Review
Gynecol, obstet. Invest. 10: 1-8 (1979)
Some Clinical and Theoretical Aspects on Prostaglandins in Obstetrics and Gynecology N. Wiqvist and L. Wilhelmsson Department of Obstetrics and Gynecology, University of Göteborg, Göteborg
Key Words. Prostaglandin analogues • Abortion • Myométrial contractility • PGI2 •
TxA2 • PGH2
Prostaglandins apparently play a fundamental role in the regulation of reproductive events. The carefully balanced endogenous release of different prostaglandins and thromboxanes selectively discharged within different tissues can be suppressed by prostaglandin synthetase inhibitors. This suppression of endogenous prostaglandins is, however, only partial and strikes blindly. Never theless, it seems possible to utilize this effect for therapeutic purposes to control pathophysiological events, such as dysmenorrhea and preterm labor to some extent. The same is true if we use prostaglandins or prostaglandin analogues as pharmaceutical agents. We can interfere in the endogenous prostaglandin balance to some extent. The uterus seems to be particularly sensitive to such an interference and activation of the myometrium may serve a variety of thera peutic purposes.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
Abstract. The present article discusses two aspects on prostaglandins, both related to the control of uterine contractility. One concerns a clinical problem, induction of abortion, and argues in favor of systemic instead of intrauterine administration of prostaglandins and the choice of E instead of F analogues. The other relates to the stimulatory effect on the myometrium of some recently detected endogenous prostaglandins. The discussion regarding the endogenous control of myométrial contractility has so far exclusively been focused upon the classical prostaglandins. It is, however, felt that substances like PGH2, PGI2 and thromboxane A2 may play a significant role in the regulation of uterine activity.
Wiqvist/Wilhelmsson
2
These useful effects are, however, not free of problems. Other organ systems react as well and unpleasant side effects appear. These remarks are supposed to underline that our present knowledge and therapeutic efforts must be considered as both rough and primitive and that we probably need some new scientific breakthrough before the prostaglandins and their inhibitors definitely outweigh other clinical methods and techniques. However, in the present situation we have to choose compounds that are available and try to administer these agents in the best possible way. This review will be restricted to some selected viewpoints within the prostaglandin field and will deal with the possible usefulness of vaginal administration of prostaglandin compounds for induction of abortion. In addition some unpublished observa tions on the effects on uterine contractility of some recently isolated endo genous prostaglandins will be presented. The intra- and extra-amniotic prostaglandin methods for induction of abor tion have turned out to be effective. They are accompanied by a low or moderate frequency of side effects and have consequently become accepted as routine methods in many departments throughout the world. The disadvantages of these methods depend upon the fact that they are invasive and require intrauterine manipulations, that there is a risk of an inadvertent injection of a large dose and that, as far as the extra-aminiotic method is concerned, there is inconvenience for the staff by iterated injections or intolerable uterine pain following a bolus dose. It would obviously be preferable if the compounds could be administered systemically, e.g. as vaginal suppositories. Table I shows the result of a multicenter study organized by the Prosta glandin Task Force of WHO. The case material comprised 310 legal abortions in the 13th-20th week of gestation induced by vaginal suppositories containing 15-methyl-PGF2c( methylester (2). Considering the fact that these cases re present second trimester abortions the efficacy must be considered as good in
Table I. Induction of abortion by vaginal suppositories containing 15-me-PGF2a methylester (1.5 mg every 3rd h) in the 13th-20th week of gestation
310
Abortion within 24 h %
88.4
Episodes of gastrointestinal side effects/abortion vomiting
diarrhea
total
2.8
2.8
5.6 Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
No. of cases
Some Clinical and Theoretical Aspects on Prostaglandins
3
