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Termination of very early pregnancy by RU 486 — An antiprogestational compound
CONTRACEPTION
TERMINATION
OF VERY
EARLY
PREGNANCY
BY RU 486
- AN ANTIPROGESTATIONAL
COMPOUND
L. Kovacs*,
M. Sas':, B.A.
Resch*,
M. Bygdeman""
"Department
of Obstetrics
and P.J.
and Gynecology, Szeged,
t*'-Department
of Obstetrics
in Human
Programme Reproduction,
World
Health
Swahn**,
Rowe**"
University
and Gynecology,
of Research,
M.L.
Medical
School,
Hungary
Stockholm,
""*Special
G. Ugocsai",
Karolinska
Hospital,
Sweden
Development
and Research
Organization,
Geneva,
Training Switzerland
ABSTRACT RU 486, a new antiprogestational compound, was given to 37 women seeking termination of pregnancy and with amenorrhea of 42 days or One patient was found at the second follow-up visit to have an less. extrauterine pregnancy. The patients received either 25 mg, 50 mg or 100 mg RU 486 twice daily for four days. All patients attended three follow-up visits, one, two and five to six weeks after the start of as well as plasma therapy. The start, duration and amount of bleeding progesterone, p-hCG and cortisol concentrations were determined for each treatment day and at the follow-up visits. All patients but three started to bleed during treatment. Frequency of complete abortion was 61% (22 out of 36 patients). In only three patients was the pregnancy unaffected by treatment. The clinical efficacy of the Most of the patients experienced treatment was not dose-dependent. only minor side effects in terms of mild uterine pain, nausea and vomiting. two patients suffered from heavy bleeding However, requiring blood transfusion and curettage. In the patients with complete abortion, B-hCG values decreased significantly but not c L the first follow-up visit. The plasma progesterone also decrease The decrease appeared earlier with the higher daily dose of RU 489, Cortisol concentrations increased during treatment with all 3 dosage regimensbut the levels remained within the normal range. It is concluded that treatment with RU 486 may provide a novel therapy for "menstrual regulation" but the efficacy of the treatment needs to be improved to compete with alternatives such as vacuum aspiration. Submitted for publication Accepted for publication
MAY 1984 VOL. 29 NO, 5
April 11, 1984 April 18, 1984
399
CONTRACEPTION
INTRODUCTION A non-surgical procedure suitable for self-administration is an attractive alternative to vacuum aspiration for termination of very early pregnancy. So far, prostaglandin analogues are the only compounds with this potential which have been investigated clinically on a large scale. The prostaglandins have the unique ability to stimulate uterine contractility resulting in abortion during very Several studies have shown that administration of early pregnancy. certain E-analogues can be as effective as a surgical procedure. The frequency of complications was, with the exception of vomiting and diarrhea, similar or less than that reported for vacuum aspiration at home, of prostaglandin analogues has (1,2). Self-administration, also been shown to be a realistic alternative in limited studies (3). Another possibility is to interfere with progesterone activity. Since progesterone plays an indispensable role during the implantation phase and during early pregnancy in animals (4) and women (5), withdrawal of progesterone or blockage of its action may result in an early abortion. Recently it was reported that oral administration of a new steroid, RU 4864, to eleven women in the sixth to eighth week of pregnancy resulted in an abortion in nine of them (6). KU 486 is a synthetic steroid with the properties of progesterone and glucocorticoid antagonist acting at the receptor level. In lower animals the compound appears free from progestogenic and glucocorticosteroid agonist activity as well as from androgenic and estrogenic action (6). In the present study the efficacy of different doses of the compound to terminate very early pregnancy was investigated.
PATIENTS AND METHODS The study included 37 healthy women with an apparently normal pregnancy judged by plasma j3-hCG and gynecological examination and an amenorrhea of 42 days or less. All subjects admitted to the study were made aware of the nature of the study and gave their informed In addition, the use of the drug has been approved both by consent. the Institutional Ethical Committee and by National Drug Regulatory Authorities. The compound, RU 486, was administered orally in three different dose levels: 1) 25 mg twice daily for four days; 2) 50 mg twice daily for four days; and 3) 100 mg twice daily for four days. The patients received the medication between 8 and 10 a.m. and between 8 and 10 p.m. The subjects fasted for four hours before and one hour after taking the drug. All patients attended three follow-up visits, one, two and five to six weeks after the start of treatment. The subjects attended and remained in the hospital for four hours on each of the treatment days during which time they received the first dose of the day. The second dose was taken by the subject at home.
3~ 17~-hydroxy-llg-~4-dimethylaminophenyl)-17~~l-propynyl) estra-4,9-dien-3-one; Roussel Uclaf, Paris, France.
