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Danazol mimics antigestagen action in first trimester termination of pregnancy
European Journal of Obstetrics & Gynecology and Reproductive Biology 99 (2001) 93±96
Danazol mimics antigestagen action in ®rst trimester termination of pregnancy S. ZalaÂnyi Keszthely Municipal Hospital, Department of Obstetrics and Gynaecology, MAÂV TEK, 6726 Szeged, Hungary Accepted 2 March 2001
Abstract Back ground: Based on steroid receptor binding and biologic activity, danazol was suspected to be an antigestagen. Objective: To compare with placebo test in ®rst trimester termination of pregnancy (TOP) as a method for predilatation of the cervix prior to application of misoprostol. Methods: 52 patients were randomised into two groups. Thereby, 26 women received 200 mg danazol vaginal suppositories three times during 2 days before administering 200 mg misoprostol and undergoing mechanical dilatation and vacuum aspiration 5 h later. The other 26 received placebo suppositories and the same treatment otherwise. Result: The uterine cervix was wider and less dilatation and time was needed for the surgical termination in the group pretreated with danazol. There were six cases of complete abortion within 5 h of administering misoprostol in the danazol group; and none in the placebo group. After danazol treatment, 16 women exhibited signs of abortion versus four receiving the inert suppositories. Conclusion: Pretreatment with 200 mg danazol suppositories three times starting 36 h before administering misoprostol for cervical dilatation enhances the effect of prostaglandin on cervical dilatation and uterine contractions in a manner similar to antigestagens. # 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Danazol; Misoprostol; Predilatation; Termination of pregnancy
1. Introduction As the majority of pregnancies is unplanned, most are unwanted leading to termination. Termination of pregnancy (TOP), although hotly debated and politically charged, remains a fact of life. The gold standard of termination of ®rst trimester pregnancy is dilatation of the cervix and evacuation of products of pregnancy. This is a very safe method under appropriate conditions but the majority of terminations takes place in unsafe circumstances resulting in serious maternal morbidity and mortality [1,2]. Termination of the ®rst pregnancy poses extra risks because the uterine cervix is very narrow or almost closed. Therefore, it is advisable to dilate the cervix before the actual procedure takes place. Predilatation can be achieved by several methods. Placing laminaria tents into the cervix is the most widely practised method, but this may cause cervical injuries, perforation and increase the risk of infection [3]. It was noted that administration of antigestagens softens and dilates the cervix [4]. Prostaglandins too cause cervical dilatation if administered systemically or locally [5]. Unfortunately, antigestagen treatment is unaffordable in the Third World because of costs and unavailable in most developed countries because of lack of government clearence. It would be tempting to introduce new antigestagens
or progesterone synthesis inhibitors. This is rather improbable taking into account the costs, marketing and political consequences of introducing such a drug. Another approach would be to ®nd a drug already marketed and possessing antigestagen properties. Danazol was such a candidate, because of its ability to reduce ®broid size, suppress endometrial tissue [6] and possibly interfere with fertilisation [7] are reminiscent of the action of mifepristone on the same tissues [8,9] and processes [10]. Although, these can be termed as antiestrogenic features, this explanation may be excluded, as danazol binds poorly to the oestrogen receptor [11]. After thorough investigation of the medical literature another paper was found describing that danazol binds to the progesterone receptor, but does not cause secretory changes in the endometrium [12], i.e. implicitly stating antigestagenic properties of the drug. Danazol is administered systemically in the dose range of 200±800 mg per day for the treatment of endometriosis [6] and metrorrhagia. It is also absorbed from the vagina resulting in higher concentrations in the pelvic organs than after oral administration [13]. This seemed an advantage if the drug were to be used for cervical dilatation prior to elective abortion. Other methods for cervical predilatation are intracervical application of laminaria tents or prostagladins into the posterior fornix of the vagina.