that close to 90% of the patients expelled the fetus within 24 h. Careful monitoring of the gastrointestinal side effects showed, however, far too high a frequency of vomiting and diarrhea with an average of totally 5.6 episodes per abortion. A fairly large proportion of these women suffered from even more frequent episodes and it is obvious that these side effects represent a serious limitation under the circumstances in question. 15-Methyl-PGF2Q, is a potent drug with a long duration of action following a single dose but there seems to be no clear indication that the side-effect rate of equipotent doses is lower than that of natural PGF2a. This conclusion is supported by a number of recent investigations. There is clinical experience that spontaneous abortions in the 8th week of gestation or earlier often are complete whereas incomplete abortions are com mon at the end of the first trimester. The idea of inducing early abortion by prostaglandin as an alternative to instrumental evacuation is based on these well-known experiences. If prostaglandin suppositories are utilized to accomplish complete expulsion of the conceptus in the 8th week of gestation or earlier it is generally sufficient to administer the drug over a period of approximately 10 h. Four suppositories containing 1.0 or 1.5 mg 15-methyl-PGF2o, methylester, given every 3rd h result in complete abortion in somewhat more than 80% of the cases. Beside the fact that an efficacy of 80-85% is unsatisfactory it should be emphasized that the gastrointestinal side-effect rate has turned out to be un acceptably high. These patients are exposed to 2 -3 episodes of vomiting and diarrhea per abortion and again a significant proportion of the women have very frequent side effects. These results should be compared with two trials carried out by the Stockholm group, that utilized suppositories containing 0.8 and 1.0 mg 16,16-dimethyl-PGE2 given as one suppository every 3rd h (fig. 1). The rate of complete abortion was approximately 90% in the 16,16-dimethyl-PGE2 series. However, the interesting difference between the two compounds refers to
O
16,16-dimethyl-PGE2
Fig. 1. Chemical structure of PGE2 and its 16,16-dimethyl analogue.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
Prostaglandin E 2
4
Wiqvist/Wilhclmsson
Table II. Vaginal administration of prostaglandin for induction of early abortion (5th—8th
week) Dose
No. of cases
Complete abortion %
Episodes/abortion vomiting diarrhea total
15-Methyl-PGF2aa
1.0 mg X 4 1.5 mg X 4
131 148
81.7 83.8
1.0 1.0
1.1 1.8
2.1 2.8
16,16-Dimethy 1-PGE ¡b
0.8 mg X 4 0.8 mg x 2 1.0 mg X 2
38 50
87.0 94.0
0.2 0.2
0.2 0.3
0.4 0.5
a WHO Prostaglandin Task Force, WHO Annual Report No. VI, Special Program on Re search in Human Reproduction, Geneva, 1977. b l.undstrom et al. (7).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
the gastrointestinal side-effect rate that was 5 times lower with the E analogue than with the F compound (table II). Similar results were recently published by Takagi et al. (1) from Japan. These authors induced early abortion by 16,16-dimethyl-trans-A2-PGE,. Only 86% of the 63 women in their series obtained a complete abortion which is hardly up to the requirements. However, a fact that is more important is that the gastrointestinal side-effect rate was low. Only 1 patient out of 63 cases ex perienced any vomiting. These results demonstrate two things. First, that the efficacy in terms of complete expulsion of the conceptus is still unsatisfactory also in early preg nancy. Second, that there seems to be a significant difference between the F and the E analogue with regard to gastrointestinal side effects in favor of the E compounds. This means that the essential method-limiting factor, the gastro intestinal side effects, may be reduced to an extent that allows the use of systemic administration, vaginal or intravenous, and hence a more convenient management of second trimester abortion, missed abortion, hydatidiform mole, etc. This short review has so far dealt with the induction of abortion, i.e. complete or incomplete expulsion of the conceptus. However, the prostaglandins have also been utilized to achieve so-called preoperative dilatation of the cervix. The idea of using prostaglandins for preoperative dilatation of the cervix is based
Some Clinical and Theoretical Aspects on Prostaglandins
5
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