400
MAY 1984 VOL. 29 NO. 5
CONTRACEPTION
On each treatment day before the administration of the compound, and at the same time on each follow-up visit (between 9 and 10 a.m.),blood samples (10 ml) were taken for the analysis of J+hCG, progesterone and cortisol in plasma. The data from the first treatment day thus represent the plasma concentration immediately prior to therapy. Urine and blood samples were also take” before, during and after therapy for the following: albumin and glucose in urine; hemoglobin; white blood cell count; sodium, potassium, SGOT, SGPT, alkaline phosphatase in blood. At the second follow-up visit, the outcome of therapy was preliminarily classified as either complete abortion, incomplete abortion or The assessment was based on the duration and uninterrupted pregnancy. amount of bleeding, plasma J3-hCG concentration, gynecological examination and, if it was not obvious that the patient had aborted If at the 14-day visit, the completely, ultrasound examination. it was assumed that the pregnancy was plasma J-hCG exceeded 2000 ILJ/l, continuing and it was terminated by vacuum aspiration. If curettage the outcome of therapy was based on a was found to be necessary, histopathological examination of the curettings. Side effects or complications were carefully noted on each treatment day and at the follow-up visits. All statistical analyses were based on the logarithm of the plasma levels and two-way analysis of variance was used to estimate the residual within-subject variation. Significance tests were based on selected contrasts between the daily mean values.
RESULTS One of the 37 patients admitted to the study was found at the second follow-up visit, to have a” examination, pregnancy which was treated conventionally.
Table
I.
Centre
by ultrasound extrauterine
Outcome of therapy with RU 486 for termination early pregnancy (total no. of patients: 37)
Dose (mg)
No. of patients
Complete abort ion
Incomplete abort ion
of
Extrauterine pregnancy
very
Pregnancy cant inued
Stockholm
25mg twice daily
10
7
1
1
1
S zeged
25mg twice daily
9
5
3
0
1
Szeged
5Omg twice daily
10
5
4
0
1
Szeged
1OOmg twice daily
8
5
3
0
0
MAY 1984 VOL. 29 NO. 5
401
CONTRACEPTION As
illustrated
in Table I, 22 out of the 36 patients with a normal 61%, were regarded to have had a complete abortion. frequency of complete abortion was not related to the dose given. Twelve patients had an incomplete abortion and in three patients (6.7%) the pregnancy remained intact. pregnancy,
or
The
All patients except three started vaginal bleeding within five days of the start of treatment. The patients receiving the two highest daily doses tended to start to bleed earlier (second to third day) than those who obtained the lowest dose (3rd to 4th day). In the majority of the successfully treated patients, the bleeding had a duration of between one and two weeks and the daily amount corresponded to their normal menstrual period. Two patients, one (group III) on the second treatment day and the other (group ) six days after start of treatment, experienced heavy bleeding resulting in hospital admission, blood transfusion and curettage. Other side effects patients reported cases) and nausea The plasma levels abortion) and of treatment at the Figures 1, 2 and
were generally of a mild nature. Almost all slight lower abdominal pain and a few headache (twelve cases).
(four
of )-hCG and progesterone (for women with complete cortisol (for all subjects) before, during and after three dose levels of the compound are summarized in 3.
SEM
logunits
nmolll
-2.8 600-
400 --2.6 \
\
/ /
\
/ d
\
-2.4
Day 1
Day 2
Day 3
Day 4
First follow-up
402
\
\
b
,
200 1
Fig.
\
1.
Second follow-up
Plasma cortisol concentration before, during and after oral treatment with 200 mg, 400 mg and 800 mg RU 486 over four days (geometric means and standard error of mean).
MAY
1984VOL.29N0.5
CONTRACEPTION
nmolll
SEM
log units
100
1.6
40
10
1.0
-Day
1
Day
2
Day
3
Day
4
First follow-up
Fig.
2.
Plasma progesterone concentration before, during and oral treatment with 200 mg, 400 mg and 800 mg RU 486 days (geometric means and standard error of mean).
after over
four
With the lowest dose level, 25 mg twice daily for four days, J-hCG values increased and progesterone values decreased slightly during the four treatment days, but a significant decrease in the successfully treated patients was not observed until the first follow-up visit, seven days after start of treatment. An increase in plasma cortisol concentration occurred during treatment (p=O.OOS), but values were not significantly different from pretreatment levels at the first two follow-up visits (Table II). Due to technical difficulties, J-hCG values were not available on the first three treatment days in one patient. However, on the fourth treatment day,B-hCG was found to be 14,200 Ill/l. With 50 mg RU 486 twice daily, JJ-hCG decreased significantly on day 4 and first follow-up visit, while progesterone The levels values started to decrease from the first treatment day. at the first follow-up visit were significantly lower than before Cortisol values increased treatment for both hormones (p&0.001). but returned to pretreatment significantly during treatment (pCO.OOl), With the levels by the time of the follow-up visits (Table III). highest dose (100 mg RU 486 twice daily), the decrease in plasma j3-hCG was significant by day 4 and at the first follow-up visit (p&0.02). There was a significant downward trend in progesterone levels during treatment (p=O.O02) and they were significantly lower at the first Cortisol values were increased during treatment (pC;O.O5), follow-up. but were not significantly elevated at the first follow-up visit compared to pretreatment values (Table IV).
