onapristone and sulprostone

In humans cervical ripening is an inflammatory reaction accompanied by an infiltration of white blood cells and the remodelling of the extracellular matrix. Similar changes occur in guinea-pigs during cervical ripening. Nitric oxide (NO) is thought to be important in the maintenance of pregnancy because it is synthesized by the uterus and inhibits contractility. Previous studies in rats also demonstrated that an NO generating system is present in the cervix and is up-regulated during labour. We studied the local effect of the NO donor sodium nitroprusside (SNP) on cervical ripening in guinea-pigs during advanced pregnancy. SNP (5 mg/injection) was administered into the cervical canal in 0.2 ml phosphate-buffered saline containing 3% hydroxycellulose twice a day either for 1 [on day 42 post coitum (p.c.)] or 2 consecutive days (days 42-43 p.c.; term day 67 + 3 p.c.). The effects were assessed 24 h after treatment by both extensibility measurements (force resistance to incremental stretch) and morphological evaluation (light and electron microscopy after in-situ fixation). The control animals were treated with the vehicle. In another experiment, the guinea-pigs were subcutaneously (s.c.) treated on day 43 p.c. with either the progesterone antagonist onapristone (3 and 10 mg/animal s.c.) or with prostaglandin E2 (PGE2) (1 and 3 mg/animal s.c.) and the PGE2 analogue sulprostone (0.03 and 0.1 mg/animal s.c.). The cervical extensibility was measured 24 h later. One-day SNP treatment tended to reduce cervical resistance, but not significantly, whereas 2 day treatment with SNP led to a significant increase in cervical extensiblity (P < 0.05) with little effect on cervical dilatation (indirect evidence of the absence of uterine contractions). The effects on cervical resistance were comparable to those achieved with 10 mg onapristone and high-dose prostaglandins (PG)s (3 mg PGE2 and 0.1 mg sulprostone) treatment. An electron microscope study of the SNP-treated animals revealed a dissolution of collagen fibres, stromal oedema, arterial dilatation, and the infiltration of macrophages, lymphocytes and granulocytes. Numerous mast cells were also present. The morphological effects of SNP were similar to those observed during normal cervical ripening at term. We conclude that the local application of a NO donor effectively induces cervical ripening without inducing labour in pregnant guinea-pigs.

Topics: Animals; Cervix Uteri; Dinoprostone; Female; Gonanes; Guinea Pigs; Hormone Antagonists; Labor, Obstetric; Microscopy, Electron; Nitric Oxide; Nitroprusside; Pregnancy; Progesterone

Three antiprogestogens of the RU 38.486, ZK 98.734, and ZK 98.299, were studied at different stages of pregnancy in the guinea pig. Treatment starting on postconception day 4 completely prevented nidation; all three compounds had comparable inhibitory potency. Treatment after nidation, starting on postconception day 8, induced decidual collapse and bleeding, but embryonic tissue was retained in nidation sites. In contrast to results in animals in nonfertile cycles, luteolysis was not induced, indicating that antiprogestogens lack the ability to induce uterine prostaglandin synthesis/liberation. On postconception day 43, RU 38.486 showed marginal abortifacient activity. The other compounds induced expulsion more rapidly and at a higher rate. The comparatively pronounced antiglucocorticoid activity of RU 38.486 may account for this difference. With RU 38.486, a high level of uterine prostaglandin sensitivity and a cervical ripening were induced consistently and fast; spontaneous labor, on the other hand, occurred after several days, if at all. Complete uterine evacuation was induced within hours by otherwise inactive doses of sulprostone in various combinations with ZK 98.299 RU 38.486 but surprisingly not with ZK 98.734. A single dose of ZK 98.299 induced an approximately thirtyfold increase in uterine prostaglandin sensitivity within 24 hours, exceeding that present before term, but did not induce spontaneous labor. This is evidence that endogenous prostaglandins were not activated, analogous to perinidation stages. Observation of antiluteolytic activity of antiprogestogens in nonpregnant animals is considered of major theoretical importance in this context. It seems that inhibition of progesterone leads to suppressed uterine prostaglandin liberation. The same effect in pregnancy could explain the inability of the uterus to expel a seriously compromised conceptus. In conclusion, we suggest that progesterone is a stimulator rather than a depressor of uterine prostaglandins in the late luteal phase and pregnancy. The ability of the conceptus to neutralize this stimulatory action of progesterone is considered to be essential for the rescue of the corpus luteum and uterine motor quiescence in the guinea pig. The clinical significance of these findings is that the high frequency of incomplete abortions and protracted, sometimes heavy bleeding in pregnant women treated with RU 38.486 may reflect decidual compromise and simultaneous uterine prostaglandin deficie

Topics: Abortion, Induced; Animals; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Embryo Implantation; Endometrium; Estrenes; Female; Gonanes; Guinea Pigs; Mifepristone; Myometrium; Pregnancy; Pregnancy, Animal; Progesterone; Prostaglandins E, Synthetic; Prostaglandins F; Uterine Contraction