on the concept that the technical performance of instrumental evacuation, particularly at the end of the first trimester, should be easier and accompanied by less immediate complications. In addition there is also the problem on long-term sequelae that may be even more important. The WHO Prostaglandin Task Force has organized a double-blind multi center study on preoperative dilatation of the cervix. Primigravid patients in the 8th—12th week of pregnancy have been given a single suppository containing 1 mg 15-methyl-PGF2a methylester or a placebo suppository. The cervical diameter was measured by Hegar dilators immediately prior to vacuum aspira tion, in one group at 3 and in another group at 12 h after insertion of the suppository. The study is not completed and available data cannot be released in published form at present. However, our department has been one of the collaborating centers and our preliminary experience, as they appear from 80 women, indicate that the single suppository induced a significant cervical dilata tion within as short an interval as 3 h. The subsequent additional surgical dilatation and vacuum aspiration could consequently be completed more easily and more rapidly than in the untreated cases. The incidence of vomiting and watery diarrhea was low and perfectly acceptable in the 3-hour group whereas the 12-hour patients experienced quite frequent gastrointestinal side effects. Discomfort from uterine pain appeared to be no problem in the 3-hour group but more than 70% of the 12-hour patients experienced severe pain and needed injectable analgesics. The 3-hour interval also has the advantage that the total procedure can be managed on an out-patient service basis. Disappointing experiences from past years have repeatedly shown that we are far from the ideal prostaglandin drug that will solve all problems. However, it is felt that the development of a potent and stable E analogue that can be administered systemically as an intravenous drip infusion or as a vaginal sup pository, depending upon the situation, would mean a considerable improve ment both with regard to the management of second trimester abortion and to a more widespread use of preoperative cervical dilatation. The second part of this paper will deal with the effect on uterine con tractility of some recently isolated endogenous prostaglandin compounds that are thought to have physiological significance particularly within the cardio vascular system. These compounds include prostacyclin, thromboxanes and endoperoxides (PGH2) (fig. 2). Virtually nothing is known regarding the possible implication of these substances in reproductive processes and certainly very little regarding their involvement in the control of myometrial contractility and
Wiqvist/Wilhelmsson
pge2
6
/VAivjvr^___ t
t
t
t
^ a /u ia t ^ -M A », (M W v N ^ — !________ 5 min
t
t
t
1
10
30
t 100ng/ml
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
Fig. 2. Eight established pathways of oxidative biotransformation of arachidonic acid. 6(9)oxy-A5-PGFia is identical with prostacyclin or PGI2. TxA, = thromboxane A2. From Pace-Asciak (6). Fig. 3. Tracings showing the effects of stepwise increased concentrations of PGE2, PGFjq and prostacyclin (PGI,). Arrows indicate the different doses administered. Note the biphasic response to PGE: with stimulation at low concentrations and inhibition of the contractility at high concentrations. The effect of PGI, is consistently that of a stimulation irrespective of dose. Wilhelmsson, L.; Lindblom, B., and Wiqvist, N. (to be published).
Some Clinical and Theoretical Aspects on Prostaglandins
7
circulatory events within the uterus. We do know that these compounds, in contrast to the primary prostaglandins, have in common the property of being spontaneously inactivated in aqueous media at body temperature and thus qualify as local hormones or regulators available on demand on the spot. We also know that, e.g., prostacyclin is one of the major products from endoperoxide metabolism in the uterus (5). The effects of these compounds on the isolated human myometrium has recently been studied in our laboratory (3, 4). The experimental technique was conventional including a mantled organ bath, adequate temperature control, isometric recording and controlled tension in accordance with Csapos maximum load principle. Care was taken to avoid warm ischemia and the specimens were kept small to avoid central ischemia and disturbances from metabolites originating from the muscle preparation. Prostacyclin and PGH2 were ad ministered immediately following defrosting and dilution and thromboxane A2 was generated in the organ bath from PGH2 by enzymatic degradation. Figure 3 illustrates the comparative effects of prostacyclin, PGE2 and PGF2ce. It is evident that prostacyclin in low or high concentration stimulates the human uterus under in vitro conditions, PGE2 stimulates at low concentra tions but inhibits the contractility in high doses. Determination of the potency of the substances in terms of EDS0, i.e. the dose corresponding to 50% of maximum response, showed that prostacyclin was somewhat less potent than
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
Fig. 4. Stimulation of myométrial contractility by PGH2 and TxA2. Wilhelmsson, L.; Lindblom, B., and Wiqvist, N. (to be published).
