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Late postcoital treatment against pregnancy with antiprogesterone RU 486
1,
FERTILITY AND STERILITY Copyright e
1988
Vol. 50, No. July Printed in U.S.A.
1988 The American Fertility Society
Late postcoital treatment against pregnancy with antiprogesterone RU 486
Pekka Liihteenmliki, M.D., Ph.D. Timo Rapeli, M.D. Mauno Kliliriliinen, M.D.
Henrik Alfthan, M.Sci. Olavi Ylikorkala, M.D., Ph.D.*
Helsinki University Central Hospital, Departments I and II of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland
Thirty female volunteers who had experienced an occasion of unprotected intercourse in midcycle were given a single oral dose of 600 mg of RU 486 1 day before the expected onset of menses. Eighteen of them (60%) had conceived, as evident by human chorionic gonadotropin elevation (>2 IU/L). Menstrual-like bleeding was induced in 29 women (97%). Only one woman became clinically pregnant, and this pregnancy was subsequently terminated by vacuum aspiration and curettage. The drug treatment was well tolerated, but it lengthened the post-treatment menstrual cycle on average by 4 days. RU 486 thus may offer an alternative for postcoital prevention of pregnancy if taken before the establishment of menses delay. The lengthening of the first post-treatment cycle may invalidate the use of RU 486 as a regular once-a-month contraceptive. Fertil Steril 50:36, 1988
Having unprotected intercourse around midcycle leads to a 35% to 67% chance of pregnancy. 1 At present, estrogens alone or in combination with norgestrel have been used for postcoital contraception, 2- 5 and the latter seem superior to the former. 5 The nonhormonal alternative is the insertion of an intrauterine device (IUD) within 5 days after coitus. 6 The efficacy of these methods is not fully established, but the hormonal methods have allowed pregnancies in <2%. 3·4·6·7 Both methods are associated with some side effects and complications.3-6 Progesterone (P) is indispensable for the onset and progress of early pregnancy. The synthetic antiprogesterone RU 486 (Mifepristone) (RousselUclaf, Paris, France) antagonizes the P action by
Received January 7, 1988; revised and accepted March 17, 1988. * Reprint requests: Olavi Ylikorkala, M.D., Department of Obstetrics and Gynecology, University of Helsinki, Haartmaninkatu 2, SF -00290 Helsinki, Finland. 36
Liihteenmiiki et al.
Postcoital contraception with RU 486
competitive inhibition at the receptor level both in the endometrium8 and in the trophoblast. 9 It induces menstrual-like bleeding and early abortion in 65% to 85% of women with established early pregnancy.8·10-12 The earlier in gestation that RU 486 is given, the better its abortifacient effect. 13 Indeed, none of 17 monkeys vulnerable to impregnation became pregnant if given RU 486 5 mg/kg on day 25 of their cycles. 14 We then studied the contraceptive effect of premenstrual administration of RU 486 in women exposed in midcycle to impregnation. MATERIALS AND METHODS
Thirty women were studied with the approval of the local ethical committee. They had regular menstrual cycles of 26 to 36 days and had been exposed to impregnation between days 11 and 16 of their cycles. Each woman had made a firm decision to apply for pregnancy termination if she became pregnant, and they all had indications sufficient for this according to Finnish abortion law. The women Fertility and Sterility
were seen in the clinic 1 day before the expected onset of menstruation. After pelvic examination and blood sample collection, each ingested a single oral dose of 600 mg RU 486. The women returned to the clinic at the onset of bleeding for further blood sampling. The effect of treatment was judged 3 weeks after the intake of RU 486 by pelvic examination, ultrasonography, and determination of serum human chorionic gonadotropin (hCG) concentrations measured by a highly specific and sensitive time-resolved immunofluorometric assay. 15 This assay is capable of detecting very low concentrations of hCG, but values above 2 IU/L in fertile women are indicative of early pregnancy. 16·17 This cutoff limit was chosen for this work.
