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Effect of prostaglandin E2 on cervical compliance in pregnant ewes
Effect of prostaglandin pregnant ewes STANLEY BETSY
J. L.
THOMAS
M.D.
DRESSER, E. OTTE,
KENNETH Cincinnati,
STYS,
E, OII cervical compliance in
PH.D. B.S.
E. CLARK,
PH.D.
Ohio
Cervical compliance increases dramatically at parturition in sheep independent of uterine activity. Recently, in vitro production of prostaglandin E, (PGEP) by the cervix has been shown to increase at parturition. This study investigated the effects of PGE? on cervical compliance and uterine blood flow in pregnant ewes. Eight animals were chronically instrumented with pressure balloons within the cervical OS and amniotic cavity, an electromagnetic flow probe on a uterine artery, and catheters in the maternal cervical OS, femoral artery, femoral, uterine, and cervical veins, and fetal hindlimb vein. PGE, (10 mg) was administered in a water-soluble gel into the cervical OS every 4 hours times three doses at least 5 days after surgical preparation (124 to 142 days’ gestation). In all eight ewes, cervical compliance increased within 8 to 12 posttreatment hours to levels comparable to that seen at spontaneous parturition. Five of the ewes did not progress into labor; compliance in these ewes returned to baseline 24 to 72 hours after the peak. Uterine blood flow was measured in five ewes during the PGEp treatment and demonstrated no significant alterations. Maternal cardiovascular and fetal respiratory parameters were monitored throughout the experiment and remained stable. The present data suggest that PGE, may be an important regulator of the biochemical and physical changes which occur in the cervix at parturition. (AM. J. OBSTET. GYNECOL. 14&415, 1981.)
D U RI N G T H E LA ST decade, several clinical trials demonstrated the effectiveness of prostaglandin E, (PGE,) in inducing labor or abortion.lw6 Whenever these studies gave any consideration to the mechanism of action of PGE,, most attention was paid to the effects of PGE, on myometrial contractility. Several in vitro studies suggested that PGEz may also act to decrease cervical resistance.‘-I0 The effects of vaginally or intracervically administered PGE, on the clinical state of the cervix also provide some evidence that PGE, may induce cervical changes as well as myometrial activity.“. I2 In addition, recent studies of the production of PGE, by the From the Department University of Cincinnati This research
of Obstetrics Medical
was supported
Received for publication Accepted January
and Gynecology, Center.
by the Whitaker
December
Foundation.
2, 1980.
2 1, 1981.
Reprint requests: Stanley J. Stys, M.D., Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, 231 Bethesda Ave., Cincinnati, Ohio 45267. 000%9378/81/120415+05$00.50/O
0
1981
The
C. V. Mosby
Co
human and sheep cervix add support to the concept that PGE, may be quite important in the biophysical changes which occur in the cervix at parturition.‘:‘. I4 In the present experiments, a chronically instrumented sheep preparation was used to evaluate PGE2induced changes in cervical compliance. This model was previously used to demonstrate changes in compliance which occurred at parturition (Fig. 1) or after administration of estrogen.‘5. ” In the present study, PGE, was placed directly into the cervical canal, and the effects on compliance were quantitatively determined. Since uterine contractile activity can be measured simultaneously, the interrelationship of changes in cervical compliance to uterine myometrial activity can also be determined. In addition, because of the potential effects of PGE, on uterine blood flow,” the capability of measuring uterine blood flow and other cardiovascular parameters was added to the previously described model. The purpose of this study was to determine whether the intracervical administration of PGE, in415
416
Stys et al.
TIME BEFORE
LABOR
(DAYS)
Fig. 1. Cervical compliance versus time before labor for three ewes with spontaneous parturition. Table I. Effect of intracervical PGE, on cervical compliance Baseline
Day oj Sheep No.
