0013-7227/78/1034-1453$02.00/0 Endocrinology Copyright © 1978 by The Endocrine Society
Vol. 103, No. 4 Printed in U.S.A.
Effect of Parturition on Serum Iodothyronine Concentrations in Fetal Sheep* ALAN H. KLEIN,f T. H. ODDIE, AND DELBERT A. FISHER Departments of Pediatrics and Medicine, UCLA-Harbor General Hospital, Torrance, California 90509 ABSTRACT. T4, T3) and rT 3 were determined by RIA on daily serum samples collected from five catheterized fetal sheep during the 2-week period before spontaneous vaginal delivery (PTD). Samples were also available from three newborn lambs during the first 4 h of life. T3 concentrations began to increase 4-6 days before spontaneous vaginal delivery, from a stable geometric mean concentration of 30 ng/dl to a mean concentration of 131 ng/dl on the day of delivery (day 0). T4 concentrations decreased in four of the animals and remained unchanged in one during this time interval. rT 3 concentrations decreased from a stable mean of 472 to 249 ng/ dl on day 0. The prenatal increase in serum T 3 levels correlated temporally with increasing fetal serum corti-
T
HE CHANGES in serum T4 and T 3 concentrations immediately before and during the onset of labor in the ovine fetus have been variable in several reports. A fall in T4 concentrations before spontaneous delivery (PTD) has been reported by Thorburn et al. (1); Nathanielsz et al. (2) were unable to confirm this. More recently, Mellor et al. (3) demonstrated a decrease in fetal T4 concentrations PTD in 11 of 21 sheep studied; no change was apparent in the 10 other animals. Nathanielsz, in 1976, described an increase in T3 concentrations associated with a decrease in T4 concentrations during cortisol-induced premature labor in sheep (4). This is in contrast to an earlier study by the same investigator in which a change in fetal T3 concentration was not observed PTD in sheep (5). There are no reports of serial serum rT3 concentrations immediately before and during the onset Received November 22,1977. Address requests for reprints to: Dr. Alan H. Klein, Harbor General Hospital, Building A-17, Division of Perinatology, 1000 West Carson Street, Torrance, California 90509. * This work was supported by Grant HD-04270 from the NICHHD, NIH. f Recipient of NIH Special Fellowship HD-05402.
sol concentrations. The mean T3 concentration increased further after delivery to a level of 487 ng/dl at 1 h of age without significant change in T4 or rT 3 levels. The following conclusions were reached: 1) fetal serum T3 concentrations increase while T4 and rT 3 concentrations decrease during the 4-6 days preceding spontaneous labor, and 2) T 3 concentrations increase further after delivery. Available evidence suggests that the prenatal increase in fetal serum T3 levels is mediated by a cortisol-induced increase in T4 to T3 conversion in fetal tissues. The mechanism(s) of the postnatal increase in serum T3 concentrations in the newborn is not clear. (Endocrinology 103: 1453, 1978)
of labor in fetal sheep. The following investigation was undertaken to clarify the changes in serum T4, T3, and rT3 concentrations during the perinatal period in this animal model. Materials and Methods Fetal jugular venous catheters were placed in five date bred pregnant ewes under local and ketamine anesthesia between 122-132 days gestation. After a period of 2-16 days, fetal plasma samples were collected daily. More frequent sampling was performed in three of the preparations during the last 24 h PTD. All fetuses were born alive. No changes in fetal serum iodothyronine concentrations were observed until the last week PTD. Therefore, only samples from the last 13 days PTD were analyzed. Neonatal samples during the first 4 h of life were available in two of the catheterized fetuses and one uncatheterized twin cohort. T4, T3, and rT 3 concentrations were measured in all samples by double antibody RIA techniques previously described (6-8). Serum cortisol concentrations were determined by specific antibody RIA techniques without chromatography (9). We have reported previously that serum iodothyronine concentrations are log-normally distributed (10). Thus, statistical analyses were performed using the paired t test on the raw data or Student's t test after logarithmic transformation and calculation of the
1453 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 November 2015. at 06:37 For personal use only. No other uses without permission. . All rights reserved.
