Pharmac. Therap. B. 1975. Vol. 1, No. 2, pp. 297-310. Pergamon Press.
Printed in Great Britain
Specialist Subject Editor: K. H. MOSLER
ENDOGENOUS PROSTAGLANDINS IN PREGNANCY AND LABOR
NORMAL
NILS WIQVIST Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden We may be said to be in the dark as to why the uterus, after remaining for months subject only to futile contractions, is suddenly thrown into powerful and efficient action and, within maybe a few hours or even less, can get rid of the burden which it has borne with such tolerance for so long a time. Michael Foster, 1888. T o DATE, none of the 'classical' hypotheses provide a satisfactory answer to the intriguing problem: what controls the initiation of labor in the h u m a n female? There is a tendency to deny the existence of a single mechanism in f a v o r of a variety of complex hormonal and mechanical events which in concert contribute to release the myometrial block and at a given m o m e n t to initiate labor. In this context the possible role of the prostaglandins represents a new approach. Recent evidence f r o m several lines of research indicates that these c o m p o u n d s m a y serve as an important link in the chain of events. The first suggestion of this possibility came in a report published by Karim in 1966. Extracts of amniotic fluid were purified, fractionated by column c h r o m a t o g r a p h y and the fractions assayed for smooth muscle stimulating activity on the guinea-pig colon. Identification of the active material b y thin layer c h r o m a t o g r a p h y indicated the presence of prostaglandins Ft,, F2~, Et and E2. A later report by the same author (Karim and Devlin, 1967) also indicated that comparatively high concentrations of PGF2~ occurred in amniotic fluid of w o m e n who aborted spontaneously and of w o m e n who were in labor at term. The c o m p o u n d could not be detected in samples taken during intact pregnancy. At approximately the same time, experiments were carried out in Stockholm in which pure prostaglandin c o m p o u n d s (PGE~, PGE2 and PGF2,) were administered to pregnant w o m e n and the effect upon the contractility of the pregnant h u m a n uterus recorded (Bygdeman et al., 1967; Wiqvist et al., 1968). It was found that these prostaglandins were specific and very active uterine stimulants following a single intravenous injection, intravenous infusion or by intramuscular injection. Subsequently, K a r i m et al. (1968) began to use PGFz~ and PGE2 by intravenous drip infusion to successfully induce labor. Also of significant interest in the early studies were data indicating the possibility of a high concentration of PGF2~ in the decidua of w o m e n in active labor (Karim, 1967). This suggested a local formation of prostaglandin within the uterus. It was also shown by Wiqvist and B y g d e m a n (1970) that small doses of PGFz, or PGE2 injected through the cervix into the extra-amniotic space, close to the site of the decidua, induced forceful uterine contractions and abortion. Subsequent prostaglandin research on the problem of the spontaneous initiation of labor has followed different lines. This work has produced data that seem to c o m p l e m e n t each other and to create a more solid basis for an understanding of the problem. Blood Levels of Prostaglandin During Pregnancy and L a b o r The prostaglandins are tissue h o r m o n e s which generally act at or close to the site of formation. H o w e v e r , the valid determination of prostaglandin concentrations in tissues is difficult considering the fact that an increased formation of these c o m p o u n d s may take place as a result of t r a u m a to the tissue when the biopsy is taken or when the 297
298
N. WIQVIST