0301-2115/01/$ ± see front matter # 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 1 - 2 1 1 5 ( 0 1 ) 0 0 3 5 7 - 8
94
S. ZalaÂnyi / European Journal of Obstetrics & Gynecology and Reproductive Biology 99 (2001) 93±96
Thus, a trial was designed to compare the ef®cacy of vaginal suppositories containing danazol and misoprostol pills for preoperative dilatation of the uterine cervix before ®rst trimester TOP. A total dose of 600 mg danazol was deemed suf®cient, based on data obtained with mifepristone [5] and divided into three suppositories containing 200 mg each, because the approved maximum single dose is 200 mg. For misoprostol 200 mg was chosen as this is effective for predilatation if administered alone vaginally. In order to diminish the risk of cervical injuries during elective abortion, nulliparous women receive cervical predilatation in Hungary. In this hospital misoprostol tablets applied intravaginally were used as an alternative to laminaria from 1 August 1996 on. In order to assess the cervical effects of danazol, a trial was designed to compare the predilatation achieved with misoprostol alone or after treatment with danazol suppositories. The trial protocol was submitted to and approved by the Research Ethics Committee of the Markusovszky Hospital, Szombathely. 2. Material and methods Nulliparous women 6±11 weeks pregnant, reporting at the district nurse for scheduling a termination, were informed of the necessity of predilatation and the available methods. Nulliparous women were selected to exclude differences in pre-treatment cervical width present in parous patients. The advantages of non-mechanical predilatation were stressed and the choice between laminaria tents and the trial drug danazol plus misoprostol was offered. If the woman chose medical treatment, she was randomised into one of two groups and received an envelope containing three suppositories. The envelopes contained two different medications, either three suppositories of 200 mg danazol (group A) or three inert suppositories (group B). Danazol suppositories were prepared from Danoval capsules (Krka, Croatia) at a local pharmacy as described elsewhere [13]. Placebo was prepared from the same vehicle and was indistinguishable from the active suppositories. At this visit the date of the operation was scheduled and the participant was instructed to place a suppository high into the vagina on the evening 2 days before and on the morning and evening preceding the operation. This procedure was designed because a 36±48 h period is necessary for the antigestagens to exert their sensitising effect before administering prostaglandins as shown in trials with RU 486 [14]. There is a 3 day re¯ection period required by the law regulating TOP. This made it possible to use the suppositories starting approximately 36 h before placing the prostaglandin and not causing any delay in the procedure. On the day of the operation the women reported at the hospital at 7 a.m. and were admitted. 2.1. Hospital treatment Laboratory tests, blood typing and a visit to the anesthetist took place on the days between scheduling and admission.
Patients were admitted to the hospital at 7 a.m. Physical and ultrasound examinations were performed to asses the duration of pregnancy. Then the vagina was cleansed with 1% polyvidon iodine (Betadine, Egis Pharmaceuticals, Hungary), a 200 mg misoprostol pill (Searle, England) was soaked in saline and placed into the posterior fornix. Saline treatment improved the dissolution of the pill. Thereafter, the patient was asked to stay in bed until the operation started between 1 and 2 p.m. Before the operation a speculum examination was performed, to assess signs of spontaneous abortion. In cases of complete abortion, only cervical dilatation and uterine length were measured but the patient was spared anaesthesia and evacuation as it was considered unnecessary [15]. The evacuation of pregnancy was performed under general anaesthesia, in the supine position. The cervix was dilated with Hegar tents if necessary. The initial and ®nal dilatation, length of uterine cavity, bleeding or passage of products of pregnancy and the time necessary to perform the entire operation were measured and recorded. The products of pregnancy were evacuated by vacuum aspiration. Patients remained at the hospital until the next morning, when an ultrasound check-up was performed to ensure the uterus was empty. Anti-D prophylaxis was provided to Rh-negative women. 2.2. Assessments Before the operation the exact size of the amniotic sac and/or crown-rump length were assessed by abdominal ultrasound and the duration of pregnancy calculated and recorded from these measurements. The cervix was exposed and the presence of bleeding, expulsion of products of pregnancy or the entire embryonic sac was checked and these episodes were classi®ed as threatened, inevitable, incomplete or complete abortion. In case of complete abortion, only cervical dilatation and the length of uterine cavity was measured, in the other cases, bleeding or expulsion was noted, then dilatation started. The size of the ®rst Hegar tent which was met with resistance was noted and recorded as the initial cervical width, then dilatation was continued until the ®nal width was reached and this again was recorded. From these two values, the necessary dilatation was calculated. Suction curettage was performed and the duration of the entire procedure (dilatation and evacuation) was also recorded on a study form together with the age of patient and duration of pregnancy assessed on ultrasound. 2.3. Statistical analysis Data were analysed using an SPSS 6.1 for Windows statistical program. Arithmetic means and standard deviation were calculated for both treatment groups and signi®cance assessed using Student's t-test, w2-test plus Pearson and Fisher's exact test, as appropriate. The study was interrupted in December 1997 and the results of 52 subjects are reported.