8
1000
0 0
0 0
0
0 0
0 0
0
100
~
0
::::
0
:J
Cb
ii
\!)
u
.s::
Cb 10
0 0
0 0
2
-------------------------------
RESULTS on~:
Altogether, 18 women (60%) had hCG levels exceeding 2 IU /L either before menstruation or at the onset of bleeding or both, but otherwise these women did not differ from the remaining 12 women (Table 1). Serum hCG concentrations are depicted in Figure 1. After RU 486 intake, all but one woman started to bleed. The women regarded the bleeding as menstruation and were able to carry on with their normal daily activities. However, 7 of the 18 hCG-positive women (38%) experienced bleeding lasting 2 or more days longer than usual, but in none of the hCG-negative women was bleeding more than 1 day longer than usual. Nevertheless, the average duration of the bleeding was similar in hCG-positive and hCG-negative women (Table 1). Their hemoglobin concentrations did not change. Three weeks after the intake of RU 486, no evidence of pregnancy could be detected in 29 women, but in one woman the amniotic sac with fetal heart movements was seen by ultrasound. This pregnancy was subsequently terminated by vacuum curettage. In both the hCG-positive and the hCGnegative women, the post-treatment cycle was lengthened on average by 4 days (Table 1). Table 1 Characteristics of 30 Study Subjects Classified by Serum hCG Concentrations (above or below 2 IU/L)
Number Average (±S.D.) age Number of previously pregnant Average (±S.D.) length of Treatment bleeding Normal cycle Post-treatment cycle Vol. 50, No. 1, July 1988
hCG > 2 IU
hCG < 2 IU
18 28.6 ± 5.0 8
27.5 ± 6.0 6
6.0 ± 3.4 28.0 ± 1.0 32.2 ± 3.2
5.3 ± 0.8 28.4 ± 1.9 32.0 ± 1.7
12
day
b~:lor,z
expactad manses
at th,z ons~Zt of menses
Figure 1 Serum concentrations of hCG in 30 women 1 day before expected menses and at the onset of menses after unprotected coitus around midcycle. One single dose of 600 mg RU 486 was given 1 day before expected menses. The closed circle indicates values for the only woman pregnant 3 weeks later..
DISCUSSION
The most reliable marker of pregnancy is the appearance of hCG in blood 7 to 10 days after fertilization.16·17 In the present study, we used serum hCG level ~2 IU /L as an indicator of fertilization, although with our very sensitive assay we can detect much lower hCG levels. 16 This was done to guarantee that the presence of hCG could indeed be taken as a sign of fertilization. Approximately half of our patients had delivered and thus proven their fertility, and they all had unprotected intercourse at the most sensitive time of the menstrual cycle. Twelve women (40%) had increased hCG levels 1 day before the expected onset of menstruation, and an additional 6 women (20%) had increased hCG levels at the onset of bleeding. Thus, the total pregnancy rate was 60%, which is in accordance with the previous data. 1 We could not demonstrate any dependence between the appearance time of hCG and the length of the menstrual cycle in our series, but the small number of observations limits any firm conclusions. In this study, all 18 women who conceived started to bleed after RU 486 intake. The bleeding was scanty in one woman whose pregnancy continued apparently normally for 3 weeks. Thus, the abortion rate was 94.4%. It has been estimated that under normal circumLiihteenmii.ki et al. Postcoital contraception with RU 486
37
stances there is a 27.6% chance of abortion due to defective ova. 18 Our success rate of 94.4% is much higher than this, suggesting that RU 486 caused, if not all, a large majority of the abortions in our volunteers. The success rates of RU 486 treatment taken during established early human pregnancies have varied between 65% and 85%.10--12 Our results do not allow us to compare the effectiveness of RU 486 with that of estrogens alone or in combination with norgestrel2- 4 or of the postcoital insertion of an IUD. 5 These methods, however, require intervention within 5 days after intercourse, whereas