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Effect of stress during labor on the concentration of cortisol and estriol in maternal plasma
Effect of stress during labor on the concentration of cortisol and estriol in maternal plasma J. M. MALTAU, M.D. 0. V. EIELSEN, M.D. K. T. STOKKE, M.D. Oslo, Norway
The effect of stress during labor on the plasma concentration of cortisol, unconjugated estriol, and human chorionic somatomammoiropin was studied in 15 heaithy primiparous women. Acco;ding to the method of pain relief the parturients were divided into two groups. One group was given continuous epidural analgesia and the other group received pethidine, diazepam, and nitrous oxide/oxygen in response to pain. In the most stressed nonepidural group there was a significant rise in the cortisol level during labor and the estriol concentration fell significantly. In the epidural group no significant changes were observed with respect to the concentration of either cortisol or estriol. These results give further support to the hypothesis that severe maternal stress may lead to a reduced concentration of estriol in maternal plasma. (AM. J. OBSTET. GYNECOL 134:681, 1979.)
DETERMINATION ofunconjugated estriol in maternal plasma has gained wide acceptance as a fetoplacental function test. 1 Fetc>placental insufficiency, however, is not the only factor influencing the estriol production. For instance, it has been shown that administration of corticosteroids to the mother leads to a marked suppression of the synthesis of estriol precursors. 2 Stress during labor is known to stimulate the maternal hypothalamic-pituitary-adrenal axis. 3 This leads to an increased concentration of cortisol in maternal plasma. The present study was undertaken to see if pain-induced stress during labor is of importance for estriol productton. The cortisol-estriol levels were determined during pain-free labor with the use of continuous epidural analgesic drugs as well as during labor with partial relief of pain by conventional centralacting analgesic drugs.
Material and methods Fifteen healthy primiparous patients (21 to 37 years old) were studied during spontaneous labor. The gestational ages varied from 37 to 42 weeks. All pregnanFrom ihe Deparimenis of Obsteirics and Gynecology, Anesthesiology, and Clinical Chemistry, Rikshospitalet. Received jar publication May 24, 1978. Accepted September 13, 1978. Reprint requests: Dr.]. M. Maltau, Department of Obstetrics and Gynecology, Rikshospitalet, Oslo 1, Norway.
0002-9378/79/140681+04$00.40/0
©
1979 The C. V. Mosby Co.
cies were uncomplicated and the study was restricted to labors starting in the morning. Oxytocin was not given. Informed consent was obtained before patients entered the study. Due to ethical reasons strict randomization was omitted. All patients knew and had chosen the method of analgesia to be utilized. The eight patients in the nonepidural group (conventional analgesia) received pethidine, 100 mg intramuscularly, as a single agent or in combination with diazepam, 10 mg orally. A 50/50 mixture of nitrous oxide and oxygen was available for self-administration. A transvaginal pudendal block was given during the second stage of labor. One of the patients did not accept central-acting analgesic or sedative drugs. The seven parturients in the epidural group received a continuous epidural analgesic drug according to our standard technique 4 early in the first stage of labor. Bupivacaine without adrenaline (Marcain, A/B Astra), 0.25%, was injected into the epidural space through an indwelling catheter. The initial dose ofbupivacaine was 25 mg. Top-up doses varying from 12 to 25 mg were administered according to the need of each patient. Other analgesics or sedatives were not given. The mean duration of labor (from admittance to delivery) was about 14 hours in both groups (range 8 to 19 hours). All neonates were healthy with Apgar scores of 9 or 10 at 5 minutes. Birth weight and placental weight were within normal ranges. Blood samples for determination of estriol, cortisol,
681
682 Maltau, Elelsen, and Stokke
july 15, 1979
Am. J. Obstet. Gynecol.
EPIDURAL _JNALGE$1A
COHYENT!OHA!..
h7
ANALGESIA
3DDO
DELIVERY
0
n=a
....,
DELIVERY
0
lzooo
il~ -·~r~ 1·5
11-8
10
CERVICAL DILATATION (cml
30mln POSTPARTUM
1·5
8·8
10
CERVICAL DILATATION (em)
3011Jin POST~ATIJII
"«· i. Piasma concentration of conisol at different stages of labor. Left: Patients receiving continuous epidural analgesic drug. Right: Patients receiving conventional analgesic drug.
Table I. Maternal plasma concentration of estriol and cortisol in the epidural group and in the nonepidural group (conventional analgesia); values are given as mean ± SD Cervical diltJtation 1-5 em
Estriol (nmol/L): 47 ± 16 EP,idural 43± 9 Nonepidural Cortisol (nmol/L): Epidural 1, 186 ± 284 Nonepi1,644 ± 433 dural
6-8 em
51± 15 36± 8* 1,367 ± 451 2,050 ± 465
JOcm
45 ± 14 29 ± 12t 1,465 ±443 2,452 ± 412:j:
*Significance of difference from the initial level: p < 0.02 tSignificance of difference from the initial level: p < 0.01 :j:Significance of difference from the initial level: p < 0.05
and human chorionic somatomammotropin (hCS) were drawn from an antecubital vein into heparinized tubes at the foHowing stages: ( l) at a cervical dilatation of l to 5 em, (2) at a cervical dilatation of 6 to 8 em, (3) at a cervical dilatation of lO em, and (4) 30 minutes after delivery. The first sample in the epidural group was taken before the analgesic drug was administered. Plasma was immediately separated from the corpuscles and stored at -20" C until analyzed. Homtoae analy.es. All samples were run in duplicate, and the complete series of samples from one patient was ar.aly£ed in the san~ run. The concenta-ation of unconjugated estriol in plasma was determined by radioimmunoassay principally according to the tne-t..ltod of Goebelsmann and associates. 5 Own antiserum directed against 6-keto-estriol 6-carboxy-methoxime:
bovine serum albumin was used. No chromatographic purification of the diethyl ether extract was performed since cross-reaction with other steroids was insignificant. The coefficient of variation (CV) (between assays) for estriol analysis was 10%. Cortisol in plasma was determined by doubie-antibody radioimmunoassay technique with reagents purchased from Diagnostic Products Corporation. The CV of the anaiysis was 8%. The plasma concentration of hCS was determined by the HPL immunoassay kit supplied by The Radiochemical Centre, Amersham, England; the CV was 7%. Statistical method. The Wikoxon two-sample test was used.
Cortisol. The concentration of cortisol in each patient at the different stages of labor is shown in Fig. 1. Table I gives the statistical data. In the "stressed" nonepidural group there was a significant increase in plasma cortisol level from the initial value early in labor to the second stage (p < 0.05). Two of the patients in this group had suffered some pain before the first blood sample was obtained. This is reflected in a high initial concentration of cortisol, especially in one of these patients. In the epidural group there was a slight and insignificant increase in cortisol. In two of the parturients there was an actual faH in cortisol concentration during labor. None of the parturients who received the epidural analgesic drug had been noticeably stressed before entering the study. Estriol. Fig. 2 shows the concentration of unconjugated estriol in w..aterttal p!asw..a at the different stages. The statistical data are given in Table I. During labor there was a significant fall in estriol
Volume 134 Number 6
Effect of stress during labor on cortisol and estriol 683
EPIDURAL ANALGESIA
CONVENTIONAL ANALGESIA DELIVERY
n•7
n• 8
0
60
·; 0
E ~
..
40
!~20r ~~~
t~~~ 1 ·5
6 ·8
CERVICAL DILATATION (em)
10
30 min
POSTPARTUM
1-5
8-8
CERVICAL DILATATION (em)
10
30 min
POSTPARTUM
Fig. 2. Plasma concentration of unconjugated estriol at different stages of labor. Left: Patients reet,iving continuous epidural analgesic drug. Right: Patients receiving conventional analgesic drug.
(p < 0.01) in the nonepidural group. In the "unstressed" group the 1range was wider and the changes less consistent. The mean values at the different stages of labor were, however, almost constant. Statistical analysis revealed no significant influence on the estriol concentration in the· epidural group. Determination of hCS was introduced as a parameter of the piacentai function. The piasma concentration was within the normal range and there was no significant difference between the two groups.