007- 1 029- 1 010-2 032- 1 039-2 047-l 051-l 052-l X -t SEM
duces
uterine
gestation
143 132
141 131 126 125 124 126 Range 124-143 d.
administration Peak
compliance compliance (cditorr}
0.03
(cditom)
0.34 0.65 0.10 0.80 0.08 0.80 0.04 0.38 0.06 0.81 0.12 0.64 0.04 0.24 0.08 c 0.02 0.58 2 0.08 0.15
of
Time of peak from first dose (hours)
23 21 21 13 20 20 27 21 20.8 t 1.4
changes in cervical compliance independent of activity and/or changes in uterine blood How.
kteri8l 8nd methods Eight ewes of mixed breed with singleton (6) or twin (2) pregnancies of known duration were studied. All animals were fasted from food and water, 48 and 24 hours, respectively, preoperatively. Beginning one day before operation, the ewes were given ampicillin sodium (1 gm), intramuscularly, each day for 5 days. Immediately before operation the sheep were sedated with Valium (10 mg) and pentobarbital (250 mg) and given a spinal anesthetic (Pontocaine, 12 mg in hyperbaric glucose). A midline incision exposed the lower uterus and upper cervix. A fetal hindlimb was exposed through a small incision in the uterine wall, and a polyvinyl catheter (Tygon microbore tubing) was threaded from the hindlimb vein to the inferior vena cava in order to monitor fetal respiratory parameters. A balloon-tipped
polyvinyl pressure catheter and ampicillin ( 1 gm) were placed in the amniotic cavity, and the incision was closed. A second uterine incision was made in the lowet segment, with care being taken not to disturb the cervical blood supply. The fetal membranes were retracted, and the internal OS of the cervix was exposed. A Hexiblc metal probe was inserted through the cervical canal into the vagina. One end of a polyvinyl catheter with a small balloon at its center’” was fastened to the proximal end of the probe. A polyvinyl infusion catheter was also fastened to the probe on one end and to the balloon tubing adjacent to the balloon. These were guided through the cervical canal and vagina by the probe. The cervical balloon catheter was fixed to the proximal end of the cervix, thus positioning the balloon and the infusion catheter in the upper third of the cervix. The cervical canal was mechanically isolated from the uterus with a purse-string suture at the internal OS. Indwelling polyvinyl catheters were placed in the left femoral artery and vein and in a left and right uterine vein and cervical vein in order to evaluate maternal hormonal and cardiovascular parameters. An electromagnetic How probe (Micron) was placed on the uterine artery of the nonpregnant horn in five ewes. The catheters and cables were exteriorized through a Hank stab incision, and maintained in a pouch. The vaginal ends of the cervical balloon catheter and the cervical infusion catheter were fastened across the back of the animal. After the operation, the ewes were housed in rectangular cages with access to food and water ad libitum and allowed to recover at least 3 days prior to testing. To test the effects of locally administered PGE, on cervical compliance, each ewe ( 124 to 142 days’ gesta-
Volume
140
Number
4
0.6
-
0.5
-
0.4
-
0.3
-
0.2
-
0.1
-
Effect
of PGEz on cervical
I 133
I 134
417
compliance
c b = “E 2 : 4 i: 5 0 i : 6 0
0
I 126
I 127
L 126
1 126
I 130
DAY
I 131
I 132
135
OF OESTATlON
Fig. 2. Cervical response to PGE, with later change during spontaneous parturition. tion) was given PGEz (10 mg) in a water-soluble gel (K-Y Jelly) intracervically every 4 hours times three doses. In addition, three animals were tested with use of the vehicle and monitored as described for the animals which received PGE,. By means of the methodology previously reported by Stys and coworkers,‘5 measurements of cervical compliance were made by infusing water at a constant rate into the cervical balloon while recording the change in cervical pressure. Cervical compliance was calculated as the ratio of volume infused to the resulting pressure change from the linear portion of several pressure-volume curves. A pressure range of 20 to 45 torr was used for the calculations of compliance, which assured that the balloon’s compliance did not affect the measurement of cervical compliance. Measurements of compliance were made prior to each test dose, at intervals of 4 to 12 hours throughout the 48 hours following the third dose, and then daily until the compliance returned to baseline. Samples of maternal blood were taken at various intervals throughout this experimental period, and fetal respiratory parameters were evaluated biweekly. Blood flow was also monitored on five ewes during the experiment.
Results The effect of the intracervical administration of PGEp on cervical compliance is demonstrated in Table I. Cervical compliance increased significantly, with peak values occurring 13 to 27 hours after administration of the initial PGE, dose. The magnitude of the increases in cervical compliance and the time frame of these changes are the same as those previously re-
Table II. Effect of intracervical PGE2 on uterine blood flow
administration
of
Baseline
Flow during treatment
Flow subsequat to treatment
Sheep No.
flow (mllmin)
(dlmin)
(mllmin)
032-l 039-2
484 430 550 230 240
460 340
047-l 051-l 052-2
484 410 460 235 207
X-cSEM
359 2 58
387
k 65
390 260 220 334
2 43
ported during spontaneous parturition (Fig. 1). These changes in cervical compliance were induced with the administration of PGE, over a wide range of gestational ages ( 124 to 143 days). Of the eight animals tested, three ewes progressed into labor within 48 hours after the changes in cervical compliance were induced. Uterine contractile activity did not increase substantially in the other five ewes tested. In these five animals, cervical compliance returned to baseline values 48 to 72 hours after the last intracervical dose of PGE,. These animals experienced spontaneous parturition several days later, again showing significant increases in cervical compliance. A typical cervical response to PGE, and the change seen several days later during spontaneous parturition are illustrated in Fig. 2 for one of the animals tested. The effects of the intracervical administration of PGE, on uterine blood flow were studied in five animals and are summarized in Table II. During the administration of PGE,, uterine blood flow increased
418
Stys et al
slightly above baseline values and then decreased slightly compared to baseline over the subsequent 12 to 24 hours. Neither change w-as significant. No substantial changes in fetal respiratory parameters were noticed during the administration of or response to the intracervical PGE,.
Comment The purpose of the present study was to determine whether PGE,, administered intracervically, induces changes in cervical compliance independent of uterine activity and/or changes in uterine blood flow. In a broader sense, this study attempted to contribute information in regard to the controlling mechanisms of uterine and cervical events at parturition and the interdependence of these events. This study demonstrated that intracervically administered PGE,, induces an increase in cervical compliance identical to that seen during spontaneous parturition. Both the time frame and the magnitude of this change in the cervix are indistinguishable from the changes which occur spontaneously at parturition (Fig. 2). Although the biochemical mechanisms of the parturitional changes in the cervix remain unresolved, the present data suggest that PGE, or its metabolites are capable of stimulating the changes in cervical collagen and/or ground substance which are thought to permit the dramatic alterations in cervical consistency necessary for the dilatation process. Recent studies by Ellwood and associates’“. ” demonstrate an increased production of PGE, and prostacyclin at parturition by cervical tissue and provide corroborating evidence of the physiologic role of PGE, in cervical softening. PGE,-induced changes in cervical compliance were also shown in the present study to be independent of uterine contractile activity. Of the eight ewes tested, only three labored in close temporal proximity to the cervical changes, but detectable increases in uterine
contractile activity occurred in these thrcae animals onh subsequent to marked changes in cervical compliance. In human studies, uterine contractile activitl \\as stimulated in a higher- percentage of cast’s than ill the present study following intracervical OI- vaginal administration of PGE 2.‘. “’ This ma\ reHect ;I relative insensitivity of the sheep uterus to PGE,. as compared to the human uterus, 11ul more likely reHec,ts a clif’f’erence in the dosage reaching the uterus in the tliffert%nt studies. The present study also investigates the effects of intracervically administered PGE, on uterine blood Now. Clark and associates” have demonstrate<1 that PGE, is a vasoconstrictor of the uterus of pregnant sheep. despite its vasodilatory effects on the uterus of nonpregnant animals. No significant effects on uterine blood flow were demonstrated in this study. As has alread) been suggested, the lack of uterine effects in this experimental model may simply indicate that little PGE:, reached the uterus. The present stud! also failed to demonstrate any adverse effects on fetal respirator! parameters subsequent to intracervical administration of PGE,. Although this is reassuring. the fact should be emphasized that the experimental protocol tras not designed to evaluate fetal effects systematically. Hopefully, the effects of PGE, on the fetus will recei1.e appropriate attention in any future clinical trials. The several clinical reports included in the list of references and the data presented in this article provide strong evidence that PGE, is an important mediator of both uterine and cervical actions during parturition. The mechanisms bv which PGE, acts on these ~wcr anatomically related but functionally dissimilar tissues are as yet not fully understood, but hold the potential for significant clinical relevance, especially if the mechanisms controlling these two functionallv distinct tissues could be controlled independently.
