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Termination of early pregnancy by a single dose of mifepristone (RU 486), a progesterone antagonist
European Journal of Obstetrics & Gynecology and Reproductive Elsevier
Biology, 28 (1988) 249-255
249
ET0 00627
Termination of early pregnancy by a single dose of mifepristone (RU 486), a progesterone antagonist Bernard
Maria
r, Fraqoise
Stampf
‘, Anne Goepp
* and Andre Ulmann
3
’ Service de Gynkcologie-Obstktrique, Villeneuve-Saint-Georges,
’ Loboratoire de Biochimie, Centre Hospitalier Intercommunal, 94190 and ’ Laboratoire Rouse/-UcIaj Direction Medicale, 93230 RomainviIle, France Accepted
for publication
10 January
1988
suuuuary Mifepristone (RU 486) is a new steroid which is a progesterone antagonist and which is able to interrupt early pregnancy without any major side-effects. The purpose of our study was to evaluate the clinical effect of a single oral dose of 600 mg on early pregnancy. The study included 150 healthy women applying for a legal abortion with an amenorrhea of no more than 42 days. Pregnancy was confirmed by clinical and ultrasound examination and plasma HCG assessment. Success was assumed by repeating these exams on the eighth day. 131 patients had a complete abortion (87.3%) with a very few side-effects. Only two patients needed curettage for heavy bleeding. Mifepristone is able to terminate early pregnancy by an easy ambulatory method under medical supervision. Termination
of early pregnancy;
Progesterone
antagonist;
Mifepristone
(RU 486)
Introduction
Abortion is a widely used method of fertility regulation. Recent demographic studies estimate an abortion rate of 300 per 1000 known pregnancies [l]. Most of these abortions are illegal, occur in developing countries and expose the mother to severe complications. Suction curettage is widely performed to induce legal abortion in Europe and North America; despite a few severe complications, aspiration is a safe surgical procedure. Thus, the need for a simple and effective medical method of terminating pregnancy is obvious, leading to ambulatory induced abortion.
Correspondence: Docteur Bernard Maria, communal, 94190 Villeneuve-Saint-Georges,
0028-2243/88/$03.50
Service de Gyntcologie-ObstCtrique, France.
0 1988 Elsevier Science Publishers
B.V. (Biomedical
Centre
Division)
Hospitalier
Inter-
250
For a decade, prostaglandins have been investigated for termination of very early pregnancy [2]. Several studies have shown that administration of PGE, analogues may be as effective as vacuum aspiration [3,4], but with gastro-intestinal side-effects, and pelvic pains [2,3]. Another way is to interfere with progesterone metabolism. Progesterone is indispensable during early pregnancy [5], as is the corpus luteum, as it is the major source of progesterone, before the luteo-placental shift. Surgical luteectomy induces critical progesterone withdrawal and terminates the menstrual cycle as well as early pregnancy [5]. The synthesis of a new steroid which binds with great affinity to progesterone receptors without any of the effects of progesterone is of great interest [6]. This progesterone antagonist is a synthetic 19-nor-steroid: 17&hydroxy-11-(6dimethylaminophenyl)-17-(l-propinyl)estra-4,9-dien-3-one, or Mifepristone (RU 486). Given during the luteal phase of the normal cycle [7-91 Mifepristone induces uterine bleeding. Administration of HCG cannot overcome the antiprogestin effect of RU 486 on the endometrium [9]. The drug does not cause bleeding in anovulatory cycles [8], because of the absence of a progesterone effect on the endometrium. Previous studies have shown that Mifepristone can interrupt pregnancy in the first month without any major side-effects [7,10]. In clinical practice, Mifepristone must be easy to use, and must show efficacy and safety for patients requiring legal abortion. The purpose of our study was to evaluate the effect of a single