The Potential of Mifepristone (Ru486) as a Female Contraceptive Drug

Abstract

SUMMARYThis article reviews the development of mifepristone (RU486) as a female contraceptive drug. Mifepristone is an orally active compound with nearly 40% bioavailability after first pass effect. The steady plasma level of mifepristone ranges from 65 nmol/l with 1 mg/day to 1 μmol/l with 10 mg/day and reaches 2.5 μmol/l, 4.5 μmol/l and 5.4 μmol/l with mifepristone 50 mg, 100 mg and 200 mg daily, respectively, over the treatment period. Inhibition of ovulation may be achieved at serum mifepristone concentration of 232.7 nmol/l. Mifepristone appears to antagonise progesterone at the pituitary level to suppress gonadotropin and steroid hormone secretion rather than to act primarily on the hypothalamus to delay or inhibit ovulation. In fact, the endometrium is most sensitive to mifepristone. Low‐dose mifepristone impairs luteal phase endometrial development and receptivity by altering endometrial parakine, cytokine and enzyme activity. Thus, low‐dose mifepristone can significantly reduce the rate of conception without inhibiting ovulation. However, further research is needed to standardise the dose and dose‐schedule to achieve the desired efficacy of low‐dose mifepristone for routine clinical use with minimal or no side‐effects.

Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis

“…Then, 0.5 × 10 6 /mL NK cells were co-cultured (E:T, 5:1) with 0.1 × 10 6 /mL PKH-67-labeled targets (K-562) in RPMI-1640 GlutaMAX™ (10% FBS) for 4 h at 37 °C. Anti-progestin effects were also determined by co-culturing NK cells from healthy premenopausal participants (EF phase; n = 15) overnight in (i) media alone, with (ii) P4 (10 µM), or with (iii) P4 (10 µM) with Mifepristone (RU486; 1.25 µM; Sigma-Aldrich; Figure 1 g); 1.25 µM Mifepristone has a ~25 mg oral equivalent [ 15 ]. TO-PRO-3 iodide (Invitrogen) was added (10% of total volume) to determine cytotoxicity (>10,000 events) using a NovoCyte ® flow cytometer (Agilent Technologies, Inc.).…”

“…Phase-specific derived NK cells from healthy premenopausal participants (EF phase; n = 13) were co-cultured overnight (24 h) in CM alone or with progesterone (P4; Sigma-Aldrich) at different final concentrations (0.1 µM to 10 µM) before being washed, checked for viability, and added to K-562 the following day (Figure 1f). Then, 0.5 × 10 6 /mL NK cells were co-cultured (E:T, 5:1) with 0.1 × 10 6 /mL PKH-67-labeled targets (K-562) in RPMI-1640 GlutaMAX™ (10% FBS) for 4 h at 37 • C. Anti-progestin effects were also determined by co-culturing NK cells from healthy premenopausal participants (EF phase; n = 15) overnight in (i) media alone, with (ii) P4 (10 µM), or with (iii) P4 (10 µM) with Mifepristone (RU486; 1.25 µM; Sigma-Aldrich; Figure 1g); 1.25 µM Mifepristone has a ~25 mg oral equivalent [15]. TO-PRO-3 iodide (Invitrogen) was added (10% of total volume) to determine cytotoxicity (>10,000 events) using a NovoCyte ® flow cytometer (Agilent Technologies, Inc.).…”