DECREASE OF UTERU-PLACENTALBLOOD FLOW DURING PROSTAGLANDIN F2~ INDUCED ABORTION M.O. Pulkkinen, Y. Pitkanen, A. Ojala and H. Hannelin ABSTRACT Pregnancy had been terminated in 6 normal midtrimester pregnant patients by the extraovular injection of 10 mg prostaglandin F2m (PGF2m). In these 6 Experimental and 3 Control patients utero-placental blood flow had been measured, by changes in the density of radioactive Indium, distributed over the uterine area, as a function of time. In comparison with Controls utero-placental blood flow decreased in the Experimental patients already at 5 minutes after PG-treatment, long before advanced cyclic IUP evolved. This finding substantiates the conclusion (1-3), based on experiments in animal "models", that decrease in utero-placental blood flow is an early step in the mechanism of PG action.
From the Department of Obstetrics and Gynecology and the Department of Radiotherapy, University of Turku, 20520, Finland.
This study had been supported by the Agency for International Development, Department of State, Contract No. AID/CSdo 3160o Accepted December 17
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INTRODUCTION Szudies in animal models and patients led to the conclusion 1,2 that the PG-Impact (PGI) terminates pregnancy e f f e c t i v e l y , because through a reduction of uterine blood flow i t compromises the endocrine function of the feto-placental u n i t . Once the normal endocrine balance had been upset, uterine a c t i v i t y and r e a c t i v i t y evolved, terminating pregnancy. This premise 1 , 2 t h a t PGF2a reduces uterine blood flow by a vasoconstriction had been substantiated by experiments in the r a t "model ''~. The present study was undertaken to examine whether or not this mechanism operates in human patients.
THE STUDY PATIENTS AND METHODS Nine normal pregnant volunteers were studied. They were 23±2 years old, para 1,1~n~ 12±1 weeks pregnant. Six women received 10 mg PGF2m extraovularly z,~, under sedation (50 mg pethidin, 10 mg diazepam, and 6°5 mg diethylperazin, i . m . ) , while 3 patients were untreated Controls. The i n t r a u t e r i n e pressure (IUP) was recorded by the "extraovular microballoon" technique 4o FIGURE1
L
~;~~.i~:.,~>
. "~,~.!~.~,~
GAMMA-CAMERAPHOTOGRAPHY AFTER I13 mlNDIUM TREATMENT Photographic images, r e f l e c t i n g the accumulation of 113m Indium in: A = aorta + i n f e r i o r vena cava, U = Utero-placental vessels, I = i l i a c vessels and G : genital vessels°
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Uterine blood flow h~been measured by the radioactive Indium method. A total of 2 m Ci ±±jm Indium was injected into the cubital vein at 0 time° The density of radioactivity over the uterine area was measured with a gamma camera (Nuclear Chicago, Pho Gamma I I I ) and with a parallel (1,000) hole 3 inches lead collimator, at 2, 15 and 45 minutes after the injection of 113m Indium. As illustrated by Figure 1, the accumulated 113m Indium yielded a photographic image of the aorta (A), the utero-placental (U), i l i a c (I) and genital (G) vessels. FIGURE 2
At 10 minutes after 113m Indium the PG-Impact (PGI) had been delivered. The 2nd picture was taken 5 minutes after PGI, when the uterine contracture was reaching maximumvalue (Figure 2). Figure 2 illustrates the uterine response to PGI and the timing of gamma camera photography. The 3rd picture was taken at 45 minutes after PGI, when uterine contracture was s t i l l high (Figure 2}. In addition to photography (visually reflecting the changes in radioactive density over the uterine area) the counts were also stored in a computer memory, to be transferred later to a digital form. Changes in the utero-placental blood flow, reflected by the changes in radioactive density, has been estimated as follows. The negatives of the gamma camera pictures were analysed by a two-beam recording microphotometer IF0-451, taking the density of the f i r s t pictures (Figure 3A and A1) as 100%. Pictures, taken from 3 Controls (not treated with PGF2~) provided the control values for the disintegration of 113m Indium. This isotope had a h a l f - l i f e of 102 minutes.
