Anti-progesterones for the interruption of pregnancy

Abstract

Therapeutic abortion can be performed effectively and safely by vacuum aspiration of the uterus up to 12 weeks of amenorrhoea. Although the operative procedure could be regarded as simple, complications do occur and attempts have been made to develop non-surgical means of terminating pregnancy in the first 3-4 weeks following the first missed menstrual period. A variety of PG analogues have been developed which induce abortion in over 90% of women when given by vaginal pessary or intramuscular injections (see Bygdeman, 1984). In a large multicentre study (WHO, 1987) 0.5 mg sulprostone, administered three times with 3 h intervals, was recently found to be equally as effective as vacuum aspiration for termination of early pregnancy. The frequencies of complete abortion were 91 and 94%, respectively. However, the widespread acceptance of PG treatment is limited by a relatively high incidence of gastrointestinal side-effects and uterine pain. Treatment with antiprogesterones, both mifepristone and epostane, effectively induces abortion during early pregnancy, but the frequency of complete abortion is too low to be clinically acceptable. It remains to be demonstrated if other antiprogesterones such as ZK 98.734 and ZK 98.299, currently under development, may change this conclusion. Administration of mifepristone induces uterine contractions and increases the sensitivity of the myometrium to prostaglandins. These effects allowed the development of sequential treatment with a low dose of mifepristone and PG analogues administered vaginally or intramuscularly. The combined therapy has been shown to be highly effective (frequency of complete abortion between 95 and 100%) and is seemingly associated with a lower frequency of side-effects than if PG analogues are used alone. Whether this medical abortion method will be a realistic alternative to vacuum aspiration during the first 8 weeks of pregnancy depends on the outcome of further clinical trials, including randomized studies comparing the two procedures. It has been shown that mifepristone crosses the placenta (Frydman et al, 1985). An important factor which needs to be verified in future studies is therefore the possible embryotoxicity of this type of compound. The risk that pregnancy continues in spite of treatment can never be excluded.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: RU-486 (or mifepristone developed by Roussel-Uclaf, France) is an antiprogesterone drug. Similar compounds have been introduced by Schering AG, Germany: ZK 98.734 and ZK 98.299. Epostane (Sterling- Winthrop, UK) is a progesterone synthesis inhibitor blocking the 3- beta-hydroxysteroid dehydrogenase enzyme system. In a WHO study 37 women at amenorrhea of 42 days or less were given 25, 50 or 100 mg mifepristone twice/day for 4 days: 22 patients had a complete abortion and 11 had an incomplete abortion. Success rate varied between 82.4% and 88.5% with a daily dose of 100 or 150 mg; 83% with 100 or 200 mg daily; and complete abortion occurred in 39% with 200 mg. 400 mg daily for 2 days produced complete abortion in 85%. 200 mg epostane 4 times/day for 7 days terminated pregnancy in 73%. 30 mg of ZK 98.734 given sc for 2 days induced complete abortion in guinea-pigs vs. 7 of 9 and 4 of 9 animals with equal doses of ZK 98.299 and mifepristone, respectively. Sequential therapy with 25 mg mifepristone twice/day produced regular uterine contractions. In administration of sulprostone (16-phenoxy-tetranor PGE2 methyl sulphonylamide); 1 mg of gemeprost (16, 16-dimethyl-trans-delta2-PGE1 methyl ester) given vaginally after mifepristone treatment; and vaginal administration of 10 mg PGE2 following 300-600 mg epostane daily for 5 days showed similar effects. In a clinical trial 25 mg mifepristone twice/day for 4 days followed by .25 mg sulprostone in injection led to complete abortion in 32 (94%) of 34 patients. All 5 women treated with 300, 400 or 600 mg doses of epostane and PGE2 daily for 5 days had abortion. Bleeding lasted 1-2 weeks in successful cases after mifepristone with blood loss of 87 +or- 9 ml and excessive bleeding in 0-5.6% of cases. Side effects were mild. Nausea occurred more often with 800 mg/day epostane than with 50 or 100 mg mifepristone. In a recent study 20 patients with 16-18 weeks of pregnancy were given 200 mg mifepristone before extra-amniotic infusion of PGE2, and the time needed to induce abortion and the total PGE2 dose required was reduced significantly.