Improved surgical outcomes in adenomyosis: a novel insight into the superiority of secretory phase adenomyomectomy

Clinically, secretory phase timing can be implemented using simple, cost-effective methods. In patients with regular cycles, scheduling surgery based on the last menstrual period, typically targeting days 17–25 of a 28-day cycle, is feasible. Additional precision may be achieved using ovulation predictor kits or mid-luteal serum progesterone levels. For patients with irregular cycles, endometrial biopsy or hormonal profiling may aid phase determination. Incorporating these strategies into preoperative planning may enhance the accuracy and the effectiveness of secretory phase-guided adenomyomectomy in routine practice.

This retrospective cohort study included patients who underwent uterus-sparing adenomyomectomy at our institution between January 2021 and April 2024. A total of 163 patients (80 in the proliferative phase group and 63 in the secretory phase group) were initially enrolled. Twenty patients were excluded due to loss to follow-up and were not included in any statistical analysis. These patients were not assigned to either the proliferative or the secretory phase groups and were excluded from recurrence assessment and survival analysis. The final analytical cohort consisted of 143 patients. A flow chart illustrating inclusion and exclusion processes has been added (Fig.  1 ). The general characteristics of the two groups are summarized in Table  1 . There was no significant difference in age between the two groups (38.88 ± 5.04 in the proliferative phase vs. 40.13 ± 5.52 in the secretory phase, P  = 0.160). However, the secretory phase group had a significantly lower BMI compared to the proliferative phase group (22.68 ± 3.15 kg/m 2 vs. 24.35 ± 3.38 kg/m 2 , P  = 0.003). Significant differences were found in parity ( P  = 0.042), with the secretory phase group having more women with two or more vaginal deliveries (44.4% vs. 27.5%). No significant differences were observed in cesarean section history, disease duration, or pelvic endometriosis complications. The most common chief complaint was dysmenorrhea (63.7% in the proliferative phase vs. 68.3% in the secretory phase), followed by prolonged menstruation (26.3% vs. 12.7%, respectively). The secretory phase group had more patients with a mass found on routine examination (19.0% vs. 10.0%, P  = 0.068). Fig. 1 Flowchart for follow-up patients Table 1 General characteristics of the study population Variables Proliferative phase ( n  = 80) Secretory phase ( n  = 63) P value Age (year) 38.88 ± 5.04 40.13 ± 5.52 0.160 Body mass index (kg/m 2 ) 24.35 ± 3.38 22.68 ± 3.15 0.003 ** Number of pregnancies 3.54 ± 1.88 3.19 ± 1.34 0.218 Parity (through vaginal delivery) 0.042 *  0 24 (30.0%) 11 (17.5%)  1 18 (22.5%) 18 (28.6%)  2 22 (27.5%) 28 (44.4%)  ≥ 3 16 (20.0%) 6 (9.5%) History of cesarean section 27 (33.8%) 15 (23.8%) 0.195 Duration of disease 4.45 ± 5.00 4.28 ± 5.01 0.840 Complicated with pelvic endometriosis 16 (20%) 16 (25.4%) 0.442 Chief complaint 0.068  Dysmenorrhea 51 (63.7%) 43 (68.3%)  Prolonged menstruation 21 (26.3%) 8 (12.7%)  Mass found on routine 8 (10.0%) 12 (19.0%) The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Flowchart for follow-up patients General characteristics of the study population The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Lesion-related preoperative parameters are summarized in Table  2 . Preoperative pretreatment was more common in the secretory phase group (25.4%) compared to the proliferative phase group (12.5%) ( P  = 0.047). There were no significant differences between the two groups in serum CA125 levels (110.77 ± 115.18 U/ml vs. 98.48 ± 71.08 U/ml), lesion location ( P  = 0.622), or maximum uterine diameter on ultrasound (8.14 ± 1.93 cm vs. 8.19 ± 1.83 cm). The maximum lesion diameter on ultrasound was also similar between the groups (5.36 ± 1.79 cm vs. 5.16 ± 1.57 cm), and no significant difference was observed in a maximum lesion diameter on MRI (4.73 ± 1.56 cm vs. 4.99 ± 1.80 cm). Table 2 Lesion-related preoperative parameters of the study population Variables Proliferative phase ( n  = 80) Secretory phase ( n  = 63) P value Preoperative pretreatment 10 (12.5%) 16 (25.4%) 0.047 * Serum CA125 (U/ml) 110.77 ± 115.18 ( n  = 74) 98.48 ± 71.08 ( n  = 54) 0.693 Lesion