KLEIN, ODDIE, AND FISHER
1454
geometric mean concentrations. Cortisol results were similarly calculated. Results Daily serum cortisol concentrations (five animals; geometric mean ± SEM) during the last 13 days PTD are shown in Fig. 1. Mean values increased progressively during the week before day 0. The geometric mean concentration on day 0 (20.6 /xg/dl) was significantly greater (paired t test; P < 0.02) than that 8 days PTD (4.7 jug/dl). Mean concentrations for the serum iodothyronines were calculated for each animal during the interval 8-13 days PTD when hormone concentrations were stable. These values were then used to calculate composite geometric baseline mean concentrations. Mean serum concentrations also were calculated for each of the animals that had more than one blood sample drawn during the last 24 h PTD; these values and the sample values available within 24 h of delivery in the other animals were used to calculate geometric mean concentrations for the day of delivery (day 0). The initial composite means and the daily mean yalues for the iodothyronines are summarized in Table 1. Daily serum T4 (four animals), T3, and rT3 (five animals) concentrations (geometric mean ± SEM) during the 13
Endo 1978 Vol 103 . No 4
days PTD are shown in Fig. 2. The mean T 4 concentrations in four of the animals for each of the 4 days before and including day 0 were significantly lower than the initial composite geometric mean T4 concentration (Table 1). Serum T4 concentrations in the fifth animal (not included) did not change during this 2week interval. During the last 50 h immediately PTD and the first 4 h of postnatal life, there was no consistent pattern of change in fetal serum T4 concentrations in any of the animals. As shown in Table 1 and Fig. 2, fetal serum T3 concentrations began to increase significantly at least 6 days PTD. The mean concentration increased from 30 ng/dl 8-13 days PTD to 131 ng/dl on day 0. As shown in Fig. 3, there was a further abrupt increase in serum T3 concentrations after birth. The geometric mean concentration of 487 ng/dl (95% interval, 151-1569 ng/dl) at 1 h of age was significantly higher than the mean concentration of 131 ng/dl in the five animals on day 0 (t test; P < 0.01). The geometric mean rT 3 concentration decreased gradually during the week PTD (Fig. 1 and Table 1); the mean concentration was significantly lower than the initial mean concentration by 3 days PTD. During the last 50 h PTD and during the first 4 h of postnatal hie, no specific pattern of change was apparent.
20
Discussion
15
During the last week before the onset of spontaneous labor, while cortisol concentrations are increasing, fetal serum T3 concentrao> w tions increase and serum T4 and rT3 concen5trations decrease (Table 1 and Fig. 2). A similar increase in serum T 3 and decrease in serum T4 concentrations has been reported in fetal sheep during cortisol induction of premature labor (5). The mechanism of these changes in serum iodothyronine concentrations is not entirely clear. The decreasing se1 1 1 H 1 h 13 12 II 10 9 8 7 6 5 4 3 2 I 0 • rum T4 concentration with an increase in T3 DAYS PRIOR TO DELIVERY DELIVERY is not easily explained on the basis of variaFIG. 1. Prenatal changes in fetal serum cortisol concentions in thyroid gland hormone secretion. Hortrations in sheep during the 2-week period PTD (geometric mone kinetic measurements were not conmean ± SEM). =
E o o
10-
f))'
1
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 November 2015. at 06:37 For personal use only. No other uses without permission. . All rights reserved.
FETAL T 3 DURING PARTURITION IN SHEEP
1455
T A B L E 1. Fetal iodothyronine concentrations before delivery Days before delivery"
T 4 (/ig/dl; n = 4) T 3 (ng/dl; n = 5) rT 3 (ng/ dl; n = 5)
8-13
6
5
4
3
2
1
0
8.4 (6.7-10.5) 6 30 (25-36) 472 (440-505)
6.6 (4.4-10.0) 37C (29-47) 447 (353-565)
6.5 (3.5-12.1) 49C (38-63) 403 (355-458)
6.2C (4.3-8.8) 59 d (48-72) 398 (319-496)
5.9C (3.6-9.6) 67 d (49-91) 333" (281-395)
6.2C (4.0-9.5) 89C (55-144) 294rf (223-387)
5.1C (2.6-9.9) 98 d (89-108) 256rf (176-371)
5.2C (2.6-10.4) 131rf (107-161) 249" (137-450)
" Paired t test vs. 8-13 days. 6 Geometric mean (95% confidence interval). e P < 0.05. rf P
Vol. 103, No. 4 Printed in U.S.A.
