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Serum progesterone, estradiol, and estriol before and during induced labor
Serum progesterone, estradiol, and estriol before and during induced labor ANTTI
KAUPPILA
AARRE
KIVELA
KIMMO
KONTULA
RISTO Oulu,
TUIMALA
Finland
To investigate the association of serum levels of pmgesbrone (P), eetradbl (Es), and estrbl (E,) with the initiation of regular contra&ins, venous bbod arampfaer were taken prior to and 3 hours after the successful inductbn of labor in 83 pk’turients by means of low amnbtomy end intravenous oxytocin infusion. The serum P level and P/E, ratb d=scmmd end serum Ez level Wear& after induction in healthy primfgravidas and in prarturienb wtth an inltial P dominance (serum P/E, ratio more than 5). There was also a decrease in the serum P level and P/E, ratb in postterm patients and parturients with a ripe cervical state. Cholesta&s of pregnancy was assocbted wfth a rise in the serum level of ES and a decrease in the P/E, ratio. In an unfkorabte cervlql state there was a rlse in the serum E, level; patients wlth an initial El dominance (serum P/E, ratb 5 or less) showed a rise in the serum P level and PIE, ratio. Healthy multigravidas and patients with pre-ectampsla did not show any hormonal changes. The onset of induced l&or seems to he associated with a rise in serum E, concentration and/or with a drop in P concentration. The increase in serum EP fevel is thought to he due to the activation of the anterior pituitary-adrenal axis. The lower P level is supposedly a result of diminished uteropfacental circufatbn. (AM. J. O&VET. GYNECOL. 137:462, 1980.)
THE EXTENSIVE investigations already carried out, the role of fetoplacental steroid hormones in the multifactorial mechanism of human labor has remained unresolved. The decrease in the peripheral progesterone (P) level preceding both preterm’ and term2, 3 labor and the rise in the serum estradiol (E,) level before preterm4 and term3 labor have been considered important factors for the spontaneous onset of uterine contractions. A value of 5 in serum P/E, ratio is reported to precede the spontaneous onset of term labor.3 Numerous other studies, as reviewed by Fuchs,5 and other recent reports 6, ’ have nevertheless yielded contradictory data. Since it is very difficult to monitor hormonal changes which are closely related to the
DESPITE
From the Departments of Obstetrics and Gynecology Clinical Chemistry, University of 0th~. Received
for
publication
Accepted
October
Reprint requests: and Gynecology, Finland. 462
February
and
15, 1979.
I, 1979. Antti Kauppikz, Department University of Oulu, SF-90220
of Obstetrics Oulu 22,
spontaneous initiation of uterine contractions, we decided to measure the serum levels of P, Ez, and E3 prior to and following artificially induced labor.
Eighty-three patients, all having a single living fetus with a gestational age of 37 weeks or more, who had a progressive labor within at least 2 hours of the induction of labor, were selected for the present investigation. The indications for the induction were as follows: postdatism (more than 10 days over the expected day of delivery-21 cases), pre-eclampsia (17 cases), and intrahepatic cholestasis of pregnancy (three cases). In the remaining 42 cases the pregnancy was normal and the induction was conducted generally close to the expected day of delivery. Following pelvic assessment a low amniotomy was performed and intravenous infusion of oxytocin (IO U/L in 5% glucose) initiated, the infusion rate being monitored electronically. The initial rate was I.7 mU/min, with a doubling of the dose every 20 minutes until regular uterine contractions were generated. The 000%9378/80/120462+05$00.50/0
@ 1980 The C. V. Mosby
Co.
Volume Number
P, Es, and E, before and during induced labor
137 4
463
I. Serum P, serum Ez, and serum P/E2 (mean + SD.) before and after induction of labor in the total series and various subgroups*
Table
Progesterone
Parameter
No.
