INTRODUCTION
As the precancerous stage of endometrioid endometrial cancer (EEC), the incidence of atypical endometrial hyperplasia (AEH) is increasing1, 2, which makes fertility-preserving treatment in young AEH patients an important issue. Oral high-dose progestins, including megestrol acetate (MA) and medroxyprogesterone acetate (MPA), are traditional choices for fertility-preserving treatment in these women 3-5 with a complete response (CR) rate around 70%-80% . However, up to 30% of patients remain insensitive to progestin 6 and the median treatment duration to achieve complete response is 6 to 7 months7-9. Multiple adverse effects occurred accompanying long treatment duration, such as edema and weight gain, which usually hindered the patient’s compliance to oral progestin 4, 8. Therefore, more optimal fertility-preserving treatment for AEH patients is urgently needed.
Levonorgestrel-releasing intrauterine system (LNG-IUS), an intrauterine high-efficient progestin (levonorgestrel) releasing system, has been recommended as the first-line fertility-preserving treatment for AEH patients10, 11. Retrospective studies suggested that LNG-IUS might provide non-inferior efficacy with the CR rates of 78.7%-90% compared with oral progestin12-14 , and was associated with less systemic symptoms such as weight gain, decrease in bone mineral density, risk of venous thrombosis and breast cancer 15-19. However, high quality evidence from randomized controlled study is still lacking to compare LNG-IUS alone with oral progestin as fertility-sparing treatment for AEH patients.
Another question that remains unclear is whether LNG-IUS combined with oral progestins may achieve higher treatment effects than LNG-IUS or oral progestins alone in AEH patients. A few retrospective or small sample-size prospective clinical studies suggested the efficacy in EEC patients might be improved when combining oral progestin with LNG-IUS20-22. A retrospective analysis 20found that the CR rates were 77.8% (7/9), 50% (2/4) or 33.3% (1/3) in EEC patients receiving oral progestin plus LNG-IUS, oral progestin only or LNG-IUS only, respectively. However, the number of patients included in these studies were too small to draw a conclusion.
In order to address these questions, we conducted this prospective phase II study with randomized controlled design, to evaluate the effect of LNG-IUS with or without oral MA on fertility-preserving outcome in AEH patients. The primary endpoint was complete response (CR) rate at 16 weeks of treatment(16-week CR rate). The secondary endpoints were CR rate at 32 weeks of treatment (32-week CR rate), adverse events, recurrent rate, and pregnancy rate.