specimen is handled. Local formation of prostaglandin in the uterus is incompletely reflected in altered plasma or serum concentrations. But because of the difficulties involved in the tissue determination of prostaglandins, several investigators have relied upon blood concentrations of the primary PGF or PGE compounds as evidence for the probable formation of endogenous prostaglandins within the uterus. The results of these studies are summarized in Table 1. Using a radioimmunoassay Caldwell et al. (1971) and Gutierrez-Cernosek et al. (1972) found higher PGF2~ concentrations in pregnant than in non-pregnant women. Brummer (1972, 1973) measuring PGF2~ and Hertelendy (1974) measuring PGE were unable to confirm this difference. None of these authors could detect any elevation of the prostaglandin concentrations in women in late pregnancy as compared to the values found in women during the first trimester. However, all investigators agree that the levels increased during labor and generally were at their maximum in the late first stage of labor. There has been some disagreement as to the validity of those methods designed to monitor primary prostaglandins in blood. Samuelsson and his collaborators have studied the kinetics of PGE and PGF in the human (Hamberg and Samuelsson, 1971; Granstr6m, 1972) as well as the total daily production rates (Samuelsson, 1973; Hamberg, 1974) and endogenous levels of the major metabolites of these prostaglandins in human plasma (Gr6en and Samuelsson, 1974). It has been demonstrated that the levels of PGF2o in the peripheral circulation that have been reported over the past few years are about 100 to 1000 times higher than those that would be expected. The endogenous serum levels of PGF2~ calculated on the basis of the studies by Samuelsson and his collaborators were in the low picogram range rather than the nanogram levels that had been reported previously. A possible explanation for the discrepancy between the experimental and the calculated levels of prostaglandin could be the formation of PGF2~ by platelets and leucocytes during the isolation of the plasma or serum possibly in combination with a non-enzymatic cyclization of poly-unsaturated fatty acids. Analytical techniques not sufficiently sensitive or specific might also have contributed to the higher values reported. 15-keto-13,14-dihydro-PGF2o is one of the major PGF2~ metabolites in peripheral human plasma (Fig. 1). Its concentration is roughly proportional to the concentration of PGF2a in the peripheral blood. It can be expected to occur in considerably higher concentrations in peripheral blood than the parent compound because it has a longer half-life (Table 2). This metabolite is not formed during collection of blood. Furthermore, it can be expected that some part of the primary prostaglandins synthesized intracellularly is released as the 15-keto-13,14-dihydro-metabolite. If PGF2a is released as such from the tissues it is quickly transformed into the same metabolite probably to a great extent by enzymes in the lungs.
HO "~OOH .o
PG dehydrogenase ,
. oH
HO ~ O O H Hd
PGFza
-
5
keto
-
15-
PGF2a
z~3 reduclase HO ~~COOH .cr
ff"bH
dihydro-PGF2a
__ *--
HO HO O ~•~ ~ O O H 15-keto-dihydro pGg2a
FIG. 1. Reactionsinvolvedin the metabolismof PGF2o.
Reference
Hertelendy
et al.
et al.
PGE (1974)
Gutierrez-Cernosek B r u m m e r (1972) Brummer 0973) Challis et al. (1974) Hillier et al. (1974)
(1972)
serum
O1"
plasma
serum serum serum plasma plasma
plasma plasma
Specimen
316
350 700 --.
-200-300
.
Non-pregnant
--
600 -600 -.
0 600-900
First
--
500-850 -300-650 -.
0 --
Second
362
400-500 600 200-550 34
0 --
Third
Pregnancy trimester
818
. 800 . -1400
-1200-3000
Early
.
.
1428
3400 300050OO . 1900 . 98 6300
Late I st stage
.
.
Labor
770
-6000
700
8000 --
2rid stage
465
---
400
13 --
Postpartum
Summary Comparison of the Levels of PGF~o and PGE in Blood (pg/ml) of Non-pregnant, Pregnant, Laboring and Postpartum Patients. Analysis by Radioimmunoassay in each Series except in that of Karim (bioassay )
PGF2 K a r i m (1968) C a i d w e l l et al. (1971)
TABLE I.
