Fertility-sparing treatment for overweight patients with early-stage endometrial cancer or atypical endometrial hyperplasia under weight loss intervention.

A total of 53 patients with AEH or EC were included, with a median age of 31 years (range 23 to 39 years) (Shown in Fig.  1 ). Twenty-nine (54.72%) patients were diagnosed with EC, and twenty-four (45.28%) were diagnosed with AEH. The median BMI of the patients was 30 kg/m 2 (range: 21.45–51.88 kg/m 2 ), and 5 (9.43%) patients had a BMI over 40 kg/m 2 . The median BFM of the patients was 31 kg (range: 16.4–86.6 kg). The median VFA was 137.4 cm 2 (range: 62.3–263.2 cm 2 ). The median PBF of 53 patients was 39.46% (32%-54%). Forty-five (84.90%) patients were nulliparous, and 17 (32.08%) women had comorbidities, including polycystic ovary syndrome (PCOS), diabetes mellitus (DM), and endometriosis. (Shown in Table  1 ). Fig. 1 The flowchart of this study Table 1 Patient’s characteristics Characteristics N = 53 Age (years) Mean ± SD 31.17 ± 3.906 Median (Range) 31 (23–39) BMI (kg/m 2 ) Median (Range) 30 (21.45–51.88) Body fat mass (kg) Median (Range) 31 (16.4–86.6) Visceral fat area (cm 2 ) Median (Range) 137.4 (62.3–263.2) Percent body fat Median (Range) 39.46% (32%-54%) Histology EC 29 (54.72%) AEH 24 (45.28%) Nulliparity 45 (84.90%) Regimen Progestin 24 (45.28%) GnRHa 29 (54.72%) Recurrence Recurrence rate 12 (22.64%) Recurrence time month (range) 26.48 (12.93–60.99) Attempts to conceive after CR 33 (62.26%) Total pregnancy rate 17 (51.52%) Miscarriage 2 (11.76%) Live birth rate 12 (70.59%) In pregnancy 3 (17.65%) BMI, body mass index; EC, endometrial carcinoma; AEH, atypical endometrial hyperplasia; CR, complete response The flowchart of this study Patient’s characteristics BMI, body mass index; EC, endometrial carcinoma; AEH, atypical endometrial hyperplasia; CR, complete response In this study, we divided all patients into two groups based on the calculated optimal cutoff values for weight, VFA, BFM, and PBF reduction, and analyzed the differences between different weight measurement indicators and their impact on treatment response and fertility outcomes (Shown in Table  2 ). Various body fat indicators did not show significant differences in patient baseline aspects (such as age, pathological type). The progestin group had a lower weight loss rate than the GnRHa group (P = 0.021). However, the two medication methods had no significant effect on body fat indicators. Grouped according to 10% weight loss, the two groups had similar CR time (6.48 ± 2.69 months vs. 6.18 ± 2.54 months, p = 0.680), recurrence rate (5/25 vs. 7/28, p  = 0.664), and pregnancy rate (8/25 vs. 9/28, p = 0.991). Those with VFA > 18% and BFM > 15% showed shorter CR time (5.74 ± 1.63 months vs. 7.44 ± 3.63 months, p  < 0.001, and 5.63 ± 1.58 months vs. 7.45 ± 3.47 months, p   15% had a lower recurrence rate ( p  = 0.043). Those with PBF > 8% also have shorter CR time (5.30 ± 1.63 months vs. 7.38 ± 2.98 months, p = 0.001) and lower recurrence rate (2/27 vs. 10/26, p = 0.007). Table 2 Relationship of multiple weight measures to clinicopathological information, treatment response, and fertility outcomes Variables Weight loss P -value Visceral fat area loss P -value Body fat mass loss P -value Percent body fat loss P -value  ≤ 10%  > 10%  ≤ 18%  > 18%  ≤ 15%  > 15%  ≤ 8%  > 8% Total 25 28 20 33 18 35 26 27 Age 0.198 0.373 0.965 0.761  ≤ 35 19 25 17 17 15 29 22 22  > 35 6 3 3 6 3 6 4 5 Histological type 0.707 0.974 0.621 0.669 AEH 12 12 9 15 9 15 11 13 EC 13 16 11 18 9 20 15 14 Regimen 0.021 0.974 0.621 0.498 Progestin 16 8 9 15 9 15 13 11 GnRHa 9 20 11 18 9 20 13 16 CR time (month) 0.680  < 0.001  < 0.001 0.001 Median 6 6 6 6 6 6 6 6 Mean ± SD 6.48  ± 2.69 6.18  ± 2.54 7.44  ± 3.63 5.74  ± 1.63 7.45  ± 3.47 5.63  ± 1.58 7.38  ± 2.98 5.30  ± 1.63 Recurrence 5 7 0.664 7 5 0.334 7 5 0.043 10 2 0.007 Pregnancy 8 9 0.991 4 13 0.143 3 14 0.085 6 11 0.168 EC, endometrial cancer; AEH: atypical hyperplasia; CR, complete response; the unit of CR time is month Relationship of multiple weight measures to clinicopathological information, treatment response, and fertility outcomes 6.48 ± 2.69 6.18 ± 2.54 7.44 ± 3.63 5.74 ± 1.63 7.45 ± 3.47 5.63 ± 1.58 7.38 ± 2.98 5.30 ± 1.63 EC, endometrial cancer; AEH: atypical hyperplasia; CR, complete response; the unit of CR time is month After meeting the admission criteria, the patient's information is input into the system, and the random unit number is formed by the computer. Twenty-four (45.28%) women received treatment with a progestin regimen, and 29 (54.72%) received GnRHa therapy. Forty-nine (92.45%) patients achieved CR, with a median CR time of 6 months (range: 3–12 months). Four women failed to achieve CR after one year of treatment with the progestin regimen. (3 achieved PR, and 1 achieved SD). After transferring from a progestin regimen to GnRHa, these patients ultimately achieved CR after 3 to 6 months. Cox regression univariate analyses were performed included the following variables: age ( p  = 0.763), tumor histology ( p  = 0.600), comorbidity with PCOS ( p  = 0.919), regimen ( p  = 0.308), weight loss > 10% ( p  = 0.702), VFA loss > 18% (p = 0.033), BFM loss > 15% ( p  = 0.046), and PBF loss > 8% ( p  = 0.014) (Table  3 ) . Subsequently, three variables (including VFA loss > 18%, BFM loss > 15%, and PBF loss > 8%) were included in the multivariate analysis. The Cox proportional hazards method with forward stepwise elimination was used to construct the final model, and a PBF loss > 8% (OR = 2.080, 95% CI = 1.136–3.809, p = 0.018) was eventually identified as an independent predictor of the time to CR. Table 3 Predictors of complete response Characteristics Univariate analysis Multivariate analysis HR (95% CI) P -value OR (95% CI) P -value Age 0.763  ≤ 35 Reference  > 35 1.121(0.540–2.326) Histological type 0.600 AEH Reference EC 0.864 (0.500–1.493) PCOS 0.919 No Reference Yes 0.967 (0.511–1.832) Regimen 0.308 Progestin Reference GnRHa 1.325 (0.770–2.281) Weight loss 0.702  ≤ 10% Reference  > 10% 1.111 (0.647–1.909) Visceral fat area loss* 0.033 0.830  ≤ 18% Reference Reference  > 18% 1.990(1.031–3.843) 1.183(0.256–5.471) Body fat mass loss* 0.046 0.307  ≤ 15% Reference Reference  > 15% 1.942 (0.983–3.838) 1.492 (0.692–3.215) Percent body fat loss* 0.014 0.018  ≤ 8% Reference Reference  > 8% 2.121(1.149–3.915) 2.080(1.136–3.809) Bold values indicate P  < 0.05 * Variables in multivariate analysis Predictors of complete response Bold values indicate P  < 0.05 * Variables in multivariate analysis As for recurrence, after achieving pathological complete remission, 34 patients received maintenance therapy, including the use of LNG-IUS, periodic oral contraceptives, or low-dose periodic progesterone until they tried to conceive. The median follow-up time was 38.80 months (range: 8.6–74.27 months). Twelve women experienced recurrence, for a recurrence rate of 22.64%. The median recurrence time was 26.48 months (range: 12.93–60.99 months). Two patients who discontinued uterine retention underwent hysterectomy with or without lymph node dissection. Ten patients underwent fertility-sparing treatment again; 8 (80%) achieved CR, and 2 (20%) underwent hysterectomy due to SD. The postoperative pathological diagnosis of the above patients who underwent hysterectomy was stage IA EC. Thirty-three (62.26%) women attempted to conceive after achieving CR. Seventeen (51.52%) women became pregnant, 12 (70.59%) of whom successfully delivered, and 3 (17.65%) were pregnant, while 2 (11.76%) of them miscarried—one in the first trimester and the other in the second trimester.

