A STUDY OF THE LUTEOLYTIC MECHANISM OF THE ANTIPROGESTERONE RU486 DURING THE LATE-LUTEAL PHASE IN PSEUDOPREGNANT RATS

The purpose of this study was to examine the possible mechanism throug h which RU486 induces luteolysis during the late-luteal phase in pseud opregnant (PSP) rats. PSP rats received a subcutaneous injection of RU 486 in sesame oil (5 mg/kg body weight) or sesame oil alone once a day between day 9 and day 11 of pseudopregnancy. Serial blood samples wer e collected on days 5, 9, 10, 11 and 12 and assayed for progesterone c ontent. To examine the possible action of RU486 through a uterine and/ or a pituitary (prolactin-dependent) mechanism, PSP rats and chronic h ysterectomized PSP rats which had been hysterectomized before PSP indu ction received a subcutaneous injection of RU486 in sesame oil (5 mg/k g body weight), sesame oil alone, prolactin in 50% polyvinylpyrrolidon e (15 IU/day), or RU486 and prolactin once a day between day 9 and day 11 of pseudopregnancy. Serial blood samples were collected on days 5, 9, 10 and 11 and assayed for progesterone content. Blood samples were also collected at 0400 h on day 12 and used for prolactin and progest erone determinations. To examine the direct effect of RU486 on corpus luteum and/or pituitary, hysterectomized rats underwent hypophysectomy and pituitary autotransplantation on dioestrus 1 and received a subcu taneous injection of RU486 in sesame oil or sesame oil alone for 3 day s between day 21 and day 23 after surgery. Serial blood samples were c ollected on days 10, 21, 22, 23 and 24 and assayed for progesterone an d prolactin contents. In ordinary PSP rats, serum progesterone levels were significantly (P<0.01) lower in the RU486-treated group than in t he control group (9+/-1 vs 53+/-7 ng/ml; mean+/-S.E.M.) On day 11. Ser um prolactin levels at 0400 h on day 12 of pseudopregnancy were signif icantly (P<0.05) lower in the RU486-treated group than in the control group (16+/-4 vs 154+/-44 ng/ml; mean+/-S.E.M.). The concomitant prola ctin treatment reversed the luteolytic effects of RU486 on day 11 of p seudopregnancy. In hysterectomized PSP rats, RU486 also suppressed ser um prolactin levels, and the concomitant prolactin treatment again rev ersed the luteolytic effects of RU486. In hysterectomized rats which w ere hypophysectomized and pituitary autotransplanted, RU486 treatment did not induce any significant changes in serum progesterone and prola ctin levels. These results indicated that RU486 induced luteolysis dur ing the late-luteal phase in PSP rats by suppressing prolactin secreti on via a hypothalamic mechanism.