o
O"
e~
~o
t~
g~
o
g~
~o
O
O
O
rn
300
N, WZQVlST TASLE 2. Plasma Concentrations of Prostaglandins in Females (pg /ml) (after Green, 1973)
During i.v. adm. PGF~ 75 p.g/min = 108.000 ~g/24 hr
Compound
reported PGF2 15-keto-dihydro-PGF2
Endogenous total synthesis of PGF,° + PGF2. 36-61 ttg/24 hr calculated
4.450+_2.660
2
105.000 + 29.300
50
reported plasma
serum
200-300 (RIA)
10-990 (RIA) 500-2.500 (RIA) 200 (MS)
20 (MS)
15-keto-13,14-dihydro-PGF2, can be measured by the gas chromatographic-mass spectrometric technique, a specific and very sensitive method. The method has recently been applied to determine endogenous plasma levels of 15-keto-13,14-dihydro-PGF2~ in normal pregnant women and in women in spontaneous and oxytocin-induced labor at term (Gr6en et al., 1974). The concentration of 15-keto-13,14-dihydro-PGF2, in the peripheral plasma during the last 6 weeks of pregnancy and prior to the onset of normal parturition was 31 __+18pg/ml plasma. There seemed to be a small increase in the level as the day of parturition approached. During active labor the plasma level of 15-keto-13,14-dihydroPGF2~ increased as to thirty times to reach values between 267 and 942pg/ml immediately before delivery. One hour after, the concentration had decreased by 20-75 per cent. The equivalent data from patients in whom labor was induced by oxytocin showed a less consistent pattern but immediately prior to delivery the values recorded were similar to those in the series not given oxytocin. PGF2~ was also analyzed in some of these cases, using the gas chromatographic-mass spectrometric technique but there was no correlation between the concentrations found and the stage of labor. Figure 2 shows the distribution of the 15-keto-13,14-dihydro-PGF2~ values as related to the degree of cervical dilatation. This graph illustrates the progressive increment in concentrations of the metabolite which occurred during the active phase of normal labor. It may be concluded that there is an increased formation and secretion of PGF2, into the systemic circulation during the course of labor. From the blood analysis there is still incomplete evidence as to the phasing of the levels of prostaglandins at the spontaneous onset of labor, and as to whether an increase in circulating prostaglandins precedes the onset of labor.
Excretion of Urinary Metabolites of Prostaglandins Methods for quantitative determination of the major urinary metabolites of PGE~, PGE2, PGF~ and PGF2, have recently been developed (Hamberg, 1973). The levels of IOOC 90C "b h N (.9 13_ i 0
80C 70C
y
6oc 50C 40C 30C
0
20C I
IOC 4-6
2
Weeks before porturilion
~ 2"5 ~'-8 ~ cm Cervicol dilo~otion during Iobor
FIG, 2. Plasma levels of 15-keto-13,14-dihydro-PGF2. during pregnancy and labor in the human. (After Green et al., 1974.)
Endogenous prostaglandins in normal pregnancy and labor
301
these metabolites in urine appear to accurately reflect the endogenous synthesis of prostaglandin. 5ot,7a-dihydroxy-ll-ketotetranor-prostane-l,16-dioic acid is the major urinary metabolite of PGF,~ and PGF2, and the compound can be determined in 24-hr samples by multiple-ion analysis. The amount excreted in the 30th and 40th week of pregnancy corresponded to 32 - 12.2/xg/24 hr representing a two- to five-fold increases compared to that seen in non-pregnant women (Hamberg, 1974). Determination of the metabolite in serial 24-hr samples of three subjects showed that there was a gradual increase as pregnancy progressed with maximum excretion at the end of gestation (Fig. 3). In one of these cases a urine sample was obtained on the day when the patient went into spontaneous labor (collected 24 to 4 hr before birth). The amount of the dioic acid metabolite in this sample abruptly increased (50.3 p.g) as compared to the amount present in the sample collected only 9 days earlier (23.0 tzg). After delivery there was a rapid normalization of the level of the metabolite.
60-
t~ E
40-
.~ ' ~
j .-- .....
/ _ ...................