This retrospective and observational descriptive study reported the treatment response and fertility outcomes of obese patients with early-stage EC and AEH who underwent fertility-sparing treatment at the Department of Obstetrics and Gynecology, Peking Union Medical College Hospital (PUMCH), the largest tertiary referral center in the country, from January 2018 to December 2023. All patients were screened, and their information was extracted from the PUMCH Endometrial Cancer Fertility-Sparing Database. The study was approved by the PUMCH Ethics Committee (I-24PJ0364, dated February 29, 2024) and was registered with the Chinese Clinical Trial Registry (ChiCTR2200067099). Patients with early-stage EC or AEH were included if the following criteria were met: (1) pathological diagnosis of AEH or grade 1 (G1) endometrioid endometrial cancer by diagnostic curettage or hysteroscopy with biopsy; (2) women aged between 18 and 40 years with a requirement for fertility; (3) All patients underwent pelvic MRI and contrast-enhanced CT to comprehensively assess the depth of myometrial invasion and to exclude extrauterine metastasis. Disease staging was determined solely based on imaging findings, and all patients were clinically presumed to be at International Federation of Gynecology and Obstetrics (FIGO) stage I; (4) normal hepatorenal function; (5) weight management in the clinical nutrition department; (6) complete follow-up data. In the previous randomized controlled trial (RCT) study (ChiCTR2200067099), patients with a percent body fat ≥ 30% were further included in this study for subgroup analysis. Patients with the following conditions were excluded: (1) contraindications of pregnancy, such as genital tract malformation and ovarian function failure; (2) contraindications of the drugs; (3) failure to follow the requirements for weight management and regular testing of relevant indicators. Since this study focused on the effects of body weight, body fat mass (BFM), percent body fat (PBF), and visceral fat area (VFA) on treatment response, the minimum sample size was initially calculated as 10 times the independent variable. In the initial screening, a total of 62 obese patients underwent fertility-sparing treatment. Nine patients did not undergo various qualified physical function indicators tests. A total of 53 patients were finally included in this study. Two regimens were used, as previously mentioned in our study(Chen et al. 2022 , 2021a ), based on national expert consensus and the protocol of our registered RCT study: (1) progestin therapy: oral 500 mg of Medroxyprogesterone Acetate once daily or 160 mg of Megestrol Acetate twice daily; (2) treatment based on gonadotropin-releasing hormone agonist (GnRHa): all patients received one of the following treatments: a: 3.75 mg GnRHa subcutaneously injected every 4 weeks combined with continuous insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena). b: 3.75 mg GnRHa subcutaneously injected every 4 weeks combined with oral letrozole 2.5 mg/day. After the diagnosis of EC or AEH, the included patients began to receive fertility-sparing treatment and weight loss intervention at the same time. The weight loss intervention was defined as a 12-week weight loss program involving diet, exercise, psychology, and behavior. The core of rapid weight loss intervention is dietary intervention, in which the carbohydrate energy supply ratio is 45 ~ 55%, the lipid energy supply ratio is 20 ~ 30%, and the protein energy supply ratio is 20 ~ 30%. It was recommended to perform at least 150 min of moderate-intensity aerobic training and 2 resistance exercises per week. The total calorie is the initial body weight × 25 × 70%kcal/kg/d (the minimum for women is not less than 1000 kcal/d). During the intervention, the dietitian would provide a detailed list of recommended foods, ranking the common vegetables in China from low to high GI, and advise participants to choose the top foods in their daily diet. Participants consumed 2 nutritional protein bars (Nutriease [Zhejiang Nutriease]) daily as an alternative to the daily lunch and dinner staple foods to help improve adherence to allowable calorie intake (Valenzuela et al. 2022 ). The characteristic of weight management in this study is that dietitians help participants change their health behaviors from an intrinsic motivation. Dietitians help participants set personal goals and identify barriers and facilitators of a healthy lifestyle at enrollment. Dietitians develop exercise plans based on participants' personal goals and exercise abilities to support