Uterine Estrogen Receptors Are Increased by RU486 in Late Pregnant Rhesus Macaques but not after Spontaneous Labor*

Abstract

Progesterone withdrawal as a mechanism for parturition in primates is controversial. The progesterone antagonist RU486, given in late pregnancy to rhesus monkeys at a dose of 47 mmol/kg.day (20 mg/kg.day), causes an increase in uterine activity, but not the expected increase in amniotic fluid prostaglandins or cervical dilatation. We, therefore, studied the effect of RU486 on estrogen receptor (ER) localization and concentration in reproductive tract tissues in rhesus monkeys during late gestation and after spontaneous labor at term. Distribution of ER in pregnant uterine tissues was studied by immunocytochemical techniques and quantified by a biochemical assay, both of which employed a monoclonal antibody specific for ER. ER was not present in amnion and chorion by immunocytochemical investigation; however, a significant increase in receptor staining was seen in decidua and myometrium after RU486 treatment compared to that in both pregnant control tissues and parturient tissues. Sucrose gradient assay of nuclear (n) and cytosolic (c) ER revealed a low level of ER (expressed as fmol of estradiol bound/mg of DNA) in pregnant and parturient decidua (pregnant: nER = 7.3 +/- 2.4, cER = 17.1 +/- 6.4; parturient, nER = 7.7 +/- 3.1, cER = 16.4 +/- 8.8) and myometrium (pregnant: nER = 21.7 +/- 4.1, cER = 20.8 +/- 5.3; parturient: nER = 30.0 +/- 2.8, cER = 10.7 +/- 6.7). In contrast, tissues collected from RU486-treated animals contained high levels of ER in decidua (nER = 52.3 +/- 16.8, cER = 240.5 +/- 145.3) and myometrium (nER = 77.0 +/- 19.2; cER = 66.5 +/- 31.6). We conclude that 1) the increase in ER in decidua and myometrium after RU486 treatment is the result of a decrease in the inhibitory action of progesterone on ER and documents the progesterone receptor antagonism by RU486 during induced myometrial contractility in late pregnant rhesus monkeys; 2) the absence of ER from amnion and chorion indicates that the normally observed increase in prostaglandin production by rhesus fetal membranes during labor is not mediated by ER; and 3) the absence of a change in the concentration of ER in decidua and myometrium from pregnant control monkeys and those in spontaneous labor indicates that an increase in ER (and, by inference, a withdrawal of receptor-mediated progesterone inhibition) is not part of the normal events in preparation for parturition in primates.

Characterization of topology-, gestation- and labor-related changes of a cassette of myometrial contraction-associated protein mRNA in the pregnant baboon myometrium

“…There were no changes of ER in the pregnant baboon myometrium associated with gestation and labor. This observation is consistent with previous reports in rhesus monkey myometrium analyzed by binding assay (Novy & Haluska 1994) and immunohistochemistry (Haluska et al 1990) and our own data obtained by RT-PCR (Wu et al 2000).…”

“…We and others have clearly demonstrated that estradiol up-regulates ER expression and progesterone down-regulates ER expression in nonpregnant uterine tissues in sheep (Wu et al 1996b), mouse (Bergman et al 1992), rhesus monkey (Okulicz et al 1993) and a human breast cancer cell line (Cho et al 1991). In addition, the observation that uterine ERs are increased by the PR antagonist RU486 in late gestation in the pregnant rhesus monkey is another example of progesterone's suppressive effect on uterine ER (Haluska et al 1990). These results suggest that the control of uterine ER is dependent on the complex interplay of estrogen and progesterone.…”

Inhibitory Effect of Progesterone on Cervical Tissue Formation in a Three-Dimensional Culture System with Human Cervical Fibroblasts1

“…To what extent glucocorticoid signaling is important in this model system is unknown. Estradiol increased synthesis of cervical-like tissue and progesterone opposed this effect, which may relate to progesterone inhibition of the ERa expression [67]. Last, we previously demonstrated that synthesis of cervical-like tissue was strongly dependent on cell nutritional environment, a mechanism that could relate to steroid hormonal environment [46,47].…”

Anti‐Inflammatory activity of 11β‐hydroxypregna‐1,4‐diene‐3,20‐dione

“…It is interesting to note that the glucocorticoid antagonist RU 486 is administered in the same single doses ( 2 mg/100 g b.w.) to humans [Lause et al, 19881 and Resus macaques (Haluska et al, 1990).…”