location 0.622  Uterine fundus 10 (12.5%) 6 (9.5%)  Anterior uterine wall 19 (23.8%) 12 (19%)  Posterior uterine wall 51 (63.7%) 45 (71.4%) Maximum uterine diameter on ultrasound (cm) 8.14 ± 1.93 ( n  = 74) 8.19 ± 1.83 ( n  = 57) 0.882 Maximum lesion diameter on ultrasound (cm) 5.36 ± 1.79 ( n  = 75) 5.16 ± 1.57 ( n  = 61) 0.484 Maximum lesion diameter on MRI (cm) 4.73 ± 1.56 ( n  = 69) 4.99 ± 1.80 ( n  = 57) 0.395 The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Lesion-related preoperative parameters of the study population The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Perioperative parameters are shown in Table  3 . The rates of combined pelvic endometriosis surgery were similar between proliferative (20.0%) and secretory phase (22.2%) groups. In terms of intraoperative lesion location, a higher proportion of lesions were located in the posterior uterine wall in both groups (70.0% in the proliferative phase and 73.0% in the secretory phase) though this difference was not statistically significant ( P  = 0.061). No significant differences were observed in operation time (144.88 ± 42.99 vs. 137.34 ± 45.51 min), estimated blood loss (67.75 ± 118.76 vs. 72.07 ± 76.88 ml), or postoperative hospital stay (3.58 ± 2.45 vs. 3.65 ± 1.36 days). Perioperative complications occurred in three patients (4.8%) in the secretory phase group, including two cases of postoperative infection with fever and one case of urinary retention, while no complications were reported in the proliferative phase group ( P  = 0.093). Table 3 Perioperative parameters of the study population Variables Proliferative phase ( n  = 80) Secretory phase ( n  = 63) P value Combined pelvic endometriosis surgery 16 (20.0%) 14 (22.2%) 0.746 Intraoperative lesion location 0.061  Uterine fundus 16 (20.0%) 5 (7.9%)  Anterior uterine wall 8 (10.0%) 12 (19%)  Posterior uterine wall 56 (70.0%) 46 (73.0%) Operation time (min) 144.88 ± 42.99 137.34 ± 45.51 0.313 Estimated blood loss (ml) 67.75 ± 118.76 72.07 ± 76.88 0.803 Perioperative complications 0 3 (4.8%) 0.093 Postoperative hospital stay (days) 3.58 ± 2.45 3.65 ± 1.36 0.815 The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Perioperative parameters of the study population The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Post-discharge follow-up in Table  4 revealed no complications in either group. A comparable proportion of patients in the proliferative phase group (45.0%) and the secretory phase group (50.7%) received postoperative pharmacological intervention, and similar rates of long-term levonorgestrel-releasing intrauterine system (LNG-IUS) management were observed (22.5% vs. 22.2%). Notably, the recurrence rate was significantly lower in the secretory phase group compared to the proliferative phase group (14.3% vs. 38.8%, P  = 0.001), suggesting a potential benefit of secretory phase timing in reducing postoperative recurrence. Table 4 Post-discharge follow-up and management of the study population Variables Proliferative phase ( n  = 80) Secretory phase ( n  = 63) P value Post-discharge complications 0 0 / Postoperative pharmacological intervention 36 (45.0%) 37 (50.7%) 0.482 LNG-IUS long-term management 18 (22.5%) 14 (22.2%) > 0.999 Recurrence 31 (38.8%) 9 (14.3%) 0.001 ** The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Post-discharge follow-up and management of the study population The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Kaplan–Meier analysis demonstrated a significantly longer recurrence-free survival (RFS) in patients who underwent adenomyomectomy during the secretory phase compared to those in the proliferative phase [median RFS: 45.19 (41.69–48.70) vs. 34.40 (29.89–38.91) months, log-rank P  = 0.001]. The cumulative survival curves revealed a clear separation between the two groups, indicating a temporal advantage associated with secretory phase surgery (Fig.  2 ). Fig. 2 Kaplan–Meier analysis of recurrence-free survival (RFS) in patients who underwent adenomyomectomy during the proliferative phase ( n  = 80) and secretory phase ( n  = 63). Patients in the proliferative phase group exhibited a significantly lower recurrence-free survival rate compared to those in the secretory phase group (log-rank test, P  = 0.001) Kaplan–Meier analysis of recurrence-free survival (RFS) in patients who underwent adenomyomectomy