Effects of Weight Management on Fertility-sparing Treatment in Overweight Patients with Endometrial Cancer and Intraepithelial Neoplasia: A Retrospective Cohort Study

Objective To evaluate the effects of weight management on fertility-sparing treatment (FST) in endometrial cancer (EC) or endometrial intraepithelial neoplasia (EIN). Design Retrospective cohort study. Setting Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. Population Overweight patients with EC or EIN who received FST from January 2020 to June 2022. Methods Patients who underwent weight management based on intensive lifestyle interventions (ILIs) were compared with those who in the control group. Cox regression model was preformed and hazard ratio (HR) with 95% confidence intervals (CI) were calculated. Mediation analysis was conducted and mediated effects with proportion were calculated. Main outcome measures The primary outcomes were the complete remission (CR) rate and body composition changes; the secondary outcomes were the relapse rate, pregnancy rate, and live birth rate. Results A total of 141 patients were retrospectively analyzed: 97 (69.8%) cases were in the intervention group undergoing ILIs and 44 (31.2%) cases were in the control group. Weight management identified as an independent protective factor for CR rate (HR 2.13, 95% CI 1.08–4.22, p =0.030). A parabolic relationship was observed between weight change and CR rate ( p-nonlinear =0.038). Mediation analysis revealed that both visceral fat area and body fat mass partially mediated the effects of weight management on the CR rate. Reproductive outcomes did not differ between groups. Conclusions Weight management, particularly targeting fat reduction, may enhance the therapeutic efficacy of FST for overweight patients with EC or EIN. Our findings advocate the integration of body composition-guided ILIs into standardized FST protocols.

Endometrial cancer (EC) is a common gynecological malignancy, increasingly diagnosed in younger women 1 . Approximately 7% of cases occur in women under 45, 70% of whom are nulliparous 2 . While hysterectomy is standard for EC and its precursor, endometrial intraepithelial neoplasia (EIN), fertility-sparing treatment (FST) is gaining attention for those wishing to preserve fertility 3 . High-dose progestin is the primary conservative treatment for EIN and well-differentiated endometrioid endometrial cancer (EEC) 4 . However, several studies have indicated that overweight patients are more likely to be resistant to progestin, which may adversely impact the oncologic and reproductive outcomes of FST 5-9 . Consequently, weight control and the maintenance of a healthy body mass index (BMI) are strongly recommended in clinical guidelines and consensus statements for patients with EEC or EIN 1011, . Weight loss of 5–10% has been shown to positively influence the complete response (CR), relapse, pregnancy and live birth rate in patients undergoing FST 12-15 . Active weight management may play a crucial role in the outcome of FST in patients with EEC or EIN 16 . Intensive lifestyle interventions (ILIs), which are the first-line approach for overweight individuals, encompass dietary modifications, increased physical activity, and behavioral therapy 1718, . ILIs have demonstrated efficacy in managing various health conditions 19 . The specific impact on FST in EC/EIN remains to be clearly elucidated. Further clinical studies are warranted to substantiate this potential relationship. In this single-center retrospective analysis, we aimed to investigate the effects of weight management on body composition, oncologic outcomes, and reproductive outcomes in overweight EC/EIN patients undergoing FST to ultimately provide robust scientific guidance.