participants in overcoming exercise barriers. Patients will communicate with a dietitian multiple times via telephone or mobile platforms (Health Butler, Nott Health, China) to assess their behavioral (eating behavior, exercise behavior) and psychological changes, provide nutritional advice, skills for dealing with high-risk situations, strategies to prevent rebound, and promote interaction between participants. To provide personalized dietary advice with improved weight and nutritional status, and track the effects and compliance of weight loss and weight maintenance. Body composition was measured using the InBody770 (InBody Co., Ltd.) direct segmental multi-frequency bioelectrical impedance analyzer. Multiple electrodes were applied to the hands and feet to record segmental impedance, reactance, and phase-angle at different frequencies; the device’s algorithms then generated estimates of body fat mass (BFM, kg), percent body fat (PBF, %), and visceral fat area (VFA, cm 2 ). In our calculations, BFM = total body weight − fat-free mass, and PBF = (BFM / total body weight) × 100%. VFA reported by the InBody770 represents an estimate of adipose tissue surrounding abdominal organs; when measurement procedures are strictly followed, InBody770 VFA correlates highly with CT-derived VFA (r = 0.922). Body weight was recorded to the nearest 0.1 kg. Measurements were performed at baseline and monthly during the 12-week weight loss intervention. Optimal cut-off values for relative reductions in weight, BFM, PBF, and VFA with respect to time to complete response (CR) were determined using X-tile software. Cut-points were chosen by maximizing the Youden index (sensitivity + specificity − 1) and then rounded to the nearest integer for clinical interpretability. The final thresholds used in analysis were ≥ 10% weight loss, ≥ 18% VFA loss, ≥ 15% BFM loss, and ≥ 8% PBF loss. The therapeutic outcomes were categorically segregated into complete response (CR), partial response (PR), stable disease (SD), and disease progression (PD), as delineated by the pathological reports after hysteroscopic surgery. CR was ascertained in the absence of any indicia of disease, with at least two successive negative biopsies. PR represents histological regression. SD was defined as the persistence of the disease PD denoted an intensification or advancement of the disease state. CR was ascertained in the absence of any indicia of disease, with at least two successive negative biopsies. PR represents histological regression. SD was defined as the persistence of the disease PD denoted an intensification or advancement of the disease state. For patients who achieved a PR or SD, 1 to 2 courses of treatment were continued. Patients with PD were immediately recommended for a hysterectomy. For patients with persistent or aggravated disease for more than 12 months, surgical treatment is recommended. During treatment, outpatient visits were arranged every month. Physical examination testing for body fat, BMI, and body weight, as well as laboratory tests for liver function, CA-125, and whole blood cell count, were performed. Transvaginal ultrasound scans were performed at each visit to assess endometrial thickness. Hysteroscopic biopsies were performed to evaluate the therapeutic effect every 3–4 months. Once CR was achieved, patients with fertility plans were encouraged to transfer to the assisted reproductive technology center for fertility guidance. Patients without fertility plans were temporarily given maintenance treatment, including oral contraceptives (estrogen-progestin oral contraceptives are preferred unless contraindicated), low-dose cyclic progesterone, or implantation of the LNG-IUS, to prevent recurrence. All patients will receive long-term follow-up after CR to record the patient's fertility outcomes and detect early signs of recurrence of the disease. Women attended follow-up visits every 3 months for the first 2 years, every 6 months for the next 3 years, and annually every year thereafter. At each follow-up visit, fertility outcomes, including gestational duration, obstetric complications, and mode of delivery, were also recorded. Physical and gynecological examinations, abdominal (including both kidneys) and pelvic ultrasound examinations, and serum tumor marker data (mainly CA-125) were also collected. If patients have any abnormal vaginal bleeding or pelvic ultrasound findings suggestive of endometrial thickening or a mass in the uterine cavity, magnetic resonance imaging and hysteroscopy with biopsy will be performed to determine whether the disease has