MAY 1984 VOL. 29 NO. 5
403
6 r
5r $
<
371 (316-435)
(52-E:)
4160 (3120-7270)
2
days 3
initialJ+hCG
values
474 (403-556)
(44-Z
6130 (4010-9350)
4
treatment
missing
401 (342-471)
(lo-::,
593 (389-906)
First follow-up visit
with 25 mg RU 486
419 (357-491)
Second follow-up visit
twice daily
for
decreased at the The differences in J-hCG values were not significant on days 1 to 4, but were significantly first follow-up (pLO.001). The decrease in progesterone values from days 1 to 4 were not significant; but were There was a significant significant between the values on days 1 to 4 and the first follow-up (p(O.001). increase in cortisol values during treatment (days 2, 3 and 4 versus day 1 and the first and second follow-ups (p=O.O05).
with
452 (385-530)
(45-Z
7070 (4630-10800)
one subject
487 (415-572)
(47-Z
5680 (3720-8680)
Complete abortion, n=ll omitting :';+ Complete abortion, n=12 *-"- All patients, n=19
-‘<
Cortisol*** (nmol/l)
Progesterone** (nmol/l)
J-hCG+c (W/l)
1
Treatment
before, during and after II. Plasma hormone concentrations 4 days (geometric mean; 95% confidence limits)
Compound
Table
zi
2
F
CONTRACEPTION
MAY 1984 VOL. 29 NO. 5
405
CONTRACEPTION
406
MAY 1984 VOL. 29 NO. 5
CONTRACEPTION
SEM
IU/I
log units
2(33mg %
10000
4.0
P
t,
1
4OOmg
b t - 3.4 2000
-
\ -- 3.0
400
-- 2.6
L
I
Day
1
Day 2
I
I
Day 3
Day 4
First follow-UD
Fig.
3.
Plasma J-hCG concentration before, during and after oral treatment with 200 mg, 400 mg and 800 mg RU 486 over four days (geometric means and standard error of mean). DISCUSSION
RU 486 is a steroid derivative which possesses a great affinity for progesterone receptors and acts as a strong antagonist of progesterone action (6). In the present study, the efficacy and safety of the compound for termination of early pregnancy in the human was evaluated. In contrast to the first study of Herrman et al. (6), the treatment in this study was limited to the first two weeks following the first missed menstrual period as compared to the sixth to eighth week of pregnancy. There were several reasons for this decision: a) the experience with prostaglandin analogues for termination of early pregnancy has indicated that the frequency of incomplete abortion increases with gestational age, especially after the seventh week of pregnancy (7); b) the estimated amount of blood loss associated with a non-surgical method for termination of pregnancy is probably related to gestational age at treatment; and c) the efficacy of an anti-progestational drug may be higher if the treatment is limited to the period of pregnancy when the corpus luteum is of importance for the maintenance of pregnancy. However, if this compound is a true anti--progestational agent,one would also expect an effect even after the luteo-placental shift in progesterone production has occurred.
MAY
1984 VOL. 29 NO. 5
407
CONTRACEPTION In the present study all but three patients started to bleed within five days following the start of treatment. The frequency of complete abortion was 61% (22 out of 36 patients) or approximately the same figure as reported by Herrman -et al. (6). The frequency of complete abortion was similar in all three treatment groups. In only three patients did the pregnancy continue unaffected. According to the study design, vacuum aspiration was performed two weeks following the start of treatment if the ,E+hCG and clinical observations indicated that the abortion may not have been complete. It is likely that the frequency of complete abortion would have been higher if vacuum aspiration had been postponed in some of the cases,thus allowing an opportunity for spontaneous expulsion of the product of conception. From a clinical point of view, such a delay of vacuum aspiration would have been possible in nine patients. Even so, the efficacy with the dose schedules used is not sufficient to compete with vacuum aspiration. The lack of dose-efficacy relationship (frequency of complete abortion) indicates that further studies on the daily amount of the drug administered and duration of treatment are necessary before the most effective treatment is established. In addition, formal human pharmacokinetic studies are yet to be undertaken with RU 486 and such studies are needed as a necessary complement for the .design of new treatment schedules. In the successfully treated patients (complete abortion),both plasma p-HCG and progesterone decreased by the first follow-up visit. With increasing doses of RU 486,the fall in plasma progesterone appeared earlier (days three and four of treatment). The same was true for the start of vaginal bleeding. Whether the effect of the anti-progestational drug was mainly on the corpus luteum or on the placenta is not possible to judge from the present