Comment During labor and delivery a considerable rise in the production of cortisol may occur, usually more marked in primiparous than in multiparous patients. 6 Pain is one of the several stimuli known to initiate such a rise. 7 In a recent study8 we have shown that the intramuscular administration of a single dose of a synthetic corticosteroid (b<~tamethasone, 12 mg) leads to a more than 50% reduction in the estriol concentration in maternal plasma within 4 hours. This effect may be due to cortisol inhibition of the synthesis of fetal adrenocorticotropic hormone (ACTH), subsequently reducing the production of estriol precursors, mainly 16a-hydroxydehydroepiandrosterone in the fetal adrenal cortex. 9 In the present study the two groups of patients differed from each other only with respect to the type and efficiency of pain relief. In other respects the groups were very similar, including the placental function as judged by the concentration of hCS. A considerable difference in the cortisol response during labor and delivery was observed. In the "stressed'" nonepiduraii group there was a marked and significant rise in the cortisol level. In the epidural group, however, only a slight and nonsignificant rise was observed. This is in concert with the results presented by Thornton and associates 7 who found that continuous
epidural analgesia was able to block the adrenocortical response to stress only to a certain extent. A fall in the concentration of unconjugated estriol was observed in every patient in the nonepidural group. In fact, the patient with the highest cortisol value also displayed the lowest estriol level. In the epidural group no significant change was observed in the estrioi concentration. In a simiiar study Okada and colleagues 10 also found a significant increase in cortisol during labor, whereas the decreases in the plasma concentration of estriol was not significant (p > 0.05). In our study, however, a significant fall in estriol was observed in the stressed group (p < 0.01). The difference between these two studies may be due to differences in parity, in the duration of labor, and in the type of aP.algesia. Simmer and associates 2 found that administration of 150 mg cortisol intravenously in three divided doses led to a sixfold increase in the plasma concentration of cortisol. This increase was followed by a reduction in maternal plasma concentration of estriol. In our study the parturients being most stressed (the nonepidural group) showed a threefold increase in cortisol as compared to the level seen in normal third-trimester pregnancies.8 Thus labor may induce a rise in the concentration of cortisol high enough to suppress fetal ACTH production and thereby also estriol synthesis. When pain is relieved by means of epidural analgesia, this effect is less pronounced. The present investigation, therefore, supports the hypothesis that an increased maternal cortisol concentration may suppress the production of estriol. This mechanism has also been suggested as an explanation of diurnal variations of estriol.U The study indicates that severe maternal stress in pregnancy may have to be considered when estriol is used as a fetoplacental function test.
July 15, 1979 Am. J. Obstet. Gynecol.
684 Maltau, Eielsen, and Stokke
REFERENCES I. Kiinzig, H.]., and Geiger, W.: Estrogens, in Biochemical methods for monitoring risk pregnancies, Contrib. Gynecol. Obstet. 2:2, 1976. 2. Simmer, H. H., Tulchinsky, D., Gold, E. M., et al.: On the regulation of estrogen production by cortisol and ACTH in human pregnancy at term, AM. J. OssTET. GvNECOL. 119:283, 1974. 3. Buchan, P. C., Milne, M. K., and Browning, M. C. K.: The effect of continuous epidural blockade on plasma 11hydroxycorticosteroid concentrations in labour, Br. ]. Obstet. Gynaecol. 80:974, 1973. 4. Maltau,J. M., and Andersen, H. T.: Continuous epidural anaesthesia with a low frequency of instrumental der-. nvenes, /\Cia vosler. vynecm. ;,canu. a-t:<±vl, 1>11:>. 5. Goebelsmann, U., Katagiri, H., Stanczyk, F. Z., eta!.: Estriol assays in obstetrics,]. Steroid Biochem. 6:703, 1975. 6. Tuimala, R. J., Kauppila, A. J. 1., and Haapalahti, J.: Response of pituitary-adrenal axis on partal stress, Obstet. Gynecol. 46:275, 1975. 7. Thornton, C. A., Carrie, L. E. S., Sayers, L., et al.: A l"
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comparison of the effect of extradural and parenteral analgesia on maternal plasma cortisol concentrations during labour and the puerperium, Br. .J. Obstet. Gynaecol. 83:631' 1976. Maltau, ]. M., Stokke, K. T., and Moe, N .: Effects of betamethasone on plasma levels of estriol, cortisol and HCS in late pregnancy, Acta Obstet. Gynecoi. Scand. 58: 1979. (In press.) Simmer, H. H., Frankland, M., and Greipel, M.: On the regulation of fetal and maternal l6a-hydroxydehydroepiandrosterone and its sulfate by cortisol and ACTH in human pregnancy at term, AM. J. OssTET. GvNECOL. 121:646, 1975. Okada, D. M., Tulchinsky, D., Ross, J. W., eta!.: Plasma estrone, estradiol, estriol, prog~stcrone, and cortisol in normal labour, AM. j. 0RSTET. GVNECOL. 119:502, 1974. Katagiri, H., Distler, W., Freeman, R. K., eta!.: Estriol in pregnancy. IV. Normal concentrations, diurnal and/or episodic variations, and day to day changes of unconjugated and total estriol in late pregnancy plasma, AM. J. 0RSTET. GYNECOL. 124:272, 1976.
The effect of stress during labor on the plasma concentration of cortisol, unconjugated estriol, and human chorionic somatomammoiropin was studied in 15 heaithy primiparous women. Acco;ding to the method of pain relief the parturients were divided into two groups. One group was given continuous epidural analgesia and the other group received pethidine, diazepam, and nitrous oxide/oxygen in response to pain. In the most stressed nonepidural group there was a significant rise in the cortisol level during labor and the estriol concentration fell significantly. In the epidural group no significant changes were observed with respect to the concentration of either cortisol or estriol. These results give further support to the hypothesis that severe maternal stress may lead to a reduced concentration of estriol in maternal plasma. (AM. J. OBSTET. GYNECOL 134:681, 1979.)
DETERMINATION ofunconjugated estriol in maternal plasma has gained wide acceptance as a fetoplacental function test. 1 Fetc>placental insufficiency, however, is not the only factor influencing the estriol production. For instance, it has been shown that administration of corticosteroids to the mother leads to a marked suppression of the synthesis of estriol precursors. 2 Stress during labor is known to stimulate the maternal hypothalamic-pituitary-adrenal axis. 3 This leads to an increased concentration of cortisol in maternal plasma. The present study was undertaken to see if pain-induced stress during labor is of importance for estriol productton. The cortisol-estriol levels were determined during pain-free labor with the use of continuous epidural analgesic drugs as well as during labor with partial relief of pain by conventional centralacting analgesic drugs.
Material and methods Fifteen healthy primiparous patients (21 to 37 years old) were studied during spontaneous labor. The gestational ages varied from 37 to 42 weeks. All pregnanFrom ihe Deparimenis of Obsteirics and Gynecology, Anesthesiology, and Clinical Chemistry, Rikshospitalet. Received jar publication May 24, 1978. Accepted September 13, 1978. Reprint requests: Dr.]. M. Maltau, Department of Obstetrics and Gynecology, Rikshospitalet, Oslo 1, Norway.
0002-9378/79/140681+04$00.40/0
©
1979 The C. V. Mosby Co.
cies were uncomplicated and the study was restricted to labors starting in the morning. Oxytocin was not given. Informed consent was obtained before patients entered the study. Due to ethical reasons strict randomization was omitted. All patients knew and had chosen the method of analgesia to be utilized. The eight patients in the nonepidural group (conventional analgesia) received pethidine, 100 mg intramuscularly, as a single agent or in combination with diazepam, 10 mg orally. A 50/50 mixture of nitrous oxide and oxygen was available for self-administration. A transvaginal pudendal block was given during the second stage of labor. One of the patients did not accept central-acting analgesic or sedative drugs. The seven parturients in the epidural group received a continuous epidural analgesic drug according to our standard technique 4 early in the first stage of labor. Bupivacaine without adrenaline (Marcain, A/B Astra), 0.25%, was injected into the epidural space through an indwelling catheter. The initial dose ofbupivacaine was 25 mg. Top-up doses varying from 12 to 25 mg were administered according to the need of each patient. Other analgesics or sedatives were not given. The mean duration of labor (from admittance to delivery) was about 14 hours in both groups (range 8 to 19 hours). All neonates were healthy with Apgar scores of 9 or 10 at 5 minutes. Birth weight and placental weight were within normal ranges. Blood samples for determination of estriol, cortisol,
681
682 Maltau, Elelsen, and Stokke
july 15, 1979
Am. J. Obstet. Gynecol.
EPIDURAL _JNALGE$1A
COHYENT!OHA!..
h7
ANALGESIA
3DDO
DELIVERY
0
n=a
....,
DELIVERY
0
lzooo
il~ -·~r~ 1·5
11-8
10
CERVICAL DILATATION (cml
30mln POSTPARTUM
1·5
8·8
10
CERVICAL DILATATION (em)
3011Jin POST~ATIJII
"«· i. Piasma concentration of conisol at different stages of labor. Left: Patients receiving continuous epidural analgesic drug. Right: Patients receiving conventional analgesic drug.