REFERENCES
1. Friedman. E. A., Sachtleben, M. R., and Green, W.: Oral prostaglandin E, for induction of labor at term, AM. J. OBSTET.
GYNECOL.
123:671,
1975.
2. Lauersen, N. H., Secher, N. J., and Wilson, K. H.: Midtrimester abortion induced by intravaginal administration of prostaglandin E, supposiiories, A;. J. OBSTET. GYNECOL. 1223947. 1975. 3. Lauersen, N. H., and Wilson, K. H.: Midtrimester abortion induced by serial intravaginal administration of prostaglandin E, suppositories in coniunction with a contraceptive diaphfagm, Prostaglandi”ns 10: 139, 1975. 4. Gabert, H. A., Brinton, 1.. and Brown. B.: Induction of labor with oral prostagl&in E2, AM. J. ~BSTET. GYNECOL. 125:333,
1976.
5. Nelson, G. H., and Bryons. C. I.: A comparison of. oral prostaglandin E, and intravenous oxytocin for induction of labor in normal and high-risk pregnancies, AM. J. OBSTET.
GYNECOL.
126:549,
1976.
6. Lauersen, N. H., and Wilson, K. H.: Induction of labor in patients
with
with
missed
abortion
and
fetal
prostglandin
death
in utero
E, suppositories. AM. J. OBSTET. GYNECOL. l27:609, 1977. 7. Najak, Z., Hillier, K., and Karim, S. M. M.: The action of prostaglandins on the human isolated non-pregnant cervix, J. Obstet. Gynaecol. Br. Commonw. 77:701. 1970. 8. Conrad, J. T., and Ueland, K.: Reduction of the stretch modulus of human cervical tissue by prostaglandin E,, AM. J. OBSTET. GYNECOL.
126:218,
1976.
Volume Number
140 4
9. Conrad, J. T., and Ueland, K.: The stretch modulus of human cervical tissue in spontaneous oxytocin-induced and prostaglandin Es-induced labor, AM. J. OBSTET. GYNE‘COL. 133: 11, 1979. 10. Hollinasworth, M., Gallimore, S., and Isherwood, C. N. M.: Effectgof prostaglandins F,, and E2 on cervical extensibility in the late pregnant rat. J. Reprod. Fertil. 58:95, 1980. 11. Calder. A. A., Embrey, M. P., and Tait, T.: Ripening of the cervix with extra-amniotic prostaglandin E2 in viscous gel before induction of labour, Br. J. Obstet. Gynaecol. 84:264, 1977. 12. Ulmsten, U., and Wingerup, L.: Cervical ripening induced by prostaglandin E, in viscous gel, Acta Obstet. Gynecol. Stand. (Suppl.) 84:1, 1979. 13. Ellwood, D. A., Mitchell, M. D., Anderson, A. B. M., and Turnbull, A. C.: The in vitro production of prostanoids
Effect
14.