study. Hen-man szt. (6) found an increase in plasma cortisol during treatment with 100 mg RU 486 twice daily for four days in early pregnant women but similar doses in the non-pregnant monkey had no effect on plasma cortisol (8). In the present study a significant increase in plasma cortisol was observed during treatment but values returned to pretreatment levels by the follow-up visit. This increase cannot be explained by diurnal variations since the blood samples were taken at the same time (between 8 and 10 a.m.) on each occasion. The changes in cortisol values seen in this study are similar to those observed during prostaglandin-induced abortion (9) and may be the result of stress rather than a direct drug-induced effect, but this cannot be ruled out in view of the known glucocortoid antagonistic activity at receptor level (6). The present study also illustrates some of the possible drawbacks of terminating very early pregnancy with an anti-progestational compound. Two patients experienced excessive bleeding which may be due to the failure of the compound to cause uterine contractions. The high incidence of incomplete abortion may have the same explanation. If the results of this preliminary study are compared with those reported for prostaglandin analogues used for termination of early pregnancy (1, 2, 3),it can be seen that RU 486 is superior in terms of frequency and intensity of uterine pain and gastro-intestinal side effects. On the other hand, prostaglandin therapy is more effective with the frequency of complete abortion reaching 85% in a multicentre study (1) and 95% in pilot studies (2,3). Excessive blood loss requiring transfusion has not been reported (1,2,3). This may be due to the different modes of action of the two groups of compounds, the prostaglandin having a strong stimulatory effect on uterine contractility.
MAY 1984 VOL. 29 NO. 5
CONTRACEPTION In the present study, one patient with an unsuspected extrauterine pregnancy on admission was treated with the compound and the pregnancy continued and laparotomy was necessary two weeks following start of treatment. However, extrauterine pregnancy poses a difficult clinical problem with any method of termination of very early pregnancy when the diagnosis is far from precise even with modern ultrasound techniques. It can be concluded from the present study that treatment with RU 486 may provide a novel therapy for menstrual regulation. The efficacy of the treatment needs, however, to be increased to compete with vacuum aspiration.
ACKNOWLEDGEMENTS RU 486 was kindly supplied by Roussel UCLAF, Paris, France. This study was undertaken with the financial support of the WHO Special Programme of Research, Development and Research Training in Human The authors thank Associate Reproduction, Geneva, Switzerland. Professor Sten Cekan and Dr.T.M.M. Farley for expert advice on the statistical analysis of the data, Astrid H;iggblad for typing the manuscript, and the nurses of the research units for supervising the patients
REFERENCES 1.
Termination of early pregnancy by WHO Prostaglandin Task Force. methyl vaginal administration of 16, 16-dimethyl-trans-a2-PGEl ester. Asia-Oceania J Obstet Gynecol 8~263-268 (1982)
2.
Bygdeman, M., Bremme, K., Christensen, N., Lundstrom, V. and Green, K. A comparison of two stable prostaglandin E analogues termination of early pregnancy and for cervical dilatation. Contraception 22: 471-483 (1980)
for
3.
Bygdeman, M., Christensen, N., Green, K., Zheng, S. and Lundstrom, Acta V. Termination of early pregnancy - future development. Obstet Gynecol Stand Suppl 113~125-129 (1983)
4.
Csapo, A.I. and Resch, B. Prevention antiprogesterone. J Steroid Biochem
5.
Csapo, A.I. and Pulkkinen, luteum in the maintenance evidence. Obstet Gynecol
6.
Herrman, W., Wyss, R., Riondel, A., Philibert, D., Teutsch, G., Sakiz, E. and Baulieu, E.E. The effects of an antiprogesterone steroid on women: Interruption of the menstrual cycle and of early pregnancy. Comptes Rendus 294~933-940 (1982)
MAY
1984 VOL. 29 NO. 5
of implantation by 11:963-969 (1979)
M. Indispensability of early pregnancy. Surv 33~69-81 (1978)
of the human Luteoectomy
corpus
409
CONTRACEPTION
7.
Bygdeman, M., Borell, U., Leader, A., Lundstriim, V., Martin, J.N., Jr., Eneroth, P. and Grken, K. Induction of first and second trimester abortion by the vaginal administration of Prostaglandin and Thromboxane 15-methyl-PGF2,,, methyl ester.In: Research (B. Samuelsson & R. Paoletti, Editors),Raven Press. New York, 1976, vol. 2, p. 693-704
8.
Healy, D.L., Baulieu, E.E. and Hodgen, G.D. Induction of menstruation by an antiprogesterone steroid (RU 486) in primates: site of action, dose-response relationships and hormonal effects. Fertil Steril 40: 253-257 (1983)
9.