Table I. Maternal plasma concentration of estriol and cortisol in the epidural group and in the nonepidural group (conventional analgesia); values are given as mean ± SD Cervical diltJtation 1-5 em
Estriol (nmol/L): 47 ± 16 EP,idural 43± 9 Nonepidural Cortisol (nmol/L): Epidural 1, 186 ± 284 Nonepi1,644 ± 433 dural
6-8 em
51± 15 36± 8* 1,367 ± 451 2,050 ± 465
JOcm
45 ± 14 29 ± 12t 1,465 ±443 2,452 ± 412:j:
*Significance of difference from the initial level: p < 0.02 tSignificance of difference from the initial level: p < 0.01 :j:Significance of difference from the initial level: p < 0.05
and human chorionic somatomammotropin (hCS) were drawn from an antecubital vein into heparinized tubes at the foHowing stages: ( l) at a cervical dilatation of l to 5 em, (2) at a cervical dilatation of 6 to 8 em, (3) at a cervical dilatation of lO em, and (4) 30 minutes after delivery. The first sample in the epidural group was taken before the analgesic drug was administered. Plasma was immediately separated from the corpuscles and stored at -20" C until analyzed. Homtoae analy.es. All samples were run in duplicate, and the complete series of samples from one patient was ar.aly£ed in the san~ run. The concenta-ation of unconjugated estriol in plasma was determined by radioimmunoassay principally according to the tne-t..ltod of Goebelsmann and associates. 5 Own antiserum directed against 6-keto-estriol 6-carboxy-methoxime:
bovine serum albumin was used. No chromatographic purification of the diethyl ether extract was performed since cross-reaction with other steroids was insignificant. The coefficient of variation (CV) (between assays) for estriol analysis was 10%. Cortisol in plasma was determined by doubie-antibody radioimmunoassay technique with reagents purchased from Diagnostic Products Corporation. The CV of the anaiysis was 8%. The plasma concentration of hCS was determined by the HPL immunoassay kit supplied by The Radiochemical Centre, Amersham, England; the CV was 7%. Statistical method. The Wikoxon two-sample test was used.
Cortisol. The concentration of cortisol in each patient at the different stages of labor is shown in Fig. 1. Table I gives the statistical data. In the "stressed" nonepidural group there was a significant increase in plasma cortisol level from the initial value early in labor to the second stage (p < 0.05). Two of the patients in this group had suffered some pain before the first blood sample was obtained. This is reflected in a high initial concentration of cortisol, especially in one of these patients. In the epidural group there was a slight and insignificant increase in cortisol. In two of the parturients there was an actual faH in cortisol concentration during labor. None of the parturients who received the epidural analgesic drug had been noticeably stressed before entering the study. Estriol. Fig. 2 shows the concentration of unconjugated estriol in w..aterttal p!asw..a at the different stages. The statistical data are given in Table I. During labor there was a significant fall in estriol
Volume 134 Number 6
Effect of stress during labor on cortisol and estriol 683
EPIDURAL ANALGESIA
CONVENTIONAL ANALGESIA DELIVERY
n•7
n• 8
0
60
·; 0
E ~
..
40
!~20r ~~~
t~~~ 1 ·5
6 ·8
CERVICAL DILATATION (em)
10
30 min
POSTPARTUM
1-5
8-8
CERVICAL DILATATION (em)
10
30 min
POSTPARTUM
Fig. 2. Plasma concentration of unconjugated estriol at different stages of labor. Left: Patients reet,iving continuous epidural analgesic drug. Right: Patients receiving conventional analgesic drug.
(p < 0.01) in the nonepidural group. In the "unstressed" group the 1range was wider and the changes less consistent. The mean values at the different stages of labor were, however, almost constant. Statistical analysis revealed no significant influence on the estriol concentration in the· epidural group. Determination of hCS was introduced as a parameter of the piacentai function. The piasma concentration was within the normal range and there was no significant difference between the two groups.
