Participants

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).

Inclusion and exclusion criteria

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.

Treatment methods

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.

Weight loss intervention

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 and weight measurements

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, cm2). 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.

Outcome variables

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.

a.

CR was ascertained in the absence of any indicia of disease, with at least two successive negative biopsies.

b.

PR represents histological regression.

c.

SD was defined as the persistence of the disease

d.

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.

Follow-up

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.

Statistical analysis

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.