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Cortisol in Fetal Fluids and the Fetal Adrenal at Parturition in the Tammar Wallaby (Macropus eugenii )¹

^a Department of Zoology, The University of Melbourne, Parkville, Victoria 3052, Australia

	ABSTRACT

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Glucocorticoid hormones may play a critical role in initiating parturition in tammar wallabies. In this study, we investigated the concentration of cortisol in fetal fluids and cortisol production by fetal adrenals over the last 3 days of the 26-day pregnancy and within 24 h postpartum. The fetal adrenals almost doubled in size between Days 24 and 26 of pregnancy, and their cortisol content increased over 10-fold during this period, from 10 pg to over 100 pg per adrenal pair. After birth, neonatal adrenals continued to grow, but cortisol content fell dramatically to 20 pg. The prepartum increase in adrenal cortisol was reflected by a substantial rise in cortisol concentrations in yolk sac fluid, allantoic fluid, and fetal blood, which were below 10 ng/ml on Day 24 and rose to over 40 ng/ml by Day 26. Cortisol concentrations in neonatal blood decreased postpartum, mirroring decreased cortisol content in neonatal adrenals. Cortisol production by the fetal adrenal was stimulated in vitro by ACTH and prostaglandin E₂, suggesting that the in vivo increase may be stimulated by release of ACTH from the fetal hypothalamic-pituitary axis and prostaglandin E₂ from the placenta. These results indicate that increasing cortisol production by the fetal adrenal is a characteristic of late pregnancy in the tammar wallaby and support the suggestion that fetal cortisol may trigger the initiation of parturition in this marsupial species.

	INTRODUCTION

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The mechanisms involved in initiating parturition in mammals are diverse (reviewed in [1]). However, maturation of the fetal adrenal and increased concentrations of the glucocorticoid cortisol in fetal blood during the last 4–8% of pregnancy have been reported in all mammals studied. In some species, rising fetal cortisol provides a signal to the placenta that is critical for the initiation of parturition [1]. In these species, treatment of the fetus with exogenous cortisol or ACTH leads to premature parturition [2, 3]. In other mammals, such as humans, monkeys, pigs, and rats, increased production of fetal cortisol does not play a clear role, and the mechanisms initiating parturition in these species have been more difficult to characterize. In both groups, however, cortisol from the fetal adrenal provides a stimulus that drives maturation of fetal organ systems [4].

The stimulus for increased cortisol synthesis by the fetal adrenal before birth originates in the fetal hypothalamus and pituitary, or the placenta, or both [5]. In sheep, production of prostaglandin E₂ (PGE₂) by the placenta and ACTH by the fetal pituitary increases prepartum [6, 7]. In humans, corticotropin-releasing factor produced at the end of pregnancy by the placenta appears to provide this stimulus [8]. In both species, synthesis of adrenal trophic factors by the placenta is increased by cortisol, providing a positive feedback system that leads to a rapid response by the fetal adrenal.

In the tammar wallaby, glucocorticoids and the fetal adrenal appear to play a role in the initiation of parturition. The adrenal cortex of the fetus differentiates on Day 21 of the 26-day pregnancy [9], and its steroidogenic enzymes are active on Day 22 [10]. Presumptive corticotrophs are present in the pituitary of the tammar neonate [11], and it is possible that ACTH is being produced by the fetus. The synthetic glucocorticoid dexamethasone induces premature birth [12], and cortisol can be detected in fetal blood on Day 25 of pregnancy [13]. Glucocorticoids are also involved in maturation of the lungs of the tammar wallaby fetus [14]. Thus endogenous cortisol of fetal origin may provide the trigger for parturition in this marsupial [14]. The choriovitelline (yolk sac) placenta of the tammar wallaby produces increasing amounts of PGE₂ and PGF₂ at the end of gestation [15, 16], and it is likely that this enters the fetal and maternal circulation. Fetal pituitary ACTH and placental PGE₂ could thus provide a prepartum stimulus for adrenal corticosteroid production.

The aim of this study was to examine cortisol production during the peripartum period in the tammar wallaby. The concentration of cortisol in fetal fluids and adrenal tissue during late pregnancy was measured, and the in vitro production of cortisol by the fetal adrenal was examined. The potential for ACTH and PGE₂ to stimulate this production was also evaluated.

