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Department of Obstetrics and Gynecology (W.X.W., T.C., K.C., V.C.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104; Department of Obstetrics and Gynecology (J.R.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157; and Department of Obstetrics and Gynecology (P.W.N.), Center for Women’s Health Research, New York University Medical School, New York, New York 10016
Address all correspondence and requests for reprints to: Dr. Wen Xuan Wu, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, RP1, Suite 470, 800 North Research Park, Oklahoma City, Oklahoma 73104. E-mail: wen_xuan_wu{at}hotmail.com.
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was measured by enzyme immunoassay. Intrauterine PG H synthase 2 mRNA and protein and placental P450c17 hydroxylase mRNA were determined by Northern, in situ hybridization, Western blot analysis, and immunocytochemistry. Data were analyzed by ANOVA.
Five of six estradiol-treated ewes delivered their fetuses within 48 h; however, the placenta was still retained 5–6 h after fetal delivery. Both maternal plasma estradiol and PGF2 increased significantly in the estradiol-treated group. Maternal and fetal plasma progesterone and cortisol were not altered in either group. There were significant increases of PGH synthase 2 mRNA and protein in myometrium, endometrium, and maternal placenta but not in fetal placenta in estradiol-treated ewes. Placental P450c17 hydroxylase mRNA was not detectable in vehicle or estradiol-treated groups.
Estradiol can, in the absence of increase in plasma cortisol, stimulate uterine PG production and induce labor, resulting in fetal delivery in the sheep. Failure of placental delivery after estradiol treatment suggests that estradiol alone is insufficient to stimulate some of the key changes required to complete delivery at the stage of gestation studied.
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Introduction |
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hydroxylase enzyme (1) accompanied by increased uterine prostaglandin (PG) production (2, 3). These endocrine and paracrine changes lead to three key features of delivery: efficient and coordinated myometrial contractions; cervical dilation; and fetal and placental delivery. It is generally accepted that estrogen can stimulate all the essential steps required to bring about the onset of labor. However, the precise nature of estrogen’s role in stimulating the uterine physical changes and the biochemical mechanisms associated with these changes in the pregnant uterus has not been defined in any species. Most studies have focused on the regulation of myometrial contractility by estrogen and progesterone. Similarly, most pharmaceutical approaches have been directed at the arrest of myometrial contraction. Information on the role of estrogen in regulation of cervical ripening and dilation is in contrast limited. Furthermore, the mechanism of separation and delivery of placenta has received very little attention. The classic view on estrogen and progesterone function might be correct only if labor can be accomplished by myometrial contractions alone.
It has long been accepted that cortisol stimulates the conversion of progesterone to estrogen in the ovine placenta through the induction of P450c17 hydroxylase enzyme (1). Estrogen then stimulates PG production. These enzymatic steps constitute the estrogen-dependent pathway of PG synthesis. However, recent studies have led several investigators including us to propose a supportive role for an additional pathway, the stimulation of intrauterine PG production by cortisol (4, 5). The involvement of this pathway is suggested by the following observations: 1) the timing of rise in fetal plasma PGE2 and endometrial and placental PG H synthase (PGHS) 2, both of which occur with a time course that precedes the rise in maternal plasma estradiol (4, 6, 7); and 2) the expression of P450c17 hydroxylase, the rate-limiting enzyme of estradiol synthesis from C21 precursors in the ovine placenta, does not increase until after the onset of the early stages of labor, well after the increase in placental PGHS2 expression (8).
We used the ovariectomized nonpregnant ewe as a model to demonstrate the ability of estrogen to stimulate PG synthesis in a well-controlled steroid environment (9). We now extend our observations to the pregnant sheep. The purpose of the present study was to determine the physiological and molecular mechanisms recruited by estrogen at a time point in gestation before the increase in fetal cortisol takes place. This approach directly addresses the role of potential estrogen-dependent and cortisol-independent actions. We administered estradiol at a dose that produces estradiol concentrations in maternal plasma observed during labor (10). In addition, we used both in vivo and in vitro techniques to obtain a clear picture at both the systemic and molecular levels of the role of estrogen in the stimulation of parturition.
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Materials and Methods |
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At 106–108 d of gestational age (dGA), ewes from which tissues were obtained were instrumented with electromyogram leads sewn into the myometrium and fetal and maternal carotid arterial and jugular venous catheters (11). Ten to 12 d after surgery (at 119 dGA), ewes were treated with vehicle (sesame oil, n = 5) or 17ß-estradiol (n = 6, 5 mg twice a day), administered im for 2 d to produce concentrations of estradiol in maternal plasma similar to those observed at term (10). At 121 dGA after 2 d of vehicle or estradiol treatment, tissues were obtained under halothane anesthesia after which the animals were euthanized. Endometrium, myometrium, and maternal and fetal placenta were collected for later RNA and protein analysis. Fetal and maternal arterial blood samples were collected on the day before vehicle or estradiol treatment and the day at necropsy. Plasma was separated from blood cells by centrifugation at 1500 x g for 10 min at 4 C. Plasma samples were frozen at -20 C for subsequent assay.