use of RU 486 allows more time to elapse. This may be an advantage, since the woman can have more time to make up her mind in regard to the possible pregnancy. It is not known whether RU 486 has any teratogenic effect; therefore, careful follow-up and ascertainment of abortion should be pursued, and in case of continued pregnancy, instrumental abortion should be performed. RU 486 has even been promoted as once-a-month contraceptive pill. Our data are far too limited to allow approximation of the true contraceptive effect, but the fact that RU 486 treatment lengthened the post-treatment cycle seems to invalidate once-amonth use of RU 486. REFERENCES 1. World Health Organization: A prospective multicentre trial
of the ovulation method of natural family planning. III. Characteristics of the menstrual cycle and of the fertile phase. Fertil Steril 40:773, 1983 2. Yuzpe AA, Thurlow HJ, Ramzy I, Leyshon JI: Postcoital contraception-a pilot study. J Reprod Med 13:53, 1974 3. Yuzpe AA, Lancee WJ: Ethinylestradiol and dl-norgestrel as a postcoital contraceptive. Fert Steril 28:932, 1977 4. Van Santen MR, Haspels AA: A comparison of high-dose estrogens versus ethinylestradiol and norgestrel combination in postcoital interception: a study in 493 women. Fertil Steril 43:206, 1985 5. Van Santen MR, Haspels AA: A comparison of high-dose estrogens versus low-dose ethinylestradiol and norgestrel
38
Liihteenmiiki et al. Postcoital contraception with RU 486
combination in postcoital interception: a study in 493 women. Fertil Steril 43:206, 1985 6. Black TRL, Goldstuck ND, Spence A: Postcoital intrauterine device insertion-a further evaluation. Contraception 22:653, 1980 7. Schilling LH: A clinical experience with postcoital contraception at a university health service. Adv Contracept 3:215, 1987 8. Herrmann W, Wyss R, Riondel A, Philibert D, Teutch G, Sakiz E, Baulieu EE: The effects of an antiprogesterone steroid on women: interruption of the menstrual cycle and of early pregnancy. C R Scanes Acad Sci (III) 294:933, 1982 9. Das C, Catt KJ: Antifertility actions of the progesterone antagonist RU 486 include direct inhibition of placental hormone secretion. Lancet 1:599, 1987 10. Cameron IT, Michie AF, Baird DT: Therapeutic abortion in early pregnancy with antiprogestogen RU 486 alone or in combination with prostaglandin analogue (Gemeprost). Contraception 34:459, 1986 11. Couzinet B, Le Strat N, Ulmann A, Baulieu EE, Schaison G: Termination of early pregnancy by the progesterone antagonist RU 486 (mifepristone). N Engl J Med 315:1565, 1986 12. Kovacs L, Sas M, Resch BA, Ugocsal G, Swahn ML, Bygdeman M, Rowe PJ: Termination of very early pregnancy by RU 486-an antiprogestational compound. Contraception 29:399, 1984 13. Elia D: Uses of RU 486: a clinical update. IPPF Medical Bulletin 20:1, 1986 14. Nieman LK, Choate TM, Chrousos GP, Healy DL, Morin M, Renquist D, Merriam GR, Spitz IM, Bardin CW, Baulieu E-E, Loriaux DL: The progesterone antagonist RU 486: A potential new contraceptive agent. N Engl J Med 316:187, 1987 15. Stenman U-H, Alfthan H, Ranta T, Vartiainen E, Jalkanen J, Seppala M: Serum levels of human chorionic gonadotropin in nonpregnant women and men are modulated by gonadotropin-releasing hormone and sex steroids. J Clin Endocrinol Metab 64:730, 1987 16. Kosasa T, Levesque L, Goldstein DP, Taymor ML: Early detection of implantation using a radioimmunoassay for human chorionic gonadotropin. J Clin Endocrinol Metab 36:622, 1973 17. Catt KJ, Dufau ML, Vaitukaitis JL: Appearance of hCG in pregnancy plasma following the initiation of implantation of the blastocyst. J Clin Endocrinol Metab 45:537, 1975 18. Hertig AI: Implantation of the human ovum. The histogenesis of some aspects of spontaneous abortion. In Progress in Infertility, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown & Co, 1975, p 411
Fertility and Sterility
FERTILITY AND STERILITY Copyright e
1988
Vol. 50, No. July Printed in U.S.A.
