Antiprogesterones

One antiprogesterone, mifepristone (RU 486), has undergone several clinical trials but it does not yet have a product licence in the United Kingdom. Other antiprogesterones such as ZK 98 734 and ZK 98 299 are being developed ().

Mifepristone (RU 486)

Mifepristone () is a derivative of norethisterone. It has an affinity for progesterone receptors about three times that of progesterone. It also has an affinity for glucocorticoid receptors about twice that of dexamethasone.

Fortunately the antiglucocorticoid activity has not been found to be important in clinical practice when it is given, as at the present time, as a single dose.

The main clinical application for mifepristone is in the medical termination of early pregnancy. When used alone, complete abortion occurs in about 85% of cases up to 6 weeks gestation but in only about 60% up to 8 weeks gestation. When prostaglandin pessaries (gemeprost, 16,16 dimethyl-trans-Δ2-PGEi methyl ester) 1 mg 3-hourly, up to 5 pessaries, were used alone, complete abortion occurred in 97% of cases but vomiting, diarrhoea and pain were common side-effects (). When oral mifepristone 400-600 mg was used in combination with a gemeprost pessary, given 48 hours later, complete abortion was achieved at up to 8 weeks gestation in 95 out of 100 women, and there were no continuing pregnancies ().

It has also been found that the administration of mifepristone prior to extra-amniotic infusion, or vaginal administration, of prostaglandin for termination of second trimester pregnancies, reduces the induction-abortion interval and also the total dose of prostaglandin required ().

There may also be a place for the use of mifepristone in the management of women with an intrauterine fetal death. In one double blind study it was found that mifepristone (200 mg t.d.s. for 2 days) shortened the time to expulsion of the fetus and placenta in comparison with placebo treatment ().

Studies have been performed to determine whether mifepristone could also be used to prevent implantation by interfering with normal corpus luteum activity. It has been shown that interruption of the luteal phase frequently occurs when mifepristone is given after the 6th day of the luteal phase but not when it is given before the 5th day. However, the effect was not seen consistently and as menstrual cycles are variable in duration, and their length may be altered by the administration of mifepristone in the previous cycle, the use of mifepristone to prevent implantation is currently not a practical proposition (). Other possible indications for the use of antiprogesterones may include the treatment of tumours containing progesterone receptors.

Epostane

Epostane impairs progesterone biosynthesis by inhibition of the enzyme 3β-hydroxysteroid dehydrogenase. It therefore blocks the conversion of pregneno-lone to progesterone and also that of dehydroepiandrosterone to androstenedione.

In a study comparing the efficacy of mifepristone and epostane in the induction of abortion at less that 7 weeks gestation, 61% of women treated with mifepristone and 73% of those treated with epostane had a complete abortion ().

 

Selections from the book: “Introduction to Clinical Reproductive Endocrinology”. Edited by Gillian C. L. Lachelin, 1991.

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