recurred. Categorical variables were analyzed using Pearson's chi-square test or Fisher's exact test based on the expected values. Continuous variables were compared and presented as medians and interquartile ranges, and the mean ± standard deviation. The analyses of survival were performed via the Kaplan–Meier method and the log-rank test. Cox regression univariate analyses were performed with CR as the endpoint; variables with P  < 0.1 were subsequently used to perform multivariate analysis via the Cox proportional hazards model. The Cox proportional hazards method with forward stepwise elimination was used for multivariate analyses. Odds ratios (ORs) with their 95% confidence intervals (CIs) were also derived. Statistical significance was considered when P  < 0.05. All significance tests were two-tailed. R software version 4.1.3 (The R Foundation for Statistical Computing, Vienna, Austria) and SPSS 26.0 (IBM SPSS Statistics, Armonk, NY: IBM Corp) were used in this study.

In conclusion, when overweight and obese patients with EC and AEH receive fertility-preserving treatment, multiple body fat indicators, especially the loss of PBF, are more meaningful for evaluating the time to CR, recurrence rate, and pregnancy rate than weight loss. Therefore, weight control and health counselling are essential throughout the life cycle of fertility retention therapy, especially for obese patients.

The incidence of EC is gradually increasing, especially in the younger population. Coupled with the postponement of childbearing age, there is a growing demand among young patients with EC for fertility preservation. The impact of changes in body indicators on oncological and reproductive outcomes during treatment remains to be evaluated. The objective of this investigation is to assess the oncological and fertility outcomes of fertility-preserving therapies in overweight patients diagnosed with EC and AEH, as well as to evaluate the impact of alterations in body weight, VFA, PBM, and BFM throughout the treatment regimen on CR, relapse rates, and the likelihood of pregnancy. Obesity and metabolic syndrome-related conditions, such as DM and PCOS, serve as risk factors for the development of endometrial cancer. Obesity was the factor most strongly associated with endometrial cancer compared to all other malignant tumors (Kim et al. 2021 ). It has been reported in the literature that weight loss surgery could reduce body weight and improve the response to fertility-sparing treatment for endometrial cancer (Gallo et al. 2023 ). Many studies have found that the relationship between obesity indicators and the incidence of endometrial cancer has been strongly supported, which is usually related to long-term estrogen exposure that lacks progesterone antagonism (Raglan et al. 2019 ). Miaomiao Li et al. reported that overweight or obese patients had a greater recurrence rate and a lower possibility of CR after progesterone therapy (Li et al. 2019 ). Park, JY et al., reported that pre- and post-treatment BMIs ≥ 25 kg/m 2 were significant predictors of poor treatment response and high recurrence (Park et al. 2017 ). However, the association between fertility-sparing treatment outcomes and weight changes was seldom mentioned, particularly for obese patients. The patients included in our study underwent a 12-week weight loss intervention, and changes in physical indicators before and after the intervention were recorded in detail. Interestingly, there was no significant correlation between weight loss greater than 10% and the time to CR ( p  = 0.702), which was inconsistent with previous research results (Shafiee et al. 2013 ). Recently, Watanabe, K et al. reported that the BMI criteria for diagnosing obesity were flawed and might underestimate the metabolic health benefits following exercise. BMI did not measure the amount of body fat or its distribution; thus, it failed to reflect whether individuals were truly obese or the extent of their obesity (Watanabe et al. 2023 ). Therefore, the VFA, BFM, PBF, and other body fat indicators can be used to objectively evaluate body fat distribution and obesity more objectively than BMI. A study regarded patients affected by EC reported that the BFM, VFA, and lipid accumulation index of the weight intervention group showed a downward trend compared with those of the control group, and the CR rate significantly improved (Chen et al. 2024 ). Our results showed that PBF > 8% ( p  = 0.018) was identified as an independent predictor of time to CR. At the same time, PBF > 8% and BFM loss > 15% have a lower recurrence rate ( p  = 0.007 and