1988 The American Fertility Society
Late postcoital treatment against pregnancy with antiprogesterone RU 486
Pekka Liihteenmliki, M.D., Ph.D. Timo Rapeli, M.D. Mauno Kliliriliinen, M.D.
Henrik Alfthan, M.Sci. Olavi Ylikorkala, M.D., Ph.D.*
Helsinki University Central Hospital, Departments I and II of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland
Thirty female volunteers who had experienced an occasion of unprotected intercourse in midcycle were given a single oral dose of 600 mg of RU 486 1 day before the expected onset of menses. Eighteen of them (60%) had conceived, as evident by human chorionic gonadotropin elevation (>2 IU/L). Menstrual-like bleeding was induced in 29 women (97%). Only one woman became clinically pregnant, and this pregnancy was subsequently terminated by vacuum aspiration and curettage. The drug treatment was well tolerated, but it lengthened the post-treatment menstrual cycle on average by 4 days. RU 486 thus may offer an alternative for postcoital prevention of pregnancy if taken before the establishment of menses delay. The lengthening of the first post-treatment cycle may invalidate the use of RU 486 as a regular once-a-month contraceptive. Fertil Steril 50:36, 1988
Having unprotected intercourse around midcycle leads to a 35% to 67% chance of pregnancy. 1 At present, estrogens alone or in combination with norgestrel have been used for postcoital contraception, 2- 5 and the latter seem superior to the former. 5 The nonhormonal alternative is the insertion of an intrauterine device (IUD) within 5 days after coitus. 6 The efficacy of these methods is not fully established, but the hormonal methods have allowed pregnancies in <2%. 3·4·6·7 Both methods are associated with some side effects and complications.3-6 Progesterone (P) is indispensable for the onset and progress of early pregnancy. The synthetic antiprogesterone RU 486 (Mifepristone) (RousselUclaf, Paris, France) antagonizes the P action by
Received January 7, 1988; revised and accepted March 17, 1988. * Reprint requests: Olavi Ylikorkala, M.D., Department of Obstetrics and Gynecology, University of Helsinki, Haartmaninkatu 2, SF -00290 Helsinki, Finland. 36
Liihteenmiiki et al.
Postcoital contraception with RU 486
competitive inhibition at the receptor level both in the endometrium8 and in the trophoblast. 9 It induces menstrual-like bleeding and early abortion in 65% to 85% of women with established early pregnancy.8·10-12 The earlier in gestation that RU 486 is given, the better its abortifacient effect. 13 Indeed, none of 17 monkeys vulnerable to impregnation became pregnant if given RU 486 5 mg/kg on day 25 of their cycles. 14 We then studied the contraceptive effect of premenstrual administration of RU 486 in women exposed in midcycle to impregnation. MATERIALS AND METHODS
Thirty women were studied with the approval of the local ethical committee. They had regular menstrual cycles of 26 to 36 days and had been exposed to impregnation between days 11 and 16 of their cycles. Each woman had made a firm decision to apply for pregnancy termination if she became pregnant, and they all had indications sufficient for this according to Finnish abortion law. The women Fertility and Sterility
were seen in the clinic 1 day before the expected onset of menstruation. After pelvic examination and blood sample collection, each ingested a single oral dose of 600 mg RU 486. The women returned to the clinic at the onset of bleeding for further blood sampling. The effect of treatment was judged 3 weeks after the intake of RU 486 by pelvic examination, ultrasonography, and determination of serum human chorionic gonadotropin (hCG) concentrations measured by a highly specific and sensitive time-resolved immunofluorometric assay. 15 This assay is capable of detecting very low concentrations of hCG, but values above 2 IU/L in fertile women are indicative of early pregnancy. 16·17 This cutoff limit was chosen for this work.