dose of 600 mg of Mifepristone on early pregnancy. Methods (I) Subjects The study included 150 healthy women applying for a legal abortion in our centre, according to the French Regulation. Women with any signs of abnormal pregnancy, pelvic inflammatory disease, use of gluco-corticoids in the previous three months, or a history of liver, gastro-intestinal or renal disease were excluded from the study. It was limited to pregnancies no more than six weeks from the last menstrual period, i.e. 42 days of amenorrhea. Pregnancy was confirmed by assessment of plasma HCG, and pelvic and ultrasound examination. The study was approved by the Ethical Committee of Institut Roussel-Uclaf (Paris). The nature of the study was explained to each subject in detail and written consent was obtained. (2) Protocol On day one, each patient underwent a careful clinical pelvic and ultrasound examination. Blood samples were drawn to measure plasma HCG, complete blood count, creatinine, glycemia, serum aspartate aminotransferase, serum alanine aminotransferase and serum y-glutamyltransferase. Mifepristone was delivered as 200 mg tablets. Each patient received 3 tablets (total dosage 600 mg) to take orally at home in the evening (7 to 8 p.m.) in one
251
single intake. The clinical events that should occur were carefully explained to each woman and a permanent telephone number was available for emergencies. A follow-up visit was scheduled on the eighth day. Clinical and ultrasound examinations and the same blood sampling as on the first day were performed again. Success was assumed if vaginal bleeding occurred between days three and eight, ultrasonic examination confirmed uterine vacuity and a decrease in plasma HCG level under the initial value was observed. Thus, patients who needed a blood transfusion or a curettage for heavy bleeding were excluded from the success group. In cases of failure, a uterine vacuum aspiration was performed. After that check, a contraceptive method was proposed for the future. (3) Technical points Ultrasound examinations were all carried out by one of us (F.S.) with a Hitachi-Diasonics DFR 100 apparatus with a 3.5 MHz probe. Plasma HCG levels were determined by inmunoenzymoassay (PHCG EIA Roche Diagnostica). The results are expressed as means + SE. Statistical analysis of variance was used to compare the groups in terms of success. Cm-square analysis was used to compare the rates, and two-tailed paired Student’s t test for the results. Differences that failed to achieve a p value of 0.05 were considered non-significant. Results (I) Study group
Our 150 women present the following characteristics: mean age 27.6 _t 0.56 years (from 15 to 47 years), mean length of amenorrhea 38.25 k 0.27 days (from 28 to 42 days), mean diameter of intrauterine sac on initial ultrasound examination 10.63 + 0.45 mm (from 0 to 31 mm), mean HCG level on day one 33 948 f 6 384 W/l and mean level of hemoglobin 13.04 + 0.08 g/dl. (2) Efficacy A total of 131 women out of 150 were considered to have The overal abortion rate was 87.3%. The remaining 19 women ing pregnancies, 2 missed abortions, 2 curettages for heavy trauterine pregnancy. Table I shows the results according amenorrhea.
a complete abortion. included 14 developbleeding and 1 exto the duration of
(3) Tolerance In most cases, daily amount and duration of bleeding were compared to an abundant menstruation. Only 2 patients reported heavy bleeding leading to curettage. Three women reported bleeding over two weeks (19 to 30 days) after a successful abortion. The mean hemoglobin level at day eight was 12.53 & 0.10 g/dl. Only 16 women had a hemoglobin level less than 11 g/dl, justifying iron therapy. None needed a transfusion. A very few other side-effects were reported: uterine contractions and pelvic pains (7 (4.6%)), transient asthenia (3 (2%)) and slight nausea (2 (1.3%)). All the biological tests remained in the normal range.
