Tamoxifen and RU39411 synergize with mifepristone to produce preimplantation pregnancy loss by increasing embryo transport (rat).
Tamoxifen is a non-steroidal antiestrogen that possesses antagonistic as well a agonistic properties, while RU39411 is an antiestrogen that is known to possess only antagonistic properties. These steroid antagonists were administered orally to rats, with or without mifepristone, an antiprogestational agent, prior to implantation on Day 2 of pregnancy. The status of pregnancy was assessed on Day 14. Low doses of tamoxifen reduced litter size and weight and inducing embryonic absorption in some animals; a dose of 0.25 mg/Kg prevented pregnancy in all animals. RU39411 also had a dose-dependent effect on pregnancy, but a higher dose (0.5 mg/Kg) was required to achieve the same degree of pregnancy prevention. Addition of mifepristone to both antiestrogens had a synergistic effect on reducing litter size and weight. To determine the mechanism by which antiestrogens terminate pregnancy in rats, oviducts and uteri of treated rats were examined for the presence of embryos on Day 3 and 4 of pregnancy, times when most embryos would be expected to be in the oviducts. Most of the embryos of the treated animals were found in the oviducts on Day 3 of pregnancy. By Day 4, only a few embryos were still present in oviducts. These observations suggest acceleration of embryo transport by Day 4 of pregnancy. There was no accumulation of embryos in the uterus. Since acceleration of embryo transport through the reproductive tract in rat is induced by low doses of estrogens, it is likely that the agonistic action of tamoxifen is responsible for pregnancy prevention in these experiments. The fact that RU39411 also prevents pregnancy by a similar mechanism suggests that this estrogen antagonist also has some estrogen agonist effects on the oviduct. The fact that both antiestrogens also affected embryo weight could suggest the action of the antihormones on other mechanisms controlling embryo development.
Kaplan-Kraicer
R
R
Department of Embryology, Sackler School of Medicine, Tel Aviv University, Israel.
Kostovetsky
I
I
Bardin
C W
CW
Shalgi
R
R
D000021:Abortifacient Agents, Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001755:Blastocyst / Q000187:drug effects*; D003338:Corpus Luteum / Q000166:cytology / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D010064:Embryo Implantation / Q000187:drug effects; D020964:Embryo Loss / Q000139:chemically induced; D047108:Embryonic Development / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D000021:Abortifacient Agents, Steroidal; D004338:Drug Combinations; D004965:Estrogen Antagonists; D013629:Tamoxifen; C060411:RU 39411; D015735:Mifepristone; D004958:Estradiol