8
1000
0 0
0 0
0
0 0
0 0
0
100
~
0
::::
0
:J
Cb
ii
\!)
u
.s::
Cb 10
0 0
0 0
2
-------------------------------
RESULTS on~:
Altogether, 18 women (60%) had hCG levels exceeding 2 IU /L either before menstruation or at the onset of bleeding or both, but otherwise these women did not differ from the remaining 12 women (Table 1). Serum hCG concentrations are depicted in Figure 1. After RU 486 intake, all but one woman started to bleed. The women regarded the bleeding as menstruation and were able to carry on with their normal daily activities. However, 7 of the 18 hCG-positive women (38%) experienced bleeding lasting 2 or more days longer than usual, but in none of the hCG-negative women was bleeding more than 1 day longer than usual. Nevertheless, the average duration of the bleeding was similar in hCG-positive and hCG-negative women (Table 1). Their hemoglobin concentrations did not change. Three weeks after the intake of RU 486, no evidence of pregnancy could be detected in 29 women, but in one woman the amniotic sac with fetal heart movements was seen by ultrasound. This pregnancy was subsequently terminated by vacuum curettage. In both the hCG-positive and the hCGnegative women, the post-treatment cycle was lengthened on average by 4 days (Table 1). Table 1 Characteristics of 30 Study Subjects Classified by Serum hCG Concentrations (above or below 2 IU/L)
Number Average (±S.D.) age Number of previously pregnant Average (±S.D.) length of Treatment bleeding Normal cycle Post-treatment cycle Vol. 50, No. 1, July 1988
hCG > 2 IU
hCG < 2 IU
18 28.6 ± 5.0 8
27.5 ± 6.0 6
6.0 ± 3.4 28.0 ± 1.0 32.2 ± 3.2
5.3 ± 0.8 28.4 ± 1.9 32.0 ± 1.7
12
day
b~:lor,z
expactad manses
at th,z ons~Zt of menses
Figure 1 Serum concentrations of hCG in 30 women 1 day before expected menses and at the onset of menses after unprotected coitus around midcycle. One single dose of 600 mg RU 486 was given 1 day before expected menses. The closed circle indicates values for the only woman pregnant 3 weeks later..
DISCUSSION
The most reliable marker of pregnancy is the appearance of hCG in blood 7 to 10 days after fertilization.16·17 In the present study, we used serum hCG level ~2 IU /L as an indicator of fertilization, although with our very sensitive assay we can detect much lower hCG levels. 16 This was done to guarantee that the presence of hCG could indeed be taken as a sign of fertilization. Approximately half of our patients had delivered and thus proven their fertility, and they all had unprotected intercourse at the most sensitive time of the menstrual cycle. Twelve women (40%) had increased hCG levels 1 day before the expected onset of menstruation, and an additional 6 women (20%) had increased hCG levels at the onset of bleeding. Thus, the total pregnancy rate was 60%, which is in accordance with the previous data. 1 We could not demonstrate any dependence between the appearance time of hCG and the length of the menstrual cycle in our series, but the small number of observations limits any firm conclusions. In this study, all 18 women who conceived started to bleed after RU 486 intake. The bleeding was scanty in one woman whose pregnancy continued apparently normally for 3 weeks. Thus, the abortion rate was 94.4%. It has been estimated that under normal circumLiihteenmii.ki et al. Postcoital contraception with RU 486
37