252
TABLE I Results according to the duration of amenorrhea Total
Amenorrhea (days)
No. of cases Failures I%
< 33
34-35
36-31
38-39
40-41
42
12 2 16.7
19 2 10.5
26 2 7.7
36 4 11.1
19 3 15.8
38 6 15.8
150 19 12.7
TABLE II Results and comparisons
NuIlipara Amenorrhea (days) Regular cycle Uterine sac diameter (mm) HCG(years) (UI/l) Age
(4) Comparison
Failure (19 =12.7%)
Success (131= 87.3%)
47% 38.58 f0.84 58% 9.89+ 1.18 22 080f f 1.09 5 294 27.53
53% 38.28 zkO.28 19% 10.74 f 0.49 35519+7219 27.59 f 0.63 I
NS
of successes and failures
As shown in Table II, there is no significant difference between characteristics on day one of successes and failures. No prediction could be made from these items. Table III shows the variations in HCG levels between days one and eight for successes. Discussion Mifepristone had been used in preliminary reports concerning termination of early pregnancy in multiple doses, from four to seven days [7,10-151. The first publication by Herman et al. [7] reported a success rate of 82% out of 11 patients with a pregnancy from six to eight weeks. Younger pregnancies are concerned in other reports: less than 55 days of amenorrhea for Haspels [ll], less than 49 days for Bigerson [12], Sin-&-Ware [13] and Swahn [14], less than 42 days for Kovacs [lo]
TABLE III Variations of the HCG level HCG (IU/l)
Success
Failures
Day 1 Day 8
35579+7219 4272*1055 p -z 0.001
2208Ok 5294 88 301 f 34710 p < 0.001
NS p < 0.001
253
and less than 38 days for Couzinet [15]. For all these authors using Mifepristone with various total doses (200 to 1000 mg) the success rate was 61 to 82%. Our study is one of the very first using a single dose of 600 mg and our results, giving a success rate of 87%, are as satisfactory as the other reports. The mechanism by which Mifepristone acts is hypothetical. Binding to the progesterone receptor in place of free progesterone is probably the first step [6]. Thus the biological effects of progesterone disappear. Histological studies have shown that Mifepristone induces decidual necrosis without any alteration of trophoblast [16,17]. Then, the drug also induces endometrial prostaglandin synthesis [17,18], stimulating myometrial contractility [14,19], and causing softening of the uterine cervix. Thus, the successful induction of abortion by Mifepristone may involve a direct antiprogesterone effect on the endometrium, inducing ovum detachment, and an indirect stimulation of prostaglandin leading to ovum expulsion. As shown by Herman [7], Kovacs [lo] and Couzinet [15], the decrease in HCG level is a consequence of trophoblast separation, and luteolysis is secondary to the decrease of HCG. The progesterone level decrease is significant on the sixth day of treatment, i.e. after the abortion has occurred [15]. Mifepristone failed to cause an abortion in 17 of our patients. Nevertheless all these women had a uterine bleeding, but less than the successful cases. On day eight, the HCG level of the failures was significantly higher than the initial level (Table III). Why an abortion did not occur is still unknown. There were no differences between the 131 women who responded and the 19 who failed. Failure could be the consequence of an insufficient amount of drug at the site of action. The pharmacological studies have pointed out that Mifepristone attaches to cu,-globulin in plasma [20] and only free Mifepristone is active. A too low free Mifepristone level could not lead to abortion. For most of the authors there is no apparent dose dependency, but there is an obvious relationship between efficacy and age of pregnancy, as best results are obtained for pregnancies of less than six weeks [6,11]. It has been suggested that insufficient prostaglandin release may explain incomplete uterine evacuation. Swahn [14] induced complete abortion by utilization of a prostaglandiu analogue. In clinical practice, Mifepristone was very well tolerated, with very few side-effects. The main problem is a possibility of heavy bleeding which needs careful medical monitoring. Mifepristone is also a