Kinoshita, K., Eneroth, P. and Bygdeman, M. Treatment with a single vaginal suppository containing 15-methyl-PGF2dmethyl ester at expected time of menstruation. Prostaglandins 17: 469-481 (1979)
410
MAY 1984 VOL. 29 NO. 5
TERMINATION
OF VERY
EARLY
PREGNANCY
BY RU 486
- AN ANTIPROGESTATIONAL
COMPOUND
L. Kovacs*,
M. Sas':, B.A.
Resch*,
M. Bygdeman""
"Department
of Obstetrics
and P.J.
and Gynecology, Szeged,
t*'-Department
of Obstetrics
in Human
Programme Reproduction,
World
Health
Swahn**,
Rowe**"
University
and Gynecology,
of Research,
M.L.
Medical
School,
Hungary
Stockholm,
""*Special
G. Ugocsai",
Karolinska
Hospital,
Sweden
Development
and Research
Organization,
Geneva,
Training Switzerland
ABSTRACT RU 486, a new antiprogestational compound, was given to 37 women seeking termination of pregnancy and with amenorrhea of 42 days or One patient was found at the second follow-up visit to have an less. extrauterine pregnancy. The patients received either 25 mg, 50 mg or 100 mg RU 486 twice daily for four days. All patients attended three follow-up visits, one, two and five to six weeks after the start of as well as plasma therapy. The start, duration and amount of bleeding progesterone, p-hCG and cortisol concentrations were determined for each treatment day and at the follow-up visits. All patients but three started to bleed during treatment. Frequency of complete abortion was 61% (22 out of 36 patients). In only three patients was the pregnancy unaffected by treatment. The clinical efficacy of the Most of the patients experienced treatment was not dose-dependent. only minor side effects in terms of mild uterine pain, nausea and vomiting. two patients suffered from heavy bleeding However, requiring blood transfusion and curettage. In the patients with complete abortion, B-hCG values decreased significantly but not c L the first follow-up visit. The plasma progesterone also decrease The decrease appeared earlier with the higher daily dose of RU 489, Cortisol concentrations increased during treatment with all 3 dosage regimensbut the levels remained within the normal range. It is concluded that treatment with RU 486 may provide a novel therapy for "menstrual regulation" but the efficacy of the treatment needs to be improved to compete with alternatives such as vacuum aspiration. Submitted for publication Accepted for publication
MAY 1984 VOL. 29 NO, 5
April 11, 1984 April 18, 1984
399
CONTRACEPTION
INTRODUCTION A non-surgical procedure suitable for self-administration is an attractive alternative to vacuum aspiration for termination of very early pregnancy. So far, prostaglandin analogues are the only compounds with this potential which have been investigated clinically on a large scale. The prostaglandins have the unique ability to stimulate uterine contractility resulting in abortion during very Several studies have shown that administration of early pregnancy. certain E-analogues can be as effective as a surgical procedure. The frequency of complications was, with the exception of vomiting and diarrhea, similar or less than that reported for vacuum aspiration at home, of prostaglandin analogues has (1,2). Self-administration, also been shown to be a realistic alternative in limited studies (3). Another possibility is to interfere with progesterone activity. Since progesterone plays an indispensable role during the implantation phase and during early pregnancy in animals (4) and women (5), withdrawal of progesterone or blockage of its action may result in an early abortion. Recently it was reported that oral administration of a new steroid, RU 4864, to eleven women in the sixth to eighth week of pregnancy resulted in an abortion in nine of them (6). KU 486 is a synthetic steroid with the properties of progesterone and glucocorticoid antagonist acting at the receptor level. In lower animals the compound appears free from progestogenic and glucocorticosteroid agonist activity as well as from androgenic and estrogenic action (6). In the present study the efficacy of different doses of the compound to terminate very early pregnancy was investigated.
PATIENTS AND METHODS The study included 37 healthy women with an apparently normal pregnancy judged by plasma j3-hCG and gynecological examination and an amenorrhea of 42 days or less. All subjects admitted to the study were made aware of the nature of the study and gave their informed In addition, the use of the drug has been approved both by consent. the Institutional Ethical Committee and by National Drug Regulatory Authorities. The compound, RU 486, was administered orally in three different dose levels: 1) 25 mg twice daily for four days; 2) 50 mg twice daily for four days; and 3) 100 mg twice daily for four days. The patients received the medication between 8 and 10 a.m. and between 8 and 10 p.m. The subjects fasted for four hours before and one hour after taking the drug. All patients attended three follow-up visits, one, two and five to six weeks after the start of treatment. The subjects attended and remained in the hospital for four hours on each of the treatment days during which time they received the first dose of the day. The second dose was taken by the subject at home.
3~ 17~-hydroxy-llg-~4-dimethylaminophenyl)-17~~l-propynyl) estra-4,9-dien-3-one; Roussel Uclaf, Paris, France.
