Contraceptive efficacy of low doses of mifepristone

FERTILITY AND STERILITYt VOL. 70, NO. 5, NOVEMBER 1998 Copyright ©1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.

CONTRACEPTION

Contraceptive efficacy of low doses of mifepristone Lena Marions, M.D., Kristina Gemzell Danielsson, M.D., Ph.D., Marja-Liisa Swahn, M.D., Ph.D., and Marc Bygdeman, M.D., Ph.D. Division of Obstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Hospital, Stockholm, Sweden

Objective: To determine whether a 5-mg dose of mifepristone is sufficient to prevent pregnancy. Design: Clinical study. Setting: Academic research center. Subject(s): Healthy, fertile, sexually active female volunteers. Intervention: Volunteers received a 5-mg dose of mifepristone once weekly, starting on cycle day 2, for up to 6 months. This was their only contraceptive method. Main Outcome Measure(s): Number of pregnancies. Result(s): The treatment resulted in a significant decrease in pregnancy rate without affecting the menstrual cycle or causing disturbing side effects. Conclusion(s): A low dose of mifepristone, which does not inhibit ovulation, reduces fertility significantly by affecting the endometrium. However, the contraceptive effect needs to be improved for the drug to compete with other contraceptive methods. (Fertil Sterilt 1998;70:813– 6. ©1998 by American Society for Reproductive Medicine.) Key Words: Antiprogestin, contraception, menstrual cycle

Mifepristone (RU486; Roussel-Uclaf, Paris, France) is a 19-norsteroid with a specific high affinity that binds to the progesterone as well as the glucocorticoid receptor. The interaction with the progesterone receptor prevents progesterone from having its biologic effect (1).

Received March 13, 1998; revised and accepted June 13, 1998. Supported by the Programme of Research, Development and Research Training, World Health Organization, Geneva, Switzerland. Reprint requests: Marc Bygdeman, M.D., Ph.D., Division of Obstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Hospital, S-171 76 Stockholm, Sweden (FAX: 46-8-31-8114; E-mail: astblad@ obgyn.ks.se). 0015-0282/98/$19.00 PII S0015-0282(98)00306-9

Mifepristone is used in several countries as a medical method to terminate pregnancy (2). However, the possibility of using mifepristone as a contraceptive has not been evaluated by many investigators. Mifepristone has a number of effects that could make it useful for this purpose. High doses of mifepristone administered in the follicular phase of the menstrual cycle inhibit follicular development and ovulation (3– 6). When mifepristone is administered immediately after ovulation, the secretory development of the endometrium is retarded (7, 8) and the expression of a number of factors of potential importance for implantation is inhibited (9 –12). The effects most likely are due to an effect of mifepristone on the progesterone en-

dometrial receptors. The plasma concentrations of E2 and progesterone are unaffected (7, 8). Clinical studies have demonstrated that the effect of mifepristone on the endometrium is sufficient to prevent pregnancy. In one study (13), 200 mg of mifepristone was administered once a month on the 2nd day after the LH peak (day LH12) to 21 women for up to 1 year. This was their only contraceptive method. Only one pregnancy occurred during a total of 124 ovulatory cycles, with sexual intercourse taking place at the time of ovulation. Mifepristone treatment is a highly effective form of emergency contraception if the drug is administered within 72 hours of a single episode of unprotected sexual intercourse (14, 15). In some women in these studies (14, 15), sexual intercourse took place at the time of ovulation and treatment was administered after ovulation. The contraceptive effect was therefore due to an effect of the drug on the endometrium. A recent study (16) demonstrated that a low dose of mifepristone (2.5 and 5 mg) given once 813

weekly starting on day 2 of the menstrual cycle did not prevent ovulation. Still, the inhibition of endometrial development and expression of factors of potential importance for implantation was similar to the inhibition produced by a high dose of mifepristone administered immediately after ovulation (12, 16). A contraceptive pill that exerts its effect mainly on the endometrium and that does not influence ovarian function is attractive. The aim of the present study was to evaluate whether a 5-mg dose of mifepristone is sufficient to prevent implantation.

MATERIALS AND METHODS Eighteen healthy, fertile, sexually active women with regular menstrual cycles (27–31 days) were recruited for the study. The mean age was 33.6 years (range, 28 – 43 years), and all of the women had been pregnant previously (mean number of pregnancies, 3.5; range, 1–7). They were treated with 5 mg of mifepristone once weekly, starting on cycle day 2. No other contraceptive method was used. All subjects returned once a month for follow-up examination at the expected time of menstruation. Information was collected at that time concerning side effects, vaginal bleeding, time of onset of menstruation, duration and amount of menstrual bleeding, and acts of sexual intercourse. Plasma hCG levels also were determined monthly. At the follow-up visits it was confirmed that the women had taken mifepristone at scheduled intervals. The study was approved by the Swedish Drug Regulatory Authorities and by the institutional review board of the Karolinska Hospital. A prerequisite for approval was that the study be interrupted if more than two pregnancies occurred. The x2 test was used to compare the observed number of pregnancies and the number of pregnancies that would have been expected if no contraceptive method had been used.