gluco-corticoid antagonist, as shown by Gaillard [21], but this effect needs a much larger dose. Couzinet [15] had observed variations in plasma ACTH and cortisol but without any clinical effects with the dose used for early abortion. Conclusion Mifepristone appears to be a simple and safe agent for termination of early pregnancy. The use of a single dose of 600 mg is very easy and leads to ambulatory abortion under medical supervision. Our rate of success is similar to those reported with prostaglandin analogues but without the painful uterine contractions and the gastro-intestinal effects. Mifepristone seems to be actually a good alternative to
254
surgical abortion for early pregnancies. To avoid the risk of failure, further studies using Mifeptistone with a prostaglandin analogue should be conducted in the near future. Acknowledgements We thank Laboratoire Roussel-Uclaf, Paris, who provided us with Mifepristone tablets. We also thank S. Helbert-Davidson, M.D., and J.P. Le Floch, M.D., from the Department of Endocrinology, Facultt de Mtdecine of Creteil, for statistical calculations. We are grateful to Mrs. Annie Hue for typing the manuscript, and to the members of our out-patient gynecological unit for carrying out that study. References 1 Mumford SD, Kessel E. Role of abortion in control of global population growth. in Lafera, JJ, ed. Termination of Pregnancy. Chn Obstet Gynecol 1986;13:19-31. 2 Bygdeman M, Christensen NJ, Green K, Zheng S, Lundstrom V. Termination of early pregnancy. Future development. Acta Obstet Gynecol Stand 1983; Suppl. 113:125-129. 3 Lundstrom V, Bygdeman M, Fotiou S, Green K, Kinoshita K. Abortion in early pregnancy by vaginal administration of 16-16 dimethyl PGE, in comparison with vacuum aspiration. Contraception 1977;16:167-173. 4 Rosen AS, Nystedt L, Bygdeman M, Lundstrom V. Acceptability of a non-surgical method to terminate very early pregnancy in comparison to vacuum aspiration. Contraception 1979;19:107-117. 5 Csapo AI, PuIkinnen M. Indispensability of the human corpus luteum in the maintenance of early pregnancy, luteectomy evidence. Obstet Gynecol Surv 1978;33:69-81. 6 Bauheu EE. RU 486: an antiprogestin steroid with contragestive activity in woman. In Bauheu EE, Segal SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:1-25. 7 Hermann W, Wyss R, Riondel A, et al. Effet dun sttrdide anti-progesterone chez la femme: interruption du cycle menstruel et de la grossesse au debut. CR Acad Sci Paris 1982;294:933-938. 8 Schaison G, George M, Lestrat N, Reinberg A, Bauheu EE. Effects of the antiprogesterone steroid RU 486 during mid luteal phase in normal women. J CIin Endocrinol Metab 1985;101:484-489. 9 Nieman LK, Choate TM, Chrousos GP, et al. The progesterone antagonist RU 486: a potential new contraceptive agent. N EngI J Med 1987;316:187-191. 10 Kovacs L, Sas M, Resch BA, et al. Termination of very early pregnancy by RU 486, an antiprogestational compound. Contraception 1984;29:399-410. 11 Haspels AA. Interruption of early pregnancy by the antiprogestational compound RU 486. In Bauheu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:199-209. 12 Bigerson L, Odhnd V, Johansson, E. Clinical effects of RU 486 administered for seven days in early pregnancy. In Bauheu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:235-241. 13 Sitruk-Ware R, Billaud L, Mowszowicz I, et al The use of RU 486 as an abortifacient in early pregnancy. In Bauheu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control New York: Plenum Press, 1985:243-248. 14 Swahn ML, Cekan S, Wang G, Lundstrom V, Bygdeman M. Pharmacokinetic and clinical studies of RU 486 for fertility regulation. In BauIieu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:249-258. 15 Couzinet B, Lestrat N, Ulmann A, BauIieu EE, Schaison G. Termination of early pregnancy by the progesterone antagonist RU 486 (mifepristone). N EngI J Med 1986;315:565-570. 16 Secchi J, LeIaque D. Toumemine C, PhiIibert D. Histopharmacology of RU 486. In BauIieu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:79-86.