Effect of Parturition on Serum Iodothyronine Concentrations in Fetal Sheep* ALAN H. KLEIN,f T. H. ODDIE, AND DELBERT A. FISHER Departments of Pediatrics and Medicine, UCLA-Harbor General Hospital, Torrance, California 90509 ABSTRACT. T4, T3) and rT 3 were determined by RIA on daily serum samples collected from five catheterized fetal sheep during the 2-week period before spontaneous vaginal delivery (PTD). Samples were also available from three newborn lambs during the first 4 h of life. T3 concentrations began to increase 4-6 days before spontaneous vaginal delivery, from a stable geometric mean concentration of 30 ng/dl to a mean concentration of 131 ng/dl on the day of delivery (day 0). T4 concentrations decreased in four of the animals and remained unchanged in one during this time interval. rT 3 concentrations decreased from a stable mean of 472 to 249 ng/ dl on day 0. The prenatal increase in serum T 3 levels correlated temporally with increasing fetal serum corti-
T
HE CHANGES in serum T4 and T 3 concentrations immediately before and during the onset of labor in the ovine fetus have been variable in several reports. A fall in T4 concentrations before spontaneous delivery (PTD) has been reported by Thorburn et al. (1); Nathanielsz et al. (2) were unable to confirm this. More recently, Mellor et al. (3) demonstrated a decrease in fetal T4 concentrations PTD in 11 of 21 sheep studied; no change was apparent in the 10 other animals. Nathanielsz, in 1976, described an increase in T3 concentrations associated with a decrease in T4 concentrations during cortisol-induced premature labor in sheep (4). This is in contrast to an earlier study by the same investigator in which a change in fetal T3 concentration was not observed PTD in sheep (5). There are no reports of serial serum rT3 concentrations immediately before and during the onset Received November 22,1977. Address requests for reprints to: Dr. Alan H. Klein, Harbor General Hospital, Building A-17, Division of Perinatology, 1000 West Carson Street, Torrance, California 90509. * This work was supported by Grant HD-04270 from the NICHHD, NIH. f Recipient of NIH Special Fellowship HD-05402.
sol concentrations. The mean T3 concentration increased further after delivery to a level of 487 ng/dl at 1 h of age without significant change in T4 or rT 3 levels. The following conclusions were reached: 1) fetal serum T3 concentrations increase while T4 and rT 3 concentrations decrease during the 4-6 days preceding spontaneous labor, and 2) T 3 concentrations increase further after delivery. Available evidence suggests that the prenatal increase in fetal serum T3 levels is mediated by a cortisol-induced increase in T4 to T3 conversion in fetal tissues. The mechanism(s) of the postnatal increase in serum T3 concentrations in the newborn is not clear. (Endocrinology 103: 1453, 1978)
of labor in fetal sheep. The following investigation was undertaken to clarify the changes in serum T4, T3, and rT3 concentrations during the perinatal period in this animal model. Materials and Methods Fetal jugular venous catheters were placed in five date bred pregnant ewes under local and ketamine anesthesia between 122-132 days gestation. After a period of 2-16 days, fetal plasma samples were collected daily. More frequent sampling was performed in three of the preparations during the last 24 h PTD. All fetuses were born alive. No changes in fetal serum iodothyronine concentrations were observed until the last week PTD. Therefore, only samples from the last 13 days PTD were analyzed. Neonatal samples during the first 4 h of life were available in two of the catheterized fetuses and one uncatheterized twin cohort. T4, T3, and rT 3 concentrations were measured in all samples by double antibody RIA techniques previously described (6-8). Serum cortisol concentrations were determined by specific antibody RIA techniques without chromatography (9). We have reported previously that serum iodothyronine concentrations are log-normally distributed (10). Thus, statistical analyses were performed using the paired t test on the raw data or Student's t test after logarithmic transformation and calculation of the
1453 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 November 2015. at 06:37 For personal use only. No other uses without permission. . All rights reserved.