p  = 0.043, respectively). Some studies have reported that higher VFA and PBF are associated with recurrence and poor survival in patients with mid- and low rectal cancers (Lee et al. 2018 ; Li et al. 2023 ). There were limited data on the relationship between body fat index changes and the efficacy of fertility-sparing therapy in patients with EC and AEH. We believe that changes in body fat indicators are more worthy of attention than changes in BMI for patients undergoing fertility-sparing treatment. The use of high-dose progestin for fertility-sparing treatment has been widely accepted as the primary therapeutic approach, and its effectiveness is satisfactory. However, progestin can bind to glucocorticoid receptors and exhibits partial glucocorticoid activity. The long-term use of progestin can lead to metabolic abnormalities such as obesity (Guillon et al. 2019 ; Yu et al. 2009 ). For individuals who are obese, incremental weight accretion may engender an elevated likelihood of therapeutic non-response, an increased frequency of recurrence, and a diminished probability of conception (Park et al. 2017 ; Cholakian et al. 2016 ; Barr et al. 2021 ). Consequently, managing obese patients poses a significant challenge for us, and selecting the most efficacious method for these individuals represents a critical decision-making process. In our research, there was no significant difference in the time to CR, recurrence rate, or pregnancy rate between patients receiving progestin therapy and those receiving GnRHa combination therapy. Among the four patients who did not achieve CR with progestin therapy, switching to a GnRHa-based regimen resulted in CR after 1 to 2 courses of treatment. Our previous studies confirmed that GnRH-a-based fertility-sparing therapy achieved good therapeutic effects and reproductive outcomes in patients with AEH or EC who had failed oral progesterone therapy (Chen et al. 2021b ). Therefore, progestin therapy may not be the most effective treatment, and the GnRHa combined regimen can be used as an alternative for obese patients (Rodolakis et al. 2023 ). The primary mechanism of action for GnRHa combination therapy is the impact of a secondary hypoestrogenic state induced by pituitary downregulation. GnRHa treatment can lead to low oestrogen-related side effects, including bone mineral density loss and vascular motor symptoms (Surrey 2023 ). Therefore, we recommend that bone mineral density should be measured regularly when using the GnRHa regimen, and whether to add-back therapy and calcium and bisphosphonates should be used is still uncertain. The pregnancy rate and live birth rate of EC patients after fertility-sparing treatment are also worthy of clinical attention. A meta-analysis of 34 articles and 559 women (408 with endometrioid carcinoma and 151 with atypical hyperplasia) who received fertility-sparing treatment showed encouraging live birth rates of 28% and 26.3%, respectively (Wei et al. 2017 ). Zhang, Y. et al., reported that weight loss could have a positive impact on pregnancy rates and increase the live birth rate among overweight and obese women with early-stage EC and AEH during or after fertility-preserving treatment. For overweight and obese women, achieving a weight loss of at least 5% significantly enhances both pregnancy and live birth rates (Zhang et al. 2021 ). Shan, Y et al. reported that the pregnancy rate and live birth rate of overweight patients after fertility-sparing treatment were 29.8% and 23.4%, respectively (Shan et al. 2021 ). The relationship between changes in body fat indices following weight management during fertility preservation in obese patients and pregnancy rates has scarcely been reported. We found that patients with VFA loss > 18% ( p  = 0.143), BFM loss > 15% ( p  = 0.085), and PBF loss > 8% ( p  = 0.168) had slightly higher pregnancy rates. A reduction in body fat indices among obese patients preserving fertility during treatment is conducive to improving pregnancy rates, and future clinical research should focus more on this aspect. The molecular subtypes of endometrial cancer also have guiding significance for patients who want to preserve their fertility during early treatment. It is currently believed that patients with no specific molecular features (NSMP) and polymerase-ε (POLE) mutation subtype are suitable for conservative treatment and are the best beneficiaries of progesterone therapy. Mismatch repair deficiency (MMRd) and P53abn subtype patients have a poor response to progesterone therapy. One study has reported that tumor-infiltrating lymphocytes may