Wiqvist/Wilhelmsson
8
PGE2 and PGF2ct. Figure 4 shows that administration of thromboxane A2 has marked stimulatory effect. PGH2 is presumably rapidly metabolized into a number of different prostaglandins and the response probably represents the sum of the effects of PGH2 as such and these metabolites. However, the net effect is a tetanic contracture, which probably indicates that the predominant metabolites that are formed under these circumstances are not those of PGEi and PGE2. These fragmentary results show that conclusions or speculations as to the physiological significance of PGF2a and PGE2 as representing the link between the myometrium and steroid hormones are only part of the truth and that the endogenous mechanisms that regulate uterine function are far more complex than originally believed. References
2
3
4
5
6 7
Takagi, S.; Sakata, H.; Yoshida, T.; Nakazawa, S; Fujii, K.T.; Tominaga, Y.;Iwasa, Y.; Ninagawa, T.; Hiroshima, T.; Tomida, Y.; Itoh, K., and Matsukawa, R.: Termination of early pregnancy by ONO-802 (16,16-dimethyl-trans-A2-PGE, methylester). Prosta glandins 14: 791-798 (1977). WHO Prostaglandin Task Force: Repeated vaginal administration of 15-mcthyl-PGF2Q methylester for termination of pregnancy in the 13th—20th week of gestation. Con traception 16: 175-181 (1977). Wilhelmsson, L.; Lindblom, B., and Wiqvist, N.: The human uterotubal junction. Contractile patterns of different smooth muscle layers and influence of PGE2, PGF2a and PGlj in vitro. Fert. Steril, (in press). Wilhelmsson, L.; Lindblom, B.; Hamberger, L.; Samsioe, G.; Samuclsson, B., and Wiqvist, N.: Endoperoxide metabolites, prostacyclin and thromboxane A2 haveapotent stimulatory effect on the human myometrium. Proc. Int. Prostaglandin Conf., Washing ton, 1979 (in press). Williams, K.I.; Dembinska-Kiec, A.; Zmuda, A., and Gryglewski, R.J.: Prostacyclin formation by myometrial and decidual fractions of the pregnant rat uterus. Prosta glandins 15: 343-350 (1978). Pace-Asciak, C.R.: in Coceani and Olley, Advances in prostaglandin and thromboxane research, vol. 4 (Raven Press, New York 1978). Lundström, V.; Bygdeman, M.; Fotiou, S.; Green, K., and Kinoshita, K.: Abortion in early pregnancy by vaginal administration of 16,16-dimethyl-PGE2 in comparison with vacuum aspiration. Contraception 16: 167-173 (1977). Received: January 17, 1979 N. Wiqvist, MD, PhD, Department of Obstetrics and Gynecology, University of Göteborg, S—413 45 Göteborg (Sweden) Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
1
Gynecol, obstet. Invest. 10: 1-8 (1979)
Some Clinical and Theoretical Aspects on Prostaglandins in Obstetrics and Gynecology N. Wiqvist and L. Wilhelmsson Department of Obstetrics and Gynecology, University of Göteborg, Göteborg
Key Words. Prostaglandin analogues • Abortion • Myométrial contractility • PGI2 •
TxA2 • PGH2
Prostaglandins apparently play a fundamental role in the regulation of reproductive events. The carefully balanced endogenous release of different prostaglandins and thromboxanes selectively discharged within different tissues can be suppressed by prostaglandin synthetase inhibitors. This suppression of endogenous prostaglandins is, however, only partial and strikes blindly. Never theless, it seems possible to utilize this effect for therapeutic purposes to control pathophysiological events, such as dysmenorrhea and preterm labor to some extent. The same is true if we use prostaglandins or prostaglandin analogues as pharmaceutical agents. We can interfere in the endogenous prostaglandin balance to some extent. The uterus seems to be particularly sensitive to such an interference and activation of the myometrium may serve a variety of thera peutic purposes.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
Abstract. The present article discusses two aspects on prostaglandins, both related to the control of uterine contractility. One concerns a clinical problem, induction of abortion, and argues in favor of systemic instead of intrauterine administration of prostaglandins and the choice of E instead of F analogues. The other relates to the stimulatory effect on the myometrium of some recently detected endogenous prostaglandins. The discussion regarding the endogenous control of myométrial contractility has so far exclusively been focused upon the classical prostaglandins. It is, however, felt that substances like PGH2, PGI2 and thromboxane A2 may play a significant role in the regulation of uterine activity.