/
.A
E
o
,~
2~
~o
4~,
H
Pp
Pregnoncy week
FIG. 3. Urinary excretion of the major metabolite of PGF,. and PGF2o,5a-,7a-dihydroxy-liketotetranor-prostane-l,16-dioic acid (tzg/24hr) in three pregnant women. Arrows indicate time of delivery. (After Hamberg, 1974.) These results confirm the rapid increase in the endogenous secretion that occurs during labor and above all are indicative of a progressively increased formation during the course of pregnancy. The data presented indicate an over-all increase in the synthesis of prostaglandins but it is not established if the uterus and its contents are the main site of formation.
Occurrence of Prostaglandin in Amniotic Fluid For several reasons analysis of the prostaglandin content of amniotic fluid appears to be a particularly attractive approach to the problem under discussion: 1. Amniotic fluid is closer to the feto-placental compartment than systemic maternal blood or urine; 2. Amniotic fluid is in intimate contact with the decidua and the concentration of prostaglandin in liquor is likely to reflect the local formation and secretion of the compound from this tissue; 3. PGF2o and probably the other prostaglandins are not rapidly metabolized to any significant degree in amniotic fluid. This allows an accumulation of the compound within the uterus (Gr6en et al., 1974); 4. Prostaglandin can be determined accurately in liquor without the risk of falsely high concentrations as a result of sampling. Levels of PGF2, in the amniotic fluid were determined by Salmon and Amy (1973) using a radioimmunoassay. Concentrations of the prostaglandin were relatively constant between 15 and 35 weeks of gestation, but an increase was observed after 36 weeks. The rise continued up to the 44th week. A still greater elevation of PGF2, levels was recorded during labor and the levels were related to the degree of cervical dilatation (Fig. 4).
302
N. WIQVIST
,2 l
,o!
/ i/
0..
/
o
/
1 o L)
i
ol
1
i
i
i
ls-~ 20.-23 24"zt 2e'-~ 32-3s :zs-:~ ~o-43
Weeks PREGNANCY
3-4
s-6
7~
g'10
Cervical dilatalion,cm
LABOR
Fla. 4. Levels of PGF2. in amniotic fluid during pregnancy and labor. Values are plotted as the mean and standard error. (After Salmon and Amy, 1973.) T w o reports have recently been published by Keirse and Turnbull (1973) and by Keirse et al. (1974) on the occurrence of P G E and P G F c o m p o u n d s in amniotic fluid. The concentration of P G E was measured by gas-liquid c h r o m a t o g r a p h y with electroncapture detection. The concentration of PGF2~ was measured using a radioimmunoassay. Table 3 shows the PGE~ levels during pregnancy before the onset of clinical labor, while Table 4 shows the P G F concentrations. Figure 5 indicates the corresponding levels during the course of labor. P G E was not detected in amniotic fluid during the 38th to 41st week of gestation by the specific but rather insensitive method applied. H o w e v e r , measurable amounts were present in the very early stages of labor and the levels then increased progressively with advancing dilatation of the cervix. The P G F c o m p o u n d s were identified during intact pregnancy by a more sensitive radioimmunoassay. Amniotic fluid contained significantly less P G F at mid-gestation than at term prior to the onset of labor (p < 0,01). The P G F content was yet higher during the early first stage of labor and increased as cervical dilatation progressed. By means of gas-liquid c h r o m a t o g r a p h y with electron-capture detection and pooled amniotic fluid samples it was also established that the PGE2 and PGF2~ c o m p o u n d s were present in far greater concentrations than the P G E I and P G F , , compounds. These findings support the results obtained f r o m the m e a s u r e m e n t of the excretion of urinary metabolites and suggest that an increased secretion of PGE2 and PGF2° precedes the initiation of labor. It has, however, also been demonstrated that prostaglandins are released as a result of uterine distension which is more predominant at the end of pregnancy than at mid-gestation and which reaches a m a x i m u m during labor (Poyser et al., 1971). The increase in amniotic fluid concentrations of prostaglandin could therefore simply represent a c o n s e q u e n c e of the stretching of myometrial fibers with labor itself being TABLE3. Amniotic Fluid PGEz Levels during Late Pregnancy Before the Onset of Clinical Labor (after Keirse and Turnbull, 1973)