Initial
(nglml)
after
Estradiol
3 hr indudon
(nglml)
Progesteronelestdiol
3 hr
after induction
Initial
Initial
after
3 hr induct&m
Parity:
Healthy primigravidas Healthy multigravidas Significance
22
179 + 73
156 f 65
20
167 -c 61
164 k 79
26 f 10 29 + 17
30 2 14 3oIr 18
7.3 rt 3.1 6.3 2 1.8
5.6 It 3.2 6.1 ~fr 2.2
N.S.
N.S.
N.S.
N.S.
N.S.
N.S.
162 2 56 182 2 48
131 ” 52 180 f 49
202
158 2 68
cfn7lp1ications:
Post term Pre-eclampsia Cholestasis of pregnancy Significance induction score: 10 or less More than 10 Significance Dominant
rt 55
N.S.
N.S.
158 -’ 56
158 k 60
191 2 62 P < 0.01
161 f 67 N.S.
23
146 r 65
60
187 2 55 P < 0.01
159 2 72 160 & 60 N.S.
40 43
significances between the values of various subgroups
rate of administration
during
labor
was adjusted
ac-
cording to the strength and duration of the contractions, with a maximal rate of 28 mU/min. Uterine activity and fetal heart with a cardiotocograph
rate were recorded continuously (Hewlett Packard). In all cases
uterine contractions started within 10 to 120 minutes (mean 76 minutes) and all were delivered vaginally within 3 to 14 hours (mean 7.3 hours). Venous blood samples were drawn immediately before and 3 hours after induction. Serum was obtained by low-speed centrifugation of the blood and stored at -20”
27 f 33 f 27 f
12 14
10
N.S. 29k 28+
15 13
27 -c- 12 31 -e 11 34 k 9
6.8 f
2.8
6.1 ” 2.0
5.3 t 1.8 6.3 -c 2.1
N.S.
N.S.
5.1 t 1.4 N.S.
31 ;t 13 30 -+ 14
6.2 k 2.5 7.2 f 2.5 P < 0.05
5.6 h 2.2 6.0 t 2.4 N.S.
7.6
rt 1.3
N.S.
N.S.
39 -+ 17 25 2 9
37 r 17 282 11
3.8 7.8
f 0.7 + 22
4.6 2 1.7 6.2 r 2.3
P < 0.001
P < 0.01
P < 0.005
P < 0.01
steroid:
Estrogen (PIE, < 5) Progesterone (P/E, > 5) Significance *The
21 17 3
C until
assayed. Serum
RIA kit (The Radiochemical
Centre,
Amer-
sham, United Kingdom). The intra-assay coefficient of variation for these methods was less than 10%. All assayswere performed in duplicate. Both absolute and relative values were used in the statistical analysis of the results with Student’s t test, the relative values being calculated
from
below the actual values (N.S. = not significant).
Table II. Serum E3 before and after induction of labor (mean + S.D.).
‘km All patients Primigravidas Multigravidas Estrogen dominance
632
Progesteronedominance
650
2 277
591 t 280 684
f
273
597 It 215 -t 298
623 543 708 547 653
-r- 290 -1- 234 + 326 k 204 f 314
P and Es concentrations
were determined by the radioimmunoassay method of Hammond, Viinikka, and Vihko” and serum E3 with a commercial
are indicated
the formula
creased from 6.7 ? 2.6 to 5.8 + 2.3. The relative rise of 11% in Es concentration (P < 0.01) and the relative decrease in P/Es ratio (P CC0.05) were both significant.
Parity. No differences in initial serum P or Ez levels or in the
P/Es ratio
were
observed
between
the 22
primiparous and 20 multiparous women among the 42 healthy parturients (Table I). The decrease in relative values for serum P and the serum PIE, ratio and the rise in the relative values for E2 in the primiparous women were significant, whereas the multiparous women did not show significant changes in serum P, Et, or P/E, values (Fig. 1). Complications of pregnancy (postdatism, prw&.ampsia, cholestasis of pregnancy). No difference between these
Results Serum progesterone and estradiol. In the total series serum P level decreased from an initial value of 174 2 62 to 160 + 63 rig/ml, serum Ez level rose from
groups (including healthy parturients) could be found in the initial serum concentrations of P and Ez or in the P/E2 ratio (Table I). The decreases in the relative
28 + 13 to 30 + 13 rig/ml,
serum P values and the PIE, ratio after induction
and serum
P/Es ratio
de-
in the
464
Kauppila
et al.