Wiqvist/Wilhelmsson
2
These useful effects are, however, not free of problems. Other organ systems react as well and unpleasant side effects appear. These remarks are supposed to underline that our present knowledge and therapeutic efforts must be considered as both rough and primitive and that we probably need some new scientific breakthrough before the prostaglandins and their inhibitors definitely outweigh other clinical methods and techniques. However, in the present situation we have to choose compounds that are available and try to administer these agents in the best possible way. This review will be restricted to some selected viewpoints within the prostaglandin field and will deal with the possible usefulness of vaginal administration of prostaglandin compounds for induction of abortion. In addition some unpublished observa tions on the effects on uterine contractility of some recently isolated endo genous prostaglandins will be presented. The intra- and extra-amniotic prostaglandin methods for induction of abor tion have turned out to be effective. They are accompanied by a low or moderate frequency of side effects and have consequently become accepted as routine methods in many departments throughout the world. The disadvantages of these methods depend upon the fact that they are invasive and require intrauterine manipulations, that there is a risk of an inadvertent injection of a large dose and that, as far as the extra-aminiotic method is concerned, there is inconvenience for the staff by iterated injections or intolerable uterine pain following a bolus dose. It would obviously be preferable if the compounds could be administered systemically, e.g. as vaginal suppositories. Table I shows the result of a multicenter study organized by the Prosta glandin Task Force of WHO. The case material comprised 310 legal abortions in the 13th-20th week of gestation induced by vaginal suppositories containing 15-methyl-PGF2c( methylester (2). Considering the fact that these cases re present second trimester abortions the efficacy must be considered as good in
Table I. Induction of abortion by vaginal suppositories containing 15-me-PGF2a methylester (1.5 mg every 3rd h) in the 13th-20th week of gestation
310
Abortion within 24 h %
88.4
Episodes of gastrointestinal side effects/abortion vomiting
diarrhea
total
2.8
2.8
5.6 Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
No. of cases
Some Clinical and Theoretical Aspects on Prostaglandins
3
that close to 90% of the patients expelled the fetus within 24 h. Careful monitoring of the gastrointestinal side effects showed, however, far too high a frequency of vomiting and diarrhea with an average of totally 5.6 episodes per abortion. A fairly large proportion of these women suffered from even more frequent episodes and it is obvious that these side effects represent a serious limitation under the circumstances in question. 15-Methyl-PGF2Q, is a potent drug with a long duration of action following a single dose but there seems to be no clear indication that the side-effect rate of equipotent doses is lower than that of natural PGF2a. This conclusion is supported by a number of recent investigations. There is clinical experience that spontaneous abortions in the 8th week of gestation or earlier often are complete whereas incomplete abortions are com mon at the end of the first trimester. The idea of inducing early abortion by prostaglandin as an alternative to instrumental evacuation is based on these well-known experiences. If prostaglandin suppositories are utilized to accomplish complete expulsion of the conceptus in the 8th week of gestation or earlier it is generally sufficient to administer the drug over a period of approximately 10 h. Four suppositories containing 1.0 or 1.5 mg 15-methyl-PGF2o, methylester, given every 3rd h result in complete abortion in somewhat more than 80% of the cases. Beside the fact that an efficacy of 80-85% is unsatisfactory it should be emphasized that the gastrointestinal side-effect rate has turned out to be un acceptably high. These patients are exposed to 2 -3 episodes of vomiting and diarrhea per abortion and again a significant proportion of the women have very frequent side effects. These results should be compared with two trials carried out by the Stockholm group, that utilized suppositories containing 0.8 and 1.0 mg 16,16-dimethyl-PGE2 given as one suppository every 3rd h (fig. 1). The rate of complete abortion was approximately 90% in the 16,16-dimethyl-PGE2 series. However, the interesting difference between the two compounds refers to
O
16,16-dimethyl-PGE2
Fig. 1. Chemical structure of PGE2 and its 16,16-dimethyl analogue.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
Prostaglandin E 2
4
Wiqvist/Wilhclmsson
Table II. Vaginal administration of prostaglandin for induction of early abortion (5th—8th
week) Dose
No. of cases
Complete abortion %
Episodes/abortion vomiting diarrhea total
15-Methyl-PGF2aa
1.0 mg X 4 1.5 mg X 4
131 148
81.7 83.8
1.0 1.0
1.1 1.8
2.1 2.8
16,16-Dimethy 1-PGE ¡b
0.8 mg X 4 0.8 mg x 2 1.0 mg X 2
38 50
87.0 94.0
0.2 0.2
0.2 0.3
0.4 0.5
a WHO Prostaglandin Task Force, WHO Annual Report No. VI, Special Program on Re search in Human Reproduction, Geneva, 1977. b l.undstrom et al. (7).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