No. of cases
*PGE: (ng/ml)
10 1 1
Printed in Great Britain
Specialist Subject Editor: K. H. MOSLER
ENDOGENOUS PROSTAGLANDINS IN PREGNANCY AND LABOR
NORMAL
NILS WIQVIST Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden We may be said to be in the dark as to why the uterus, after remaining for months subject only to futile contractions, is suddenly thrown into powerful and efficient action and, within maybe a few hours or even less, can get rid of the burden which it has borne with such tolerance for so long a time. Michael Foster, 1888. T o DATE, none of the 'classical' hypotheses provide a satisfactory answer to the intriguing problem: what controls the initiation of labor in the h u m a n female? There is a tendency to deny the existence of a single mechanism in f a v o r of a variety of complex hormonal and mechanical events which in concert contribute to release the myometrial block and at a given m o m e n t to initiate labor. In this context the possible role of the prostaglandins represents a new approach. Recent evidence f r o m several lines of research indicates that these c o m p o u n d s m a y serve as an important link in the chain of events. The first suggestion of this possibility came in a report published by Karim in 1966. Extracts of amniotic fluid were purified, fractionated by column c h r o m a t o g r a p h y and the fractions assayed for smooth muscle stimulating activity on the guinea-pig colon. Identification of the active material b y thin layer c h r o m a t o g r a p h y indicated the presence of prostaglandins Ft,, F2~, Et and E2. A later report by the same author (Karim and Devlin, 1967) also indicated that comparatively high concentrations of PGF2~ occurred in amniotic fluid of w o m e n who aborted spontaneously and of w o m e n who were in labor at term. The c o m p o u n d could not be detected in samples taken during intact pregnancy. At approximately the same time, experiments were carried out in Stockholm in which pure prostaglandin c o m p o u n d s (PGE~, PGE2 and PGF2,) were administered to pregnant w o m e n and the effect upon the contractility of the pregnant h u m a n uterus recorded (Bygdeman et al., 1967; Wiqvist et al., 1968). It was found that these prostaglandins were specific and very active uterine stimulants following a single intravenous injection, intravenous infusion or by intramuscular injection. Subsequently, K a r i m et al. (1968) began to use PGFz~ and PGE2 by intravenous drip infusion to successfully induce labor. Also of significant interest in the early studies were data indicating the possibility of a high concentration of PGF2~ in the decidua of w o m e n in active labor (Karim, 1967). This suggested a local formation of prostaglandin within the uterus. It was also shown by Wiqvist and B y g d e m a n (1970) that small doses of PGFz, or PGE2 injected through the cervix into the extra-amniotic space, close to the site of the decidua, induced forceful uterine contractions and abortion. Subsequent prostaglandin research on the problem of the spontaneous initiation of labor has followed different lines. This work has produced data that seem to c o m p l e m e n t each other and to create a more solid basis for an understanding of the problem. Blood Levels of Prostaglandin During Pregnancy and L a b o r The prostaglandins are tissue h o r m o n e s which generally act at or close to the site of formation. H o w e v e r , the valid determination of prostaglandin concentrations in tissues is difficult considering the fact that an increased formation of these c o m p o u n d s may take place as a result of t r a u m a to the tissue when the biopsy is taken or when the 297
298
N. WIQVIST