15.
16.
17.
of PGE2 on cervical
compliance
419
by the human cervix during pregnancy: Preliminary observations, Br. J. Obstet. Gynaecol. 87:210, 1980. Ellwood, D. A., Mitchell, M. D., Anderson, A. B. M., and Turnbull, A. C.: Specific changes in the in vitro production of prostanoids by the ovine cervix at parturition. Prostaglandins 19:479; 1980. Stvs. S. a.I.. Clewell. W. H.. and Meschia, G.: Changes in,.. >., cervtcal compliance at parturition independent of urerine activity, AM. J. OBSTET. GYNECOL. 130:414, 1978. Stys, S. J., Clark, K. E., Clewell, W. H., and Meschia, G.: Hormonal effects on cervical compliance in sheep, in Naftolin, F., and Stubblefield, P. C., editors: Dilatation of the Uterine Cervix, New York, 1980, Raven Press. Clark, K. E., Stys, S. J,, and Austin, J. E.: PGI, and PGD, vasodilatory effects on the uterine vascular bed, in International Symposium on Uterine and Placental Blood Flow, New? York, 1980, Masson Publishers.
J. L.
THOMAS
M.D.
DRESSER, E. OTTE,
KENNETH Cincinnati,
STYS,
E, OII cervical compliance in
PH.D. B.S.
E. CLARK,
PH.D.
Ohio
Cervical compliance increases dramatically at parturition in sheep independent of uterine activity. Recently, in vitro production of prostaglandin E, (PGEP) by the cervix has been shown to increase at parturition. This study investigated the effects of PGE? on cervical compliance and uterine blood flow in pregnant ewes. Eight animals were chronically instrumented with pressure balloons within the cervical OS and amniotic cavity, an electromagnetic flow probe on a uterine artery, and catheters in the maternal cervical OS, femoral artery, femoral, uterine, and cervical veins, and fetal hindlimb vein. PGE, (10 mg) was administered in a water-soluble gel into the cervical OS every 4 hours times three doses at least 5 days after surgical preparation (124 to 142 days’ gestation). In all eight ewes, cervical compliance increased within 8 to 12 posttreatment hours to levels comparable to that seen at spontaneous parturition. Five of the ewes did not progress into labor; compliance in these ewes returned to baseline 24 to 72 hours after the peak. Uterine blood flow was measured in five ewes during the PGEp treatment and demonstrated no significant alterations. Maternal cardiovascular and fetal respiratory parameters were monitored throughout the experiment and remained stable. The present data suggest that PGE, may be an important regulator of the biochemical and physical changes which occur in the cervix at parturition. (AM. J. OBSTET. GYNECOL. 14&415, 1981.)
D U RI N G T H E LA ST decade, several clinical trials demonstrated the effectiveness of prostaglandin E, (PGE,) in inducing labor or abortion.lw6 Whenever these studies gave any consideration to the mechanism of action of PGE,, most attention was paid to the effects of PGE, on myometrial contractility. Several in vitro studies suggested that PGEz may also act to decrease cervical resistance.‘-I0 The effects of vaginally or intracervically administered PGE, on the clinical state of the cervix also provide some evidence that PGE, may induce cervical changes as well as myometrial activity.“. I2 In addition, recent studies of the production of PGE, by the From the Department University of Cincinnati This research
of Obstetrics Medical
was supported
Received for publication Accepted January
and Gynecology, Center.
by the Whitaker
December
Foundation.
2, 1980.
2 1, 1981.