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PROSTAGLANDINS RESULTS The decrease in radioactive density, as a function of time a f t e r l13m Indium is i l l u s t r a t e d by Figure 3A, B and C. In the Controls, sequential photography at O, 15 and 45 minutes a f t e r l13m Indium, only showed a s l i g h t change in radioactive density (Compare A, B and C). This f~nding i l l u s t r a t e s that the c i r c u l a t i n g blood sustained supplying llJm Indium to the utero-placental vessels. In contrast in PGF2~ patients, the pictures taken at similar times showed rapid elimination of r a d i o a c t i v i t y from the utero-placental vessels. This finding suggests reduction in utero-placental blood flow. FIGURE 3
GAMMA-CAMERA PHOTOGRAPHYOF THE RELATIVE CHANGESIN DENSITY AFTER I13 mlNDIUM AND FGF2a TREATMENT A,B and C: Controls (no PGF2~) at 2, 15 and 45 minutes after I13 m Indium AI,BI, and CI: Before and 15 and 45 minutes after PGF2~ treatment.
The stored information (in the computer) revealed a change in the density r a t i o : uterine/pelvic-vessels. This r a t i o was 2 before and 1.7 a f t e r PG tr~@~ment, confirming the visual impression of decreased density of itJm Indium in the utero-placental vessels. The sequential changes in the l13m Indium density of the 6 patients who were treated with PG also r e f l e c t e d the e f f e c t of PG on blood flow (Table I ) . A correlation was evident between the degree of the PG provoked uterine contracture and decrease in density. Contractures, more than 80 mm Hg, reduced density by 25% while those less than 80 mm Hg only reduced i t by 20%, when contractures were maximal.
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TABLE I
THE EFFECTOF EXTRAOVULARPGF2~TREATMENT ON THE 113m INDIUMDENSITYOF THE UTERINEAREA At Photography #1
113m Density Experimental(6) Control(3) 11.3-+1.2(100%)
Resting Pressure Experimental(6) Control(3)
13.2-+0.2(100%) 6-+1 (100%)
5+-I(100%)
#2
9'3±0.9( 82%)* 12.8+-0.3(97%) 75+-12(1250%)~
6-+1(120%)
#3
7.5-+0.8( 65%)t 11.2+-1.1(85%) 70+-9 (1170%)~
5-+i(100%)
All values are Means +- S.E.
*(P < 0.05),
~P < 0.01), ~(P < 0.001)
Photography #I: before 113m Indium treatment and #2 and #3 at 15 and 45 minutes respectively after 113m Indium treatment. The 6 Experimental patients received PG at 10 minutes after 113m Indium treatment, while the 3 Controls received no PG. The salient point of the present study is the demonstration (Table I) that in the 3 Controls, who had no change in resting pressure during the 45 minutes observation period, there was l i t t l e reduction in the density of 113m Indium at 15 minutes (3%) and at 45 minutes (15%) after treatment with this isotope. In contrast, in the 6 Experimental patients, who showed a drastic increase in resting pressure in between 5 (1250%) and 45 minutes (1170%) after PGI, the corresponding reductions in radioactive density were s i g n i f i c a n t l y greater (18%, P < 0.05 and 35%, P < 0.01, respectively). TABLE I I THE EFFECT OF EXTRAOVULARPGF2~ TREATMENT ON PLASMA PROGESTERONELEVELS #of Age Cases Years 6
21-+3
Gest.age IAT Weeks Hours 12+-1
14+-2
Progesterone ~g/ml Before & After Treatment Before 3 Hours After at Abortion 41-+4(100%)
All values are Means -+ S.E.
20-+3(49%)**
15-+3(37%)*
**(P < 0.01), *(P < 0.001)
Table II i l l u s t r a t e s , what had been repeatedly demonstrated already (1-10)o Effective PG treatment (a single extraovular dose of 10 mg PGF2~) provoked s i g n i f i c a n t and continued reduction (51% already at 3 hours, P < 0.01, and 63% at 14 hours, P < 0.001) in plasma progesterone levels, long before i t induced abortion in 14-+2 hours.
