Investigations into the mechanism of the antifertility action of minimal doses of megestrol acetate in the rabbit

Abstract

Summary . Experiments have been performed to investigate the mechanism by which low doses of megestrol acetate have an antifertility action. . It was found that the dose of megestrol acetate required to prevent pregnancy in nine of ten New Zealand White rabbits when given on 3 consecutive days, the last of which was the day of insemination, was 50 μg/kg daily. . This treatment reduced the numbers of sperm recoverable from the uterus at various times after insemination, but egg transfer experiments showed that neither egg viability nor fertilization was affected on day 1 of pregnancy. . Treatment with megestrol acetate for 3 days caused the fertilized eggs to enter the uterus approximately 48 h prematurely. Treatment with megestrol acetate for longer periods caused a similar but more marked increase in the rate of transport of eggs in the oviduct. . Megestrol acetate did not modify oviduct opening pressure, but the volume of oviduct fluid secretion was reduced earlier and transport of fluid through the oviduct was accelerated compared with controls. . Transfer of eggs on various days from the uteri of untreated rabbits to the uteri of treated rabbits indicated that the development of the endometrium which occurs in pregnancy may be advanced by megestrol administration. Histological examination of the endometrial proliferation induced by megestrol acetate confirmed that this was so. . It is concluded that the antifertility action of megestrol acetate in doses that do not necessarily inhibit ovulation is due to a combination of accelerated egg transport and advanced endometrial development.

Investigation of the influence of progesterone on mouse embryo transport by using antiprogestational steroids

“…This work, reviewed by Chang (1976), indicates that progestagens given after ovulation do not produce marked or consistent changes in the rate of egg transport but when given before ovulation cause acceleration and premature entry of embryos into the uterus. Preovulatory progesterone might be active by virtue of its metabolic conversion to oestrogen, but Kendle & Telford (1970) showed similar acceleration following administration of megestrol acetate, a progestagen which does not have oestrogenic activity and is not easily aromatized metabolically (David, Edwards, Fellows & Plummer, 1963). Accele¬ ration of egg transport was also observed in these experiments when administration of megestrol acetate was continued up to the day of autopsy (Day 1, 2 or 3 of pregnancy), indicating that the effect was due to progestagen administration and not to progestagen withdrawal.…”

Some Biological Properties of Rmi 12,936, a New Synthetic Antiprogestational Steroid

“…The dose required, however, is very much greater than that required to produce vaginal cornification (see Bennett, Kendle, Vallance & Vickery, 1966). Evidence in the rabbit (Chang, 1966;Kendle & Telford, 1970) indicates the importance of progesterone in the control of egg transport. It is therefore probable that the pharmacological effects of oestrogen are a reflection of their weak antiprogestational activity.…”

“…Continuous administration of low doses of progestins offer the closest approach at present, but the problems of compara¬ tively low efficacy and incidence of endometrial side-effects persist (see Mears, Vessey, Andolsek & Oven, 1969;Board, 1971). Animal studies have indicated that this regimen probably advances the changes characteristic of early preg¬ nancy in the maternal reproductive tract, causing asynchrony between the development of the ovum and that of its environment (Kendle & Telford, 1970). This method appears to cause only minimal alterations of physiological processes and it is unlikely that any regimen based on daily administration of drugs can produce greater freedom from side-effects while achieving absolute efficacy.…”

Egg Transport in the Fallopian Tube

“…Progesterone or synthetic progestogens given for 3 days prior to ovulation consistently in duce accelerated transport [14,29,[42][43][44]. Eggs can be recovered from the uterus 12 h after ovulation in rabbits treated with 2.5 mg progesterone 48 and 24 h prior to HCG and at the time of HCG [42], When the same dose of progesterone is given with HCG and every 24 h thereafter, a mar ginal delay in transport is observed [42].…”