KLEIN, ODDIE, AND FISHER
1454
geometric mean concentrations. Cortisol results were similarly calculated. Results Daily serum cortisol concentrations (five animals; geometric mean ± SEM) during the last 13 days PTD are shown in Fig. 1. Mean values increased progressively during the week before day 0. The geometric mean concentration on day 0 (20.6 /xg/dl) was significantly greater (paired t test; P < 0.02) than that 8 days PTD (4.7 jug/dl). Mean concentrations for the serum iodothyronines were calculated for each animal during the interval 8-13 days PTD when hormone concentrations were stable. These values were then used to calculate composite geometric baseline mean concentrations. Mean serum concentrations also were calculated for each of the animals that had more than one blood sample drawn during the last 24 h PTD; these values and the sample values available within 24 h of delivery in the other animals were used to calculate geometric mean concentrations for the day of delivery (day 0). The initial composite means and the daily mean yalues for the iodothyronines are summarized in Table 1. Daily serum T4 (four animals), T3, and rT3 (five animals) concentrations (geometric mean ± SEM) during the 13
Endo 1978 Vol 103 . No 4
days PTD are shown in Fig. 2. The mean T 4 concentrations in four of the animals for each of the 4 days before and including day 0 were significantly lower than the initial composite geometric mean T4 concentration (Table 1). Serum T4 concentrations in the fifth animal (not included) did not change during this 2week interval. During the last 50 h immediately PTD and the first 4 h of postnatal life, there was no consistent pattern of change in fetal serum T4 concentrations in any of the animals. As shown in Table 1 and Fig. 2, fetal serum T3 concentrations began to increase significantly at least 6 days PTD. The mean concentration increased from 30 ng/dl 8-13 days PTD to 131 ng/dl on day 0. As shown in Fig. 3, there was a further abrupt increase in serum T3 concentrations after birth. The geometric mean concentration of 487 ng/dl (95% interval, 151-1569 ng/dl) at 1 h of age was significantly higher than the mean concentration of 131 ng/dl in the five animals on day 0 (t test; P < 0.01). The geometric mean rT 3 concentration decreased gradually during the week PTD (Fig. 1 and Table 1); the mean concentration was significantly lower than the initial mean concentration by 3 days PTD. During the last 50 h PTD and during the first 4 h of postnatal hie, no specific pattern of change was apparent.
20
Discussion
15
During the last week before the onset of spontaneous labor, while cortisol concentrations are increasing, fetal serum T3 concentrao> w tions increase and serum T4 and rT3 concen5trations decrease (Table 1 and Fig. 2). A similar increase in serum T 3 and decrease in serum T4 concentrations has been reported in fetal sheep during cortisol induction of premature labor (5). The mechanism of these changes in serum iodothyronine concentrations is not entirely clear. The decreasing se1 1 1 H 1 h 13 12 II 10 9 8 7 6 5 4 3 2 I 0 • rum T4 concentration with an increase in T3 DAYS PRIOR TO DELIVERY DELIVERY is not easily explained on the basis of variaFIG. 1. Prenatal changes in fetal serum cortisol concentions in thyroid gland hormone secretion. Hortrations in sheep during the 2-week period PTD (geometric mone kinetic measurements were not conmean ± SEM). =
E o o
10-
f))'
1
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 November 2015. at 06:37 For personal use only. No other uses without permission. . All rights reserved.
FETAL T 3 DURING PARTURITION IN SHEEP
1455
T A B L E 1. Fetal iodothyronine concentrations before delivery Days before delivery"
T 4 (/ig/dl; n = 4) T 3 (ng/dl; n = 5) rT 3 (ng/ dl; n = 5)
8-13
6
5
4
3
2
1
0
8.4 (6.7-10.5) 6 30 (25-36) 472 (440-505)
6.6 (4.4-10.0) 37C (29-47) 447 (353-565)
6.5 (3.5-12.1) 49C (38-63) 403 (355-458)
6.2C (4.3-8.8) 59 d (48-72) 398 (319-496)
5.9C (3.6-9.6) 67 d (49-91) 333" (281-395)
6.2C (4.0-9.5) 89C (55-144) 294rf (223-387)
5.1C (2.6-9.9) 98 d (89-108) 256rf (176-371)
5.2C (2.6-10.4) 131rf (107-161) 249" (137-450)
" Paired t test vs. 8-13 days. 6 Geometric mean (95% confidence interval). e P < 0.05. rf P
