Non-competitive anti-oestrogenic activity of progesterone antagonists in primate models.
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.
Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk 23507.
G D
GD
Hodgen
J F
JF
van Uem
C F
CF
Chillik
D R
DR
Danforth
J P
JP
Wolf
J
J
Neulen
R F
RF
Williams
K
K
Chwalisz
D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004717:Endometrium / Q000187:drug effects*; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D007986:Luteinizing Hormone / Q000378:metabolism; D008252:Macaca fascicularis / Q000502:physiology; D015735:Mifepristone / Q000494:pharmacology*; D010052:Ovariectomy; D010903:Pituitary Gland, Anterior / Q000187:drug effects; D011323:Primates / Q000502:physiology*; D011374:Progesterone / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D006063:Chorionic Gonadotropin; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone