Progesterone antagonism of the oestrogen receptor and oestrogen-induced uterine growth

Abstract

PROGESTERONE has long been considered an antagonist of oestrogen action¹. The delicate balance and interactions between these ovarian hormones are essential for many reproductive functions. Early studies in chick oviducts and uteri of rats and mice have shown that the simultaneous administration of progesterone and oestrogen resulted in inhibition or modification of oestrogen-induced growth of these target organs^2–5. One possible mechanism by which progesterone could be antagonistic to oestrogen is by suppressing the quantity of cytoplasmic oestrogen receptor. It is generally held that the mechanism by which oestrogen, O, stimulates uterine growth depends on the binding of O to cytoplasmic receptors, R_c, to form R_CO complexes⁶. These R_CO complexes are translocated to nuclear sites where they probably stimulate nuclear events that cause the uterus to grow⁷. Translocation and nuclear accumulation of receptor–oestrogen complexes, R_nO, are accompanied by a concomitant decrease in the quantity of R_c (ref. 8). During the period when R_c is reduced, the uterus is insensitive to additional exogenous oestrogen⁹. Gradually R_c is replenished by processes which may involve reutilisation and/or resynthesis⁸. Work from our laboratory indicates that the mechanism of action of non-steroidal oestrogen antagonists resides in their inability to stimulate the replenishment of the cytoplasmic oestrogen receptor, R_c, thereby rendering oestrogen responsive tissues less sensitive to oestrogen^10,11. The possibility that progesterone might also act as an oestrogen antagonist by reducing the amount of oestrogen R_c has been suggested^12,13. In this report, we demonstrate that progesterone does decrease the quantity of oestrogen receptors by interfering with the replenishment of R_c and that this decrease results in a reduced sensitivity of uterine tissue to oestrogen.