Study population The inclusion criteria were as follows: (1) pathologically confirmed EIN or well-differentiated (grade 1) EEC in accordance with the World Health Organization pathological classification (2020); (2) disease limited to the endometrium, with no suspicious or metastatic lesions on imaging; (3) underwent FST at the Obstetrics and Gynecology Hospital of Fudan University from January 2020 to June 2022; (4) overweight or obese (BMI ≥24 kg/m 2 ); (5) aged between 18 and 45 years; and (6) no contraindications to medical treatment or pregnancy. The exclusion criteria were as follows: (1) high-dose progestin treatment history for more than one month before the initial evaluation and treatment at our center; (2) recurrent EIN or EEC; (3) required surgery, transferred to other hospitals or lost to follow-up within 3 months of treatment; and (4) incomplete necessary medical records. A total of 169 patients met the inclusion criteria. Among these patients, 1 had a history of progestin treatment for 3 months at another hospital, and 13 had a history of EIN or EEC. We did not analyze these patients because of the potential effects of their previous treatment, particularly those who had poorer outcomes in initial centers. Before the first hysteroscopy was performed to assess FST efficacy, 1 patient required hysterectomy, 3 patients required transfer to other hospitals, and 6 patients were lost to follow-up. Additionally, 4 patients had incomplete records. Ultimately, 141 patients were retrospectively analyzed. All the patients were followed up until June 2024. This study was approved by the Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University (2022-09). All patients received comprehensive information about the risks of surgery and FST. All patients signed informed consent for the FST and the use of their clinical data for research purposes. Weight management Patients were categorized into the intervention group and the control group based on their weight management approach. The intervention group were required to attend the Weight Loss Clinic at our center, receiving expert ILIs guidance. The guidance included the following: (1) Dietary intervention: professional nutritionists developed personalized meal plans based on body composition analyses and dietary questionnaires. The recipes aimed to reduce daily energy intake by 500–1,000 kcal below the target energy intake, using energy-restricted balanced diets (45–55% carbohydrates, 15–20% proteins, and 20–30% fats) or high-protein diets (40% carbohydrates, 30% proteins, and 30% fats). Other dietary interventions, such as intermittent fasting, were dynamically adjusted in response to weight loss outcomes. (2) Exercise intervention: patients were typically prescribed 40–60 minutes of moderate-intensity aerobic exercise daily, in addition to 10–20 minutes of resistance training on alternate days. The plan involved choosing suitable exercises and gradually increasing the intensity. (3) Behavioral education: patients participate in biweekly education sessions, either in person or through digital formats such as video messages and receive motivational and scientific content via posters. The key components included daily self-monitoring of body weight, dietary intake, and physical activity, as well as regular measurements of waist and hip circumference. Patients were also encouraged to avoid a sedentary lifestyle; adhere to consistent meal timings; eat at a controlled pace; ensure adequate hydration; refrain from binge drinking; limit dining out; and reduce the consumption of foods high in sugar, fat, and salt. Moreover, patients were advised to actively seek encouragement and support from their family and social networks to foster long-term adherence and promote a supportive environment for sustainable health behavior changes. Patients in the weight management group are required to join the online platform (WeChat application) established by the professional team to track their daily diet, exercise, and behavior, enabling timely data recording. Conversely, patients in the control group did not receive any specific weight management intervention program. Fertility-sparing treatment All patients received one of the following progestin-based therapies: (1) oral megestrol acetate (MA) at a dosage of 160 mg/day or (2) insertion of the levonorgestrel intrauterine system (LNG-IUS). Hysteroscopy was performed every 3 months to evaluate the efficacy of the FST 20 . CR was defined as the absence of hyperplasia or cancer after treatment, with pathology revealing secretory or proliferative endometrium. Original regimen for an additional 3 months was used for patients who achieved CR for the first time. If CR was confirmed at the subsequent hysteroscopy evaluation, patients were advised to prepare for natural pregnancy or assisted reproductive technology (ART) as soon as possible. For patients who had given birth or wished to