%
%
120
120
110
100
100
90
90
80
80 P
70 P Fig. 1. The relative changes and progesterone/estradiol healthy primiparous (white column) women. * = P < 0.001.
E2 in serum ratio after column) 0.05; **
P/E2 progesterone, estradiol, induction of delivery in and multiparous (black = P < 0.01; *** = P <
postterm patients were significant, whereas the preeclampsia women did not show any significant changes (Fig. 2). The mean decrease of 15% in serum Pin three women with intrahepatic cholestasis of pregnancy was not significant, but the rise of 29% in the serum EZ concentration and decrease of 33% in the P/E, ratio were significant (P < 0.01). Cervical state. A modified Bishop’s score was used for the assessment of cervical ripeness. The 43 patients with a cervical score of more than 10 had a mean initial level of serum P significantly higher than that observed in the 40 patients with a score of 10 or less (Table I). The relative rise in the serum Ez level in the women with a score of 10 or less and the relative decreases in the serum P level and in the serum P/E2 ratio in the women with a score of more than 10 were all significant (Fig. 3). Initial serum PIE2 balance. When the patients were divided into two groups according to their initial P/E, ratio, 60 emerged with a ratio of more than 5 (P dominance) and 23 with 5 or less (E dominance). These groups differed significantly in their initial serum levels of P, Ez, and initial P/E, ratio (Table I). In relative terms there was a rise in serum P and the P/E2 ratio in the E-dominant women, ,whereas the P-dominant ones displayed a significant drop in these measures and a
E2
P/E2
Fig. 2. The relative changes in serum progesterone, estradiol, and progesterone/estradiol ratio after induction of delivery in postterm (white column) and pre-eclamptic (black column) women. Meaning of asterisks as in Fig. 1. significant rise in serum Ez concentration after the induction of labor (Fig. 4). !3erum estriol. Serum estriol values did not show any significant changes after induction in either the total material or the various subgroups (Table II).
Comment The initiation of induced labor was dften associated with a rise in serum level of EP, a drop in serum P, and a drop in the P/E, ratio. These findings are very similar to those recorded between women in labor and not in labor preterm4 and at term.g. lo Similar changes have also been observed in serial serum hormone determinations before and at term in carefully selected healthy primigravid patients.” It is significant that the most prominent hormonal changes in our series were seen in the uncomplicated primiparous patients. It may be postulated that the rise in serum E2 and decrease in serum P are effects rather than causes of’ the uterine contractions, as the different changes in serum P and E2 concentrations after the onset of utrrine contractions are explicable in terms of differences in the regulation of their synthesis. Since the placenta appears to be completely autonomous as regards the uteroplacental blood production of P,” a diminished flow due to the uterine contractions may alone explain the decrease in P production. Placental synthesis of E2, on the other hand, is crucially dependent on the supply of the main precursor of estrogens, dehydroepiandrosterone sulfate (DHEA-S), from both the fetal and ma-
Volume Number
P, E,, and E3 before and during induced labor
135 4
%
O/O
120
130 120
T
465
T44 [1
110 90 80
100
P
E2
PIE2
Fig. 3. The relative changes in serum progesterone, estradiol, and progesteroneiestradiol ratio after induction of delivery in women with unfavorable (white column) and favorable (black column) cervical state. Meaning of asterisks as in Fig. 1.