RESULTS At the beginning of the study, we intended to recruit 20 women for 6 months of treatment. Because three pregnancies occurred before the end of treatment, the study was interrupted when 18 women had been treated for 1– 6 months for a total of 63 cycles. One subject was excluded from the study because she vomited shortly after taking a tablet in midcycle during the third treatment cycle. A pregnancy test was subsequently positive. During the remaining 60 cycles, three pregnancies occurred. They all were terminated by medical abortion with administration of mifepristone and administration of gemeprost. The mean frequency of sexual intercourse was 2.2 acts per week. If ovulation occurred 14 days before onset of menstruation, it was calculated that at least one act of sexual intercourse occurred during the period 3 days before and 1 814

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day after ovulation in at least 45 cycles, resulting in a probability of pregnancy of 0.067. Calculated from the day of sexual intercourse in each cycle, the expected number of pregnancies would have been 14, according to Wilcox et al. (17), had no treatment been given. If several acts of sexual intercourse took place during the fertile days of the cycle, only the one with the highest probability factor was used. The reduction in pregnancy rate from expected to actually occurring was statistically significant (P , .05). The mean duration of the menstrual cycles was slightly prolonged, from a mean of 28.5 days (range, 27–31 days) before treatment to a mean of 29.4 days (range, 24.5–36.5 days) during treatment. One subject reported 1 month without bleeding. The mean duration of the menstrual bleeding was unchanged, i.e., 5 days (range, 4 – 6 days) before and 4.5 days (range, 3.5– 6.0 days) during treatment. Not included in calculation of the latter figure was the duration of bleeding in one patient who in one treatment cycle had prolonged bleeding while being treated with penicillin. One subject also noted irregular bleeding around the time of ovulation in her fifth treatment cycle. Four subjects reported pelvic pain during the 1st treatment month. No other complications were reported.

DISCUSSION The possibility that an antiprogestin administered around the time of ovulation could inhibit implantation by interaction at the receptor level was suggested by Baulieu more than 20 years ago (18). Two hundred milligrams of mifepristone given once monthly on cycle day LH12, for up to 12 months in the study by Gemzell-Danielsson et al. (13), and 600 mg of mifepristone given for emergency contraception (14, 15) are both highly effective in preventing pregnancy. In women in the postovulatory treatment study (13) and in many of the women in the postcoital studies (14, 15), the contraceptive effect of mifepristone must have been due to the inhibitory effect of mifepristone on endometrial development and function. Previous studies have shown that the endometrium is more sensitive to mifepristone treatment than are follicular development and ovulation (16). In bonnet monkeys, a low dose of the antiprogestin onapristone (Schering AG, Berlin, Germany), which did not inhibit ovulation, significantly reduced fertility (19). The present study is the first, however, in which the contraceptive effect of a low dose of mifepristone that does not inhibit ovulation was studied in humans. We intended to treat 20 women with a 5-mg dose of mifepristone once weekly for 6 months, starting on cycle day 2 in the first menstrual cycle. Because of ethical reasons, it was decided before the study began that it would be terminated if more than two pregnancies occurred. Because such was the case, Vol. 70, No. 5, November 1998

only 18 women were treated during 1– 6 months or totally during 63 cycles. With this limited experience, it is difficult to evaluate the contraceptive effect of the treatment, if any. In the present study, calculated on the cycles in which the women had sexual intercourse during 3 days before to 1 day after ovulation, the probability of pregnancy was 0.067, which is lower than that reported in a World Health Organization study (0.49) (20), in which no contraceptive method was used. Our results also are encouraging given the expected number of pregnancies (n 5 14) in our study and especially given that all of the women in our study had proven fertility. Although ovulation was not measured objectively, the regular bleeding pattern in all cycles but one makes it unlikely that the contraceptive effect was due to ovulation inhibition. It is possible that a higher dose of mifepristone would have been more effective. However, it has been shown that weekly administration of 10 mg of mifepristone inhibits ovulation (21). It is likely, therefore, that increasing the dose would cause an unacceptable degree of irregularity of menstrual cycles. An alternative would be to shorten the interval, e.g., 5 mg every 5th day instead of weekly. In a recent study (22), 10 mg of mifepristone was shown to be highly effective for emergency contraception, even when the treatment was given up to 5 days after unprotected sexual intercourse. There was a slight increase in menstrual cycle length during treatment. This also was observed in the pilot study (16) and was due most likely to a delay in ovulation in women who happened to take the weekly dose of mifepristone just before ovulation. A number of markers for endometrial receptivity have been suggested. Because both 200 mg of mifepristone given on day LH12 (13) and 5 mg of mifepristone given once a week seem to prevent implantation by influencing endometrial function, with the former therapy being more effective, comparing the effect of the two treatments on the endometrium could be valuable. Both treatments inhibited the expression of leukemia inhibitory factor (12) and integrins (23) and the down-regulation of progesterone receptor concentrations (16). However, 5 mg of mifepristone administered weekly had a less pronounced effect than 200 mg of mifepristone given on day LH12 on endometrial morphology at the time of implantation. With the low dose, there was a significant decrease in the number of glands and glandular diameter. The same effect was found after administration of 200 mg of mifepristone, but in addition, here an increase in glandular and stromal mitosis was demonstrated (24). Thus, it seems that the effect on endometrial development is a more reliable predictor of contraceptive efficacy than are markers for endometrial receptivity such as leukemia inhibitory factor and integrin. Few side effects or complications were reported, and none of them were severe enough to warrant termination of FERTILITY & STERILITYt