specimen is handled. Local formation of prostaglandin in the uterus is incompletely reflected in altered plasma or serum concentrations. But because of the difficulties involved in the tissue determination of prostaglandins, several investigators have relied upon blood concentrations of the primary PGF or PGE compounds as evidence for the probable formation of endogenous prostaglandins within the uterus. The results of these studies are summarized in Table 1. Using a radioimmunoassay Caldwell et al. (1971) and Gutierrez-Cernosek et al. (1972) found higher PGF2~ concentrations in pregnant than in non-pregnant women. Brummer (1972, 1973) measuring PGF2~ and Hertelendy (1974) measuring PGE were unable to confirm this difference. None of these authors could detect any elevation of the prostaglandin concentrations in women in late pregnancy as compared to the values found in women during the first trimester. However, all investigators agree that the levels increased during labor and generally were at their maximum in the late first stage of labor. There has been some disagreement as to the validity of those methods designed to monitor primary prostaglandins in blood. Samuelsson and his collaborators have studied the kinetics of PGE and PGF in the human (Hamberg and Samuelsson, 1971; Granstr6m, 1972) as well as the total daily production rates (Samuelsson, 1973; Hamberg, 1974) and endogenous levels of the major metabolites of these prostaglandins in human plasma (Gr6en and Samuelsson, 1974). It has been demonstrated that the levels of PGF2o in the peripheral circulation that have been reported over the past few years are about 100 to 1000 times higher than those that would be expected. The endogenous serum levels of PGF2~ calculated on the basis of the studies by Samuelsson and his collaborators were in the low picogram range rather than the nanogram levels that had been reported previously. A possible explanation for the discrepancy between the experimental and the calculated levels of prostaglandin could be the formation of PGF2~ by platelets and leucocytes during the isolation of the plasma or serum possibly in combination with a non-enzymatic cyclization of poly-unsaturated fatty acids. Analytical techniques not sufficiently sensitive or specific might also have contributed to the higher values reported. 15-keto-13,14-dihydro-PGF2o is one of the major PGF2~ metabolites in peripheral human plasma (Fig. 1). Its concentration is roughly proportional to the concentration of PGF2a in the peripheral blood. It can be expected to occur in considerably higher concentrations in peripheral blood than the parent compound because it has a longer half-life (Table 2). This metabolite is not formed during collection of blood. Furthermore, it can be expected that some part of the primary prostaglandins synthesized intracellularly is released as the 15-keto-13,14-dihydro-metabolite. If PGF2a is released as such from the tissues it is quickly transformed into the same metabolite probably to a great extent by enzymes in the lungs.
HO "~OOH .o
PG dehydrogenase ,
. oH
HO ~ O O H Hd
PGFza
-
5
keto
-
15-
PGF2a
z~3 reduclase HO ~~COOH .cr
ff"bH
dihydro-PGF2a
__ *--
HO HO O ~•~ ~ O O H 15-keto-dihydro pGg2a
FIG. 1. Reactionsinvolvedin the metabolismof PGF2o.
Reference
Hertelendy
et al.
et al.
PGE (1974)
Gutierrez-Cernosek B r u m m e r (1972) Brummer 0973) Challis et al. (1974) Hillier et al. (1974)
(1972)
serum
O1"
plasma
serum serum serum plasma plasma
plasma plasma
Specimen
316
350 700 --.
-200-300
.
Non-pregnant
--
600 -600 -.
0 600-900
First
--
500-850 -300-650 -.
0 --
Second
362
400-500 600 200-550 34
0 --
Third
Pregnancy trimester
818
. 800 . -1400
-1200-3000
Early
.
.
1428
3400 300050OO . 1900 . 98 6300
Late I st stage
.
.
Labor
770
-6000
700
8000 --
2rid stage
465
---
400
13 --
Postpartum
Summary Comparison of the Levels of PGF~o and PGE in Blood (pg/ml) of Non-pregnant, Pregnant, Laboring and Postpartum Patients. Analysis by Radioimmunoassay in each Series except in that of Karim (bioassay )
PGF2 K a r i m (1968) C a i d w e l l et al. (1971)
TABLE I.
