Effects of the levonorgestrel intrauterine system on the endometrium after long-term exposure to mifepristone: Secondary outcomes of a randomized controlled trial.

Objective: Long-term treatment with progesterone receptor modulators (PRM) is associated with a distinct histological entity termed progesterone receptor modulator associated endometrial changes (PAEC). While accumulating evidence implies that these changes are benign and reversible after cessation of treatment, there are currently no data underpinning their development. Consequently, as a precaution, endometrial shedding is recommended after long-term PRM intake. Avoiding endometrial shedding after treatment with a PRM and prior to the start of a progestin treatment would be beneficial for women in reproductive age to avoid pregnancy and bleeding. However, the endometrial morphology with such a treatment regimen is unknown. The aim of this study was to delineate the endometrial morphology following continuous long-term treatment with the PRM mifepristone and subsequent placement of a levonorgestrel intrauterine system (LNG-IUS) without prior shedding of the endometrium.

Study Design: This study reports the secondary outcome from a double-blinded randomized controlled trial conducted at Karolinska University Hospital, Sweden, November 2009 to January 2015. Healthy women aged 18-43 years with regular menstrual cycles were included. Eligible women were randomized to receive either 50 mg of mifepristone (n = 29) or a comparator (n = 29), every other day for two months followed by insertion of an LNG-IUS 52 mg. Endometrial biopsies were obtained at baseline and three months after placement of the device. The samples were histologically assessed. The main outcome measure of this sub-study was the endometrial morphology including presence of PAEC three months after LNG-IUS insertion.

Results: Nine and eight paired biopsies from the mifepristone and comparator group, respectively, were included in the histological analysis. There were no differences in baseline characteristics between the groups and all baseline endometrial biopsies were physiological. Three months after LNG-IUS placement the endometrial morphology was still benign without PAEC in all samples treated with either mifepristone or comparator. A progestin effect on the endometrium was seen in all samples.

Conclusions: Placement of an LNG-IUS immediately following two months' treatment with the PRM mifepristone, without any prior shedding of the endometrium, may represent a feasible approach in terms of endometrial safety. However, larger studies are needed to confirm our results.