Reprint requests: Stanley J. Stys, M.D., Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, 231 Bethesda Ave., Cincinnati, Ohio 45267. 000%9378/81/120415+05$00.50/O
0
1981
The
C. V. Mosby
Co
human and sheep cervix add support to the concept that PGE, may be quite important in the biophysical changes which occur in the cervix at parturition.‘:‘. I4 In the present experiments, a chronically instrumented sheep preparation was used to evaluate PGE2induced changes in cervical compliance. This model was previously used to demonstrate changes in compliance which occurred at parturition (Fig. 1) or after administration of estrogen.‘5. ” In the present study, PGE, was placed directly into the cervical canal, and the effects on compliance were quantitatively determined. Since uterine contractile activity can be measured simultaneously, the interrelationship of changes in cervical compliance to uterine myometrial activity can also be determined. In addition, because of the potential effects of PGE, on uterine blood flow,” the capability of measuring uterine blood flow and other cardiovascular parameters was added to the previously described model. The purpose of this study was to determine whether the intracervical administration of PGE, in415
416
Stys et al.
TIME BEFORE
LABOR
(DAYS)
Fig. 1. Cervical compliance versus time before labor for three ewes with spontaneous parturition. Table I. Effect of intracervical PGE, on cervical compliance Baseline
Day oj Sheep No.
007- 1 029- 1 010-2 032- 1 039-2 047-l 051-l 052-l X -t SEM
duces
uterine
gestation
143 132
141 131 126 125 124 126 Range 124-143 d.
administration Peak
compliance compliance (cditorr}
0.03
(cditom)
0.34 0.65 0.10 0.80 0.08 0.80 0.04 0.38 0.06 0.81 0.12 0.64 0.04 0.24 0.08 c 0.02 0.58 2 0.08 0.15
of
Time of peak from first dose (hours)
23 21 21 13 20 20 27 21 20.8 t 1.4
changes in cervical compliance independent of activity and/or changes in uterine blood How.
kteri8l 8nd methods Eight ewes of mixed breed with singleton (6) or twin (2) pregnancies of known duration were studied. All animals were fasted from food and water, 48 and 24 hours, respectively, preoperatively. Beginning one day before operation, the ewes were given ampicillin sodium (1 gm), intramuscularly, each day for 5 days. Immediately before operation the sheep were sedated with Valium (10 mg) and pentobarbital (250 mg) and given a spinal anesthetic (Pontocaine, 12 mg in hyperbaric glucose). A midline incision exposed the lower uterus and upper cervix. A fetal hindlimb was exposed through a small incision in the uterine wall, and a polyvinyl catheter (Tygon microbore tubing) was threaded from the hindlimb vein to the inferior vena cava in order to monitor fetal respiratory parameters. A balloon-tipped
polyvinyl pressure catheter and ampicillin ( 1 gm) were placed in the amniotic cavity, and the incision was closed. A second uterine incision was made in the lowet segment, with care being taken not to disturb the cervical blood supply. The fetal membranes were retracted, and the internal OS of the cervix was exposed. A Hexiblc metal probe was inserted through the cervical canal into the vagina. One end of a polyvinyl catheter with a small balloon at its center’” was fastened to the proximal end of the probe. A polyvinyl infusion catheter was also fastened to the probe on one end and to the balloon tubing adjacent to the balloon. These were guided through the cervical canal and vagina by the probe. The cervical balloon catheter was fixed to the proximal end of the cervix, thus positioning the balloon and the infusion catheter in the upper third of the cervix. The cervical canal was mechanically isolated from the uterus with a purse-string suture at the internal OS. Indwelling polyvinyl catheters were placed in the left femoral artery and vein and in a left and right uterine vein and cervical vein in order to evaluate maternal hormonal and cardiovascular parameters. An electromagnetic How probe (Micron) was placed on the uterine artery of the nonpregnant horn in five ewes. The catheters and cables were exteriorized through a Hank stab incision, and maintained in a pouch. The vaginal ends of the cervical balloon catheter and the cervical infusion catheter were fastened across the back of the animal. After the operation, the ewes were housed in rectangular cages with access to food and water ad libitum and allowed to recover at least 3 days prior to testing. To test the effects of locally administered PGE, on cervical compliance, each ewe ( 124 to 142 days’ gesta-
