Non-competitive anti-oestrogenic activity of progesterone antagonists in primate models

Abstract

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 Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

“…Studies in knockout mice and by pharmacological modulation in nonhuman primates have revealed a direct role for the progesterone receptor in ovarian function and endometrial growth (Conneely et al, 2001;Slayden et al, 2001a;Brenner et al, 2010), suppressing the proliferative effects of estrogen on the endometrium (Wolf et al, 1989;Hodgen et al, 1994;Slayden and Brenner, 2004;Slayden et al, 2006;Brenner et al, 2010).…”

Progesterone Influence on Neurite Outgrowth Involves Microglia

“…RU-486 is a different type II P4 receptor antagonist with higher antiglucocorticoid activity than ORG (50,51). These effects of RU-486 resemble its blockade of the P4-dependent dendritic loss after proestrus (1).…”

Mifepristone alters expression of endometrial steroid receptors and their cofactors in new users of medroxyprogesterone acetate

“…Mifepristone and other PR antagonists have been shown to exert an antiproliferative effect on the endometrium of nonhuman primates (10,11) and women (12,13) and in Ishikawa endometrial adenocarcinoma cells (14). Data also suggest that the endometrial androgen receptor (AR) may play an important role in these effects (15)(16)(17)(18)(19).…”