postpone pregnancy preparation, LNG-IUS, oral contraceptives (e.g., Diane-35), or low-dose progestin (e.g., dydrogesterone) were recommended as maintenance therapy to prevent relapse. The LNG-IUS was the preferred option; however, if the patient declined the LNG-IUS or was unsuitable for it, oral contraceptives or low-dose progestin were administered instead. During the follow-up, patients were reviewed every 3 months with ultrasound and every 6 months for endometrial pathology evaluations. Patients who exhibited stable disease for more than 6 months, partial response for more than 9 months, or progressive disease at any time during treatment were strongly recommended for hysterectomy. Alternative treatments were provided for patients who refused surgery according to recommendations from the multidisciplinary team. Patients were actively managed to ensure medication adherence and to track any adverse effects. D ata collection and assessment Body composition data, serum samples and endometrial pathology data were collected at baseline and every 3 months during the FST. Body composition was assessed via an InBody human composition analyzer, which measures body weight, body fat mass (BFM), skeletal muscle mass (SMM), and visceral fat area (VFA). The serum samples were examined in the laboratory of the Obstetrics and Gynecology Hospital, and the following parameters were measured: glucose, lipids, insulin, uric acid (UA), sex hormones, and anti-Mullerian hormone (AMH). The tests were repeated if the results exceeded the normal range. Overweight was defined as a BMI of 24–28 kg/m 2, and obesity was defined as a BMI ≥28.0 kg/m 2 . Dyslipidemia was diagnosed based on the Chinese Adult Dyslipidemia Prevention Guide (2016). Polycystic ovary syndrome (PCOS) was diagnosed on the basis of the Rotterdam Consensus Criteria 21 . The diagnostic criteria for insulin resistance (IR), metabolic syndrome (MetS), hyperuricemia (HUA) and diminished ovarian reserve (DOR) were described in our previous articles 522-25, . The primary outcomes of this study were (1) the cumulative CR rate at the 24th week of the FST and (2) changes in body composition during the FST. The secondary outcomes included (1) the relapse rate and (2) the pregnancy and live birth rate among patients who attempted pregnancy immediately after achieving CR. Statistical analysis The categorical variables are presented as frequencies and percentages, and differences between groups were assessed via the Chi-square test or Fisher’s exact test, where appropriate. The continuous variables are presented as the mean ± standard deviation or median with interquartile range (IQR), depending on distribution normality, and were compared via Student’s t test or the Mann‒Whitney U test, as appropriate. The Kaplan‒Meier method was used to evaluate the cumulative CR rate and median time to CR, and the log-rank test was used for comparisons among groups. Restricted cubic spline (RCS) with four knots placed at the 5th, 35th, 65th, and 95th percentiles were used to explore potential nonlinear associations between variables and therapeutic efficacy. Cox regression model was used to analyze the effects of variables on therapeutic efficacy. Mediation analysis was conducted to assess whether body composition changes mediated the effect of weight management on therapeutic efficacy. A logistic regression model was used for the mediator, and a parametric survival regression model (Weibull distribution) was used for the outcome. Estimates of the total effect, direct effect, indirect (mediated) effect, and proportion mediated were obtained via 5,000 bootstrap simulations. A p value < 0.05 (two-tailed) was considered statistically significant. All the statistical analyses were performed in SPSS (version 23.0, IBM Corp, Armonk, NY, USA) and R software (version 4.4.3, R Foundation for Statistical Computing, Vienna, Austria). Basic characteristics Ultimately, 141 patients were retrospectively analyzed in this study, including 105 patients with EIN (74.5%) and 36 patients with EEC (25.5%). As shown in Table S1, the median age at diagnosis was 31 years (IQR, 28 to 34 years), the median BMI was 28.1 kg/m² (IQR, 25.9 to 31.3 kg/m²), and the median follow-up duration was 29.4 months (IQR, 20.1 to 35.7 months). A total of 85.1% of the patients were nulliparous at diagnosis. The study population was categorized into two groups based on their approach to weight management, with 97 patients (68.8%) in the intervention group receiving ILIs and 44 patients (31.2%) in the control group. No significant differences in baseline characteristics were observed between the two groups. Body composition changes Table 1 presents the longitudinal changes in body composition and therapeutic outcomes of the FST. The overall population experienced consistent reductions in weight (−2.4% ± 7.9%), BFM (−4.7% ± 16.8%), VFA (median, −4.0%, IQR, -17.3 to 8.0%), and SMM (−1.3% ± 6.2%) from