Volume
140
Number
4
0.6
-
0.5
-
0.4
-
0.3
-
0.2
-
0.1
-
Effect
of PGEz on cervical
I 133
I 134
417
compliance
c b = “E 2 : 4 i: 5 0 i : 6 0
0
I 126
I 127
L 126
1 126
I 130
DAY
I 131
I 132
135
OF OESTATlON
Fig. 2. Cervical response to PGE, with later change during spontaneous parturition. tion) was given PGEz (10 mg) in a water-soluble gel (K-Y Jelly) intracervically every 4 hours times three doses. In addition, three animals were tested with use of the vehicle and monitored as described for the animals which received PGE,. By means of the methodology previously reported by Stys and coworkers,‘5 measurements of cervical compliance were made by infusing water at a constant rate into the cervical balloon while recording the change in cervical pressure. Cervical compliance was calculated as the ratio of volume infused to the resulting pressure change from the linear portion of several pressure-volume curves. A pressure range of 20 to 45 torr was used for the calculations of compliance, which assured that the balloon’s compliance did not affect the measurement of cervical compliance. Measurements of compliance were made prior to each test dose, at intervals of 4 to 12 hours throughout the 48 hours following the third dose, and then daily until the compliance returned to baseline. Samples of maternal blood were taken at various intervals throughout this experimental period, and fetal respiratory parameters were evaluated biweekly. Blood flow was also monitored on five ewes during the experiment.
Results The effect of the intracervical administration of PGEp on cervical compliance is demonstrated in Table I. Cervical compliance increased significantly, with peak values occurring 13 to 27 hours after administration of the initial PGE, dose. The magnitude of the increases in cervical compliance and the time frame of these changes are the same as those previously re-
Table II. Effect of intracervical PGE2 on uterine blood flow
administration
of
Baseline
Flow during treatment
Flow subsequat to treatment
Sheep No.
flow (mllmin)
(dlmin)
(mllmin)
032-l 039-2
484 430 550 230 240
460 340
047-l 051-l 052-2
484 410 460 235 207
X-cSEM
359 2 58
387
k 65
390 260 220 334
2 43
ported during spontaneous parturition (Fig. 1). These changes in cervical compliance were induced with the administration of PGE, over a wide range of gestational ages ( 124 to 143 days). Of the eight animals tested, three ewes progressed into labor within 48 hours after the changes in cervical compliance were induced. Uterine contractile activity did not increase substantially in the other five ewes tested. In these five animals, cervical compliance returned to baseline values 48 to 72 hours after the last intracervical dose of PGE,. These animals experienced spontaneous parturition several days later, again showing significant increases in cervical compliance. A typical cervical response to PGE, and the change seen several days later during spontaneous parturition are illustrated in Fig. 2 for one of the animals tested. The effects of the intracervical administration of PGE, on uterine blood flow were studied in five animals and are summarized in Table II. During the administration of PGE,, uterine blood flow increased
418
Stys et al
slightly above baseline values and then decreased slightly compared to baseline over the subsequent 12 to 24 hours. Neither change w-as significant. No substantial changes in fetal respiratory parameters were noticed during the administration of or response to the intracervical PGE,.