treatment. In general, regular menstrual cycles persisted although the mean cycle length increased slightly. Menstruation did not occur in only 1 of 63 cycles, and in another one spotting occurred. Four women reported slight pelvic pain during the first treatment cycle. The reason for this discomfort is unclear. Endometrial contraception with a low dose of antiprogestin that does not influence ovarian function and ovulation is attractive. We demonstrated, for the first time, that a 5-mg dose of mifepristone administered once weekly has some contraceptive effect. However, the failure rate is too high for this treatment to be clinically acceptable. The outcome of the study supports the conclusion that other treatment schedules, e.g., those that may be more effective without an increase in the frequency of menstrual disorders, should be evaluated. References 1. Moguilewsky M, Philibert D. Biochemical profile of RU 486. In: Baulieu EE, Segal SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York, Plenum, 1985;87–97. 2. Bygdeman M. Termination of pregnancy up to 8 or 9 weeks. In: Baird DT, Grimes DA, Van Look PFA, eds. Modern methods of inducing abortion. Oxford, Blackwell Science, 1995;39 –53. 3. Liu JH, Garzo G, Monis Strenkel C, Ulmann A, Yen SCC. Disruption of follicular maturation and delay of ovulation after administration of the antiprogestin RU 486. J Clin Endocrinol Metab 1987;65:1135– 40. 4. Shoupe D, Mishell DR, Page MA, Madkour H, Spitz JM, Lobo RA. Effects of the antiprogesterone RU 486 in normal follicular phase. Am J Obstet Gynecol 1987;157:1421– 6. 5. Luukkainen T, Heikinheimo O, Haukkamaa M, La¨hteenma¨ki P. Inhibition of folliculogenesis and ovulation by the antiprogesterone RU 486. Fertil Steril 1988;49:361–3. 6. Swahn ML, Johannisson E, Daniore V, de la Torre B, Bygdeman M. The effect of RU 486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium. Hum Reprod 1988;3:915–21. 7. Swahn ML, Bygdeman M, Xing S, Cekan S, Masironi B, Johannisson E. The effect of RU 486 administered during the early luteal phase on bleeding pattern, hormonal parameters and endometrium. Hum Reprod 1990;5:402– 8. 8. Dockery, Ismail RMJ, Li TC, Warren MA, Cooke ID. The effect of a single dose of mifepristone (RU 486) on the fine structure of the human endometrium during the luteal phase. Hum Reprod 1997;12:1778 – 84. 9. Berthois Y, Salat-Baroux J, Cornat J, De Brux J, Kopps F, Maric Martin P. A multiparametric analysis of endometrial estrogen and progesterone receptors after postovulatory administration of mifepristone. Fertil Steril 1991;55:547–54. 10. Ma¨entausta O, Svalander P, Gemzell-Danielsson K, Bygdeman M, Vihko R. The effects of an antiprogestin, mifepristone, and an antiestrogen, tamoxifen, on endometrial 17b-hydroxysteroid dehydrogenase and progestin and estrogen receptors during the luteal phase of the menstrual cycle: an immunohistochemical study. J Clin Endocrinol Metab 1993;77:913– 8. 11. Cameron ST, Critchely HOP, Buckley CH, Kelly RW, Baird DT. Effect of two antiprogestins (mifepristone and onapristone) on endometrial factors of potential importance for implantation. Fertil Steril 1997;67: 1046 –53. 12. Gemzell Danielsson K, Swahn ML, Bygdeman M. The effect of various doses of mifepristone on endometrial leukaemia inhibitory factor expression in the midluteal phase: an immunohistochemical study. Hum Reprod 1997;12:1293–7. 13. Gemzell-Danielsson K, Swahn ML, Svalander P, Bygdeman M. Early luteal phase treatment with RU 486 for fertility regulation. Hum Reprod 1993;8:870 –3. 14. Glasier AF, Thong KJ, Dewar M, Mackie M, Baird DT. Mifepristone (RU 486) compared with high-dose estrogen and progesterone emergency postcoital contraception. N Engl J Med 1992;327:1041– 4. 15. Webb AMC, Russel J, Elstein M. Comparison of Yuzpe regimen, danazol and mifepristone (RU 486) in oral postcoital contraception. Br Med J 1992;305:927–31. 16. Gemzell-Danielsson K, Westlund P, Johannisson E, Swahn ML, Seppa¨la¨ M, Bygdeman M. Effect of low weekly doses of mifepristone on ovarian function and endometrial development. Hum Reprod 1996;11: 256 – 64.

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