ternal adrenals” and labor is both a physic and physical stress, which would induce a rise in the circulating ACTH level,“3 which in turn stimulates the release of DHEA-SJ4 The above-mentioned changes in serum P and E2 concentrations were not. however, typical of all the patients studied, for the multiparous women and women with pre-eclampsia did not react to the initiation of labor with an)- hormonal changes at all. It is possible that the delivery is less stressful in multiparous than in primiparous parturients. It has been noted, for instance, that the serum cortisol level during labor is lower in multiparous than in primiparous women,15 and it is also general17 known that labor progresses rapidly in pre-eclamptic women as well as in multiparturients. The patients with an unfavorable cervical state reacted to the initiation of labor by increasing the secretion of El,. This is highly logical, as theoretical considerations”’ and empirical observations” support the importance of E2 for cervical ripening. The patients with a favorable cervix, on the other hand, displayed a withdrawal of the action of P in the uterine muscle. There ii; apparently a tendency toward an optimal level of P and E, and an optimal P/E2 balance at the onset of
REFERENCES
1. Csapo, A. I., Pohanka, 0.. and Kaihola, H. L.: Progesterone deficiency and premature labor, Br. Med. J. 1:137, 197-t.
90 80
P
E2
Fig. 4. The relative changes in serum progesterone, and progesteroneiestradiol ratio after induction of women with estrogen dominance (initial P/El ratio column) and progesterone dominance (P/E2 ratio column). Meaning of asterisks as in Fig. 1.
estradiol, delivery in ~5) (white >5) (black
labor which according to our data could be about 160 rig/ml for P, about 30 rig/ml for E2, and about 5.5 to 6.0 for the P/E2 ratio, figures which correlate with those reported to be essential for labor both preterm4 and at term,3 A physiologic drive for an ideal hormonal milieu and balance was strikingly demonstrated by the opposite postinduction hormonal changes observed in the initially P-dominant and E-dominant parturients, the E-dominant women reacting by increasing their serum level of P, and the P-dominant ones by increasing their serum E2 and reducing the concentration of’ P. The central role of prostaglandins as intrinsic factors in the mechanism of human labor is substantiated by many clinical observations, as recently reviewed.s* IR, ” Both their synthesis and their metabolism are under the control of P and E, (for reviews, see McDonald and associates1s and Flower”“). An ideal, well-balanced equilibrium vf P and E2 is probably a premise for the fluent production and metabolism of prostaglandins during human delivery.
2. Csapo, A. I., Knobil, E., van der Molen, H. J., and Wiest, W. G.: Peripheral plasma progesterone levels during human pregnancy and labor, AM. J. OBVFET. GYNECOL. 110:630, 1971.
466
s.
4.
5.
6.
7.
8.
9
10
11.
Kauppila et al.
Turnbull, A. C., Patten, P. T., Flint, A. P. F., Keirse, M. J. N. C., Jeremy, J. Y., and Anderson, A. B. M.: Significant fall in progesterone and rise in oestradiol levels in human peripheral plasma before onset of labor, Lancet l:lOl, 1974. Tamby Raja, R. L., Anderson, A. B. M., and Turnbull, A. C.: Endocrine changes in premature labor, Br. Med. J. 2:67, 1974. Fuchs, F.: Endocrinology of labor, in Fuchs, F., and Klopper, A., editors: Endocrinology of Pregnancy, New York, 1977, Harper & Row, pp. 327-349. Coats, P., Florensa, E., Youssefnejadian, E., and Craft, I.: Plasma steroids in the foetal and maternal circulation at normal delivery and elective caesarean section, Acta Obstet. Gvnecol. Stand. 57: 121. 1978. Boroditsky, R. S., Reyes, F. I:, Winter, J, S. D., and Faiman, C.: Maternal serum estrogen and progesterone concentrations preceding normal labor, Obstet. Gynecol. 51:686, 1978. Hammond, G. L., Viinikka, L., and Vihko, R.: Automation of radioimmunoassays for some steroids with use of both iodinated and tritiated ligands, Clin. Chem. 23:1250, 1977. Pokoly, T. B., and Jordan, V. C.: Relation of steroids and prostaglandins at vaginal delivery and cesarean section, Obstet. Gynecol. 46:577, 1975. Kauppila, A., and Puukka, M.: Cytosol estrogen receptor in human myometrium at term of pregnancy. (a&t.), VIII World Congress of Gvnecologv and Obsterics 1976, International C&gress Series 39%, Amsterdam, 1976, Excerpta Medica, p. 12. Klopper, A., and Fuchs, F.: Progestagens, in Fuchs, F.,
June 15, 1980 Am. J. Obstet. G~necd
12.