400
MAY 1984 VOL. 29 NO. 5
CONTRACEPTION
On each treatment day before the administration of the compound, and at the same time on each follow-up visit (between 9 and 10 a.m.),blood samples (10 ml) were taken for the analysis of J+hCG, progesterone and cortisol in plasma. The data from the first treatment day thus represent the plasma concentration immediately prior to therapy. Urine and blood samples were also take” before, during and after therapy for the following: albumin and glucose in urine; hemoglobin; white blood cell count; sodium, potassium, SGOT, SGPT, alkaline phosphatase in blood. At the second follow-up visit, the outcome of therapy was preliminarily classified as either complete abortion, incomplete abortion or The assessment was based on the duration and uninterrupted pregnancy. amount of bleeding, plasma J3-hCG concentration, gynecological examination and, if it was not obvious that the patient had aborted If at the 14-day visit, the completely, ultrasound examination. it was assumed that the pregnancy was plasma J-hCG exceeded 2000 ILJ/l, continuing and it was terminated by vacuum aspiration. If curettage the outcome of therapy was based on a was found to be necessary, histopathological examination of the curettings. Side effects or complications were carefully noted on each treatment day and at the follow-up visits. All statistical analyses were based on the logarithm of the plasma levels and two-way analysis of variance was used to estimate the residual within-subject variation. Significance tests were based on selected contrasts between the daily mean values.
RESULTS One of the 37 patients admitted to the study was found at the second follow-up visit, to have a” examination, pregnancy which was treated conventionally.
Table
I.
Centre
by ultrasound extrauterine
Outcome of therapy with RU 486 for termination early pregnancy (total no. of patients: 37)
Dose (mg)
No. of patients
Complete abort ion
Incomplete abort ion
of
Extrauterine pregnancy
very
Pregnancy cant inued
Stockholm
25mg twice daily
10
7
1
1
1
S zeged
25mg twice daily
9
5
3
0
1
Szeged
5Omg twice daily
10
5
4
0
1
Szeged
1OOmg twice daily
8
5
3
0
0
MAY 1984 VOL. 29 NO. 5
401
CONTRACEPTION As
illustrated
in Table I, 22 out of the 36 patients with a normal 61%, were regarded to have had a complete abortion. frequency of complete abortion was not related to the dose given. Twelve patients had an incomplete abortion and in three patients (6.7%) the pregnancy remained intact. pregnancy,
or
The
All patients except three started vaginal bleeding within five days of the start of treatment. The patients receiving the two highest daily doses tended to start to bleed earlier (second to third day) than those who obtained the lowest dose (3rd to 4th day). In the majority of the successfully treated patients, the bleeding had a duration of between one and two weeks and the daily amount corresponded to their normal menstrual period. Two patients, one (group III) on the second treatment day and the other (group ) six days after start of treatment, experienced heavy bleeding resulting in hospital admission, blood transfusion and curettage. Other side effects patients reported cases) and nausea The plasma levels abortion) and of treatment at the Figures 1, 2 and
were generally of a mild nature. Almost all slight lower abdominal pain and a few headache (twelve cases).
(four
of )-hCG and progesterone (for women with complete cortisol (for all subjects) before, during and after three dose levels of the compound are summarized in 3.
SEM
logunits
nmolll
-2.8 600-
400 --2.6 \
\
/ /
\
/ d
\
-2.4
Day 1
Day 2
Day 3
Day 4
First follow-up
402
\
\
b
,
200 1
Fig.
\
1.
Second follow-up
Plasma cortisol concentration before, during and after oral treatment with 200 mg, 400 mg and 800 mg RU 486 over four days (geometric means and standard error of mean).
MAY
1984VOL.29N0.5
CONTRACEPTION
nmolll
SEM
log units
100
1.6
40
10
1.0
-Day
1
Day
2
Day
3
Day
4
First follow-up
Fig.
2.
Plasma progesterone concentration before, during and oral treatment with 200 mg, 400 mg and 800 mg RU 486 days (geometric means and standard error of mean).
after over
four
With the lowest dose level, 25 mg twice daily for four days, J-hCG values increased and progesterone values decreased slightly during the four treatment days, but a significant decrease in the successfully treated patients was not observed until the first follow-up visit, seven days after start of treatment. An increase in plasma cortisol concentration occurred during treatment (p=O.OOS), but values were not significantly different from pretreatment levels at the first two follow-up visits (Table II). Due to technical difficulties, J-hCG values were not available on the first three treatment days in one patient. However, on the fourth treatment day,B-hCG was found to be 14,200 Ill/l. With 50 mg RU 486 twice daily, JJ-hCG decreased significantly on day 4 and first follow-up visit, while progesterone The levels values started to decrease from the first treatment day. at the first follow-up visit were significantly lower than before Cortisol values increased treatment for both hormones (p&0.001). but returned to pretreatment significantly during treatment (pCO.OOl), With the levels by the time of the follow-up visits (Table III). highest dose (100 mg RU 486 twice daily), the decrease in plasma j3-hCG was significant by day 4 and at the first follow-up visit (p&0.02). There was a significant downward trend in progesterone levels during treatment (p=O.O02) and they were significantly lower at the first Cortisol values were increased during treatment (pC;O.O5), follow-up. but were not significantly elevated at the first follow-up visit compared to pretreatment values (Table IV).
