Endometrial receptivity and development of new contraceptive methods

Abstract: Ovulation and endometrial development as well as contraceptive efficacy was studied after treatment with the antiprogestin mifepristone. Mechanism of action after treatment with the gestagen levonorgestrel or mifepristone in doses effective for emergency contraception was also evaluated. Mifepristone binds to the progesterone receptor and blocks the action. The effect in reproductive pathways depends on when the drug is administered and the dose given. Subjects were treated with different doses of mifepristone, 0.5 mg daily, 5mg once weekly or 200 mg as a single dose in early luteal phase. To study the effect of emergency contraception treatment, levonorgestrel 1.5 mg divided into 2 doses or 10 ing mifepristone was administered either 2 days before or 2 days after the luteinizing hormone (LH) surge. An endometrial biopsy was performed during the expected time of implantation (6-8 days after LH surge). Immunohistochemistry and electron microscopy were used for analysis of implantation on markers and ovarian steroid production was followed by daily urine samples. After treatment with 200 ing mifepristone in early luteal phase the expression of the enzymes involved in prostaglandin synthesis, COX-1 and COX-2, was significantly reduced. The expression of integrin subunits alpha4 and beta3, suggested as important for blastocyst implantation, was also reduced. This effect was also shown after administration with 5mg weekly and 0.5 mg daily. When 10 ing mifepristone was administered in early luteal phase no effect on above markers was found however the down regulation of progesterone receptors that normally occur during the expected time of implantation was inhibited. No effect on endometrial development was found after treatment with 1.5 ing levonorgestrel in early luteal phase. Preovulatory treatment with 10 mg mifepristone and also 1.5 mg levonorgestrel suppressed or delayed the LH surge in all subjects. When 5 mg mifepristone was administered once weekly to 17 women during 60 cycles, 3 pregnancies occurred leading to an estimated contraceptive efficacy of 78%. Treatment with 0.5 mg mifepristone daily to 32 women during 141 cycles resulted in 5 pregnancies and an estimated contraceptive efficacy of 85%. In conclusion these results indicate that mifepristone and levonorgestrel in doses effective for emergency contraception mainly affect ovulation and that higher doses of mifepristone i.e. 200 mg show more pronounced effect on endometrial development. These studies also show that mifepristone in low doses that do not affect ovulation significantly reduces pregnancy rate compared to if no contraceptive method is used. However the effect is not sufficient for this regimen to be used on a regular basis.