Comment The purpose of the present study was to determine whether PGE,, administered intracervically, induces changes in cervical compliance independent of uterine activity and/or changes in uterine blood flow. In a broader sense, this study attempted to contribute information in regard to the controlling mechanisms of uterine and cervical events at parturition and the interdependence of these events. This study demonstrated that intracervically administered PGE,, induces an increase in cervical compliance identical to that seen during spontaneous parturition. Both the time frame and the magnitude of this change in the cervix are indistinguishable from the changes which occur spontaneously at parturition (Fig. 2). Although the biochemical mechanisms of the parturitional changes in the cervix remain unresolved, the present data suggest that PGE, or its metabolites are capable of stimulating the changes in cervical collagen and/or ground substance which are thought to permit the dramatic alterations in cervical consistency necessary for the dilatation process. Recent studies by Ellwood and associates’“. ” demonstrate an increased production of PGE, and prostacyclin at parturition by cervical tissue and provide corroborating evidence of the physiologic role of PGE, in cervical softening. PGE,-induced changes in cervical compliance were also shown in the present study to be independent of uterine contractile activity. Of the eight ewes tested, only three labored in close temporal proximity to the cervical changes, but detectable increases in uterine
contractile activity occurred in these thrcae animals onh subsequent to marked changes in cervical compliance. In human studies, uterine contractile activitl \\as stimulated in a higher- percentage of cast’s than ill the present study following intracervical OI- vaginal administration of PGE 2.‘. “’ This ma\ reHect ;I relative insensitivity of the sheep uterus to PGE,. as compared to the human uterus, 11ul more likely reHec,ts a clif’f’erence in the dosage reaching the uterus in the tliffert%nt studies. The present study also investigates the effects of intracervically administered PGE, on uterine blood Now. Clark and associates” have demonstrate<1 that PGE, is a vasoconstrictor of the uterus of pregnant sheep. despite its vasodilatory effects on the uterus of nonpregnant animals. No significant effects on uterine blood flow were demonstrated in this study. As has alread) been suggested, the lack of uterine effects in this experimental model may simply indicate that little PGE:, reached the uterus. The present stud! also failed to demonstrate any adverse effects on fetal respirator! parameters subsequent to intracervical administration of PGE,. Although this is reassuring. the fact should be emphasized that the experimental protocol tras not designed to evaluate fetal effects systematically. Hopefully, the effects of PGE, on the fetus will recei1.e appropriate attention in any future clinical trials. The several clinical reports included in the list of references and the data presented in this article provide strong evidence that PGE, is an important mediator of both uterine and cervical actions during parturition. The mechanisms bv which PGE, acts on these ~wcr anatomically related but functionally dissimilar tissues are as yet not fully understood, but hold the potential for significant clinical relevance, especially if the mechanisms controlling these two functionallv distinct tissues could be controlled independently.
REFERENCES
1. Friedman. E. A., Sachtleben, M. R., and Green, W.: Oral prostaglandin E, for induction of labor at term, AM. J. OBSTET.
GYNECOL.
123:671,
1975.
2. Lauersen, N. H., Secher, N. J., and Wilson, K. H.: Midtrimester abortion induced by intravaginal administration of prostaglandin E, supposiiories, A;. J. OBSTET. GYNECOL. 1223947. 1975. 3. Lauersen, N. H., and Wilson, K. H.: Midtrimester abortion induced by serial intravaginal administration of prostaglandin E, suppositories in coniunction with a contraceptive diaphfagm, Prostaglandi”ns 10: 139, 1975. 4. Gabert, H. A., Brinton, 1.. and Brown. B.: Induction of labor with oral prostagl&in E2, AM. J. ~BSTET. GYNECOL. 125:333,
1976.
5. Nelson, G. H., and Bryons. C. I.: A comparison of. oral prostaglandin E, and intravenous oxytocin for induction of labor in normal and high-risk pregnancies, AM. J. OBSTET.
GYNECOL.
126:549,
1976.
6. Lauersen, N. H., and Wilson, K. H.: Induction of labor in patients
with
with
missed
abortion
and
fetal
prostglandin
death
in utero
E, suppositories. AM. J. OBSTET. GYNECOL. l27:609, 1977. 7. Najak, Z., Hillier, K., and Karim, S. M. M.: The action of prostaglandins on the human isolated non-pregnant cervix, J. Obstet. Gynaecol. Br. Commonw. 77:701. 1970. 8. Conrad, J. T., and Ueland, K.: Reduction of the stretch modulus of human cervical tissue by prostaglandin E,, AM. J. OBSTET. GYNECOL.
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