S. ZalaÂnyi / European Journal of Obstetrics & Gynecology and Reproductive Biology 99 (2001) 93±96
95
Table 1 Characteristics of patients and results of treatmenta
Age (years) Duration of pregnancy (weeks) Uterine length (cm) Cervical width (mm) Dilatation (mm) Duration (min) Complete abortion Incomplete abortion Inevitable abortion
Group A Danazol Misoprostol
Group B Placebo Misoprostol
Mean
S.D.
Mean
S.D.
21.46 7.00 8.69 7.94 0.48 7.57 6 4 6
4.4 1.26 1.41 1.51 0.73 2.71
19.65 7.59 9.35 7.06 1.13 9.35 0 1 3
2.53 1.48 1.23 0.82 1.11 2.87
Significance
NSb NSb NSb 0.01b 0.02b 0.036b 0.009c 0.01d NSb,d NSb,d
a
Values are given in mean (S.D.). NS not significant. Student's t-test. c Pearson test. d Fisher's exact test. b
3. Results A total of 26 women each were recruited for both groups A and B. There were no signi®cant differences in the age, duration of pregnancy and length of uterine cavity (Table 1). The cervix was more widely open in group A women pretreated with danazol than in group B (7.94 versus 7.06 mm). This resulted in less further dilatation (0.48 versus 1.13 mm) and shorter operating time (7.53 versus 9.35 min). The shorter operating time may be explained by the time for shorter dilatation and the observation that the products of pregnancy attached less ®rmly to the decidua in group A. There were highly signi®cantly (P 0:01) more (6 versus 0) subjects in group A than in group B presenting with complete abortion at the time scheduled for the operation, that is 5 h after the application of misoprostol. There were more subjects with bleeding in group A (6 versus 3). In group A 16 women exhibited some signs of abortion while only 4 in group B, which is a signi®cant difference. The overall impression was that the 200 mg danazol vaginal suppositories applied three times starting 36 h before misoprostol application increased the ef®cacy of misoprostol in preparing the cervix. Moreover, danazol acted very similarly to mifepristone in that 16 out of 26 patients exhibited signs of abortion in group A who received this drug plus misoprostol, while only one incomplete and three inevitable abortions were noted in group B women treated with misoprostol alone; this too, is a signi®cant difference. These results are summarised in the Table 1. There were no complications of the procedure in either group of patients.
nulliparous women awaiting TOP by dilatation and vacuum aspiration. The antigestagenic action of danazol was suspected [10,11] before initiating the trial. The combination danazol plus misoprostol proved to be more ef®cacious than misoprostol alone in producing predilatation, signi®cantly decreasing the need for further dilatation and shortening operating time. All these effects are desirable because they diminish the chance of cervical injury or perforation and late sequelae of TOP. To our surprise, the combination of danazol plus misoprostol initiated abortion in 62% (16 of 26) of women. This was an unexpected result of the treatment and supports the initial notion that danazol is an antigestagen. This feature of danazol was not described in the literature available to the author, but was surmised from its binding characteristics to the progesterone receptor [11,12] and the fact that it does not cause secretory transformation of the endometrium [11]. This corresponds to the classical description of an antigestagen. It is encouraging that a new antigestagen has been discovered because danazol is available worldwide, is less expensive than mifepristone and is not burdened with the political charge of mifepristone being the ``abortion pill''. There is only the slight problem that it has to be formulated as a vaginal suppository. Its antigestagen ef®cacy if administered orally should be further investigated and compared to mifepristone. It was not the aim of the study to ®nd an abortifacient combination and these results should not be interpreted as such, but it seems to be a new lead towards an inexpensive combination of an antigestagen plus prostaglandin.
References 4. Discussion This is the ®rst trial of danazol being used in combination with misoprostol for predilatation of the uterine cervix of
[1] Diczfalusy E. Reproductive health: a rendezvous with human dignity. Contraception 1995;52:1±12. [2] Sharing responsibility. Women, society and abortion worldwide. Alan Guttmacher Institute, 1999.