during the proliferative phase ( n  = 80) and secretory phase ( n  = 63). Patients in the proliferative phase group exhibited a significantly lower recurrence-free survival rate compared to those in the secretory phase group (log-rank test, P  = 0.001) Multivariate Cox proportional hazards regression analysis revealed that surgical timing was significantly associated with the risk of recurrence. Surgery performed during the proliferative phase was associated with a significantly lower risk of recurrence compared to the secretory phase (HR 0.277, 95% CI 0.114–0.673, P  = 0.005). No significant associations were observed between recurrence and other variables, including age, BMI, history of cesarean section, disease duration, serum CA125 level, lesion size on MRI, coexisting pelvic endometriosis, pre- or postoperative medical treatments, LNG-IUS management, or lesion location (all P  > 0.05) (Table 5 ). Table 5 Multivariate Cox proportional hazards regression analysis of factors associated with recurrence Variables HR (95% CI) p value Surgical timing (secretory vs. proliferative) 0.277 (0.114–0.673) 0.005 ** Age (years) 0.951 (0.880–1.028) 0.206 BMI (kg/m 2 ) 1.041 (0.927–1.169) 0.500 History of cesarean section (per delivery) 0.837 (0.500–1.401) 0.498 Duration of disease (years) 1.105 (0.958–1.076) 0.612 Serum CA125 level (U/ml) 1.001 (0.998–1.004) 0.581 Preoperative pretreatment (yes vs. no) 1.027 (0.355–2.971) 0.961 Maximum lesion diameter on MRI (cm) 1.002 (0.980–1.026) 0.835 Coexisting pelvic endometriosis (yes vs. no) 0.524 (0.227–1.211) 0.130 Postoperative pharmacological intervention (yes vs. no) 0.756 (0.346–1.651) 0.482 LNG-IUS long-term management (yes vs. no) 1.333 (0.454–3.913) 0.601 Lesion location (ref: posterior wall)  Uterine fundus 0.284 (0.026–3.161) 0.306  Anterior wall 1.009 (0.411–2.487) 0.984 The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Multivariate Cox proportional hazards regression analysis of factors associated with recurrence The values are presented as mean ± standard or number (percentage) * P  < 0.05, ** P  < 0.01, *** P  < 0.001

This retrospective cohort study was conducted at the department of gynecology, affiliated Meizhou Hospital of Shantou University Medical College, involving patients diagnosed with adenomyosis who underwent uterus-sparing adenomyomectomy between January 2021 and April 2024. Inclusion criteria were: (1) histologically confirmed adenomyosis, (2) no previous adenomyosis-related surgery, (3) absence of any malignancy involving the uterus or adnexal structures, and (4) complete follow-up data for ≥ 12 months postoperatively. This study was approved by the Research Ethics Committee of the Meizhou People’s Hospital (2024-C-94). Informed consent was obtained at the time of hospital admission. General characteristics, lesion-related preoperative parameters, and perioperative details were extracted from medical records. Post-discharge follow-up information was collected through outpatient clinic records and telephone interviews. General characteristics included age, body mass index (BMI), gravidity, parity, history of cesarean section, disease duration, coexisting pelvic endometriosis, and chief complaint. Lesion-related preoperative parameters comprised preoperative hormonal treatment (including administration of GnRH-a, oral contraceptive pills, mifepristone or the LNG-IUS), preoperative serum CA125 levels, lesion location as determined by ultrasound or MRI, maximum uterine diameter on ultrasound, and the maximum lesion diameter identified on ultrasound or MRI. Perioperative parameters included concomitant surgery for pelvic endometriosis, intraoperative lesion location, operative time, estimated blood loss, perioperative complications, and length of postoperative hospital stay. Post-discharge follow-up and management included documentation of postoperative complications, pharmacological interventions, continued LNG-IUS use, recurrence status, and time to recurrence. Pharmacological intervention involved the use of one of the following treatments—GnRH-a, oral contraceptives, or mifepristone—based on individual patient needs. Recurrence was defined as either the return and gradual worsening of dysmenorrhea or the radiological evidence suggestive of adenomyoma as identified by ultrasound or MRI. Data were analyzed using SPSS version 