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DISCUSSION The present results are consistant with the premise i-3 that the "PG-Impact" (PGI) effectively terminates pregnancy because, through sustained vasoconstriction in the utero-placental vessels, i t suppresses the endocrine function of the feto-placental unit. In the 3 Controls, the density of 113m Indium over the uterine area (sustained by circulating 113m Indium) only decreased slightly during 45 minutes, while, in the 6 Experimental patients, who were exposed to PGI, 113m Indium density decreased significantly. This finding demonstrates that PGI reduces utero-placental blood flow, long before advanced cyclic IUP evolves. However, while the experiments in the rat "model''3 provided direct evidence that PG provokes instant vasoconstriction in the omentum uteri, preceding the full development of uterine contracture, the present clinical study did not reveal whether the PG-induced reduction of utero-placental blood flow was the cause or consequence of uterine contracture. The sequence of events might be clarified by serial measurements of radioactive density and resting pressure during the i n i t i a l period of 5 minutes after PGI. However, regardless of the primary event (suppression of uteroplacental blood flow followed by myometrial contracture or vice versa), i t is apparent that these prompt and unphysiological uterine responses to PGI occur long before progesterone-withdrawal, the evolution of advanced cyclic IUP and clinical progress in cervical dilatation manifest. Thus the conclusion 1,2 that PGI Therapy is effective i f i t provokes a "regulatory imbalance", before achieving uterine stimulation, is substantiated by the present observations. REFERENCES 1. 2. 3. 4. 5. 6. 7.
Csapo, A.I.: Prostaglandins 3: 245, 1973. Csapo, A.I.: Population Report 4: 633,1974. Csepli, J. and Csapo,A.I.: Prost~glandins 1: 235, 1972. Csapo, A.I.: Obst. Gynec. Survey 25: 403,-1970. Saldana, L, Schulman, H., Yang, W.H.: Prostaglandins 3: 847, 1973. Pitkanen, Y. and Rauramo, L.: Prostaglandins 5: 269,--1974. Tyak, A.J., Lambadarios, C., Parsons, R.J., Stewart, C.R., Cooke, I.D.: J. Obst. and Gynec. Brit. Comm. 81: 52, 1974. 8. Enkola, K.: Prostaglandins 5: 115, 19~. 9. Zoltan, I . , Csillag, M., Zsolnai, B., Zubek, L., Moksony, I . , Matanyi, S.: Prostaglandins 6: 211, 1974. 10. Craft, I . , Carriere, E., Youssefnejadian, E.:Obst.&Gyn.44: 135, 1974. ACKNOWLEDGEMENTS
The authors are grateful to Professor A.I. Csapo for consultation during this study; to Dr. Pekka Makela for densitometry and to the Upjohn Company for the supply of PGF2~.
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From the Department of Obstetrics and Gynecology and the Department of Radiotherapy, University of Turku, 20520, Finland.
This study had been supported by the Agency for International Development, Department of State, Contract No. AID/CSdo 3160o Accepted December 17
PROSTAGLANDINS JANUARY 1975
VOL. 9 NO. 1
61
PROSTAGLANDINS
INTRODUCTION Szudies in animal models and patients led to the conclusion 1,2 that the PG-Impact (PGI) terminates pregnancy e f f e c t i v e l y , because through a reduction of uterine blood flow i t compromises the endocrine function of the feto-placental u n i t . Once the normal endocrine balance had been upset, uterine a c t i v i t y and r e a c t i v i t y evolved, terminating pregnancy. This premise 1 , 2 t h a t PGF2a reduces uterine blood flow by a vasoconstriction had been substantiated by experiments in the r a t "model ''~. The present study was undertaken to examine whether or not this mechanism operates in human patients.