96
S. ZalaÂnyi / European Journal of Obstetrics & Gynecology and Reproductive Biology 99 (2001) 93±96
[3] Grimes DA, Cates W. Complications from legally-induced abortion: a review. Obstet Gynaecol Surv 1979;34:177±91. [4] Elger W, Shi SQ, FaÈnrich M, et al. The mechanism of action of new antiprogestins. In: Diczfalusy E, editor. Fertility regulation today and tomorrow. New York: Raven Press, 1987. p. 75±94. [5] Bygdeman M. Termination of pregnancy up to 8 or 9 weeks. In: Baird DT, Grimes DA, Van Look PFA, editors. Modern methods of inducing abortion. Oxford: Blackwell, 1995. p. 39±53. [6] Mahmod TA, Templeton A. Pathophysiology of mild endometriosis: review of literature. Hum Reprod 1990;5:765±84. [7] Webb AMC, Russell J, Elstein M. Comparison of Yuzpe regimen, danazol and mifepristone (RU 486) in oral postcoital contraception. BMJ 1992;305:927±31. [8] Murphy AA, Morales AJ, Kettel LM, Yen SSC. Regression of uterine leiomyomata to the antiprogesterone RU 486:dose-response effect. Fertil Steril 1995;64:187±90. [9] Murphy AA, Morales AJ, Kettel LM, et al. Treatment of endometriosis with antiprogesterone (RU 486). Fertil Steril 1996;65: 23±8.
[10] Messinis IE, Templeton A. The effect of the antiprogestin mifepristone on maturation and in vitro fertilization of human oocytes. Br J Obstet Gynaecol 1988;95:592±5. [11] Tamaya T, Wada K, Fujimoto J, et al. Danazol binding to steroid receptors in the human uterine endometrium. Fertil Steril 1984;41:732±5. [12] Barbieri RL, Lee H, Ryan KJ. Danazol binding to rat androgen, glucocorticoid, progesterone and estrogen receptors: correlation with biologic activity. Fertil Steril 1979;31:182±6. [13] Mizutani T, Nishiyama S, Amakawa I. Danazol concentrations in ovary, uterus and serum and their effect on the hypothalamicpituitary-ovarian axis during vaginal administration of a danazol suppository. Fertil Steril 1995;63:1184±9. [14] Thong KJ, Baird DT. Induction of abortion with mifepristone and misoprostol in early pregnancy. Br J Obstet Gynaecol 1992;99: 1004±7. [15] Nielsen S, Hahlin M, OdeÂn A. Using a logistic model to identify women with first trimester spontaneous abortion suitable for expectant management. Br J Obstet Gynaecol 1996;103:1230±5.
Danazol mimics antigestagen action in ®rst trimester termination of pregnancy S. ZalaÂnyi Keszthely Municipal Hospital, Department of Obstetrics and Gynaecology, MAÂV TEK, 6726 Szeged, Hungary Accepted 2 March 2001
Abstract Back ground: Based on steroid receptor binding and biologic activity, danazol was suspected to be an antigestagen. Objective: To compare with placebo test in ®rst trimester termination of pregnancy (TOP) as a method for predilatation of the cervix prior to application of misoprostol. Methods: 52 patients were randomised into two groups. Thereby, 26 women received 200 mg danazol vaginal suppositories three times during 2 days before administering 200 mg misoprostol and undergoing mechanical dilatation and vacuum aspiration 5 h later. The other 26 received placebo suppositories and the same treatment otherwise. Result: The uterine cervix was wider and less dilatation and time was needed for the surgical termination in the group pretreated with danazol. There were six cases of complete abortion within 5 h of administering misoprostol in the danazol group; and none in the placebo group. After danazol treatment, 16 women exhibited signs of abortion versus four receiving the inert suppositories. Conclusion: Pretreatment with 200 mg danazol suppositories three times starting 36 h before administering misoprostol for cervical dilatation enhances the effect of prostaglandin on cervical dilatation and uterine contractions in a manner similar to antigestagens. # 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Danazol; Misoprostol; Predilatation; Termination of pregnancy
1. Introduction As the majority of pregnancies is unplanned, most are unwanted leading to termination. Termination of pregnancy (TOP), although hotly debated and politically charged, remains a fact of life. The gold standard of termination of ®rst trimester pregnancy is dilatation of the cervix and evacuation of products of pregnancy. This is a very safe method under appropriate conditions but the majority of terminations takes place in unsafe circumstances resulting in serious maternal morbidity and mortality [1,2]. Termination of the ®rst pregnancy poses extra risks because the uterine cervix is very narrow or almost closed. Therefore, it is advisable to dilate the cervix before the actual procedure takes place. Predilatation can be achieved by several methods. Placing laminaria tents into the cervix is the most widely practised method, but this may cause cervical injuries, perforation and increase the risk of infection [3]. It was noted that administration of antigestagens softens and dilates the cervix [4]. Prostaglandins too cause cervical dilatation if administered systemically or locally [5]. Unfortunately, antigestagen treatment is unaffordable in the Third World because of costs and unavailable in most developed countries because of lack of government clearence. It would be tempting to introduce new antigestagens
