Clinical Applications of Mifepristone (RU486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda (1993) / Chapter Skim
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B4. Potential Contraceptive Effects of Antigestogens
B4. Potential Contraceptive Effects of Antigestogens
Pages 148-163
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From page 148... ...
In contrast, in midfollicular phase, gonadotropin levels are suppressed and follicular development is arrested. In the early luteal phase, the corpus luteum forms normally, but the development of secretory endometrium is retarded.
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From page 149... ...
, has been shown to be a highly effective alternative to vacuum aspiration to induce abortion in the first nine weeks of pregnancy and has been licensed for this use in France, Great Britain, Sweden, and China (Baird, 1993~. The political controversy surrounding the "abortion pill" has obscured the fact that antigestogens have many other potential therapeutic uses.
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From page 150... ...
, the corpus luteum functions normally and menstruation occurs at the appropriate time (Swahn et al., 1990~. In the mid- and late luteal phase, however, doses of >50 mg~day mifepristone suppress LH and progesterone, and result in premature luteal regression in approximately 50 percent of cases (Schaison et al., 1985; Garzo et al., 1988; Swahn et al., 1988)
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From page 151... ...
Note that follicular development is arrested and ovulation delayed for more than 14 days. SOURCE: Shoupe et al.
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From page 152... ...
Taboo -20 -16 -12 -8 -A 0 ~ ~ +8 +12 416 CYCLE DAY FIGURE B4.2 The effect of 50 mg/day mifepristone from days 20 to 23 of the ovarian cycle. Five women had only a single episode of bleeding, which was associated with luteal regression.
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From page 153... ...
Thus antigestogens may increase the effective local concentration of prostaglandins both by provoking their release and by inhibiting their local metabolism (Kelly and Buckman, 1990~. In summary, in the follicular phase of the cycle, mifepristone inhibits follicular development and ovulation through an effect on the secretion of gonadotropins but has little effect on the endometrium.
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From page 154... ...
A single dose of 2 mg was the minimum dosage that suppressed ovulation consistently, whereas 1 mg/day resulted in variable effects on cycle length (Figure B4.3~. In some women, ovulation apparently occurred normally; in others, there was suppression of ovulation or evidence of luteinized unruptured follicle.
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From page 155... ...
The mechanism by which these low doses of mifepristone prevent ovulation probably involves inhibition of the positive feedback mechanism. In the normal cycle, in the few hours prior to the onset of the LH surge, there is a rise in the concentration of progesterone due to increased secretion by the preovulatory follicle (Hoff et al., 1983~.
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From page 156... ...
This delay probably occurs in those women given mifepristone during the follicular phase, with the subsequent arrest of follicular development and ovulation. Ovulation is delayed until a new follicle is recruited.
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From page 157... ...
In seven of eight cycles there was reduced stromal edema as well as delayed development of the endometrial glands. Asynchrony of endometrial histology has been described following single doses of mifepristone during the luteal phase with an increase in the number of apoptotic bodies, suggesting programmed cell death (Li et al., 1988b)
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From page 158... ...
In summary, although administration of mifepristone will induce bleeding and disrupt pregnancy in the majority of women during the luteal phase, the failure rate is too high for it to be used as a regular method of contraception, although in combination with a prostaglandin it may be effective as a late post-coital pill. FUTURE DEVELOPMENTS The ideal contraceptive would prevent pregnancy without disrupting the ovarian or menstrual cycle.
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From page 159... ...
A1though abnormalities have been reported in the secretory endometrium after single doses as low as 5 mg and after daily administration of 1 ma, a dose insufficient to inhibit ovulation consistently, it is not known whether these are incompatible with the establishment of pregnancy. Although mifepristone does not bind (at least in vitro)
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From page 160... ...
When started in the follicular phase of the cycle, mifepristone inhibits ovulation and would clearly be contraceptive. However, the effects on the endometrium and on bleeding patterns of different modes of administration require investigation.
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From page 161... ...
Couzinet, B., Le Strat, N., Silvestre, L., et al. Late luteal administration of the antiprogesterone RU 486 in normal women: Effects on the menstrual cycle events and fertility control in a long telll~ study.
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From page 162... ...
Variable effects of RU 486 on endometrial maintenance in the luteal phase extended by exogenous hCG. Clinical Endocrinology 31:15-23, 1989.
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From page 163... ...
Permezel, J.M., Lenton, E.A., Roberts, I., et al. Acute effects of progesterone and the antiprogestin RU 486 on gonadotrophin secretion in the follicular phase of the menstrual cycle.
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