Comment During labor and delivery a considerable rise in the production of cortisol may occur, usually more marked in primiparous than in multiparous patients. 6 Pain is one of the several stimuli known to initiate such a rise. 7 In a recent study8 we have shown that the intramuscular administration of a single dose of a synthetic corticosteroid (b<~tamethasone, 12 mg) leads to a more than 50% reduction in the estriol concentration in maternal plasma within 4 hours. This effect may be due to cortisol inhibition of the synthesis of fetal adrenocorticotropic hormone (ACTH), subsequently reducing the production of estriol precursors, mainly 16a-hydroxydehydroepiandrosterone in the fetal adrenal cortex. 9 In the present study the two groups of patients differed from each other only with respect to the type and efficiency of pain relief. In other respects the groups were very similar, including the placental function as judged by the concentration of hCS. A considerable difference in the cortisol response during labor and delivery was observed. In the "stressed'" nonepiduraii group there was a marked and significant rise in the cortisol level. In the epidural group, however, only a slight and nonsignificant rise was observed. This is in concert with the results presented by Thornton and associates 7 who found that continuous
epidural analgesia was able to block the adrenocortical response to stress only to a certain extent. A fall in the concentration of unconjugated estriol was observed in every patient in the nonepidural group. In fact, the patient with the highest cortisol value also displayed the lowest estriol level. In the epidural group no significant change was observed in the estrioi concentration. In a simiiar study Okada and colleagues 10 also found a significant increase in cortisol during labor, whereas the decreases in the plasma concentration of estriol was not significant (p > 0.05). In our study, however, a significant fall in estriol was observed in the stressed group (p < 0.01). The difference between these two studies may be due to differences in parity, in the duration of labor, and in the type of aP.algesia. Simmer and associates 2 found that administration of 150 mg cortisol intravenously in three divided doses led to a sixfold increase in the plasma concentration of cortisol. This increase was followed by a reduction in maternal plasma concentration of estriol. In our study the parturients being most stressed (the nonepidural group) showed a threefold increase in cortisol as compared to the level seen in normal third-trimester pregnancies.8 Thus labor may induce a rise in the concentration of cortisol high enough to suppress fetal ACTH production and thereby also estriol synthesis. When pain is relieved by means of epidural analgesia, this effect is less pronounced. The present investigation, therefore, supports the hypothesis that an increased maternal cortisol concentration may suppress the production of estriol. This mechanism has also been suggested as an explanation of diurnal variations of estriol.U The study indicates that severe maternal stress in pregnancy may have to be considered when estriol is used as a fetoplacental function test.
July 15, 1979 Am. J. Obstet. Gynecol.
684 Maltau, Eielsen, and Stokke
REFERENCES I. Kiinzig, H.]., and Geiger, W.: Estrogens, in Biochemical methods for monitoring risk pregnancies, Contrib. Gynecol. Obstet. 2:2, 1976. 2. Simmer, H. H., Tulchinsky, D., Gold, E. M., et al.: On the regulation of estrogen production by cortisol and ACTH in human pregnancy at term, AM. J. OssTET. GvNECOL. 119:283, 1974. 3. Buchan, P. C., Milne, M. K., and Browning, M. C. K.: The effect of continuous epidural blockade on plasma 11hydroxycorticosteroid concentrations in labour, Br. ]. Obstet. Gynaecol. 80:974, 1973. 4. Maltau,J. M., and Andersen, H. T.: Continuous epidural anaesthesia with a low frequency of instrumental der-. nvenes, /\Cia vosler. vynecm. ;,canu. a-t:<±vl, 1>11:>. 5. Goebelsmann, U., Katagiri, H., Stanczyk, F. Z., eta!.: Estriol assays in obstetrics,]. Steroid Biochem. 6:703, 1975. 6. Tuimala, R. J., Kauppila, A. J. 1., and Haapalahti, J.: Response of pituitary-adrenal axis on partal stress, Obstet. Gynecol. 46:275, 1975. 7. Thornton, C. A., Carrie, L. E. S., Sayers, L., et al.: A l"
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.•
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,.. ..
An.1
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comparison of the effect of extradural and parenteral analgesia on maternal plasma cortisol concentrations during labour and the puerperium, Br. .J. Obstet. Gynaecol. 83:631' 1976. Maltau, ]. M., Stokke, K. T., and Moe, N .: Effects of betamethasone on plasma levels of estriol, cortisol and HCS in late pregnancy, Acta Obstet. Gynecoi. Scand. 58: 1979. (In press.) Simmer, H. H., Frankland, M., and Greipel, M.: On the regulation of fetal and maternal l6a-hydroxydehydroepiandrosterone and its sulfate by cortisol and ACTH in human pregnancy at term, AM. J. OssTET. GvNECOL. 121:646, 1975. Okada, D. M., Tulchinsky, D., Ross, J. W., eta!.: Plasma estrone, estradiol, estriol, prog~stcrone, and cortisol in normal labour, AM. j. 0RSTET. GVNECOL. 119:502, 1974. Katagiri, H., Distler, W., Freeman, R. K., eta!.: Estriol in pregnancy. IV. Normal concentrations, diurnal and/or episodic variations, and day to day changes of unconjugated and total estriol in late pregnancy plasma, AM. J. 0RSTET. GYNECOL. 124:272, 1976.