or progesterone synthesis inhibitors. This is rather improbable taking into account the costs, marketing and political consequences of introducing such a drug. Another approach would be to ®nd a drug already marketed and possessing antigestagen properties. Danazol was such a candidate, because of its ability to reduce ®broid size, suppress endometrial tissue [6] and possibly interfere with fertilisation [7] are reminiscent of the action of mifepristone on the same tissues [8,9] and processes [10]. Although, these can be termed as antiestrogenic features, this explanation may be excluded, as danazol binds poorly to the oestrogen receptor [11]. After thorough investigation of the medical literature another paper was found describing that danazol binds to the progesterone receptor, but does not cause secretory changes in the endometrium [12], i.e. implicitly stating antigestagenic properties of the drug. Danazol is administered systemically in the dose range of 200±800 mg per day for the treatment of endometriosis [6] and metrorrhagia. It is also absorbed from the vagina resulting in higher concentrations in the pelvic organs than after oral administration [13]. This seemed an advantage if the drug were to be used for cervical dilatation prior to elective abortion. Other methods for cervical predilatation are intracervical application of laminaria tents or prostagladins into the posterior fornix of the vagina.
0301-2115/01/$ ± see front matter # 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 1 - 2 1 1 5 ( 0 1 ) 0 0 3 5 7 - 8
94
S. ZalaÂnyi / European Journal of Obstetrics & Gynecology and Reproductive Biology 99 (2001) 93±96
Thus, a trial was designed to compare the ef®cacy of vaginal suppositories containing danazol and misoprostol pills for preoperative dilatation of the uterine cervix before ®rst trimester TOP. A total dose of 600 mg danazol was deemed suf®cient, based on data obtained with mifepristone [5] and divided into three suppositories containing 200 mg each, because the approved maximum single dose is 200 mg. For misoprostol 200 mg was chosen as this is effective for predilatation if administered alone vaginally. In order to diminish the risk of cervical injuries during elective abortion, nulliparous women receive cervical predilatation in Hungary. In this hospital misoprostol tablets applied intravaginally were used as an alternative to laminaria from 1 August 1996 on. In order to assess the cervical effects of danazol, a trial was designed to compare the predilatation achieved with misoprostol alone or after treatment with danazol suppositories. The trial protocol was submitted to and approved by the Research Ethics Committee of the Markusovszky Hospital, Szombathely. 2. Material and methods Nulliparous women 6±11 weeks pregnant, reporting at the district nurse for scheduling a termination, were informed of the necessity of predilatation and the available methods. Nulliparous women were selected to exclude differences in pre-treatment cervical width present in parous patients. The advantages of non-mechanical predilatation were stressed and the choice between laminaria tents and the trial drug danazol plus misoprostol was offered. If the woman chose medical treatment, she was randomised into one of two groups and received an envelope containing three suppositories. The envelopes contained two different medications, either three suppositories of 200 mg danazol (group A) or three inert suppositories (group B). Danazol suppositories were prepared from Danoval capsules (Krka, Croatia) at a local pharmacy as described elsewhere [13]. Placebo was prepared from the same vehicle and was indistinguishable from the active suppositories. At this visit the date of the operation was scheduled and the participant was instructed to place a suppository high into the vagina on the evening 2 days before and on the morning and evening preceding the operation. This procedure was designed because a 36±48 h period is necessary for the antigestagens to exert their sensitising effect before administering prostaglandins as shown in trials with RU 486 [14]. There is a 3 day re¯ection period required by the law regulating TOP. This made it possible to use the suppositories starting approximately 36 h before placing the prostaglandin and not causing any delay in the procedure. On the day of the operation the women reported at the hospital at 7 a.m. and were admitted. 2.1. Hospital treatment Laboratory tests, blood typing and a visit to the anesthetist took place on the days between scheduling and admission.