	MATERIALS AND METHODS

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Animals

Adult female tammars of Kangaroo Island (South Australia) origin were housed in open grassed enclosures, as previously described [12, 17]. Care and treatment of animals conformed to the Australian National Health and Medical Research Council guidelines, and all experiments were approved by Institutional Animal Experimentation Ethics Committees. Timed pregnancies were obtained by removal of pouch young (RPY), which reactivates blastocysts in embryonic diapause. The day of RPY is therefore designated Day 0 of gestation, with birth normally occurring 26.4 ± 1.0 days later [17]. Pregnancy was confirmed during laparotomy, and fetal fluids (yolk sac fluid [YSF], allantoic fluid, and fetal plasma) were collected as previously described [18]. Fluid samples were stored at -20ÅC until assayed. Fetal adrenal glands were dissected out and either immediately snap-frozen and stored as per fluid samples or placed directly into complete cell medium for tissue culture. Adrenal glands from an additional 14 neonates were dissected and weighed fresh on a 5-decimal-place balance.

Cortisol Production

Adrenals from fetuses between Day 23 and Day 26 of gestation were placed in 24-well culture dishes in 1 ml of Medium 199 (Sigma, St. Louis, MO) and were sealed in an incubation chamber, gassed with 95% O₂:5% CO₂, and maintained at 37ÅC. Tissues were allowed to equilibrate for 1 h before pretreatment samples (100 µl) were taken. Adrenal pairs (left and right) were divided and randomly assigned to control or treatment groups. One adrenal always served as a control (no treatment), and the other received either 100 ng/ml synthetic ACTH (Synacthen; Ciba-Geigy, Pendle Hill, NSW, Australia) or 100 ng/ml PGE₂ (Sigma). After treatment, the incubation chamber was re-gassed and returned to 37ÅC. Final samples (200 µl) were taken after 24 h and stored at -20ÅC until assayed. Fetal adrenals treated with ACTH were from Day 24.4 ± 1.0 (n = 10) and those treated with PGF₂ were from Day 24.7 ± 0.9 (n = 4).

Cortisol Assay

Fetal and neonatal adrenal glands were thawed and homogenized in 12 x 75-mm glass tubes in 100 µl 1.0 M NaOH using a glass stirring rod. The homogenate was neutralized with 100 µl 1.0 M HCl, and a 10-µl aliquot was assayed for protein content [19], since significant dehydration of the glands occurs after freezing because of their minute size of less than 0.7 mg each. Cortisol was determined by RIA using a double-antibody, [¹²⁵I]cortisol assay kit from Pantex (Santa Monica, CA). The standard protocol was modified to increase assay sensitivity and to account for the different sample volumes and type. Additional standards were included, and all reagent volumes in the assay protocol were halved, except for the [¹²⁵I]cortisol tracer, which was reduced to 40%. To control for differences in sample composition (YSF, allantoic fluid, plasma, culture media, and tissue homogenate) and volume, a double-extraction step was performed as follows. Fluid samples, and distilled water (dH₂O) to make up 200 µl, were vortexed in 12 x 75-mm glass tubes (30-sec bursts every 5 min for 15 min) with 1 ml dichloromethane (CH₂Cl₂). Adrenal homogenates were similarly treated but were vortexed over a 60-min period. The dichloromethane was drawn off from beneath the aqueous samples, transferred to clean tubes, and evaporated to dryness. The aqueous fractions were then extracted a second time, and the solvent was dried down in tubes from the first extraction. The dried extraction tubes were used as sample tubes in the assay protocol.

Assay Validation

The efficiency of the extraction procedure was 91% and 99%, as determined by recovery of [³H]cortisol from tammar YSF and adult plasma, respectively. The sensitivity of the assay, defined as the lowest concentration that differed from the zero standard by more than twice the standard deviation, was below 25 pg of cortisol per tube. Accuracy was determined by assay of adult plasma to which known amounts of cortisol had been added and was within 13.8%. The interassay coefficient of variation (CV) for YSF (n = 5 assays) and adult plasma (n = 5 assays) samples containing 53.7 ± 3.6 (mean ± SD) and 111.3 ± 26.4 ng of cortisol per ml were 6.7% and 14.7%, respectively. The intraassay CV for YSF (n = 4 tubes) and adult plasma (n = 4 tubes) samples containing 56.4 ± 5.9 and 106.1 ± 9.2 ng of cortisol per milliliter were 10.5% and 8.7%, respectively. Parallelism was confirmed by assaying increasing volumes of both a nonzero and zero YSF sample. Extraction blanks were consistently below assay sensitivity.

