Failure of luteolysis and extension of the interoestrous interval in sheep treated with the progesterone antagonist mifepristone (RU 486)

The progesterone antagonist mifepristone (RU 486) was injected i.m. into ewes during the early luteal phase of the oestrous cycle to test the hypothesis that duration of uterine exposure to progesterone from the corpus luteum initiates luteolysis through the proper timing of endometrial oxytocin receptor expression and pulsatile secretion of PGF(2α), coincident with release of luteal oxytocin. In Expt 1, duration of cycle, the PGF(2α) metabolite 15-keto-13,14,-dihydro-PGF(2α) (PGFM) and oxytocin concentrations were measured in ewes treated on days 5, 6, 7 and 8 of the oestrous cycle with either 2.5 or 5.0 mg RU 486 kg^-1 day^-1 (n = 4 per group); control ewes (n = 6) were injected i.m. with 80% ethanol (diluent). In Expt 2, the presence of functional uterine oxytocin receptors was determined indirectly on day 12 of the cycle by measuring the plasma PGFM response to oxytocin challenge (20 iu, i.v.) in diluent-treated ewes (n = 3) and in ewes treated with 2.5 mg RU 486 kg^-1 day^-1 on days 6, 7 and 8 of the oestrous cycle. Duration of the oestrous cycle of control ewes (16 ± 1 days) was extended beyond day 24 (day 0 = oestrus) in 10 of 11 ewes treated with RU 486 as determined by daily exposure of ewes to a ram and by measurement of progesterone concentrations in plasma in the two experiments. Luteolysis (days 14-16) in control ewes was preceded (days 12-15) by pulsatile release of PGFM in plasma and by the presence of functional endometrial oxytocin receptors that responded to oxytocin challenge (day 12) with a significant increase in plasma PGFM concentrations. RU 486 treatment prevented pulsatile PGFM release on days 12-15 and release of PGF(2α) following oxytocin challenge on day 12 but not on day 20 when oxytocin administration was repeated. The absence of pulsatile PGFM release in ewes treated with RU 486 on days 12,13,14 and 15 in Expt 1 was associated with different plasma oxytocin activity in treated and control ewes in that plasma oxytocin increased from days 12 to 14 in mifepristone-treated but not in control ewes. We conclude that adequate progesterone exposure during the early to mid-luteal phase of the oestrous cycle is essential for initiation of ovarian-uterine mechanisms that lead to luteolysis in ewes.