MAY 1984 VOL. 29 NO. 5
403
6 r
5r $
<
371 (316-435)
(52-E:)
4160 (3120-7270)
2
days 3
initialJ+hCG
values
474 (403-556)
(44-Z
6130 (4010-9350)
4
treatment
missing
401 (342-471)
(lo-::,
593 (389-906)
First follow-up visit
with 25 mg RU 486
419 (357-491)
Second follow-up visit
twice daily
for
decreased at the The differences in J-hCG values were not significant on days 1 to 4, but were significantly first follow-up (pLO.001). The decrease in progesterone values from days 1 to 4 were not significant; but were There was a significant significant between the values on days 1 to 4 and the first follow-up (p(O.001). increase in cortisol values during treatment (days 2, 3 and 4 versus day 1 and the first and second follow-ups (p=O.O05).
with
452 (385-530)
(45-Z
7070 (4630-10800)
one subject
487 (415-572)
(47-Z
5680 (3720-8680)
Complete abortion, n=ll omitting :';+ Complete abortion, n=12 *-"- All patients, n=19
-‘<
Cortisol*** (nmol/l)
Progesterone** (nmol/l)
J-hCG+c (W/l)
1
Treatment
before, during and after II. Plasma hormone concentrations 4 days (geometric mean; 95% confidence limits)
Compound
Table
zi
2
F
CONTRACEPTION
MAY 1984 VOL. 29 NO. 5
405
CONTRACEPTION
406
MAY 1984 VOL. 29 NO. 5
CONTRACEPTION
SEM
IU/I
log units
2(33mg %
10000
4.0
P
t,
1
4OOmg
b t - 3.4 2000
-
\ -- 3.0
400
-- 2.6
L
I
Day
1
Day 2
I
I
Day 3
Day 4
First follow-UD
Fig.
3.
Plasma J-hCG concentration before, during and after oral treatment with 200 mg, 400 mg and 800 mg RU 486 over four days (geometric means and standard error of mean). DISCUSSION
RU 486 is a steroid derivative which possesses a great affinity for progesterone receptors and acts as a strong antagonist of progesterone action (6). In the present study, the efficacy and safety of the compound for termination of early pregnancy in the human was evaluated. In contrast to the first study of Herrman et al. (6), the treatment in this study was limited to the first two weeks following the first missed menstrual period as compared to the sixth to eighth week of pregnancy. There were several reasons for this decision: a) the experience with prostaglandin analogues for termination of early pregnancy has indicated that the frequency of incomplete abortion increases with gestational age, especially after the seventh week of pregnancy (7); b) the estimated amount of blood loss associated with a non-surgical method for termination of pregnancy is probably related to gestational age at treatment; and c) the efficacy of an anti-progestational drug may be higher if the treatment is limited to the period of pregnancy when the corpus luteum is of importance for the maintenance of pregnancy. However, if this compound is a true anti--progestational agent,one would also expect an effect even after the luteo-placental shift in progesterone production has occurred.
MAY
1984 VOL. 29 NO. 5
407
CONTRACEPTION In the present study all but three patients started to bleed within five days following the start of treatment. The frequency of complete abortion was 61% (22 out of 36 patients) or approximately the same figure as reported by Herrman -et al. (6). The frequency of complete abortion was similar in all three treatment groups. In only three patients did the pregnancy continue unaffected. According to the study design, vacuum aspiration was performed two weeks following the start of treatment if the ,E+hCG and clinical observations indicated that the abortion may not have been complete. It is likely that the frequency of complete abortion would have been higher if vacuum aspiration had been postponed in some of the cases,thus allowing an opportunity for spontaneous expulsion of the product of conception. From a clinical point of view, such a delay of vacuum aspiration would have been possible in nine patients. Even so, the efficacy with the dose schedules used is not sufficient to compete with vacuum aspiration. The lack of dose-efficacy relationship (frequency of complete abortion) indicates that further studies on the daily amount of the drug administered and duration of treatment are necessary before the most effective treatment is established. In addition, formal human pharmacokinetic studies are yet to be undertaken with RU 486 and such studies are needed as a necessary complement for the .design of new treatment schedules. In the successfully treated patients (complete abortion),both plasma p-HCG and progesterone decreased by the first follow-up visit. With increasing doses of RU 486,the fall in plasma progesterone appeared earlier (days three and four of treatment). The same was true for the start of vaginal bleeding. Whether the effect of the anti-progestational drug was mainly on the corpus luteum or on the placenta is not possible to judge from the present study. Hen-man szt. (6) found an increase in plasma cortisol during treatment with 100 mg RU 486 twice daily for four days in early pregnant women but similar doses in the non-pregnant monkey had no effect on plasma cortisol (8). In the present study a