Statistics

Statistical analysis was performed using SYSTAT (SPSS Inc., Chicago, IL), and data are graphed as mean ± standard error of the mean (SEM); p values of less than 0.05 were considered significant.

	RESULTS

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Adrenal Cortisol

Adrenal gland pairs from neonates weighed 1.56 ± 0.18 mg (n = 14) on the day of birth. The protein content of fetal and neonatal adrenals increased linearly from Day 24 pregnancy to Day 0 postpartum (Fig. 1a). Cortisol content and concentration in fetal adrenals increased progressively from Day 24 of pregnancy to reach a maximum at term on Day 26 (Fig. 1, b and c). Total cortisol content of fetal adrenal pairs increased significantly (t-test, p < 0.01), from 12.3 ± 11.9 pg on Day 24 to 133.4 ± 83.9 pg by Day 26. Cortisol concentration, expressed per milligram of protein, also increased significantly (t-test, p < 0.05), from 2.7 ± 2.7 ng/mg (n = 6) on Day 24 to 11.5 ± 13.0 ng/mg on Day 26. Within 24 h postpartum, cortisol content and concentration in fetal adrenals had decreased significantly (t-test), falling to 20.1 ± 11.6 pg (p < 0.01) and 1.7 ± 1.4 ng/mg (p < 0.01), respectively.

View larger version (14K): [in this window] [in a new window]   FIG. 1. a) Protein content, b) total cortisol content, and c) cortisol concentration of fetal and neonatal adrenals over the last 3 days of pregnancy and within 24 h postpartrum (PP). Protein content increased linearly (r = 1.00, m = 2.71). Numbers in parentheses indicate sample size, and error bars are SEM.

Adrenal Production

Basal production of cortisol by fetal adrenals in vitro was 16.4 ± 10.2 ng/adrenal per 24 h. Stimulation of adrenal glands with either ACTH or PGE₂ (Fig. 2) resulted in significant increases in cortisol production (paired t-test; ACTH: p < 0.001; PGE₂: p < 0.05).

View larger version (24K): [in this window] [in a new window]   FIG. 2. Cortisol production by fetal adrenals in vitro after 24-h tissue culture. Treatment with a) ACTH and b) PGE2 significantly increased basal cortisol production (paired t-test, both p < 0.05). Numbers in parentheses indicate sample size, and error bars are SEM.

Fetal Fluid Cortisol

The cortisol concentration of YSF, allantoic fluid, and fetal plasma (Fig. 3) increased progressively from Day 24 pregnancy to reach a maximum at term on Day 26. In all fetal fluids, cortisol levels were significantly elevated on Day 26 compared with Day 24 values (t-test, all p < 0.01). Within 24 h postpartum, mean plasma cortisol was half the mean Day 26 gestation levels although this decrease was not significant (p > 0.05).

View larger version (13K): [in this window] [in a new window]   FIG. 3. Cortisol concentrations in a) YSF and b) allantoic fluid over the last 3 days of pregnancy and c) fetal/neonatal plasma within 24 h postpartum (PP). Numbers in parentheses indicate sample size, and error bars are SEM.

	DISCUSSION

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Cortisol concentrations in fetal fluids of the tammar wallaby increased dramatically over the last 7–8% of pregnancy. This pattern is found in all eutherian species that have been studied and is reported here for the first time in a marsupial. The source of rising cortisol is likely to be the fetal adrenal, because its cortisol content parallels the increases in fetal fluids during this period. Production of cortisol by fetal adrenals in vitro is stimulated by ACTH and PGE₂, suggesting that the fetal pituitary and placenta may provide the stimulus for increased cortisol in vivo. Within 24 h postpartum, cortisol in neonatal plasma and adrenals decreases to low levels. These results clearly indicate that fetal adrenal cortisol synthesis increases at the end of pregnancy and that it is responsive to trophic stimulation from ACTH and PGE₂ during this period. Thus, despite the dramatic differences in the developmental profiles of marsupial and eutherian mammals, maturation of the fetal adrenal and increasing levels of fetal cortisol may be a common event at parturition.

