We have summarized some of the studies containing basic biological data suggesting potential therapeutic utility of the anti-proliferative activity of antiprogestins on uterine tissues. The non-competitive anti-oestrogenic effects of RU486 were examined using oestradiol treated ovariectomized monkeys given RU486, progesterone or both. The oestradiol-induced luteinizing hormone surge of control animals was abrogated by progesterone and/or RU486. Secretory transformation by progesterone was inhibited by RU486 co-administration. RU486 alone (1 mg/kg) induced endometrial secretory transformation, but higher doses (5 mg/kg) induced inhibited proliferation and secretory activity. Thus, in the presence of progesterone, RU486 is antagonistic but, in its absence, RU486 exhibits endometrial progestational effects at low doses and an anti-proliferative (anti-oestrogenic) effect at higher doses. These data encourage continued evaluation of RU486 as a potential contraceptive agent acting at the pituitary and/or endometrial level. Our study also demonstrates that after physiological oestradiol replacement therapy, oestradiol receptor concentrations rise dramatically following antiprogestin treatment; this effect was dose-dependent.

The hormonal mechanisms of parturition in primates remain controversial. Even so, the well-known decrease of plasma progesterone concentration near term is considered by many as the 'labour inducer'. The progesterone antagonist RU 486, which blocks progesterone activity at the cellular receptor level, appears to be a useful hormonal tool by which to study this tissue. Here, we tested its capacity to induce labour and delivery. A total of 23 Cynomolgus monkeys (Macaca fascicularis), within 9-17 days of expected term, were assigned to four different protocols to study various doses, routes and regimens of RU 486 administration. Observations included uterine contractile patterns, pharmacokinetics of RU 486 in plasma and passage of RU 486 into breast milk. None of the protocols tested successfully induced labour resulting in vaginal delivery within 24 h. Instead, the data demonstrate that blockade of progesterone activity by the progesterone antagonist was not sufficient by itself to achieve parturition in these primates. Uterine myometrial contractile activity under RU 486 exposure was not sufficient to induce labour and delivery. Moreover, the progesterone antagonist concentration in breast milk was very low, indicating little passage to suckling newborn infants.

After administration of RU 486 to pregnant cynomolgus monkeys, placental morphology varied from normal to pathological. In all cases (n = 5) circulating and placental PAPP-A levels were markedly suppressed by 76.0 per cent and 55.5 per cent, respectively. When fetal demise occurred within 24 h prior to caesarian section, morphological changes consistent with an active inflammatory (polymorphonuclear leukocytosis) reaction was readily observed at the utero-placental interface, degrading the chorionic villi. Whereas heparin-Sepharose fractionated aqueous extracts of placentae inhibited human neutrophil (or granulocyte) elastase (HGE) activity, extracts of placenta being degraded by host phagocytic-proteolytic defense system were rich in HGE activity. This study establishes: (1) the cynomolgus monkey as a model for PAPP-A studies, (2) that haemochorially implanted placentae produce PAPP-A, a heparin-binding inhibitor of HGE, (3) that administration of progesterone receptor antagonist suppressed placental PAPP-A synthesis, and (4) disrupted protease-protease inhibitor equilibrium at the feto-maternal interface. Thus supporting a role for progesterone in placental PAPP-A production and maintenance of a placental barrier against maternal phagocytic-proteolytic defenses.

Placentae obtained from RU 486 treated cynomolgus monkeys, with successful pregnancy outcome, could not be distinguished, by microscopic or macroscopic examination, from normal placental morphology of untreated females. However, circulating PAPP-A levels were markedly depressed in RU 486 treated (114.8 +/- 13.1 IU/l) than in control animals (477.2 +/- 150 IU/l), suggesting compromised placental physiology. Microscopic examination of placental tissue obtained from animals with fetal demise, after RU 486 administration, revealed pathological changes. When fetal demise occurred recently (less than 24 h), active villus destruction by infiltrating polymorphonuclear leukocytes was readily observed. Whereas aqueous extracts of placentae, whether obtained by cesarean section or spontaneous delivery, inhibited neutrophil elastase (HGE) activity, extracts of placenta being degraded by host phagocytic-proteolytic defense system were rich in HGE activity. Thus suggesting that parturition was not mediated by leukocyte lysosomal proteases, such as HGE, and that hemochorrially implanted placentae produce PAPP-A, a specific inhibitor of HGE. Administration of RU 486 decreased placental PAPP-A production and secretion, culminating with a neutrophilic infiltration into placental intervillous blood spaces, destruction of villus structure and fetal demise.

The noncompetitive antiestrogenic effects of RU 486 were examined using estradiol (E2)-treated ovariectomized monkeys given RU 486, progesterone (P), or both. The E2-induced luteinizing-hormone (LH) surge of control animals was abrogated by P and/or RU 486. Secretory transformation by P was inhibited by RU 486 coadministration. RU 486 alone (1 mg/kg) induced endometrial secretory transformation, but higher doses (5 mg/kg) inhibited proliferation and secretory activity. Thus in the presence of P, RU 486 is antagonistic but, in absence of P, exhibits endometrial progestational effects at low doses and an antiproliferative (antiestrogenic) effect at higher doses. These data encourage continued evaluation of RU 486 as a potential contraceptive agent acting at the pituitary and/or endometrial level.

A progesterone antagonist (RU 486), combined with oxytocin, was effective in achieving cervical dilation, labor induction, and early delivery in near-term monkeys. Effects of RU 486 included accelerated flow of colostrum and transiently enhanced weight gain in infants. No overt toxicity on fetuses, mothers, or newborns was detected with the use of a single oral dose of 25 mg.

The progesterone antagonist RU 486 dramatically increases myometrial contractility of the pregnant uterus, making it a potential adjunctive therapy for labor induction or therapeutic pregnancy termination. Sixteen female cynomolgus monkeys were studied during the second or third trimester of pregnancy. Hysterotomies were performed with the animals under anesthesia, providing access to the intact placental vasculature. RU 486 (25 mg) was injected intravenously into the mothers. Serial blood samples were drawn from the maternal and fetal-placental compartments for a period of 2 hours. RU 486 achieved a gradient equilibrium between the maternal and fetal-placental circulation within 5 minutes, suggesting free passage by simple diffusion. The clearance kinetics of immunoreactive RU 486 are consistent with an open three-compartment system in mother and fetus. The fetal-placental index decreased from 31.2% to 17.8% between the second and the third trimester of pregnancy. There was no acute toxicity of the RU 486 noticed during the experimental course.