GnRH-a can suppress estrogen levels and endometrial hyperplasia within 14 days of the first administration. Additionally, GnRH-a can inhibit the growth of endometrial cancer cells by directly binding to GnRH receptors on the surface of tumor cells [10, 12]. The most common adverse effects include post-menopausal symptoms such as hot flashes, night sweats, insomnia, headaches, irritability, sleep disturbances, mood changes, vulva and vaginal dryness. Pain, redness, and inflammation may occur at the injection site.

Aromatase inhibitors (AIs) work by inhibiting aromatase function in peripheral tissues, such as fat and muscle, thus preventing the conversion of androstenedione into estrone and estradiol. This reduces the levels of circulating estrogen, thereby diminishing the growth stimulation of endometrial cancer cells. This approach is employed to treat endometrial atypical hyperplasia and early endometrial cancer [15, 21]. Adverse effects of AIs may include bone loss, bone pain, joint pain, palpitations, hot flashes, headache, dizziness, fatigue, nausea, vomiting, constipation, diarrhea, irregular vaginal bleeding, and weight gain.

The LNG-IUD is approved for contraception, treatment of idiopathic menorrhagia, and prevention of endometrial hyperplasia. The most common adverse reactions are irregular vaginal bleeding, amenorrhea, intermenstrual bleeding and spotting, abdominal/pelvic pain, and ovarian cysts. The device is not recommended for use in women with known or suspected pregnancy, congenital uterine abnormalities, breast cancer, unexplained vaginal bleeding, reproductive tract infections, and other specific conditions.

Systemic progestogen therapy, such as MA 160 mg/MPA 500 mg orally once a day, is effective for the treatment of hormone-sensitive hyperplasia and tumors. However, PRs are often downregulated, resulting in a relatively short duration of effectiveness. Furthermore, systemic therapy is associated with low compliance rates due to adverse effects, including nausea, thromboembolic complications such as deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, weight gain, abnormal vaginal bleeding, and an increased risk of breast cancer.

Treatment of adverse events

Any adverse events will be addressed by local investigators in accordance with current good clinical practice guidelines and will be informed to the Ethics Review Committee of Peking Union Medical College Hospital and Chinese Academy of Medical Sciences. A case report form will be used to document the details of each adverse event, including its nature, time of onset and resolution, severity, treatment administered, and outcome. If deemed necessary, follow-up examinations will be conducted to ensure patient safety. In the event that the physician overseeing the trial identifies any harm to a participant or signs of treatment ineffectiveness, the participant will be withdrawn from the study, and the results of these participants will be analyzed separately as a non-CR group.

Criteria for discontinuation of trial treatment

The criteria for discontinuing trial medication are as follows:

1.

Participant refusal to continue or withdrawal of consent.

2.

Cancelation of the entire study.

3.

Violation of the research protocol.

4.

Protocol treatment will be discontinued if it does not result in remission, based on the following criteria: no treatment response or CR by 24 weeks, or disease progression at any time.

5.

Severe adverse events (progressive or persistent) that may be related to the medication, such as hemorrhagic shock due to massive vaginal bleeding, severe allergic reactions, thrombosis, or liver function damage. Additionally, newly diagnosed malignancies, such as breast cancer, will be evaluated by two chief physicians before the trial is halted.

6.

Any situation in which the use of GnRH-a, letrozole, LNG-IUD, or MA/MPA treatment cannot be continued, as determined by the physician’s judgment.

Follow‐up evaluations

While the study duration is 2 years, the treatment and follow-up of patients will be long-term. Patients who have achieved complete remission and have completed childbirth will be recommended for a hysterectomy. Patients with fertility requirements or those unwilling to undergo a hysterectomy will be closely monitored for signs of recurrence.