the gastrointestinal side-effect rate that was 5 times lower with the E analogue than with the F compound (table II). Similar results were recently published by Takagi et al. (1) from Japan. These authors induced early abortion by 16,16-dimethyl-trans-A2-PGE,. Only 86% of the 63 women in their series obtained a complete abortion which is hardly up to the requirements. However, a fact that is more important is that the gastrointestinal side-effect rate was low. Only 1 patient out of 63 cases ex perienced any vomiting. These results demonstrate two things. First, that the efficacy in terms of complete expulsion of the conceptus is still unsatisfactory also in early preg nancy. Second, that there seems to be a significant difference between the F and the E analogue with regard to gastrointestinal side effects in favor of the E compounds. This means that the essential method-limiting factor, the gastro intestinal side effects, may be reduced to an extent that allows the use of systemic administration, vaginal or intravenous, and hence a more convenient management of second trimester abortion, missed abortion, hydatidiform mole, etc. This short review has so far dealt with the induction of abortion, i.e. complete or incomplete expulsion of the conceptus. However, the prostaglandins have also been utilized to achieve so-called preoperative dilatation of the cervix. The idea of using prostaglandins for preoperative dilatation of the cervix is based
Some Clinical and Theoretical Aspects on Prostaglandins
5
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
on the concept that the technical performance of instrumental evacuation, particularly at the end of the first trimester, should be easier and accompanied by less immediate complications. In addition there is also the problem on long-term sequelae that may be even more important. The WHO Prostaglandin Task Force has organized a double-blind multi center study on preoperative dilatation of the cervix. Primigravid patients in the 8th—12th week of pregnancy have been given a single suppository containing 1 mg 15-methyl-PGF2a methylester or a placebo suppository. The cervical diameter was measured by Hegar dilators immediately prior to vacuum aspira tion, in one group at 3 and in another group at 12 h after insertion of the suppository. The study is not completed and available data cannot be released in published form at present. However, our department has been one of the collaborating centers and our preliminary experience, as they appear from 80 women, indicate that the single suppository induced a significant cervical dilata tion within as short an interval as 3 h. The subsequent additional surgical dilatation and vacuum aspiration could consequently be completed more easily and more rapidly than in the untreated cases. The incidence of vomiting and watery diarrhea was low and perfectly acceptable in the 3-hour group whereas the 12-hour patients experienced quite frequent gastrointestinal side effects. Discomfort from uterine pain appeared to be no problem in the 3-hour group but more than 70% of the 12-hour patients experienced severe pain and needed injectable analgesics. The 3-hour interval also has the advantage that the total procedure can be managed on an out-patient service basis. Disappointing experiences from past years have repeatedly shown that we are far from the ideal prostaglandin drug that will solve all problems. However, it is felt that the development of a potent and stable E analogue that can be administered systemically as an intravenous drip infusion or as a vaginal sup pository, depending upon the situation, would mean a considerable improve ment both with regard to the management of second trimester abortion and to a more widespread use of preoperative cervical dilatation. The second part of this paper will deal with the effect on uterine con tractility of some recently isolated endogenous prostaglandin compounds that are thought to have physiological significance particularly within the cardio vascular system. These compounds include prostacyclin, thromboxanes and endoperoxides (PGH2) (fig. 2). Virtually nothing is known regarding the possible implication of these substances in reproductive processes and certainly very little regarding their involvement in the control of myometrial contractility and
Wiqvist/Wilhelmsson
pge2
6
/VAivjvr^___ t
t
t
t
^ a /u ia t ^ -M A », (M W v N ^ — !________ 5 min
t
t
t
1
10
30
t 100ng/ml
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
Fig. 2. Eight established pathways of oxidative biotransformation of arachidonic acid. 6(9)oxy-A5-PGFia is identical with prostacyclin or PGI2. TxA, = thromboxane A2. From Pace-Asciak (6). Fig. 3. Tracings showing the effects of stepwise increased concentrations of PGE2, PGFjq and prostacyclin (PGI,). Arrows indicate the different doses administered. Note the biphasic response to PGE: with stimulation at low concentrations and inhibition of the contractility at high concentrations. The effect of PGI, is consistently that of a stimulation irrespective of dose. Wilhelmsson, L.; Lindblom, B., and Wiqvist, N. (to be published).