25.0 (SPSS Inc., Chicago, USA). Patients were categorized into secretory and proliferative phase groups based on the menstrual phase at the time of surgery. Phase classification was primarily determined through histological evaluation of endometrial tissue obtained either 1–2 days prior to surgery or on the day of surgery by endometrial curettage. In cases where pathology results were not available, menstrual phase was inferred from the patient’s self-reported menstrual history, including the date of the last menstrual period and the average cycle length. For patients with irregular cycles, classification was based on the best available clinical estimation. Continuous variables were compared using Student’ t test or Mann–Whitney U test, while categorical variables were compared using chi-square test or Fisher’s exact test. Kaplan–Meier analysis was used to assess recurrence-free survival, with statistical significance set at P  < 0.05. Additionally, Cox proportional hazards regression analysis was performed to evaluate the impact of potential confounders on the time to recurrence.

This study provides novel evidence that the timing of adenomyomectomy within the menstrual cycle significantly influences postoperative outcomes in patients with adenomyosis. We found that surgery performed during the secretory phase was associated with a significantly lower recurrence rate and prolonged recurrence-free survival compared to the proliferative phase, even after adjusting for potential confounders. These findings highlight surgical timing as an important, yet often overlooked, determinant of long-term treatment efficacy. As previously noted, cyclical histological and vascular changes during the secretory phase, including stromal edema and enhanced vascularization, may improve intraoperative lesion visualization and facilitate more precise excision [ 4 , 5 ]. More importantly, this phase is characterized by relative quiescence of endometrial stem cells, which may reduce the risk of postoperative lesion regrowth [ 7 , 8 ]. Our findings are consistent with current understanding of hormone-mediated regulation of uterine tissue. Prior studies have shown that progesterone inhibits proliferation of both eutopic and ectopic endometrial cells, contributing to symptom relief in adenomyosis [ 9 , 10 ]. Moreover, unpublished data from our laboratory demonstrated reduced proliferative activity in epithelial stem cells derived from adenomyotic foci during the secretory phase, supporting the notion that this window may be biologically optimal for achieving complete lesion removal and minimizing recurrence [ 11 ]. Given that adenomyomectomy often breaches the uterine cavity and disrupts the endometrial basalis, performing surgery when basalis layer stem cells are relatively inactive may further mitigate the risk of lesion regeneration [ 12 – 14 ]. While factors, such as age, BMI, prior cesarean section, lesion size, and postoperative hormonal therapy, have traditionally been considered in recurrence risk stratification, none showed significant associations with recurrence in our multivariate analysis [ 15 , 16 ]. The higher rate of preoperative hormonal treatment in the secretory phase group may reflect a treatment-induced shift in endometrial characteristics as agents such as progestins. Although preoperative hormonal therapy was adjusted for in the model and did not reach statistical significance, its potential impact on lesion morphology and intraoperative visualization cannot be entirely excluded. This reinforces the potential role of surgical timing as an independent and modifiable prognostic factor, offering clinicians a practical means of improving long-term outcomes through optimized surgical scheduling [ 17 ]. Clinically, secretory phase timing can be implemented using simple, cost-effective methods. In patients with regular cycles, scheduling surgery based on the last menstrual period, typically targeting days 17–25 of a 28-day cycle, is feasible. Additional precision may be achieved using ovulation predictor kits or mid-luteal serum progesterone levels. For patients with irregular cycles, endometrial biopsy or hormonal profiling may aid phase determination. Incorporating these strategies into preoperative planning may enhance the accuracy and the effectiveness of secretory phase-guided adenomyomectomy