthesia using 4 ports of laparoscopy. One 20 mm incision at the umbilicus, two lateral 5 mm ports at the left side, and another at the right side. The surgeon primarily used the two left-sided ports in most procedures. All recruited cases were performed by a single surgeon, Lee CL. After systematic exploration, terlipressin (GLYPRESSIN, Ferring) was prepared using 1 mg of terlipressin (One vial of GLYPRESSIN 5 mL containing 0.2 mg/mL terlipressin) diluted with 15 mL of normal saline and injected through the suprapubic area to the myometrium. The resection technique was described by Dubuisson et al . and Grimbizis et al .[ 14 15 ] In brief, the incision was made by monopolar diathermy at the uterine serosa to expose along the adenomyoma. During excision, a 1 cm thickness of myometrium was preserved and the cavity was filled with methylene blue to identify the possible intrusion into the cavity. The defect was repaired at the myometrial base from the muscular to the serosa layer to minimize dead space. After the procedure, the spray-type anti-adhesion barrier (Tisseel, Baxter Deerfield, IL) was applied to the raw surface. All specimens were removed within LiNA EasyBag (LiNA, EB125) through the umbilical port and sent to confirm pathologic diagnosis. Visual analog scale (VAS) scores in the aspect of dysmenorrhea, dyspareunia, and chronic pelvic pain were evaluated at the 6 th , 12 th , and 24 th week postoperative. The pain scale was subdivided into ten grades. “No pain” was considered 0 points and “the maximum pain that you could imagine” was designated as 10 points. Heavy menstrual bleeding was defined as the use of at least 5 pads/day. The severity was graded as mild (5–7 pads/day), moderate (7–9 pads/day), and severe (9 pads/day).[ 8 ] Differences in the VAS score were classified into 4 groups; (1) Complete remission: VAS score = 0; (2) Significant remission: Score reduction at least 3 grades but > 0; (3) Partial remission: Score reduction 1–3; and (4) No remission: No changes of VAS score.[ 16 ] Recurrence of symptoms was defined as complete remission or significant remission was achieved but recurred with increasing VAS score at least 3 points. Infertility treatment and postoperative complications, such as hematoma and infection, were also recorded. SPSS version 26 (SPSS Inc., IBM, New York, USA) was used to perform statistical analyses. For continuous variables, mean with standard deviation was used in normally distributed data, and median with interquartile range was used in abnormally distributed data. The categorical data were reported as proportion with percentage. Student’s t -test and Mann–Whitney U -test were used to compare continuous variables. Chi-square and Fischer exact test were used to compare the frequency between groups. P < 0.05 was considered to be statistically significant.