THE STUDY PATIENTS AND METHODS Nine normal pregnant volunteers were studied. They were 23±2 years old, para 1,1~n~ 12±1 weeks pregnant. Six women received 10 mg PGF2m extraovularly z,~, under sedation (50 mg pethidin, 10 mg diazepam, and 6°5 mg diethylperazin, i . m . ) , while 3 patients were untreated Controls. The i n t r a u t e r i n e pressure (IUP) was recorded by the "extraovular microballoon" technique 4o FIGURE1
L
~;~~.i~:.,~>
. "~,~.!~.~,~
GAMMA-CAMERAPHOTOGRAPHY AFTER I13 mlNDIUM TREATMENT Photographic images, r e f l e c t i n g the accumulation of 113m Indium in: A = aorta + i n f e r i o r vena cava, U = Utero-placental vessels, I = i l i a c vessels and G : genital vessels°
62
JANUARY
1975
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PROSTAGLANDINS
Uterine blood flow h~been measured by the radioactive Indium method. A total of 2 m Ci ±±jm Indium was injected into the cubital vein at 0 time° The density of radioactivity over the uterine area was measured with a gamma camera (Nuclear Chicago, Pho Gamma I I I ) and with a parallel (1,000) hole 3 inches lead collimator, at 2, 15 and 45 minutes after the injection of 113m Indium. As illustrated by Figure 1, the accumulated 113m Indium yielded a photographic image of the aorta (A), the utero-placental (U), i l i a c (I) and genital (G) vessels. FIGURE 2
At 10 minutes after 113m Indium the PG-Impact (PGI) had been delivered. The 2nd picture was taken 5 minutes after PGI, when the uterine contracture was reaching maximumvalue (Figure 2). Figure 2 illustrates the uterine response to PGI and the timing of gamma camera photography. The 3rd picture was taken at 45 minutes after PGI, when uterine contracture was s t i l l high (Figure 2}. In addition to photography (visually reflecting the changes in radioactive density over the uterine area) the counts were also stored in a computer memory, to be transferred later to a digital form. Changes in the utero-placental blood flow, reflected by the changes in radioactive density, has been estimated as follows. The negatives of the gamma camera pictures were analysed by a two-beam recording microphotometer IF0-451, taking the density of the f i r s t pictures (Figure 3A and A1) as 100%. Pictures, taken from 3 Controls (not treated with PGF2~) provided the control values for the disintegration of 113m Indium. This isotope had a h a l f - l i f e of 102 minutes.
JANUARY 1975
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63
PROSTAGLANDINS RESULTS The decrease in radioactive density, as a function of time a f t e r l13m Indium is i l l u s t r a t e d by Figure 3A, B and C. In the Controls, sequential photography at O, 15 and 45 minutes a f t e r l13m Indium, only showed a s l i g h t change in radioactive density (Compare A, B and C). This f~nding i l l u s t r a t e s that the c i r c u l a t i n g blood sustained supplying llJm Indium to the utero-placental vessels. In contrast in PGF2~ patients, the pictures taken at similar times showed rapid elimination of r a d i o a c t i v i t y from the utero-placental vessels. This finding suggests reduction in utero-placental blood flow. FIGURE 3
GAMMA-CAMERA PHOTOGRAPHYOF THE RELATIVE CHANGESIN DENSITY AFTER I13 mlNDIUM AND FGF2a TREATMENT A,B and C: Controls (no PGF2~) at 2, 15 and 45 minutes after I13 m Indium AI,BI, and CI: Before and 15 and 45 minutes after PGF2~ treatment.
The stored information (in the computer) revealed a change in the density r a t i o : uterine/pelvic-vessels. This r a t i o was 2 before and 1.7 a f t e r PG tr~@~ment, confirming the visual impression of decreased density of itJm Indium in the utero-placental vessels. The sequential changes in the l13m Indium density of the 6 patients who were treated with PG also r e f l e c t e d the e f f e c t of PG on blood flow (Table I ) . A correlation was evident between the degree of the PG provoked uterine contracture and decrease in density. Contractures, more than 80 mm Hg, reduced density by 25% while those less than 80 mm Hg only reduced i t by 20%, when contractures were maximal.
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TABLE I
THE EFFECTOF EXTRAOVULARPGF2~TREATMENT ON THE 113m INDIUMDENSITYOF THE UTERINEAREA At Photography #1
113m Density Experimental(6) Control(3) 11.3-+1.2(100%)
Resting Pressure Experimental(6) Control(3)
13.2-+0.2(100%) 6-+1 (100%)
5+-I(100%)
#2
9'3±0.9( 82%)* 12.8+-0.3(97%) 75+-12(1250%)~
6-+1(120%)
#3
7.5-+0.8( 65%)t 11.2+-1.1(85%) 70+-9 (1170%)~
5-+i(100%)
All values are Means +- S.E.