17 Hermann WL, Schindler AM, Wyss R, Bischof P. Effects of the antiprogesterone RU 486 in early pregnancy and during the menstrual cycle. In Baulieu EE, Segal SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:179-198. 18 Kelly RW, Healy DL, Cameron MJ, Cameron IT, Baird DT. RU 486 stimulation of PFG,, production in isolated endometrial cells in short term cultures. In Baulieu EE, Segal SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:259-262. 19 Christensen NJ, Green K. Endogenous prostaglandin synthesis and abortion. Acta Obstet Gynecol Stand 1983; Suppl 113:109-111. 20 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 Press, 1985:87-97. 21 Gaillard RC, Riondel A, Muller AF, Hennann W, Baulieu EE. RU 486: Studies of its antiglucocorticosteroid activity in man. In Baulieu EE, Segal SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:331-337.
Biology, 28 (1988) 249-255
249
ET0 00627
Termination of early pregnancy by a single dose of mifepristone (RU 486), a progesterone antagonist Bernard
Maria
r, Fraqoise
Stampf
‘, Anne Goepp
* and Andre Ulmann
3
’ Service de Gynkcologie-Obstktrique, Villeneuve-Saint-Georges,
’ Loboratoire de Biochimie, Centre Hospitalier Intercommunal, 94190 and ’ Laboratoire Rouse/-UcIaj Direction Medicale, 93230 RomainviIle, France Accepted
for publication
10 January
1988
suuuuary Mifepristone (RU 486) is a new steroid which is a progesterone antagonist and which is able to interrupt early pregnancy without any major side-effects. The purpose of our study was to evaluate the clinical effect of a single oral dose of 600 mg on early pregnancy. The study included 150 healthy women applying for a legal abortion with an amenorrhea of no more than 42 days. Pregnancy was confirmed by clinical and ultrasound examination and plasma HCG assessment. Success was assumed by repeating these exams on the eighth day. 131 patients had a complete abortion (87.3%) with a very few side-effects. Only two patients needed curettage for heavy bleeding. Mifepristone is able to terminate early pregnancy by an easy ambulatory method under medical supervision. Termination
of early pregnancy;
Progesterone
antagonist;
Mifepristone
(RU 486)
Introduction
Abortion is a widely used method of fertility regulation. Recent demographic studies estimate an abortion rate of 300 per 1000 known pregnancies [l]. Most of these abortions are illegal, occur in developing countries and expose the mother to severe complications. Suction curettage is widely performed to induce legal abortion in Europe and North America; despite a few severe complications, aspiration is a safe surgical procedure. Thus, the need for a simple and effective medical method of terminating pregnancy is obvious, leading to ambulatory induced abortion.
Correspondence: Docteur Bernard Maria, communal, 94190 Villeneuve-Saint-Georges,
0028-2243/88/$03.50
Service de Gyntcologie-ObstCtrique, France.
0 1988 Elsevier Science Publishers
B.V. (Biomedical
Centre
Division)
Hospitalier
Inter-
250
For a decade, prostaglandins have been investigated for termination of very early pregnancy [2]. Several studies have shown that administration of PGE, analogues may be as effective as vacuum aspiration [3,4], but with gastro-intestinal side-effects, and pelvic pains [2,3]. Another way is to interfere with progesterone metabolism. Progesterone is indispensable during early pregnancy [5], as is the corpus luteum, as it is the major source of progesterone, before the luteo-placental shift. Surgical luteectomy induces critical progesterone withdrawal and terminates the menstrual cycle as well as early pregnancy [5]. The synthesis of a new steroid which binds with great affinity to progesterone receptors without any of the effects of progesterone is of great interest [6]. This progesterone antagonist is a synthetic 19-nor-steroid: 17&hydroxy-11-(6dimethylaminophenyl)-17-(l-propinyl)estra-4,9-dien-3-one, or Mifepristone (RU 486). Given during the luteal phase of the normal cycle [7-91 Mifepristone induces uterine bleeding. Administration of HCG cannot overcome the antiprogestin effect of RU 486 on the endometrium [9]. The drug does not cause bleeding in anovulatory cycles [8], because of the absence of a progesterone effect on the