the initiation of the FST to the achievement of CR. Compared with the control group, the intervention group presented significant trends in weight loss (−4.2% vs. +1.5%, p <0.001), BFM loss (−8.3% vs. +3.6%, p <0.001), VFA loss (−6.7% vs. +3,9%, p <0.001), and SMM loss (−2.1% vs. +0.3%, p =0.073) ( Figure S1 ). Oncological outcomes The therapeutic intensity of progestin-based therapies remained comparable between the groups ( p =0.725). After 24 weeks of the FST, the intervention group demonstrated a significantly greater CR rate than the control group did (44.3% vs. 25.0%, p =0.026) ( Figure S1 ). Although the median time to CR showed a numerical advantage in the intervention group (6.2 months vs 7.4 months), the difference was not statistically significant ( p =0.924). Ultimately, 139 of 141 patients (98.6%) achieved CR, with a median treatment duration of 6.5 months (IQR, 3.5 to 9.6 months). Among non-responders, one exhibited SD for 11 months, whereas the other demonstrated PR for 7 months. Both patients ultimately opted for surgery. No serious adverse events related to progestin therapy or hysteroscopic surgery were reported. Multivariate Cox regression analysis revealed that weight management was an independent protective factor for the cumulative CR rate at the 24th week of the FST [hazard ratio (HR) 2.13, 95% confidence interval (CI) 1.08–4.22, p =0.030] after adjusting for age, weight status, histology, progestin therapy, and comorbidities. HUA was an independent risk factor for the 24w-CR rate (HR 0.52, 95% CI 0.28–0.98, p =0.044) (Figure 1). Among the 139 patients who achieved CR, 15 cases (10.8%) experienced disease relapse. Of these, 12 cases occurred during maintenance therapy (1 case on oral contraceptives, 2 cases on LNG-IUS, and 9 cases on low-dose progestin), whereas the remaining 3 cases relapsed following live birth or abortion in the absence of timely maintenance therapy. Comparative analysis revealed no significant difference in the relapse rate between the intervention and control groups (10.5% vs. 11.4%, p =0.882) (Table 1). Reproductive outcomes Patients were advised to pursue pregnancy after CR as soon as possible. A total of 72 patients attempted pregnancy immediately. Compared with the control group, the intervention group demonstrated a significantly greater likelihood of using ART (76.1% vs. 50.0%, p =0.024). At the last follow-up, 41 patients (56.9%) successfully achieved pregnancy, and 31 patients (43.1%) achieved live birth. However, no significant differences in reproductive outcomes were observed between the two groups ( p =0.690). Body composition changes and treatment outcomes To further analyze the mechanisms by which weight management influences the efficacy of FST, we examined the impact of body composition changes on treatment outcomes. At the 24th week of the FST, no significant difference in the cumulative CR rate was observed between weight loss patients and non-loss patients (41.9% vs. 32.7%, p =0.409) (Figure 2A). To delineate specific targets for weight management, we conducted a nonlinear analysis. The RCS model demonstrated a significant parabolic relationship between weight change and the probability of CR after adjusting for age, baseline BMI, histology, progestin therapy, and weight management modality ( p -nonlinear=0.038) (Figure 2B). Notably, the apex of this curve was observed at a weight change of -3.0%. Relative to the reference value (weight change of -3.0%), the HRs were 0.98 (95% CI, 0.88-1.09) and 0.78 (95% CI, 0.49-1.25), with weight changes of -5.0% and -10.0%, respectively. In contrast, an increase in weight of more than 5% during treatment was significantly associated with a reduced probability of achieving CR (Table S2). The cumulative CR rate at the 24th week of the FST was significantly greater in patients with BFM loss than in those without BFM loss (48.5% vs. 28.8%, p =0.047) (Figure 2C). An analogous trend was observed in the analysis of VFA, with a markedly higher CR rate in patients with VFA loss (51.8% vs. 27.3%, p =0.010) ( Figure 2D). Conversely, changes in SMM did not exhibit a statistically significant association with the probability of achieving CR (Figure 2E). Mediation effect of body composition changes Given the observed associations between body composition changes and the cumulative CR rate, we conducted mediation analyses to investigate whether these changes mediate the effect of weight management on treatment outcomes. As shown in Figure 3, both VFA and BFM loss partially mediated the association between weight management and the cumulative CR rate after adjusting for age, baseline weight management, histology, and progestin therapy. For VFA, the average causal mediation effect (ACME) was -1.13 (95% CI: -1.98 to -0.29, p =0.042), accounting for approximately 14.2% of the total effect. For BFM, the ACME was -1.58 (95% CI: -2.51 to -0.65, p =0.018), with a mediated proportion of 19.3%.