The profiles for increasing cortisol concentration were similar in all fetal fluids and adrenal tissue over the period examined, and levels were comparable in YSF, allantoic fluid, and fetal plasma. On each day of pregnancy, variability in measured cortisol concentrations was high. Some of this variation may be explained by the methodological difficulties of collecting samples from the different fetal compartments of the tiny marsupial fetus, which weighs only 400 mg at birth [9]. However, much of the variability appears to be due to small differences in the timing of fetal maturation and the rapidity of the change occurring in the last 2 days of gestation: in this species, the entire period of organogensis takes only 7 days [9].

Exogenous glucocorticoid hormones induce premature birth in tammars accompanied by normal profiles of maternal hormones [12], so it is possible that fetal cortisol is the trigger for parturition in this marsupial. The tammar may be similar in this regard to species such as the sheep, goat, cow, and rabbit, in which fetal cortisol is directly involved in the onset of parturition, although the mechanism clearly differs between species. In these eutherian species, progesterone is necessary for the maintenance of pregnancy, and fetal cortisol leads to its withdrawal before parturition by altering placental steroidogenesis (such as in the sheep) or by inducing luteolysis (such as in the goat) [1–3, 20]. In addition to decreasing progesterone levels, there is an increase in estrogen production by the placenta, and the combined effects of these changes leads to the initiation of parturition. In the tammar, however, progesterone is not necessary for the maintenance of pregnancy once it is established, and the withdrawal of progesterone is not necessary for parturition [9]. Similarly, estrogen does not appear to play a role. In contrast, both prostaglandin and mesotocin, which increase dramatically at parturition, are necessary for birth [21–24].

In eutherian mammals, interactions between the fetal hypothalamic-pituitary-adrenal (HPA) axis and the placenta stimulate the fetal adrenal at term [5, 25, 26], and results reported here provide evidence for a similar mechanism in the tammar wallaby. Production of PGE₂ by the placenta at the end of pregnancy in the sheep provides an important trophic drive to the fetal HPA axis [27], and the resulting increase in cortisol stimulates further PGE₂ release, creating a positive feedback loop. Prostaglandin synthesis by the tammar placenta and endometrium increases over the last 2 days of pregnancy [15, 16], paralleling fetal cortisol concentrations. Cortisol synthesis by the fetal adrenal of the tammar is stimulated by PGE₂ in vitro, suggesting an adrenocorticotrophic role for increased placental PGE₂ production during parturition in this marsupial [15, 16]. Cortisol synthesis by the fetal adrenal in vitro is also stimulated by ACTH, which suggests that the corticotrophs in the pituitary [11] may stimulate cortisol as in eutherians [28, 29].

Previous studies have clearly shown that the tammar fetus sets the timing of its own birth and that synthetic glucocorticoids initiate a physiologically normal, but premature, parturition in the tammar. Cortisol production by the fetal adrenal increases progressively over the last 3 days of pregnancy. Placental PGE₂ and ACTH released from the fetal pituitary may contribute to this adrenal stimulation, which results in the accumulation of large amounts of cortisol in YSF, allantoic fluid, and fetal plasma. Taken together, our results suggest that endogenous cortisol of fetal adrenal origin provides the stimulus for spontaneous parturition in this marsupial species.

	ACKNOWLEDGMENTS

 
We thank Anne Duns and Dr. Jenny Harry for assistance with assays and sample collection. Animals were held under permit numbers RP-92–099 and RP-95–088 from the Department of Conservation and Natural Resources, Victoria, Australia.

	FOOTNOTES

 
¹ This work was supported by grant AO9602716 to M.B.R. and G.S. from the Australian Research Council.

² Correspondence. FAX: 61 3 9344 7909; m.renfree{at}zoology.unimelb.edu.au

³ Current address: 195 LSA, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.

Accepted: October 21, 1998.

Received: July 28, 1998.

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