To investigate the efficacy of weight management plus levonorgestrel intrauterine system (LNG-IUS) or megestrol acetate (MA) in obese patients with endometrial atypical hyperplasia (EAH) asking for conservative therapy.
Background: High-efficacy progesterone, such as levonorgestrel intrauterine system (LNG-IUS), megestrol acetate (MA), and medroxyprogesterone acetate(MPA), is the first-line treatment for women with endometrial atypical hyperplasia (EAH) who want to preserve fertility. About 70% to 80% of those patients can achieve complete remission (CR) with a median CR time of about 6 months, but about 20% to 30% of those patients get no response or need longer time to get CR (over one year or even longer). Overweight or obesity is an independent risk factor for fertility-sparing treatment response and pregnancy outcomes in young females with EAH or early endometrioid cancer (EEC). Evidence showed that obesity can cause lower CR rates and longer time to get CR and lower birth rates in EAH or EEC patients asking for conservative therapy. Weight management has been proved to improve metabolic disorders, ovarian functions, and pregnancy outcomes. Metformin, as a diabetes drug, has been proved to increase CR rates in EAH or EEC patients treated with MA for fertility. Weight management has raised more and more attention and has been proved to benefit metabolic and pregnancy outcomes. Based on previous research and published studies, the hypothesise is that weight management plus progestin therapy may raise CR rates and pregnancy outcomes in young female EAH patients asking for fertility conservation. Enhanced lifestyle management (diet control, exercise, and daily behavioral guidance) may improve metabolic conditions, increase CR rates and pregnancy outcomes in obese EAH patients who want to preserve fertility. Till now, no similar studies were found, so this study is designed to explore the efficacy of weight control in EAH fertility-sparing patients to provide new evidence for improving conservative treatment. Objective: To investigate whether weight management plus LNG-IUS/MA can improve the efficacy of preserving fertility in obese EAH women who want fertility conservation. Design: This study is designed according to Simon's Two-Stage Design. Based on BMI and treatment plans, four single-arms are designed. This study is prospective, open-label. EAH Patients requiring conservation treatment with BMI ≥ 24 kg/m2 will be recruited in this study and they will be divided into four arms, the first group recruits overweight (24kg/ m2≤BMI\<28kg/m2) patients treated with LNG-IUS, the second group recruits overweight (24kg/ m2≤BMI\<28kg/m2) patients treated with MA, the third group recruits obese (BMI≥28kg/m2) patients treated with LNG-IUS, and the last group recruits obese (BMI≥28kg/m2) patients treated with MA. The sample size is calculated based on Simon's Two-Stage Design and previous CR rates. All enrolled patients will receive enhanced lifestyle management to control weight and take LNG-IUS/MA for treating EAH. Hysteroscopic examination, metabolic and inflammatory indicators will be performed every 12 to16 weeks while other indexes will be evaluated every month, including weight, heart rates, blood pressure, body fat tests, and so on. For the progestin efficacy evaluation, CR is defined as the remission of EAH to proliferative or secretory endometrium; partial response (PR) is defined as regression to simple or complex hyperplasia without atypia; no response (NR) is defined as the persistence of the disease, and progressive disease (PD) is defined as disease progression in patients. Two months' maintenance treatment will be recommended for patients with CR, and participants will be followed up for 2 years. Outcomes: Primary outcome is the CR rates of the four arms. Secondary outcomes include pregnancy rates, live birth rates, weight loss, insulin resistance, chronic inflammation indicators, time to achieve CR and recurrence rates, and so on. Safety and side events during the whole trial will be monitored in two years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
172
dietary guidance, exercise guidance, lifestyle intervention
enrolled participants will take Megestrol Acetate 160mg daily
enrolled patients will be treated with LNG-IUS.
Obstetrics and Gynecology Hospital of Fudan University
Shanghai, China
RECRUITINGPathological complete response (CR) rates
The 28-week CR rates will be calculated in four arms
Time frame: From date of recruitment until the date of CR, assessed up to 28 weeks.
Pregnancy outcomes
For participants have a desire for fertility, pregnancies, births and related outcomes will be counted, and the rate of pregnancy will be counted as number of pregnancies/ number of patients trying to fertility in the following period.
Time frame: up to 2 years after complete response of the last participant
Weight change
The investigators will record body weight every month and calculate its change in kilograms.
Time frame: From date of recruitment, assessed up to 28 weeks.
Body composition change
The investigators will detect body composition with InBody machine and calculate changes of the indicated indexes.
Time frame: From date of recruitment, assessed up to 28 weeks.
Blood pressures change
Record blood pressures (systolic and diastolic pressures) every 12-16 weeks and count the change during the trial.
Time frame: From date of recruitment, assessed up to 28 weeks.
Heart rates change
Record heart rates (beats per minute) every 12-16 weeks and count the change.
Time frame: From date of recruitment, assessed up to 28 weeks.
Blood glucose change
Assess fasting glucose levels each 3 to 4 months and calculate changes in mmol/L.
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Time frame: From date of recruitment, assessed up to 28 weeks.
Blood lipids change
Assess blood lipids levels each 3 to 4 months and calculate changes during the trial.
Time frame: From date of recruitment, assessed up to 28 weeks.
Insulin resistance change
Test fasting insulin levels each 3 to 4 months, and count HOMA-IR index (Homeostatic Model Assessment for Insulin Resistance) with fasting insulin and fasting glucose as follow: Insulin (pmol/L)\*glucose (mmol/L)/22.5, and compare the HOMA-IR change during the treatment.
Time frame: Baseline，3months and 6months after enrolled.
Ovarian reserve function
Detect serum Anti-Mullerian Hormone (AMH) each 3 or 4 months and calculate its change.
Time frame: From date of recruitment, assessed up to 28 weeks.
Quality of life change
Collect the questionnaire SF-36 and count scores change through conservative treatment.
Time frame: From date of recruitment, assessed up to 28 weeks.
Impact of Weight on Quality of Life
Collect questionnaire IWQOL- LITE and count scores change through conservative treatment.
Time frame: From date of recruitment, assessed up to 28 weeks.
Physical activities change
Collect physical activities questionnaire(IPAQ) and compare scores changes through conservative treatment.
Time frame: From date of recruitment, assessed up to 28 weeks.
Chronic inflammatory index (TNF-α) change
The investigators will detect the levels of TNF-α (fmol/ml) in serum and calculate changes through the whole treatment period.
Time frame: baseline, 3 months and 6 months after treatment.
Chronic inflammatory index (IL-1) change
The investigators will detect serum index IL-1 in U/ml and calculate changes through the whole treatment period.
Time frame: baseline, 3 months and 6 months after treatment.
Chronic inflammatory index (IL-6) change
The investigators will detect serum index IL-6 in U/ml and calculate changes through the whole treatment period.
Time frame: baseline, 3 months and 6 months after treatment.
Time of pathological complete response (CR)
Time of histologic regression from EAH to proliferative or secretory endometrium
Time frame: From date of recruitment until the date of CR, assessed up to 2 years.
Incidence of adverse events
Adverse events related with MA, LNG-IUS and weight control. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be recorded, as well as incidence of adverse events.
Time frame: From date of recruitment until the date of CR, assessed up to 2 years.
Relapse rates
All enrolled patients will be followed up for 2 years. During the following-up period, if patients recur after complete regression, they will be counted and the number of recurrence will be divided by number of patients followed up, then the investigators can get the relapse rates.
Time frame: up to 2 years after the treatment for each patient