This study systematically evaluated the clinical efficacy and underlying mechanisms of ILI-based weight management in FST for EEC and EIN. In this retrospective cohort of 141 overweight patients (BMI ≥24 kg/m²), weight management emerged as an independent protective factor for CR, with novel evidence highlighting the partial mediating roles of VFA and BFM in this association. However, no significant improvement in long-term reproductive outcomes was observed. Weight management improved body composition Obesity is a well-established risk factor for both the development and progression of EEC and EIN. The association is driven by multiple mechanisms, including dysregulated sex hormone metabolism, aberrant insulin/insulin-like growth factor (IGF) signaling, and adipokine-associated pathophysiology. Subclinical inflammation, which is closely linked to adipokine dysregulation, is also recognized as a key pathogenic mechanism 26-28 . Guidelines strongly advocate weight management as a critical adjunct to FST in patients with EEC and EIN, emphasizing its potential to improve the remission rate 10 . ILIs are currently established as the first-line approach for weight management, aiming to prevent and manage obesity-related comorbidities through three core components: controlled caloric intake, structured physical activity, and behavioral modification 1718 , . In our study, patients receiving ILIs during the FST achieved significantly greater reductions in weight (−4.2% vs. +1.5%), BFM (−8.3% vs. +3.6%), and VFA (−6.7% vs. +3.9%) than controls did (all p <0.001). Theoretically, weight loss should be attributable primarily to adipose tissue reduction, which can lower circulating estrogen levels via decreased aromatase activity and increase sex hormone‑binding globulin levels to modulate estradiol bioavailability 29 . In obesity, adipose tissue—particularly visceral fat—secretes elevated levels of leptin and reduced levels of lipocalin, exacerbating systemic inflammation 30 . Fat loss has been shown to improve metabolic health by reducing the levels of inflammatory markers such as C-reactive protein, interleukin-6 and tumor necrosis factor-α 31 . However, weight loss is often accompanied by a reduction in non-adipose tissue, especially SMM 32 . In the present study, we observed a trend toward decreased SMM in the intervention group during the FST (–2.1% vs. +0.3%, p =0.073). SMM is recognized as an independent marker of metabolic health, with IR at this site representing a key driver of type 2 diabetes risk 33 . Moreover, the SMM is the primary site of fat oxidation and plays a unique role in systemic fat homeostasis via aerobic metabolism 34 . Previous studies have demonstrated that increased SMM enhances insulin sensitivity, attenuates insulin/IGF signaling, and improves IR at this site 35 . The incorporation of a high‑protein diet during weight management can mitigate SMM loss; future research should explore the combined effects of high‑protein intake and resistance training to preserve SMM and optimize metabolic benefits. Weight management improved the oncological outcomes In this study, we found that ILIs administered during the FST were associated with a significantly higher CR rate at 24 weeks than were those in the control group (44.3% vs. 25.0%, p =0.026). Weight management emerged as an independent protective factor for the 24-week CR rate (HR 2.13, 95% CI 1.08–4.22, p =0.030), which is consistent with prior studies 1636 , . In overweight and obese patients, excessive adiposity can induce progesterone resistance and impair FST efficacy by promoting peripheral and local estrogen overproduction, disrupting endometrial stromal cell function, and creating an inflammatory endometrial microenvironment 273738 , . Notably, we reported for the first time that reductions in BFM and VFA were significantly associated with the 24‑week CR rate ( p =0.047 and p =0.010, respectively). Mediation analysis further demonstrated that reductions in VFA and BFM partially mediated the beneficial effect of weight management on CR, accounting for 14.2% and 19.3% of the total effect, respectively. These findings suggest that adiposity-related changes in body composition might increase progesterone efficacy by lowering estrogen levels, improving insulin sensitivity, and reducing the levels of inflammatory mediators. Notably, weight change and the probability of CR exhibited a significant nonlinear, parabolic relationship in our study ( p -nonlinear=0.038), with an optimal weight loss of approximately 3% at 24 weeks of the FST. This finding challenged the traditional assumption that greater weight loss linearly increased the likelihood of CR in overweight and obese patients, suggesting instead that moderate weight loss yielded maximal efficacy. We hypothesized that this phenomenon might be influenced by concurrent changes in SMM during the FST. Although SMM reduction did not significantly affect CR rates (37.9% vs. 39.1%, p =0.783), excessive weight loss might attenuate the benefits of fat loss. Further investigation is warranted to elucidate the mechanisms underlying the parabolic association between weight change and FST efficacy. In this study, we focused primarily on overweight and obese patients, as normal‑weight or underweight individuals (BMI <24 kg/m²) were less likely to undergo weight management interventions. However, repeated weight‑loss attempts in these patients could mask imbalances between adipose and muscle tissue despite a healthy BMI, resulting in a lower resting metabolic rate, reduced physical capacity, and increased risk of metabolic diseases 39 . In our previous study, we reported that FST efficacy was suboptimal in underweight patients (BMI <18.5 