Action

RU-486 or Mifepristone is a potent antiprogesterone, a progesterone antagonist, which blocks the action of progesterone on the pregnant uterus providing a medical approach to termination of early pregnancy. The first effective antiprogestin was Mifepristone which is a derivative of the progestin norethindrone (fig.1. Right)

RU-486 is a synthetic norsteroid which acts reversbly at receptor level, having a high affinity for the human progesterone receptor. At higher doses RU-486 has potent antiglucocorticoid activity and weak andriogenic activity indicating that some of the action may be mediated by it's metabolites.

To understand how RU-486 works it is necessary to summarize the hormonal control of events in the ovary and uterus during the menstrual cycle and during early pregnancy.

There are two phases to the menstrual cycle (fig.2.)

	The follicular phase
	Luteal phase

In the follicular phase, follicle stimulating hormone (FSH) and lutenizing hormone (LH) interact to promote the maturation of ovum and the secretion of oestrogen by the ovary. In the follicle, LH causes the thecal cells to secrete testosterone and FSH activates the enzymes in the granular cells which convert it to oestrogen.

(fig.1.) The chemical structure of Norethindrone and Mifepristone

The chemical structure of Norethindrone and Mifepristone

Throughout the follicular phase the levels of oestrogen rise leading to a positive feedback effect on the hypothalamus causing a surge in FSH and LH. This directly causes ovulation on the 14th day.

After ovulation comes the luteal phase. The follucular cells now become the corpus luteum and begins to secrete progesterone in addition to oestrogens. This combination of progesterone and oestrogen inhibits further secretion of releasing factors and lowers LH and FSH levels drastically. In the uterus during the Luteal phase progesterone causes the enlarged glandular epithelium to synthesise and store glycogen, and the endometrium to undergo decidualization.

These changes are necessary for implantation of the embryo which occurs during the second week after fertilisation. Progesterone also helps decrease the responsiveness of the smooth muscle of the uterus to contractile, excitory agents such as prostoglandins.

Summary of the hormonal control in the ovary(fig 2)

By inhibiting the anterior pituitary from producing FSH, the progesterone also prevents further follicles from developing during pregnancy. After the first 3 or 4 months of pregnancy the corpus luteum begins to regress and the placenta takes over the job of secreting progesterone and oestrogen.