13.
14.
15.
16. 17.
18.
19.
20.
and Klopper, A., editors: Endocrinology of Pregnancy, New York, 1,977, Harper & Row, pp. 99-122. Crystle, C. D., Dubin, N. H., Grannis, G. F., Stevens, V. C., and Townsley, J. D.: Investigation of precursor availability in the regulation of estrogen synthesis in normal human pregnancy, Obstet. Gynecol. 42:718, 1973. Kauppila, A., Tuimala, R., and Haapalahti, J.: Maternal adrenocorticotrophic hormone and cortisol during labour and vaginal delivery, J. Obstet. Gynaecol. Br. Commonw. 81:691, 1974. Schindler, A. E., Munding, M., Walk, T., Bartholomae, J., and Nieschlag, E.: Changes of plasma dehydroepiandrosterone during labor, J. Endocrinol. 67:305, 1975. Tuimala, R., Kauppila, A., and Haapalahti, J.: Response of pituitary-adrenal axis on partal stress, Obstet. Gynecol. 46:275, 1975. Liggins, G. C.: Ripening of the cervix, Sem. Perinatol. 2:261, 1978. Gordon, A. J., and Calder, A. A.: Oestradiol applied locally to ripen the unfavourable cervix, Lancet. 2:1319. 1977. Liggins, G. C., Forster, C. S., Grieves, S. A., and Schwartz, A. L.: Control of parturition in man, Biol. Reprod. 16:39, 1977. MacDonald, P. C., Porter, J. C., Schwartz, B. E., and Johnston, J. M.: Initiation of parturition in the human female, Sem. Perinatol. 2:273, 1978. Flower, R. J.: The role of prostaglandins in parturition, with special reference to the rat, in Ciba Foundation Symposium 47: The Fetus and Birth, Amsterdam, 1977, Elsevier, Excerpta Medica, pp. 297-3 18.
KAUPPILA
AARRE
KIVELA
KIMMO
KONTULA
RISTO Oulu,
TUIMALA
Finland
To investigate the association of serum levels of pmgesbrone (P), eetradbl (Es), and estrbl (E,) with the initiation of regular contra&ins, venous bbod arampfaer were taken prior to and 3 hours after the successful inductbn of labor in 83 pk’turients by means of low amnbtomy end intravenous oxytocin infusion. The serum P level and P/E, ratb d=scmmd end serum Ez level Wear& after induction in healthy primfgravidas and in prarturienb wtth an inltial P dominance (serum P/E, ratio more than 5). There was also a decrease in the serum P level and P/E, ratb in postterm patients and parturients with a ripe cervical state. Cholesta&s of pregnancy was assocbted wfth a rise in the serum level of ES and a decrease in the P/E, ratio. In an unfkorabte cervlql state there was a rlse in the serum E, level; patients wlth an initial El dominance (serum P/E, ratb 5 or less) showed a rise in the serum P level and PIE, ratio. Healthy multigravidas and patients with pre-ectampsla did not show any hormonal changes. The onset of induced l&or seems to he associated with a rise in serum E, concentration and/or with a drop in P concentration. The increase in serum EP fevel is thought to he due to the activation of the anterior pituitary-adrenal axis. The lower P level is supposedly a result of diminished uteropfacental circufatbn. (AM. J. O&VET. GYNECOL. 137:462, 1980.)
THE EXTENSIVE investigations already carried out, the role of fetoplacental steroid hormones in the multifactorial mechanism of human labor has remained unresolved. The decrease in the peripheral progesterone (P) level preceding both preterm’ and term2, 3 labor and the rise in the serum estradiol (E,) level before preterm4 and term3 labor have been considered important factors for the spontaneous onset of uterine contractions. A value of 5 in serum P/E, ratio is reported to precede the spontaneous onset of term labor.3 Numerous other studies, as reviewed by Fuchs,5 and other recent reports 6, ’ have nevertheless yielded contradictory data. Since it is very difficult to monitor hormonal changes which are closely related to the
DESPITE
From the Departments of Obstetrics and Gynecology Clinical Chemistry, University of 0th~. Received
for
publication
Accepted
October
Reprint requests: and Gynecology, Finland. 462
February
and
15, 1979.