o
O"
e~
~o
t~
g~
o
g~
~o
O
O
O
rn
300
N, WZQVlST TASLE 2. Plasma Concentrations of Prostaglandins in Females (pg /ml) (after Green, 1973)
During i.v. adm. PGF~ 75 p.g/min = 108.000 ~g/24 hr
Compound
reported PGF2 15-keto-dihydro-PGF2
Endogenous total synthesis of PGF,° + PGF2. 36-61 ttg/24 hr calculated
4.450+_2.660
2
105.000 + 29.300
50
reported plasma
serum
200-300 (RIA)
10-990 (RIA) 500-2.500 (RIA) 200 (MS)
20 (MS)
15-keto-13,14-dihydro-PGF2, can be measured by the gas chromatographic-mass spectrometric technique, a specific and very sensitive method. The method has recently been applied to determine endogenous plasma levels of 15-keto-13,14-dihydro-PGF2~ in normal pregnant women and in women in spontaneous and oxytocin-induced labor at term (Gr6en et al., 1974). The concentration of 15-keto-13,14-dihydro-PGF2, in the peripheral plasma during the last 6 weeks of pregnancy and prior to the onset of normal parturition was 31 __+18pg/ml plasma. There seemed to be a small increase in the level as the day of parturition approached. During active labor the plasma level of 15-keto-13,14-dihydroPGF2~ increased as to thirty times to reach values between 267 and 942pg/ml immediately before delivery. One hour after, the concentration had decreased by 20-75 per cent. The equivalent data from patients in whom labor was induced by oxytocin showed a less consistent pattern but immediately prior to delivery the values recorded were similar to those in the series not given oxytocin. PGF2~ was also analyzed in some of these cases, using the gas chromatographic-mass spectrometric technique but there was no correlation between the concentrations found and the stage of labor. Figure 2 shows the distribution of the 15-keto-13,14-dihydro-PGF2~ values as related to the degree of cervical dilatation. This graph illustrates the progressive increment in concentrations of the metabolite which occurred during the active phase of normal labor. It may be concluded that there is an increased formation and secretion of PGF2, into the systemic circulation during the course of labor. From the blood analysis there is still incomplete evidence as to the phasing of the levels of prostaglandins at the spontaneous onset of labor, and as to whether an increase in circulating prostaglandins precedes the onset of labor.
Excretion of Urinary Metabolites of Prostaglandins Methods for quantitative determination of the major urinary metabolites of PGE~, PGE2, PGF~ and PGF2, have recently been developed (Hamberg, 1973). The levels of IOOC 90C "b h N (.9 13_ i 0
80C 70C
y
6oc 50C 40C 30C
0
20C I
IOC 4-6
2
Weeks before porturilion
~ 2"5 ~'-8 ~ cm Cervicol dilo~otion during Iobor
FIG, 2. Plasma levels of 15-keto-13,14-dihydro-PGF2. during pregnancy and labor in the human. (After Green et al., 1974.)
Endogenous prostaglandins in normal pregnancy and labor
301
these metabolites in urine appear to accurately reflect the endogenous synthesis of prostaglandin. 5ot,7a-dihydroxy-ll-ketotetranor-prostane-l,16-dioic acid is the major urinary metabolite of PGF,~ and PGF2, and the compound can be determined in 24-hr samples by multiple-ion analysis. The amount excreted in the 30th and 40th week of pregnancy corresponded to 32 - 12.2/xg/24 hr representing a two- to five-fold increases compared to that seen in non-pregnant women (Hamberg, 1974). Determination of the metabolite in serial 24-hr samples of three subjects showed that there was a gradual increase as pregnancy progressed with maximum excretion at the end of gestation (Fig. 3). In one of these cases a urine sample was obtained on the day when the patient went into spontaneous labor (collected 24 to 4 hr before birth). The amount of the dioic acid metabolite in this sample abruptly increased (50.3 p.g) as compared to the amount present in the sample collected only 9 days earlier (23.0 tzg). After delivery there was a rapid normalization of the level of the metabolite.
60-
t~ E
40-
.~ ' ~
j .-- .....
/ _ ...................
/
.A
E
o
,~
2~
~o
4~,
H
Pp
Pregnoncy week
FIG. 3. Urinary excretion of the major metabolite of PGF,. and PGF2o,5a-,7a-dihydroxy-liketotetranor-prostane-l,16-dioic acid (tzg/24hr) in three pregnant women. Arrows indicate time of delivery. (After Hamberg, 1974.) These results confirm the rapid increase in the endogenous secretion that occurs during labor and above all are indicative of a progressively increased formation during the course of pregnancy. The data presented indicate an over-all increase in the synthesis of prostaglandins but it is not established if the uterus and its contents are the main site of formation.