*(P < 0.05),
~P < 0.01), ~(P < 0.001)
Photography #I: before 113m Indium treatment and #2 and #3 at 15 and 45 minutes respectively after 113m Indium treatment. The 6 Experimental patients received PG at 10 minutes after 113m Indium treatment, while the 3 Controls received no PG. The salient point of the present study is the demonstration (Table I) that in the 3 Controls, who had no change in resting pressure during the 45 minutes observation period, there was l i t t l e reduction in the density of 113m Indium at 15 minutes (3%) and at 45 minutes (15%) after treatment with this isotope. In contrast, in the 6 Experimental patients, who showed a drastic increase in resting pressure in between 5 (1250%) and 45 minutes (1170%) after PGI, the corresponding reductions in radioactive density were s i g n i f i c a n t l y greater (18%, P < 0.05 and 35%, P < 0.01, respectively). TABLE I I THE EFFECT OF EXTRAOVULARPGF2~ TREATMENT ON PLASMA PROGESTERONELEVELS #of Age Cases Years 6
21-+3
Gest.age IAT Weeks Hours 12+-1
14+-2
Progesterone ~g/ml Before & After Treatment Before 3 Hours After at Abortion 41-+4(100%)
All values are Means -+ S.E.
20-+3(49%)**
15-+3(37%)*
**(P < 0.01), *(P < 0.001)
Table II i l l u s t r a t e s , what had been repeatedly demonstrated already (1-10)o Effective PG treatment (a single extraovular dose of 10 mg PGF2~) provoked s i g n i f i c a n t and continued reduction (51% already at 3 hours, P < 0.01, and 63% at 14 hours, P < 0.001) in plasma progesterone levels, long before i t induced abortion in 14-+2 hours.
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PROSTAGLANDINS
DISCUSSION The present results are consistant with the premise i-3 that the "PG-Impact" (PGI) effectively terminates pregnancy because, through sustained vasoconstriction in the utero-placental vessels, i t suppresses the endocrine function of the feto-placental unit. In the 3 Controls, the density of 113m Indium over the uterine area (sustained by circulating 113m Indium) only decreased slightly during 45 minutes, while, in the 6 Experimental patients, who were exposed to PGI, 113m Indium density decreased significantly. This finding demonstrates that PGI reduces utero-placental blood flow, long before advanced cyclic IUP evolves. However, while the experiments in the rat "model''3 provided direct evidence that PG provokes instant vasoconstriction in the omentum uteri, preceding the full development of uterine contracture, the present clinical study did not reveal whether the PG-induced reduction of utero-placental blood flow was the cause or consequence of uterine contracture. The sequence of events might be clarified by serial measurements of radioactive density and resting pressure during the i n i t i a l period of 5 minutes after PGI. However, regardless of the primary event (suppression of uteroplacental blood flow followed by myometrial contracture or vice versa), i t is apparent that these prompt and unphysiological uterine responses to PGI occur long before progesterone-withdrawal, the evolution of advanced cyclic IUP and clinical progress in cervical dilatation manifest. Thus the conclusion 1,2 that PGI Therapy is effective i f i t provokes a "regulatory imbalance", before achieving uterine stimulation, is substantiated by the present observations. REFERENCES 1. 2. 3. 4. 5. 6. 7.
Csapo, A.I.: Prostaglandins 3: 245, 1973. Csapo, A.I.: Population Report 4: 633,1974. Csepli, J. and Csapo,A.I.: Prost~glandins 1: 235, 1972. Csapo, A.I.: Obst. Gynec. Survey 25: 403,-1970. Saldana, L, Schulman, H., Yang, W.H.: Prostaglandins 3: 847, 1973. Pitkanen, Y. and Rauramo, L.: Prostaglandins 5: 269,--1974. Tyak, A.J., Lambadarios, C., Parsons, R.J., Stewart, C.R., Cooke, I.D.: J. Obst. and Gynec. Brit. Comm. 81: 52, 1974. 8. Enkola, K.: Prostaglandins 5: 115, 19~. 9. Zoltan, I . , Csillag, M., Zsolnai, B., Zubek, L., Moksony, I . , Matanyi, S.: Prostaglandins 6: 211, 1974. 10. Craft, I . , Carriere, E., Youssefnejadian, E.:Obst.&Gyn.44: 135, 1974. ACKNOWLEDGEMENTS
The authors are grateful to Professor A.I. Csapo for consultation during this study; to Dr. Pekka Makela for densitometry and to the Upjohn Company for the supply of PGF2~.
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