endometrium. Previous studies have shown that Mifepristone can interrupt pregnancy in the first month without any major side-effects [7,10]. In clinical practice, Mifepristone must be easy to use, and must show efficacy and safety for patients requiring legal abortion. The purpose of our study was to evaluate the effect of a single dose of 600 mg of Mifepristone on early pregnancy. Methods (I) Subjects The study included 150 healthy women applying for a legal abortion in our centre, according to the French Regulation. Women with any signs of abnormal pregnancy, pelvic inflammatory disease, use of gluco-corticoids in the previous three months, or a history of liver, gastro-intestinal or renal disease were excluded from the study. It was limited to pregnancies no more than six weeks from the last menstrual period, i.e. 42 days of amenorrhea. Pregnancy was confirmed by assessment of plasma HCG, and pelvic and ultrasound examination. The study was approved by the Ethical Committee of Institut Roussel-Uclaf (Paris). The nature of the study was explained to each subject in detail and written consent was obtained. (2) Protocol On day one, each patient underwent a careful clinical pelvic and ultrasound examination. Blood samples were drawn to measure plasma HCG, complete blood count, creatinine, glycemia, serum aspartate aminotransferase, serum alanine aminotransferase and serum y-glutamyltransferase. Mifepristone was delivered as 200 mg tablets. Each patient received 3 tablets (total dosage 600 mg) to take orally at home in the evening (7 to 8 p.m.) in one
251
single intake. The clinical events that should occur were carefully explained to each woman and a permanent telephone number was available for emergencies. A follow-up visit was scheduled on the eighth day. Clinical and ultrasound examinations and the same blood sampling as on the first day were performed again. Success was assumed if vaginal bleeding occurred between days three and eight, ultrasonic examination confirmed uterine vacuity and a decrease in plasma HCG level under the initial value was observed. Thus, patients who needed a blood transfusion or a curettage for heavy bleeding were excluded from the success group. In cases of failure, a uterine vacuum aspiration was performed. After that check, a contraceptive method was proposed for the future. (3) Technical points Ultrasound examinations were all carried out by one of us (F.S.) with a Hitachi-Diasonics DFR 100 apparatus with a 3.5 MHz probe. Plasma HCG levels were determined by inmunoenzymoassay (PHCG EIA Roche Diagnostica). The results are expressed as means + SE. Statistical analysis of variance was used to compare the groups in terms of success. Cm-square analysis was used to compare the rates, and two-tailed paired Student’s t test for the results. Differences that failed to achieve a p value of 0.05 were considered non-significant. Results (I) Study group
Our 150 women present the following characteristics: mean age 27.6 _t 0.56 years (from 15 to 47 years), mean length of amenorrhea 38.25 k 0.27 days (from 28 to 42 days), mean diameter of intrauterine sac on initial ultrasound examination 10.63 + 0.45 mm (from 0 to 31 mm), mean HCG level on day one 33 948 f 6 384 W/l and mean level of hemoglobin 13.04 + 0.08 g/dl. (2) Efficacy A total of 131 women out of 150 were considered to have The overal abortion rate was 87.3%. The remaining 19 women ing pregnancies, 2 missed abortions, 2 curettages for heavy trauterine pregnancy. Table I shows the results according amenorrhea.
a complete abortion. included 14 developbleeding and 1 exto the duration of
(3) Tolerance In most cases, daily amount and duration of bleeding were compared to an abundant menstruation. Only 2 patients reported heavy bleeding leading to curettage. Three women reported bleeding over two weeks (19 to 30 days) after a successful abortion. The mean hemoglobin level at day eight was 12.53 & 0.10 g/dl. Only 16 women had a hemoglobin level less than 11 g/dl, justifying iron therapy. None needed a transfusion. A very few other side-effects were reported: uterine contractions and pelvic pains (7 (4.6%)), transient asthenia (3 (2%)) and slight nausea (2 (1.3%)). All the biological tests remained in the normal range.
