We have examined the influence of progestins (progesterone, R5020) and antiprogestins (RU486, ZK98299, Org 31710 and Org 31806) on the rate of proliferation of wild type T47D cells cultured in whole fetal bovine serum (FBS) or in single charcoal stripped fetal bovine serum (SSFBS). All of the progesterone antagonists RU486, ZK98299 and two novel antiprogestins Org 31710 and Org 31806 inhibited cell proliferation when cells were cultured in FBS. In contrast, all of the antiprogestins with the exception of ZK98299 enhanced cell growth when cells were cultured in SSFBS. This stimulatory effect of RU486 was observed only at a high concentration of the ligand (1 microM). The effect of R5020, however, was concentration independent. The number of cells in the presence of RU486 was approximately 600% followed by R5020 approximately 400% above control values after a 28 day culturing period. In contrast, when the cells were grown in the presence of medium containing non-stripped whole serum, RU486 inhibited the extent of cell proliferation by 45%. Estradiol (E2) stimulated the rate of proliferation in cells cultured in SSFBS. Similar to when cells were cultured in whole serum, the antiprogestins inhibited cell growth in E2-supplemented SSFBS. Detection of the growth enhancement effects of progesterone receptor (PR) ligands such as RU486 and R5020 on the cells grown in charcoal-stripped medium appear to require the removal of E2 by charcoal stripping of the serum.

1998-07-01·IDrugs : the investigational drugs journal

Org-31806 Organon NV.

Article

作者: Skinner, D C

Org-31806 is a progestogen antagonist under development by Organon with potential for the treatment of cancer and menstruation disorders [164312].

1997-07-01·The Journal of Clinical Endocrinology & Metabolism2区 · 医学

Tonic Support of Luteinizing Hormone Secretion by Adrenal Progesterone in the Ovariectomized Monkey Replaced with Midfollicular Phase Levels of Estradiol¹

2区 · 医学

Article

作者: Linna Xia-Zhang ; Ennian Xiao ; David Shanen ; Michel Ferin

Although it is known that progesterone facilitates the estradiol-induced gonadotropin surge at midcycle, its effect on LH secretion at other times of the follicular phase remains to be investigated. In this study, we investigate the role of progesterone on tonic LH secretion in the ovariectomized primate replaced with estradiol at levels representative of the follicular phase. The experiments were performed in nine ovariectomized rhesus monkeys, either unreplaced with estradiol or after a 5-day estradiol therapy to mimic early follicular (10-36 pg/mL; low dose) and midfollicular (medium dose; 40-75 pg/mL) concentrations. We used two antiprogesterone compounds, RU-486 (5 mg) and ORG-31806 (1 mg), to antagonize endogenous progesterone activity and studied their acute effects on LH secretion in each group. LH concentrations were measured at 15-min intervals for a 3-h baseline period and during a 5-h period after antagonist administration. LH concentrations remained unchanged after either antiprogesterone compound or diluent (ethanol) administration in the estrogen-unreplaced monkeys or after low dose estradiol replacement. However, both antiprogesterone compounds significantly decreased LH secretion in monkeys pretreated with the medium dose of estradiol; by 5 h, the mean (+/-SE) areas under the LH curve were 54.8 +/- 4.1% and 64.0 +/- 4.2% after RU-486 and ORG-31806, respectively (P < 0.05 vs. unreplaced and low dose estrogen-replaced groups). To exclude the possibility that the LH response reflects an agonist action of the progesterone antagonist, LH responses to progesterone infusions (at three doses to reproduce preovulatory, luteal, and pharmacological levels) were also examined in monkeys pretreated with midfollicular levels of estradiol. In none of these was there a decrease in LH; rather, progesterone infusions resulted in an increase in LH secretion in all three groups (to 115-194% of baseline in seven of eight monkeys). Finally, we determined that at the dose used in our protocol, neither of the two progesterone antagonists was able to prevent dexamethasone-induced cortisol suppression, thus excluding the possibility that results after progesterone antagonist administration may reflect a putative antiglucocorticoid activity of these compounds. When the doses of the antiprogesterone compounds were increased 6 times, only RU-486 counteracted the effect of dexamethasone on cortisol. In summary, our data indicate support by progesterone of tonic LH secretion in the nonhuman primate under estrogenic conditions similar to the midfollicular phase of the menstrual cycle. Significantly, because the experiments were performed in ovariectomized monkeys, and endogenous progesterone was most probably of adrenal origin, the data also demonstrate a role of the hypothalamo-pituitary-adrenal axis in support of gonadotropin secretion.

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