Patients were admitted to the hospital at 7 a.m. Physical and ultrasound examinations were performed to asses the duration of pregnancy. Then the vagina was cleansed with 1% polyvidon iodine (Betadine, Egis Pharmaceuticals, Hungary), a 200 mg misoprostol pill (Searle, England) was soaked in saline and placed into the posterior fornix. Saline treatment improved the dissolution of the pill. Thereafter, the patient was asked to stay in bed until the operation started between 1 and 2 p.m. Before the operation a speculum examination was performed, to assess signs of spontaneous abortion. In cases of complete abortion, only cervical dilatation and uterine length were measured but the patient was spared anaesthesia and evacuation as it was considered unnecessary [15]. The evacuation of pregnancy was performed under general anaesthesia, in the supine position. The cervix was dilated with Hegar tents if necessary. The initial and ®nal dilatation, length of uterine cavity, bleeding or passage of products of pregnancy and the time necessary to perform the entire operation were measured and recorded. The products of pregnancy were evacuated by vacuum aspiration. Patients remained at the hospital until the next morning, when an ultrasound check-up was performed to ensure the uterus was empty. Anti-D prophylaxis was provided to Rh-negative women. 2.2. Assessments Before the operation the exact size of the amniotic sac and/or crown-rump length were assessed by abdominal ultrasound and the duration of pregnancy calculated and recorded from these measurements. The cervix was exposed and the presence of bleeding, expulsion of products of pregnancy or the entire embryonic sac was checked and these episodes were classi®ed as threatened, inevitable, incomplete or complete abortion. In case of complete abortion, only cervical dilatation and the length of uterine cavity was measured, in the other cases, bleeding or expulsion was noted, then dilatation started. The size of the ®rst Hegar tent which was met with resistance was noted and recorded as the initial cervical width, then dilatation was continued until the ®nal width was reached and this again was recorded. From these two values, the necessary dilatation was calculated. Suction curettage was performed and the duration of the entire procedure (dilatation and evacuation) was also recorded on a study form together with the age of patient and duration of pregnancy assessed on ultrasound. 2.3. Statistical analysis Data were analysed using an SPSS 6.1 for Windows statistical program. Arithmetic means and standard deviation were calculated for both treatment groups and signi®cance assessed using Student's t-test, w2-test plus Pearson and Fisher's exact test, as appropriate. The study was interrupted in December 1997 and the results of 52 subjects are reported.
S. ZalaÂnyi / European Journal of Obstetrics & Gynecology and Reproductive Biology 99 (2001) 93±96
95
Table 1 Characteristics of patients and results of treatmenta
Age (years) Duration of pregnancy (weeks) Uterine length (cm) Cervical width (mm) Dilatation (mm) Duration (min) Complete abortion Incomplete abortion Inevitable abortion
Group A Danazol Misoprostol
Group B Placebo Misoprostol
Mean
S.D.
Mean
S.D.
21.46 7.00 8.69 7.94 0.48 7.57 6 4 6
4.4 1.26 1.41 1.51 0.73 2.71
19.65 7.59 9.35 7.06 1.13 9.35 0 1 3
2.53 1.48 1.23 0.82 1.11 2.87
Significance
NSb NSb NSb 0.01b 0.02b 0.036b 0.009c 0.01d NSb,d NSb,d
a
Values are given in mean (S.D.). NS not significant. Student's t-test. c Pearson test. d Fisher's exact test. b
3. Results A total of 26 women each were recruited for both groups A and B. There were no signi®cant differences in the age, duration of pregnancy and length of uterine cavity (Table 1). The cervix was more widely open in group A women pretreated with danazol than in group B (7.94 versus 7.06 mm). This resulted in less further dilatation (0.48 versus 1.13 mm) and shorter operating time (7.53 versus 9.35 min). The shorter operating time may be explained by the time for shorter dilatation and the observation that the products of pregnancy attached less ®rmly to the decidua in group A. There were highly signi®cantly (P 0:01) more (6 versus 0) subjects in group A than in group B presenting with complete abortion at the time scheduled for the operation, that is 5 h after the application of misoprostol. There were more subjects with bleeding in group A (6 versus 3). In group A 16 women exhibited some signs of abortion while only 4 in group B, which is a signi®cant difference. The overall impression was that the 200 mg danazol vaginal suppositories applied three times starting 36 h before misoprostol application increased the ef®cacy of misoprostol in preparing the cervix. Moreover, danazol acted very similarly to mifepristone in that 16 out of 26 patients exhibited signs of abortion in group A who received this drug plus misoprostol, while only one incomplete and three inevitable abortions were noted in group B women treated with misoprostol alone; this too, is a signi®cant difference. These results are summarised in the Table 1. There were no complications of the procedure in either group of patients.