252
TABLE I Results according to the duration of amenorrhea Total
Amenorrhea (days)
No. of cases Failures I%
< 33
34-35
36-31
38-39
40-41
42
12 2 16.7
19 2 10.5
26 2 7.7
36 4 11.1
19 3 15.8
38 6 15.8
150 19 12.7
TABLE II Results and comparisons
NuIlipara Amenorrhea (days) Regular cycle Uterine sac diameter (mm) HCG(years) (UI/l) Age
(4) Comparison
Failure (19 =12.7%)
Success (131= 87.3%)
47% 38.58 f0.84 58% 9.89+ 1.18 22 080f f 1.09 5 294 27.53
53% 38.28 zkO.28 19% 10.74 f 0.49 35519+7219 27.59 f 0.63 I
NS
of successes and failures
As shown in Table II, there is no significant difference between characteristics on day one of successes and failures. No prediction could be made from these items. Table III shows the variations in HCG levels between days one and eight for successes. Discussion Mifepristone had been used in preliminary reports concerning termination of early pregnancy in multiple doses, from four to seven days [7,10-151. The first publication by Herman et al. [7] reported a success rate of 82% out of 11 patients with a pregnancy from six to eight weeks. Younger pregnancies are concerned in other reports: less than 55 days of amenorrhea for Haspels [ll], less than 49 days for Bigerson [12], Sin-&-Ware [13] and Swahn [14], less than 42 days for Kovacs [lo]
TABLE III Variations of the HCG level HCG (IU/l)
Success
Failures
Day 1 Day 8
35579+7219 4272*1055 p -z 0.001
2208Ok 5294 88 301 f 34710 p < 0.001
NS p < 0.001
253
and less than 38 days for Couzinet [15]. For all these authors using Mifepristone with various total doses (200 to 1000 mg) the success rate was 61 to 82%. Our study is one of the very first using a single dose of 600 mg and our results, giving a success rate of 87%, are as satisfactory as the other reports. The mechanism by which Mifepristone acts is hypothetical. Binding to the progesterone receptor in place of free progesterone is probably the first step [6]. Thus the biological effects of progesterone disappear. Histological studies have shown that Mifepristone induces decidual necrosis without any alteration of trophoblast [16,17]. Then, the drug also induces endometrial prostaglandin synthesis [17,18], stimulating myometrial contractility [14,19], and causing softening of the uterine cervix. Thus, the successful induction of abortion by Mifepristone may involve a direct antiprogesterone effect on the endometrium, inducing ovum detachment, and an indirect stimulation of prostaglandin leading to ovum expulsion. As shown by Herman [7], Kovacs [lo] and Couzinet [15], the decrease in HCG level is a consequence of trophoblast separation, and luteolysis is secondary to the decrease of HCG. The progesterone level decrease is significant on the sixth day of treatment, i.e. after the abortion has occurred [15]. Mifepristone failed to cause an abortion in 17 of our patients. Nevertheless all these women had a uterine bleeding, but less than the successful cases. On day eight, the HCG level of the failures was significantly higher than the initial level (Table III). Why an abortion did not occur is still unknown. There were no differences between the 131 women who responded and the 19 who failed. Failure could be the consequence of an insufficient amount of drug at the site of action. The pharmacological studies have pointed out that Mifepristone attaches to cu,-globulin in plasma [20] and only free Mifepristone is active. A too low free Mifepristone level could not lead to abortion. For most of the authors there is no apparent dose dependency, but there is an obvious relationship between efficacy and age of pregnancy, as best results are obtained for pregnancies of less than six weeks [6,11]. It has been suggested that insufficient prostaglandin release may explain incomplete uterine evacuation. Swahn [14] induced complete abortion by utilization of a prostaglandiu analogue. In clinical practice, Mifepristone was very well tolerated, with very few side-effects. The main problem is a possibility of heavy bleeding which needs careful medical monitoring. Mifepristone is also a gluco-corticoid antagonist, as shown