play a role in identifying POLE-mutated ECs when sequencing is not possible (Raffone et al. 2021 ). There are no typical molecular features in patients with the NSMP subtype. Travaglino, A et al. found that CTNNB1 mutations are significantly associated with recurrence of early-stage endometrioid endometrial cancer, especially NSMP, which appears to be useful in guiding fertility-sparing treatment (Travaglino et al. 2022 ). Our investigation concentrated on the association between changes in body fat and oncologic and reproductive outcomes in patients with EC who retained fertility. Utilizing extensive clinical and follow-up data, we observed that, compared to BMI, indices such as VFA, PBF, and BFM emerge as superior indicators. Although our study also had several limitations. First, our study was a single-center retrospective study; therefore, multicenter prospective trials are needed to confirm our findings and to evaluate the effects of standardized, prespecified treatment strategies. Second, we did not analyze glycolipid metabolic parameters (for example, measures of insulin resistance or detailed lipid profiles) in relation to tumor response during the weight-loss intervention, which limits mechanistic interpretation. Third, we focused only on the relationships between body fat changes during 12 weeks of weight intervention and tumor and pregnancy outcomes; longer-term alterations in body fat and their association with oncologic and fertility outcomes remain unknown and should be evaluated in studies with larger sample sizes and extended follow-up. Finally, although 69.81% of patients received maintenance therapy after achieving CR, which can affect recurrence risk, routine endometrial histology was not performed at every scheduled visit and was obtained only when imaging or symptoms raised suspicion; this surveillance strategy may have missed subclinical recurrence and thus could bias recurrence estimates.

Endometrial cancer (EC) is one of the three most common malignant tumors of the female reproductive tract, with a rising global incidence trend (Kim et al. 2021 ). It is primarily due to the increasing prevalence of obesity (Crosbie et al. 2022 ). Endometrial cancer is commonly thought to occur in postmenopausal women. Around 4% of women diagnosed with EC were younger than 40 years of age due to a significant increase in the proportion of obese people. Women are nulliparous in 70% of these cases (Burleigh et al. 2015 ; Garg and Soslow 2014 ; Abdol Manap et al. 2022 ). Postmenopausal bleeding or abnormal uterine bleeding are the most common symptoms of EC (Pennant et al. 2017 ). Standard treatment requires at least hysterectomy and bilateral salpingo-oophorectomy and, if indicated, sentinel lymph node biopsy or pelvic and/or para-aortic lymph node dissection (Raimondo et al. 2024 ). Younger women with endometrial cancer tend to have earlier stages of disease and better histological types (Feinberg et al. 2019 ). Therefore, the option of fertility-sparing therapy should be considered in young patients with early-stage EC who wish to preserve fertility. To date, many studies have reported fertility preservation treatments in younger patients and have shown encouraging results in terms of tumor prognosis and reproductive outcomes (Gunderson et al. 2012 ; Guillon et al. 2019 ; Chen et al. 2022 ). Several studies have documented an increased incidence of EC among women who have not given birth, absence of a history of ovulatory cycles, excessive body weight, and a confirmed history of diabetes (Dossus et al. 2009 ; Ghanbari Andarieh et al. 2016 ; Zhao et al. 2021 ; Wu et al. 2019 ). Moreover, morbid obesity is associated with increased mortality and disease recurrence (Calle et al. 2003 ). Although EC is closely related to obesity, the relationship between changes in body weight indicators and conservation therapy in patients with EC has not been clearly determined. Therefore, our study aimed to evaluate the effects of changes in body fat under weight management on the time to complete response (CR) of fertility-sparing therapy in patients with early-stage EC and atypical hyperplasia (AEH). In previous studies, our preliminary results showed that weight loss of more than 10% had a positive effect on CR, recurrence rate, and pregnancy rates, but it did not show a statistically significant difference in multivariate analysis (Chen et al. 2022 ). Therefore, we further explored the various body fat indicators other than simple weight measurement, which could have a significant guiding effect on treatment response and fertility outcomes.