nulliparous women awaiting TOP by dilatation and vacuum aspiration. The antigestagenic action of danazol was suspected [10,11] before initiating the trial. The combination danazol plus misoprostol proved to be more ef®cacious than misoprostol alone in producing predilatation, signi®cantly decreasing the need for further dilatation and shortening operating time. All these effects are desirable because they diminish the chance of cervical injury or perforation and late sequelae of TOP. To our surprise, the combination of danazol plus misoprostol initiated abortion in 62% (16 of 26) of women. This was an unexpected result of the treatment and supports the initial notion that danazol is an antigestagen. This feature of danazol was not described in the literature available to the author, but was surmised from its binding characteristics to the progesterone receptor [11,12] and the fact that it does not cause secretory transformation of the endometrium [11]. This corresponds to the classical description of an antigestagen. It is encouraging that a new antigestagen has been discovered because danazol is available worldwide, is less expensive than mifepristone and is not burdened with the political charge of mifepristone being the ``abortion pill''. There is only the slight problem that it has to be formulated as a vaginal suppository. Its antigestagen ef®cacy if administered orally should be further investigated and compared to mifepristone. It was not the aim of the study to ®nd an abortifacient combination and these results should not be interpreted as such, but it seems to be a new lead towards an inexpensive combination of an antigestagen plus prostaglandin.
References 4. Discussion This is the ®rst trial of danazol being used in combination with misoprostol for predilatation of the uterine cervix of
[1] Diczfalusy E. Reproductive health: a rendezvous with human dignity. Contraception 1995;52:1±12. [2] Sharing responsibility. Women, society and abortion worldwide. Alan Guttmacher Institute, 1999.
96
S. ZalaÂnyi / European Journal of Obstetrics & Gynecology and Reproductive Biology 99 (2001) 93±96
[3] Grimes DA, Cates W. Complications from legally-induced abortion: a review. Obstet Gynaecol Surv 1979;34:177±91. [4] Elger W, Shi SQ, FaÈnrich M, et al. The mechanism of action of new antiprogestins. In: Diczfalusy E, editor. Fertility regulation today and tomorrow. New York: Raven Press, 1987. p. 75±94. [5] Bygdeman M. Termination of pregnancy up to 8 or 9 weeks. In: Baird DT, Grimes DA, Van Look PFA, editors. Modern methods of inducing abortion. Oxford: Blackwell, 1995. p. 39±53. [6] Mahmod TA, Templeton A. Pathophysiology of mild endometriosis: review of literature. Hum Reprod 1990;5:765±84. [7] Webb AMC, Russell J, Elstein M. Comparison of Yuzpe regimen, danazol and mifepristone (RU 486) in oral postcoital contraception. BMJ 1992;305:927±31. [8] Murphy AA, Morales AJ, Kettel LM, Yen SSC. Regression of uterine leiomyomata to the antiprogesterone RU 486:dose-response effect. Fertil Steril 1995;64:187±90. [9] Murphy AA, Morales AJ, Kettel LM, et al. Treatment of endometriosis with antiprogesterone (RU 486). Fertil Steril 1996;65: 23±8.
[10] Messinis IE, Templeton A. The effect of the antiprogestin mifepristone on maturation and in vitro fertilization of human oocytes. Br J Obstet Gynaecol 1988;95:592±5. [11] Tamaya T, Wada K, Fujimoto J, et al. Danazol binding to steroid receptors in the human uterine endometrium. Fertil Steril 1984;41:732±5. [12] Barbieri RL, Lee H, Ryan KJ. Danazol binding to rat androgen, glucocorticoid, progesterone and estrogen receptors: correlation with biologic activity. Fertil Steril 1979;31:182±6. [13] Mizutani T, Nishiyama S, Amakawa I. Danazol concentrations in ovary, uterus and serum and their effect on the hypothalamicpituitary-ovarian axis during vaginal administration of a danazol suppository. Fertil Steril 1995;63:1184±9. [14] Thong KJ, Baird DT. Induction of abortion with mifepristone and misoprostol in early pregnancy. Br J Obstet Gynaecol 1992;99: 1004±7. [15] Nielsen S, Hahlin M, OdeÂn A. Using a logistic model to identify women with first trimester spontaneous abortion suitable for expectant management. Br J Obstet Gynaecol 1996;103:1230±5.