by Gaillard [21], but this effect needs a much larger dose. Couzinet [15] had observed variations in plasma ACTH and cortisol but without any clinical effects with the dose used for early abortion. Conclusion Mifepristone appears to be a simple and safe agent for termination of early pregnancy. The use of a single dose of 600 mg is very easy and leads to ambulatory abortion under medical supervision. Our rate of success is similar to those reported with prostaglandin analogues but without the painful uterine contractions and the gastro-intestinal effects. Mifepristone seems to be actually a good alternative to
254
surgical abortion for early pregnancies. To avoid the risk of failure, further studies using Mifeptistone with a prostaglandin analogue should be conducted in the near future. Acknowledgements We thank Laboratoire Roussel-Uclaf, Paris, who provided us with Mifepristone tablets. We also thank S. Helbert-Davidson, M.D., and J.P. Le Floch, M.D., from the Department of Endocrinology, Facultt de Mtdecine of Creteil, for statistical calculations. We are grateful to Mrs. Annie Hue for typing the manuscript, and to the members of our out-patient gynecological unit for carrying out that study. References 1 Mumford SD, Kessel E. Role of abortion in control of global population growth. in Lafera, JJ, ed. Termination of Pregnancy. Chn Obstet Gynecol 1986;13:19-31. 2 Bygdeman M, Christensen NJ, Green K, Zheng S, Lundstrom V. Termination of early pregnancy. Future development. Acta Obstet Gynecol Stand 1983; Suppl. 113:125-129. 3 Lundstrom V, Bygdeman M, Fotiou S, Green K, Kinoshita K. Abortion in early pregnancy by vaginal administration of 16-16 dimethyl PGE, in comparison with vacuum aspiration. Contraception 1977;16:167-173. 4 Rosen AS, Nystedt L, Bygdeman M, Lundstrom V. Acceptability of a non-surgical method to terminate very early pregnancy in comparison to vacuum aspiration. Contraception 1979;19:107-117. 5 Csapo AI, PuIkinnen M. Indispensability of the human corpus luteum in the maintenance of early pregnancy, luteectomy evidence. Obstet Gynecol Surv 1978;33:69-81. 6 Bauheu EE. RU 486: an antiprogestin steroid with contragestive activity in woman. In Bauheu EE, Segal SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:1-25. 7 Hermann W, Wyss R, Riondel A, et al. Effet dun sttrdide anti-progesterone chez la femme: interruption du cycle menstruel et de la grossesse au debut. CR Acad Sci Paris 1982;294:933-938. 8 Schaison G, George M, Lestrat N, Reinberg A, Bauheu EE. Effects of the antiprogesterone steroid RU 486 during mid luteal phase in normal women. J CIin Endocrinol Metab 1985;101:484-489. 9 Nieman LK, Choate TM, Chrousos GP, et al. The progesterone antagonist RU 486: a potential new contraceptive agent. N EngI J Med 1987;316:187-191. 10 Kovacs L, Sas M, Resch BA, et al. Termination of very early pregnancy by RU 486, an antiprogestational compound. Contraception 1984;29:399-410. 11 Haspels AA. Interruption of early pregnancy by the antiprogestational compound RU 486. In Bauheu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:199-209. 12 Bigerson L, Odhnd V, Johansson, E. Clinical effects of RU 486 administered for seven days in early pregnancy. In Bauheu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:235-241. 13 Sitruk-Ware R, Billaud L, Mowszowicz I, et al The use of RU 486 as an abortifacient in early pregnancy. In Bauheu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control New York: Plenum Press, 1985:243-248. 14 Swahn ML, Cekan S, Wang G, Lundstrom V, Bygdeman M. Pharmacokinetic and clinical studies of RU 486 for fertility regulation. In BauIieu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:249-258. 15 Couzinet B, Lestrat N, Ulmann A, BauIieu EE, Schaison G. Termination of early pregnancy by the progesterone antagonist RU 486 (mifepristone). N EngI J Med 1986;315:565-570. 16 Secchi J, LeIaque D. Toumemine C, PhiIibert D. Histopharmacology of RU 486. In BauIieu EE, SegaI SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985:79-86.
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