in routine practice. This study has several strengths. To our knowledge, it is the first to systematically evaluate the impact of menstrual phase on recurrence following adenomyomectomy. Rigorous statistical adjustment and comprehensive follow-up enhance the robustness of our conclusions. However, several limitations merit consideration. The retrospective design introduces inherent risks of selection bias and residual confounding. Despite efforts to determine menstrual phase through clinical and histological criteria, hormonal variability may have led to misclassification in some cases. The sample size, although sufficient for primary analyses, may have limited power for certain subgroup comparisons. Lastly, external validation in larger prospective cohorts is needed to confirm these findings and refine recommendations for surgical timing. In conclusion, our results suggest that the secretory phase represents a physiologically favorable window for adenomyomectomy, associated with lower recurrence risk and improved long-term outcomes. Incorporating menstrual phase into surgical planning may offer a simple and cost-effective strategy to optimize treatment efficacy in patients with adenomyosis. Further prospective research is warranted to validate these observations and elucidate the underlying biological mechanisms.

Adenomyosis is a prevalent benign gynecological disorder characterized by the ectopic presence of endometrial glands and stroma within the myometrium, often leading to dysmenorrhea, menorrhagia, uterine enlargement, and subfertility [ 1 ]. While hysterectomy remains the definitive treatment for women not desiring future fertility, uterus-sparing surgeries, particularly adenomyomectomy, have become increasingly important for patients seeking symptom relief and preservation of reproductive potential [ 2 ]. Despite advancements in surgical techniques, the long-term efficacy of adenomyomectomy is frequently compromised by high postoperative recurrence rates [ 2 ]. Previous studies have identified several factors influencing recurrence, including the completeness of lesion excision, the surgical approach, the preoperative use of gonadotropin-releasing hormone agonists (GnRH-a), and the postoperative hormonal therapy [ 3 ]. However, the impact of surgical timing within the menstrual cycle, a potentially modifiable factor, has received limited attention in the literature. The menstrual cycle induces cyclical morphological and vascular changes in both endometrium and myometrium, mediated by fluctuating levels of estrogen and progesterone. During the secretory phase, under the influence of progesterone, the endometrium undergoes glandular dilation, stromal edema, and increased vascularization, while the myometrium becomes relatively softer and more distinguishable from surrounding tissue. These physiological changes may theoretically enhance intraoperative visualization and facilitate more complete resection of adenomyotic lesions [ 4 ]. Conversely, during the proliferative phase, the endometrium is denser and more proliferative, which may hinder the clear demarcation between normal and affected tissues, potentially compromising surgical precision [ 5 ]. Our team previously identified and established a method for the long-term in vitro culture and expansion of human endometrial epithelial stem cells (eESCs), marked by SSEA-1 expression [ 6 ]. In unpublished data, we observed that isolating eESCs from adenomyotic lesions during the secretory phase was notably challenging, suggesting a relative quiescence of epithelial activity in this phase. This observation led us to hypothesize that the secretory phase may represent a period of reduced endometrial proliferation within adenomyotic lesions, potentially decreasing the likelihood of postoperative recurrence. To date, few studies have systematically evaluated the impact of surgical timing during different phases of the menstrual cycle on postoperative outcomes in adenomyosis. In clinical practice, the decision regarding surgical timing is often driven by scheduling logistics rather than physiological optimization. To our knowledge, this is the first study to systematically assess the impact of menstrual cycle phase on surgical outcomes in adenomyosis, providing novel insights into optimizing surgical timing for better long-term results.