Some Clinical and Theoretical Aspects on Prostaglandins
7
circulatory events within the uterus. We do know that these compounds, in contrast to the primary prostaglandins, have in common the property of being spontaneously inactivated in aqueous media at body temperature and thus qualify as local hormones or regulators available on demand on the spot. We also know that, e.g., prostacyclin is one of the major products from endoperoxide metabolism in the uterus (5). The effects of these compounds on the isolated human myometrium has recently been studied in our laboratory (3, 4). The experimental technique was conventional including a mantled organ bath, adequate temperature control, isometric recording and controlled tension in accordance with Csapos maximum load principle. Care was taken to avoid warm ischemia and the specimens were kept small to avoid central ischemia and disturbances from metabolites originating from the muscle preparation. Prostacyclin and PGH2 were ad ministered immediately following defrosting and dilution and thromboxane A2 was generated in the organ bath from PGH2 by enzymatic degradation. Figure 3 illustrates the comparative effects of prostacyclin, PGE2 and PGF2ce. It is evident that prostacyclin in low or high concentration stimulates the human uterus under in vitro conditions, PGE2 stimulates at low concentra tions but inhibits the contractility in high doses. Determination of the potency of the substances in terms of EDS0, i.e. the dose corresponding to 50% of maximum response, showed that prostacyclin was somewhat less potent than
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
Fig. 4. Stimulation of myométrial contractility by PGH2 and TxA2. Wilhelmsson, L.; Lindblom, B., and Wiqvist, N. (to be published).
Wiqvist/Wilhelmsson
8
PGE2 and PGF2ct. Figure 4 shows that administration of thromboxane A2 has marked stimulatory effect. PGH2 is presumably rapidly metabolized into a number of different prostaglandins and the response probably represents the sum of the effects of PGH2 as such and these metabolites. However, the net effect is a tetanic contracture, which probably indicates that the predominant metabolites that are formed under these circumstances are not those of PGEi and PGE2. These fragmentary results show that conclusions or speculations as to the physiological significance of PGF2a and PGE2 as representing the link between the myometrium and steroid hormones are only part of the truth and that the endogenous mechanisms that regulate uterine function are far more complex than originally believed. References
2
3
4
5
6 7
Takagi, S.; Sakata, H.; Yoshida, T.; Nakazawa, S; Fujii, K.T.; Tominaga, Y.;Iwasa, Y.; Ninagawa, T.; Hiroshima, T.; Tomida, Y.; Itoh, K., and Matsukawa, R.: Termination of early pregnancy by ONO-802 (16,16-dimethyl-trans-A2-PGE, methylester). Prosta glandins 14: 791-798 (1977). WHO Prostaglandin Task Force: Repeated vaginal administration of 15-mcthyl-PGF2Q methylester for termination of pregnancy in the 13th—20th week of gestation. Con traception 16: 175-181 (1977). Wilhelmsson, L.; Lindblom, B., and Wiqvist, N.: The human uterotubal junction. Contractile patterns of different smooth muscle layers and influence of PGE2, PGF2a and PGlj in vitro. Fert. Steril, (in press). Wilhelmsson, L.; Lindblom, B.; Hamberger, L.; Samsioe, G.; Samuclsson, B., and Wiqvist, N.: Endoperoxide metabolites, prostacyclin and thromboxane A2 haveapotent stimulatory effect on the human myometrium. Proc. Int. Prostaglandin Conf., Washing ton, 1979 (in press). Williams, K.I.; Dembinska-Kiec, A.; Zmuda, A., and Gryglewski, R.J.: Prostacyclin formation by myometrial and decidual fractions of the pregnant rat uterus. Prosta glandins 15: 343-350 (1978). Pace-Asciak, C.R.: in Coceani and Olley, Advances in prostaglandin and thromboxane research, vol. 4 (Raven Press, New York 1978). Lundström, V.; Bygdeman, M.; Fotiou, S.; Green, K., and Kinoshita, K.: Abortion in early pregnancy by vaginal administration of 16,16-dimethyl-PGE2 in comparison with vacuum aspiration. Contraception 16: 167-173 (1977). Received: January 17, 1979 N. Wiqvist, MD, PhD, Department of Obstetrics and Gynecology, University of Göteborg, S—413 45 Göteborg (Sweden) Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:39:01 PM
1