I, 1979. Antti Kauppikz, Department University of Oulu, SF-90220
of Obstetrics Oulu 22,
spontaneous initiation of uterine contractions, we decided to measure the serum levels of P, Ez, and E3 prior to and following artificially induced labor.
Eighty-three patients, all having a single living fetus with a gestational age of 37 weeks or more, who had a progressive labor within at least 2 hours of the induction of labor, were selected for the present investigation. The indications for the induction were as follows: postdatism (more than 10 days over the expected day of delivery-21 cases), pre-eclampsia (17 cases), and intrahepatic cholestasis of pregnancy (three cases). In the remaining 42 cases the pregnancy was normal and the induction was conducted generally close to the expected day of delivery. Following pelvic assessment a low amniotomy was performed and intravenous infusion of oxytocin (IO U/L in 5% glucose) initiated, the infusion rate being monitored electronically. The initial rate was I.7 mU/min, with a doubling of the dose every 20 minutes until regular uterine contractions were generated. The 000%9378/80/120462+05$00.50/0
@ 1980 The C. V. Mosby
Co.
Volume Number
P, Es, and E, before and during induced labor
137 4
463
I. Serum P, serum Ez, and serum P/E2 (mean + SD.) before and after induction of labor in the total series and various subgroups*
Table
Progesterone
Parameter
No.
Initial
(nglml)
after
Estradiol
3 hr indudon
(nglml)
Progesteronelestdiol
3 hr
after induction
Initial
Initial
after
3 hr induct&m
Parity:
Healthy primigravidas Healthy multigravidas Significance
22
179 + 73
156 f 65
20
167 -c 61
164 k 79
26 f 10 29 + 17
30 2 14 3oIr 18
7.3 rt 3.1 6.3 2 1.8
5.6 It 3.2 6.1 ~fr 2.2
N.S.
N.S.
N.S.
N.S.
N.S.
N.S.
162 2 56 182 2 48
131 ” 52 180 f 49
202
158 2 68
cfn7lp1ications:
Post term Pre-eclampsia Cholestasis of pregnancy Significance induction score: 10 or less More than 10 Significance Dominant
rt 55
N.S.
N.S.
158 -’ 56
158 k 60
191 2 62 P < 0.01
161 f 67 N.S.
23
146 r 65
60
187 2 55 P < 0.01
159 2 72 160 & 60 N.S.
40 43
significances between the values of various subgroups
rate of administration
during
labor
was adjusted
ac-
cording to the strength and duration of the contractions, with a maximal rate of 28 mU/min. Uterine activity and fetal heart with a cardiotocograph
rate were recorded continuously (Hewlett Packard). In all cases
uterine contractions started within 10 to 120 minutes (mean 76 minutes) and all were delivered vaginally within 3 to 14 hours (mean 7.3 hours). Venous blood samples were drawn immediately before and 3 hours after induction. Serum was obtained by low-speed centrifugation of the blood and stored at -20”
27 f 33 f 27 f
12 14
10
N.S. 29k 28+
15 13
27 -c- 12 31 -e 11 34 k 9
6.8 f
2.8
6.1 ” 2.0
5.3 t 1.8 6.3 -c 2.1
N.S.
N.S.
5.1 t 1.4 N.S.
31 ;t 13 30 -+ 14
6.2 k 2.5 7.2 f 2.5 P < 0.05
5.6 h 2.2 6.0 t 2.4 N.S.
7.6
rt 1.3
N.S.
N.S.
39 -+ 17 25 2 9
37 r 17 282 11
3.8 7.8
f 0.7 + 22
4.6 2 1.7 6.2 r 2.3
P < 0.001
P < 0.01
P < 0.005
P < 0.01
steroid:
Estrogen (PIE, < 5) Progesterone (P/E, > 5) Significance *The
21 17 3
C until
assayed. Serum
RIA kit (The Radiochemical
Centre,
Amer-
sham, United Kingdom). The intra-assay coefficient of variation for these methods was less than 10%. All assayswere performed in duplicate. Both absolute and relative values were used in the statistical analysis of the results with Student’s t test, the relative values being calculated
from
below the actual values (N.S. = not significant).
Table II. Serum E3 before and after induction of labor (mean + S.D.).
‘km All patients Primigravidas Multigravidas Estrogen dominance
632
Progesteronedominance
650
2 277
591 t 280 684
f
273
597 It 215 -t 298
623 543 708 547 653
-r- 290 -1- 234 + 326 k 204 f 314
P and Es concentrations
were determined by the radioimmunoassay method of Hammond, Viinikka, and Vihko” and serum E3 with a commercial
are indicated
the formula
creased from 6.7 ? 2.6 to 5.8 + 2.3. The relative rise of 11% in Es concentration (P < 0.01) and the relative decrease in P/Es ratio (P CC0.05) were both significant.
Parity. No differences in initial serum P or Ez levels or in the
P/Es ratio
were
observed
between
the 22
primiparous and 20 multiparous women among the 42 healthy parturients (Table I). The decrease in relative values for serum P and the serum PIE, ratio and the rise in the relative values for E2 in the primiparous women were significant, whereas the multiparous women did not show significant changes in serum P, Et, or P/E, values (Fig. 1). Complications of pregnancy (postdatism, prw&.ampsia, cholestasis of pregnancy). No difference between these
Results Serum progesterone and estradiol. In the total series serum P level decreased from an initial value of 174 2 62 to 160 + 63 rig/ml, serum Ez level rose from
groups (including healthy parturients) could be found in the initial serum concentrations of P and Ez or in the P/E2 ratio (Table I). The decreases in the relative
28 + 13 to 30 + 13 rig/ml,
serum P values and the PIE, ratio after induction
and serum
P/Es ratio
de-
in the
464
Kauppila
et al.
%
%
120
120
110
100
100
90
90
80
80 P
70 P Fig. 1. The relative changes and progesterone/estradiol healthy primiparous (white column) women. * = P < 0.001.
E2 in serum ratio after column) 0.05; **
P/E2 progesterone, estradiol, induction of delivery in and multiparous (black = P < 0.01; *** = P <
postterm patients were significant, whereas the preeclampsia women did not show any significant changes (Fig. 2). The mean decrease of 15% in serum Pin three women with intrahepatic cholestasis of pregnancy was not significant, but the rise of 29% in the serum EZ concentration and decrease of 33% in the P/E, ratio were significant (P < 0.01). Cervical state. A modified Bishop’s score was used for the assessment of cervical ripeness. The 43 patients with a cervical score of more than 10 had a mean initial level of serum P significantly higher than that observed in the 40 patients with a score of 10 or less (Table I). The relative rise in the serum Ez level in the women with a score of 10 or less and the relative decreases in the serum P level and in the serum P/E2 ratio in the women with a score of more than 10 were all significant (Fig. 3). Initial serum PIE2 balance. When the patients were divided into two groups according to their initial P/E, ratio, 60 emerged with a ratio of more than 5 (P dominance) and 23 with 5 or less (E dominance). These groups differed significantly in their initial serum levels of P, Ez, and initial P/E, ratio (Table I). In relative terms there was a rise in serum P and the P/E2 ratio in the E-dominant women, ,whereas the P-dominant ones displayed a significant drop in these measures and a
E2
P/E2
Fig. 2. The relative changes in serum progesterone, estradiol, and progesterone/estradiol ratio after induction of delivery in postterm (white column) and pre-eclamptic (black column) women. Meaning of asterisks as in Fig. 1. significant rise in serum Ez concentration after the induction of labor (Fig. 4). !3erum estriol. Serum estriol values did not show any significant changes after induction in either the total material or the various subgroups (Table II).