stances there is a 27.6% chance of abortion due to defective ova. 18 Our success rate of 94.4% is much higher than this, suggesting that RU 486 caused, if not all, a large majority of the abortions in our volunteers. The success rates of RU 486 treatment taken during established early human pregnancies have varied between 65% and 85%.10--12 Our results do not allow us to compare the effectiveness of RU 486 with that of estrogens alone or in combination with norgestrel2- 4 or of the postcoital insertion of an IUD. 5 These methods, however, require intervention within 5 days after intercourse, whereas use of RU 486 allows more time to elapse. This may be an advantage, since the woman can have more time to make up her mind in regard to the possible pregnancy. It is not known whether RU 486 has any teratogenic effect; therefore, careful follow-up and ascertainment of abortion should be pursued, and in case of continued pregnancy, instrumental abortion should be performed. RU 486 has even been promoted as once-a-month contraceptive pill. Our data are far too limited to allow approximation of the true contraceptive effect, but the fact that RU 486 treatment lengthened the post-treatment cycle seems to invalidate once-amonth use of RU 486. REFERENCES 1. World Health Organization: A prospective multicentre trial
of the ovulation method of natural family planning. III. Characteristics of the menstrual cycle and of the fertile phase. Fertil Steril 40:773, 1983 2. Yuzpe AA, Thurlow HJ, Ramzy I, Leyshon JI: Postcoital contraception-a pilot study. J Reprod Med 13:53, 1974 3. Yuzpe AA, Lancee WJ: Ethinylestradiol and dl-norgestrel as a postcoital contraceptive. Fert Steril 28:932, 1977 4. Van Santen MR, Haspels AA: A comparison of high-dose estrogens versus ethinylestradiol and norgestrel combination in postcoital interception: a study in 493 women. Fertil Steril 43:206, 1985 5. Van Santen MR, Haspels AA: A comparison of high-dose estrogens versus low-dose ethinylestradiol and norgestrel
38
Liihteenmiiki et al. Postcoital contraception with RU 486
combination in postcoital interception: a study in 493 women. Fertil Steril 43:206, 1985 6. Black TRL, Goldstuck ND, Spence A: Postcoital intrauterine device insertion-a further evaluation. Contraception 22:653, 1980 7. Schilling LH: A clinical experience with postcoital contraception at a university health service. Adv Contracept 3:215, 1987 8. Herrmann W, Wyss R, Riondel A, Philibert D, Teutch G, Sakiz E, Baulieu EE: The effects of an antiprogesterone steroid on women: interruption of the menstrual cycle and of early pregnancy. C R Scanes Acad Sci (III) 294:933, 1982 9. Das C, Catt KJ: Antifertility actions of the progesterone antagonist RU 486 include direct inhibition of placental hormone secretion. Lancet 1:599, 1987 10. Cameron IT, Michie AF, Baird DT: Therapeutic abortion in early pregnancy with antiprogestogen RU 486 alone or in combination with prostaglandin analogue (Gemeprost). Contraception 34:459, 1986 11. Couzinet B, Le Strat N, Ulmann A, Baulieu EE, Schaison G: Termination of early pregnancy by the progesterone antagonist RU 486 (mifepristone). N Engl J Med 315:1565, 1986 12. Kovacs L, Sas M, Resch BA, Ugocsal G, Swahn ML, Bygdeman M, Rowe PJ: Termination of very early pregnancy by RU 486-an antiprogestational compound. Contraception 29:399, 1984 13. Elia D: Uses of RU 486: a clinical update. IPPF Medical Bulletin 20:1, 1986 14. Nieman LK, Choate TM, Chrousos GP, Healy DL, Morin M, Renquist D, Merriam GR, Spitz IM, Bardin CW, Baulieu E-E, Loriaux DL: The progesterone antagonist RU 486: A potential new contraceptive agent. N Engl J Med 316:187, 1987 15. Stenman U-H, Alfthan H, Ranta T, Vartiainen E, Jalkanen J, Seppala M: Serum levels of human chorionic gonadotropin in nonpregnant women and men are modulated by gonadotropin-releasing hormone and sex steroids. J Clin Endocrinol Metab 64:730, 1987 16. Kosasa T, Levesque L, Goldstein DP, Taymor ML: Early detection of implantation using a radioimmunoassay for human chorionic gonadotropin. J Clin Endocrinol Metab 36:622, 1973 17. Catt KJ, Dufau ML, Vaitukaitis JL: Appearance of hCG in pregnancy plasma following the initiation of implantation of the blastocyst. J Clin Endocrinol Metab 45:537, 1975 18. Hertig AI: Implantation of the human ovum. The histogenesis of some aspects of spontaneous abortion. In Progress in Infertility, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown & Co, 1975, p 411
Fertility and Sterility