Occurrence of Prostaglandin in Amniotic Fluid For several reasons analysis of the prostaglandin content of amniotic fluid appears to be a particularly attractive approach to the problem under discussion: 1. Amniotic fluid is closer to the feto-placental compartment than systemic maternal blood or urine; 2. Amniotic fluid is in intimate contact with the decidua and the concentration of prostaglandin in liquor is likely to reflect the local formation and secretion of the compound from this tissue; 3. PGF2o and probably the other prostaglandins are not rapidly metabolized to any significant degree in amniotic fluid. This allows an accumulation of the compound within the uterus (Gr6en et al., 1974); 4. Prostaglandin can be determined accurately in liquor without the risk of falsely high concentrations as a result of sampling. Levels of PGF2, in the amniotic fluid were determined by Salmon and Amy (1973) using a radioimmunoassay. Concentrations of the prostaglandin were relatively constant between 15 and 35 weeks of gestation, but an increase was observed after 36 weeks. The rise continued up to the 44th week. A still greater elevation of PGF2, levels was recorded during labor and the levels were related to the degree of cervical dilatation (Fig. 4).
302
N. WIQVIST
,2 l
,o!
/ i/
0..
/
o
/
1 o L)
i
ol
1
i
i
i
ls-~ 20.-23 24"zt 2e'-~ 32-3s :zs-:~ ~o-43
Weeks PREGNANCY
3-4
s-6
7~
g'10
Cervical dilatalion,cm
LABOR
Fla. 4. Levels of PGF2. in amniotic fluid during pregnancy and labor. Values are plotted as the mean and standard error. (After Salmon and Amy, 1973.) T w o reports have recently been published by Keirse and Turnbull (1973) and by Keirse et al. (1974) on the occurrence of P G E and P G F c o m p o u n d s in amniotic fluid. The concentration of P G E was measured by gas-liquid c h r o m a t o g r a p h y with electroncapture detection. The concentration of PGF2~ was measured using a radioimmunoassay. Table 3 shows the PGE~ levels during pregnancy before the onset of clinical labor, while Table 4 shows the P G F concentrations. Figure 5 indicates the corresponding levels during the course of labor. P G E was not detected in amniotic fluid during the 38th to 41st week of gestation by the specific but rather insensitive method applied. H o w e v e r , measurable amounts were present in the very early stages of labor and the levels then increased progressively with advancing dilatation of the cervix. The P G F c o m p o u n d s were identified during intact pregnancy by a more sensitive radioimmunoassay. Amniotic fluid contained significantly less P G F at mid-gestation than at term prior to the onset of labor (p < 0,01). The P G F content was yet higher during the early first stage of labor and increased as cervical dilatation progressed. By means of gas-liquid c h r o m a t o g r a p h y with electron-capture detection and pooled amniotic fluid samples it was also established that the PGE2 and PGF2~ c o m p o u n d s were present in far greater concentrations than the P G E I and P G F , , compounds. These findings support the results obtained f r o m the m e a s u r e m e n t of the excretion of urinary metabolites and suggest that an increased secretion of PGE2 and PGF2° precedes the initiation of labor. It has, however, also been demonstrated that prostaglandins are released as a result of uterine distension which is more predominant at the end of pregnancy than at mid-gestation and which reaches a m a x i m u m during labor (Poyser et al., 1971). The increase in amniotic fluid concentrations of prostaglandin could therefore simply represent a c o n s e q u e n c e of the stretching of myometrial fibers with labor itself being TABLE3. Amniotic Fluid PGEz Levels during Late Pregnancy Before the Onset of Clinical Labor (after Keirse and Turnbull, 1973)
No. of cases
*PGE: (ng/ml)
10 1 1