Comment The initiation of induced labor was dften associated with a rise in serum level of EP, a drop in serum P, and a drop in the P/E, ratio. These findings are very similar to those recorded between women in labor and not in labor preterm4 and at term.g. lo Similar changes have also been observed in serial serum hormone determinations before and at term in carefully selected healthy primigravid patients.” It is significant that the most prominent hormonal changes in our series were seen in the uncomplicated primiparous patients. It may be postulated that the rise in serum E2 and decrease in serum P are effects rather than causes of’ the uterine contractions, as the different changes in serum P and E2 concentrations after the onset of utrrine contractions are explicable in terms of differences in the regulation of their synthesis. Since the placenta appears to be completely autonomous as regards the uteroplacental blood production of P,” a diminished flow due to the uterine contractions may alone explain the decrease in P production. Placental synthesis of E2, on the other hand, is crucially dependent on the supply of the main precursor of estrogens, dehydroepiandrosterone sulfate (DHEA-S), from both the fetal and ma-
Volume Number
P, E,, and E3 before and during induced labor
135 4
%
O/O
120
130 120
T
465
T44 [1
110 90 80
100
P
E2
PIE2
Fig. 3. The relative changes in serum progesterone, estradiol, and progesteroneiestradiol ratio after induction of delivery in women with unfavorable (white column) and favorable (black column) cervical state. Meaning of asterisks as in Fig. 1.
ternal adrenals” and labor is both a physic and physical stress, which would induce a rise in the circulating ACTH level,“3 which in turn stimulates the release of DHEA-SJ4 The above-mentioned changes in serum P and E2 concentrations were not. however, typical of all the patients studied, for the multiparous women and women with pre-eclampsia did not react to the initiation of labor with an)- hormonal changes at all. It is possible that the delivery is less stressful in multiparous than in primiparous parturients. It has been noted, for instance, that the serum cortisol level during labor is lower in multiparous than in primiparous women,15 and it is also general17 known that labor progresses rapidly in pre-eclamptic women as well as in multiparturients. The patients with an unfavorable cervical state reacted to the initiation of labor by increasing the secretion of El,. This is highly logical, as theoretical considerations”’ and empirical observations” support the importance of E2 for cervical ripening. The patients with a favorable cervix, on the other hand, displayed a withdrawal of the action of P in the uterine muscle. There ii; apparently a tendency toward an optimal level of P and E, and an optimal P/E2 balance at the onset of
REFERENCES
1. Csapo, A. I., Pohanka, 0.. and Kaihola, H. L.: Progesterone deficiency and premature labor, Br. Med. J. 1:137, 197-t.
90 80
P
E2
Fig. 4. The relative changes in serum progesterone, and progesteroneiestradiol ratio after induction of women with estrogen dominance (initial P/El ratio column) and progesterone dominance (P/E2 ratio column). Meaning of asterisks as in Fig. 1.
estradiol, delivery in ~5) (white >5) (black
labor which according to our data could be about 160 rig/ml for P, about 30 rig/ml for E2, and about 5.5 to 6.0 for the P/E2 ratio, figures which correlate with those reported to be essential for labor both preterm4 and at term,3 A physiologic drive for an ideal hormonal milieu and balance was strikingly demonstrated by the opposite postinduction hormonal changes observed in the initially P-dominant and E-dominant parturients, the E-dominant women reacting by increasing their serum level of P, and the P-dominant ones by increasing their serum E2 and reducing the concentration of’ P. The central role of prostaglandins as intrinsic factors in the mechanism of human labor is substantiated by many clinical observations, as recently reviewed.s* IR, ” Both their synthesis and their metabolism are under the control of P and E, (for reviews, see McDonald and associates1s and Flower”“). An ideal, well-balanced equilibrium vf P and E2 is probably a premise for the fluent production and metabolism of prostaglandins during human delivery.
2. Csapo, A. I., Knobil, E., van der Molen, H. J., and Wiest, W. G.: Peripheral plasma progesterone levels during human pregnancy and labor, AM. J. OBVFET. GYNECOL. 110:630, 1971.
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