Statistical analysis

Interim analyses will be performed to help researchers assess the progress of the trial, evaluate safety and efficacy, and make necessary adjustments to the study design. Prior to formal analysis, data cleaning and preparation will be performed. Once data collection and cleaning are complete, formal data analysis will be carried out utilizing the SPSS Statistics software package (version 26.0). To maintain randomization benefits and avoid biases, we will combine intention-to-treat analysis with imputation methods to handle missing data. We will select the appropriate imputation method based on the nature of the missing data. We will use the mixed models to handle the complex data by using maximum likelihood or Bayesian approaches to estimate model parameters, taking missing data into account. The significance level will be set at 0.05, and the confidence interval will be established at 95%.

The AEH and EC CR rates, along with their 95% CIs, will be calculated for both groups. Quality of life will be assessed in patients at baseline, week 1, and months 3, 6, 9, 12, 18, and 24. Other data acquisition and analyses will include the calculation of the complete response rate for the trial treatment period, the rate of trial continuation for GnRH-a plus letrozole or LNG-IUD and MA/MPA, the determination of the proportion of patients that become pregnant at least once during the trial period, the assessment of pregnancy outcomes (miscarriage, stillbirth, live birth, and weeks of gestation), and the evaluation of the proportion of patients that give birth to a child. Data will be reported as mean and standard deviation (SD), median and interquartile range (IQR), or number and percentage (%) depending on whether the data are continuous or categorical and assuming normality. The Kolmogorov–Smirnov normality test will be used to check the normality of continuous variables. For comparisons between 2 groups, Student’s t-test or the Mann–Whitney U test will be used according to the normality assumption. The chi-square test will be employed to compare the number of cases and percentages between groups.

Primary endpoints

The cumulative complete response rates of GnRH-a plus letrozole or LNG-IUD will be compared to classical progesterone (megestrol acetate and/or medroxyprogesterone acetate) 24 weeks after treatment initiation.

Secondary endpoints

Secondary endpoints include the complete response rate after 3 months of treatment and the median complete response time, the proportion of recurrence and the death rate, the proportion of patients who become pregnant at least once during the trial period, outcomes of pregnant patients (miscarriage, stillbirth, live birth, and weeks of gestation), outcomes of all cases expressing the desire to become pregnant, and the proportion of patients giving birth to a child.

Safety endpoints

In the analysis of secondary safety endpoints, we will evaluate the number and rate of adverse events in a safety analysis set, with particular attention to events graded as 3 or higher (or 2 or higher for neurotoxicity).

Data management, monitoring, safety, and auditing

Our study team will make maximum effort to have participants complete the study follow-up assessments. The study team will contact participants via telephone to collect as much outcome data as possible. All data obtained until the time of withdrawal will be retained in the study. A comprehensive data management plan is implemented to ensure data quality, security, and storage. This includes using standardized CRF templates and guidelines for data entry, conducting regular quality checks and validation procedures, and implementing strict protocols for data security and storage.

A data monitoring plan and detailed routine verifications of the electronic case report forms (eCRFs) will be proposed. An independent data monitoring committee (DMC) is established to ensure the safety and efficacy of the trial. The DMC will regularly review the progress of the trial, including recruitment, data collection and analysis, and serious adverse events, provide advice to improve the quality, and will have access to interim investigator’s brochure. Lead investigators will be steering committee results and make the final decision to terminate the trial. The principal investigator, a gynecologic oncologist from Peking Union Medical College Hospital, is responsible for designing and revising the research protocol, drafting the investigator’s brochure (IB), and creating the case report forms (CRFs). The steering committee meetings will be organized by the principal investigator. In each participating center, the lead investigator and 2–3 research physicians will be identified to be responsible for identification, recruitment, data collection, and completion of CRFs, along with follow up of study patients and adherence to study protocol and investigator’s brochure. The researchers will develop a lay summary of the results for participants and update the registry with the study results, which will promote transparency and allow other researchers, healthcare professionals, and the public to access the outcomes of the trial.

Confidentiality

Only the informed consent forms will contain patient names and will be stored locally in a safe location at each participating center. Personal data about participants is retained using an identifier in the eCRFs. Only the authorized research team will be granted access to personal information about participants.

Publication of results

The trial results will be presented as abstracts at International Gynecologic Cancer Society (IGCS) annual global meetings. We will publish the final data in a peer-reviewed medical journal to expand the dissemination.