kg/m 2 ), most of whom had dyslipidemia 25 . ILIs were able to significantly improve lipid profiles 40 . Accordingly, we recommend that non‑overweight/obese patients undergo regular body composition assessments during the FST and receive tailored guidance from healthcare professionals. Furthermore, our study identified HUA as an independent predictor of the 24-week CR rate (HR 0.52, 95% CI 0.28–0.98, p =0.044), corroborating our previous findings 25 . Monitoring and managing UA levels during the FST for EEC and EIN may improve therapeutic outcomes. Given the close association between multiple metabolic abnormalities and FST efficacy in EEC and EIN, future studies should examine how weight management influences metabolic parameters—such as glucose, insulin, lipids, and UA—to elucidate the mechanisms underpinning improved oncological outcomes. Role of weight management in the reproductive outcomes Guidelines recommend that overweight and obese women lose weight or maintain a healthy BMI promptly after FST to improve pregnancy and live birth rates 10 . Chen et al . reported that weight loss of 10% or more positively impacted the pregnancy rate following the FST 12 . Zhang et al . reported that weight loss of 5 % or more significantly increased both pregnancy and live birth rates in overweight and obese patients 13 . Weight loss may enhance ovulatory function and endometrial receptivity in overweight and obese patients by restoring the estrogen–progestogen balance. EC patients often present with IR, PCOS, or MetS, which increase the risk of infertility and pregnancy complications. Weight loss can ameliorate these metabolic abnormalities, thereby improving overall reproductive health. Although weight management significantly improved oncological outcomes in our cohort, it did not significantly affect long‑term reproductive outcomes. There were no significant differences in the pregnancy rate (58.7% vs. 53.8%, p =0.690) or live birth rate (41.3% vs. 46.2%, p =0.690) between the intervention and control groups, in contrast to previous studies. We propose several potential explanations. First, our study assessed the impact of weight management during FST up to CR; however, most patients initiated fertility attempts after achieving CR, and continued weight management during this period might have been more influential on reproductive outcomes. Second, the COVID‑19 pandemic has limited our ability to collect follow‑up data on body composition changes post‑treatment. Third, a greater proportion of patients in the intervention group underwent ART (76.1% vs. 50.0%, p =0.024), potentially obscuring the effect of weight management on spontaneous conception. Finally, the median follow‑up of 29.4 months might have been insufficient to capture all fertility events, particularly among patients who delayed conception. Extended follow‑up and implementation of weight management after CR may be necessary to fully elucidate its impact on reproductive outcomes. Other potential mechanisms warrant consideration. Rapid weight loss may disrupt the hypothalamic‒pituitary‒ovarian axis, impairing ovarian function and potentially offsetting the fertility benefits gained from metabolic improvements. Additionally, prolonged exposure to progestin may alter endometrial receptivity, underscoring the need for further research to elucidate the temporal interplay between weight loss and endometrial repair. Strengths and limitations In this study, we systematically evaluated the role of ILI-based weight management in the FST for EC and EIN. We demonstrated that weight management significantly improved oncological outcomes in overweight and obese patients. Notably, we reported for the first time that reductions in BFM and VFA were correlated with FST efficacy, partially mediating the beneficial effects of weight management. Furthermore, we also observed a nonlinear relationship between weight change and treatment efficacy, suggesting that moderate weight loss may optimize outcomes. The strengths of this study include its relatively large sample size, comprehensive follow‑up, and standardized intervention protocols, which together increase the robustness and reliability of our findings. This study also has several limitations. First, its retrospective design and nonrandomized intervention assignment may introduce selection bias. Second, disruptions caused by the COVID‑19 pandemic led to incomplete adherence data for some patients, excluding these patients may have resulted in an underestimation of the true effect of the intervention. Additionally, mechanistic insights are limited by the absence of molecular‑level data, such as data on adipokine profiles and inflammatory markers. Implications for clinical practice and future research This study provides a theoretical foundation for optimizing weight management strategies in EEC and EIN patients undergoing FST. In overweight and obese patients, ILI-based weight management can help improve oncological outcomes. Based on the evidence in this study, we recommend integrating weight management into standardized FST protocols, incorporating body composition changes into efficacy assessments, and establishing a multidisciplinary oncology–endocrine–nutrition–reproductive team to develop individualized weight management plans. In future studies, we will conduct randomized controlled trials to determine optimal weight management targets across different weight statuses and to clarify the most effective regimen, timing and duration. We will also prioritize strategies to increase patient adherence to weight management recommendations and deliver tailored guidance for patients undergoing FST, thereby improving oncological and reproductive outcomes.