significant increase in plasma cortisol was observed during treatment but values returned to pretreatment levels by the follow-up visit. This increase cannot be explained by diurnal variations since the blood samples were taken at the same time (between 8 and 10 a.m.) on each occasion. The changes in cortisol values seen in this study are similar to those observed during prostaglandin-induced abortion (9) and may be the result of stress rather than a direct drug-induced effect, but this cannot be ruled out in view of the known glucocortoid antagonistic activity at receptor level (6). The present study also illustrates some of the possible drawbacks of terminating very early pregnancy with an anti-progestational compound. Two patients experienced excessive bleeding which may be due to the failure of the compound to cause uterine contractions. The high incidence of incomplete abortion may have the same explanation. If the results of this preliminary study are compared with those reported for prostaglandin analogues used for termination of early pregnancy (1, 2, 3),it can be seen that RU 486 is superior in terms of frequency and intensity of uterine pain and gastro-intestinal side effects. On the other hand, prostaglandin therapy is more effective with the frequency of complete abortion reaching 85% in a multicentre study (1) and 95% in pilot studies (2,3). Excessive blood loss requiring transfusion has not been reported (1,2,3). This may be due to the different modes of action of the two groups of compounds, the prostaglandin having a strong stimulatory effect on uterine contractility.
MAY 1984 VOL. 29 NO. 5
CONTRACEPTION In the present study, one patient with an unsuspected extrauterine pregnancy on admission was treated with the compound and the pregnancy continued and laparotomy was necessary two weeks following start of treatment. However, extrauterine pregnancy poses a difficult clinical problem with any method of termination of very early pregnancy when the diagnosis is far from precise even with modern ultrasound techniques. It can be concluded from the present study that treatment with RU 486 may provide a novel therapy for menstrual regulation. The efficacy of the treatment needs, however, to be increased to compete with vacuum aspiration.
ACKNOWLEDGEMENTS RU 486 was kindly supplied by Roussel UCLAF, Paris, France. This study was undertaken with the financial support of the WHO Special Programme of Research, Development and Research Training in Human The authors thank Associate Reproduction, Geneva, Switzerland. Professor Sten Cekan and Dr.T.M.M. Farley for expert advice on the statistical analysis of the data, Astrid H;iggblad for typing the manuscript, and the nurses of the research units for supervising the patients
REFERENCES 1.
Termination of early pregnancy by WHO Prostaglandin Task Force. methyl vaginal administration of 16, 16-dimethyl-trans-a2-PGEl ester. Asia-Oceania J Obstet Gynecol 8~263-268 (1982)
2.
Bygdeman, M., Bremme, K., Christensen, N., Lundstrom, V. and Green, K. A comparison of two stable prostaglandin E analogues termination of early pregnancy and for cervical dilatation. Contraception 22: 471-483 (1980)
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3.
Bygdeman, M., Christensen, N., Green, K., Zheng, S. and Lundstrom, Acta V. Termination of early pregnancy - future development. Obstet Gynecol Stand Suppl 113~125-129 (1983)
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Csapo, A.I. and Resch, B. Prevention antiprogesterone. J Steroid Biochem
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Csapo, A.I. and Pulkkinen, luteum in the maintenance evidence. Obstet Gynecol
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Herrman, W., Wyss, R., Riondel, A., Philibert, D., Teutsch, G., Sakiz, E. and Baulieu, E.E. The effects of an antiprogesterone steroid on women: Interruption of the menstrual cycle and of early pregnancy. Comptes Rendus 294~933-940 (1982)
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1984 VOL. 29 NO. 5
of implantation by 11:963-969 (1979)
M. Indispensability of early pregnancy. Surv 33~69-81 (1978)
of the human Luteoectomy
corpus
409
CONTRACEPTION
7.
Bygdeman, M., Borell, U., Leader, A., Lundstriim, V., Martin, J.N., Jr., Eneroth, P. and Grken, K. Induction of first and second trimester abortion by the vaginal administration of Prostaglandin and Thromboxane 15-methyl-PGF2,,, methyl ester.In: Research (B. Samuelsson & R. Paoletti, Editors),Raven Press. New York, 1976, vol. 2, p. 693-704
8.
Healy, D.L., Baulieu, E.E. and Hodgen, G.D. Induction of menstruation by an antiprogesterone steroid (RU 486) in primates: site of action, dose-response relationships and hormonal effects. Fertil Steril 40: 253-257 (1983)
9.
Kinoshita, K., Eneroth, P. and Bygdeman, M. Treatment with a single vaginal suppository containing 15-methyl-PGF2dmethyl ester at expected time of menstruation. Prostaglandins 17: 469-481 (1979)
410
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