In this study, we retrospectively analyzed 141 overweight patients with EEC and EIN who underwent FST. We demonstrated that ILI–based weight management was an independent protective factor for achieving CR. Notably, CR correlated more strongly with reductions in adiposity—as measured by BFM and VFA—than with weight loss. Weight management may optimize treatment oncological outcomes by modulating body composition distribution, although its long‑term protective effects on reproductive outcomes require further validation. Future work should develop an integrated oncology–endocrine–nutrition–reproductive intervention model to enable full‑cycle management from disease remission through fertility preservation. Acknowledgments We appreciate Chunyun Xu for providing us with expert suggestions in the field of nutrition. Furthermore, we thank all the patients who participated in this study. Disclosure of interests The authors declare no potential conflicts of interest. Contributions to Authorship Sijia Liu: Formal analysis, investigation, validation, data curation, writing—original draft. Li Li : Formal analysis, investigation, data curation, methodology. Pengfei Wu : Investigation, methodology, validation. Lulu Wang : Formal analysis, investigation, validation. Qujia Gama : Investigation, methodology. Manrong Wang : Investigation. Jinyu Zhang : Methodology. Liping Jin : Supervision. Xuezhen Luo : Writing—review and editing. Weiwei Shan : Conceptualization, funding acquisition, supervision, project administration, writing—review and editing. Bingyi Yang : Conceptualization, funding acquisition, supervision, project administration, writing—review and editing. All the authors have read and agreed to the published version of the manuscript. Details of Ethics Approval The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University (approval number 2022-09). Informed consent was obtained from all the subjects involved in the study. Written informed consent was obtained from the patients to publish this paper. Funding This work was supported by the Shanghai Municipal Commission of Health and Family Planning (Grant No. 20224Y0080), Shanghai Municipal Health Commission Health Industry Clinical Research Youth Program (Grant No. 20214Y0219), and Obstetrics and Gynecology Hospital of Fudan University (Grant No. FC2021CR202). Data availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Supporting Informations Figure S1. Effects of weight management on body composition changes and the cumulative CR rate. (A) Body composition changes from the initiation of the FST to the achievement of CR with or without weight management. (B) Cumulative CR rate at the 24th week of the FST with or without weight management. The p -value between two groups was evaluated by Student’s t-test or the Mann–Whitney U test. The cumulative CR rate was evaluated via the Kaplan–Meier method and compared via the log-rank test. Abbreviations: CR, complete remission; BFM, body fat mass; VFA, visceral fat area; SMM, skeletal muscle mass; FST, fertility-sparing treatment. Table S1. Baseline characteristics of the study population. Table S2 . Non-linear analysis between weight change and cumulative CR rate.

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(B) Non-linear analysis between weight change and the cumulative CR rate at the 24th week of the FST. (C) Cumulative CR rate at the 24th week of the FST with or without BFM loss. (D) Cumulative CR rate at the 24th week of the FST with or without VFA loss. (E) Cumulative CR rate at the 24th week of the FST with or without SMM loss. The cumulative CR rate was evaluated via the Kaplan–Meier method and compared via the log-rank test. Non-linear analysis was performed on the RCS model. The HR and 95% CI were evaluated via Cox regression analysis adjusted by age, baseline weight status, histology, progestin therapy, and weight management. Abbreviations: CR, complete remission; CI, confidence interval; BFM, body fat mass; VFA, visceral fat area; SMM, skeletal muscle mass; FST, fertility-sparing treatment; RCS, restricted cubic spline. Figure 3. Mediation effects of changes in body composition on the association between weight management and cumulative CR rate. (A) Mediation effect of VFA loss. (B) Mediation effect of BFM loss. A logistic regression model was used for the mediator, and a parametric survival regression model with a Weibull distribution was used for the outcome. The estimated proportions were obtained via 5,000 bootstrap simulations. All models were adjusted for age, baseline weight status, histology, and progestin therapy. Abbreviations: CR, complete remission; VFA, visceral fat area; BFM, body fat mass. Supplementary Material File (table 1.doc) - Download - 51.00 KB Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 304views 145downloads Citations Download citation Sijia Liu, Li Li, Pengfei Wu, et al. Effects of Weight Management on Fertility-sparing Treatment in Overweight Patients with Endometrial Cancer and Intraepithelial Neoplasia: A Retrospective Cohort Study. Authorea. 21 July 2025. DOI: https://doi.org/10.22541/au.175310318.84475279/v1 DOI: https://doi.org/10.22541/au.175310318.84475279/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.