Fetal placenta was also collected from ewes in spontaneous term labor at 147–148 dGA (n = 4) and ewes in cortisol-induced labor at 130 dGA (n = 4). Cortisol (0.83–1.25 mg/ml, Upjohn, Kalamazoo, MI) in saline (n = 4) was infused at a rate of 0.5 ml/min into the fetal jugular vein beginning at 127 dGA. A total of 10 mg cortisol/d was administered for 24 h and then 15 mg/d for up to 72 h. Labor was defined as having occurred when the myometrial electromyogram record showed a clear switch from contractures to contractions followed by contraction activity for at least 5 h (11) and confirmed at necropsy with the observation of cervical dilation.
RIA
The RIAs for maternal and fetal plasma estradiol, progesterone, and cortisol were performed using commercially available 125I RIA kits (Diagnostic Products Co., Los Angeles, CA). The sensitivity of the assays was 8 pg/ml for estradiol, 20 pg/ml for progesterone, and 2 ng/ml for cortisol. The specificity was provided by the manufacturer. The intraassay coefficients of variation of estradiol, progesterone, and cortisol RIAs were 8, 4, and 5%, respectively.
Enzyme immunoassay (EIA)
EIA for maternal plasma PGF2 was performed using commercially available PGF2 EIA kit (Cayman Chemical, Ann Arbor, MI). Two dilutions of each sample were assayed and each dilution was assayed in duplicate. The sensitivity for the assay was 8 pg/ml. The specificity was provided by the manufacturer. The intraassay coefficients of variation determined at middle point on the standard curve was 10%.
Northern analysis
Total RNA was extracted from fetal and maternal placenta separately. Polyadenylated RNA was extracted from myometrium and endometrium by oligo dT cellulose affinity chromatography using a commercial kit (Invitrogen, San Diego, CA). Samples of total RNA (30 µg) or polyadenylated RNA (2 µg) were separated by electrophoresis on a 1.4% (wt/vol) agarose-0.66 M formaldehyde gel and transferred onto a nylon membrane (NEN Life Science Products, Boston, MA) and then subjected to Northern blot analysis for PGHS2 and P450c17 hydroxylase mRNAs as described previously (5, 7). ß-Actin or 18S were used to control RNA loading.
In situ hybridization
Frozen sections (4 µm thick) cut onto commercially prepared poly-L-lysine-coated slides (Sigma Chemical Co., St. Louis, MO) were fixed in freshly prepared 4% paraformaldehyde in 0.1 M phosphate buffer (20 min), washed twice in 0.1 M phosphate buffer, immersed in triethanolamine-HCl [3.71 g tetraethylammonium, 2 ml 6 M NaOH, and 198 ml water] (pH 8.0) and then tetraethylammonium and acetic anhydride (0.25%) for 10 min. They were then washed in 2x saline sodium citrate (SSC) for 5 min and briefly in 70% ethanol and allowed to air dry. The specimens were incubated for 2 h in a humidified container (55 C) with 70 µl prehybridization buffer [50% deionized formamide, 0.3 M NaCl, 20 mM Tris-HCl (pH 8.0), 5 mM EDTA, 10 mM sodium phosphate buffer (pH 8.0), 1x Denhardt’s solution] and for at least 16 h in hybridization buffer (i.e. prehybridization buffer plus probe 1 x 106 cpm/specimen in 70 µl). Control slides were hybridized in the presence of an excess of unlabeled antisense RNA or labeled sense RNA. Slides were then washed three times in 4 x SSC and 4 mM dithiothreitol (DTT, Sigma); three times in NTE buffer [0.5 M NaCl, 10 mM Tris-HCl, and 5 mM EDTA (pH 8.0)] at 37 C (second NTE wash was for 30 min with 30 µg/ml ribonuclease A); 2x SSC and 1 mM DTT for 45 min; 0.1x SSC and 1 mM DTT at 60 C for 30 min; and finally 0.1x SSC at room temperature for 30 min. The slides were then dehydrated in a graded series of ethanol plus 0.3 M ammonium acetate. They were air dried and exposed to autographic films for 2–4 d and then dipped in emulsion (NTB2, VWR, Kodak, South Plainfield, NJ) and exposed for 1–4 wk at 4 C. After developing and fixing, they were counterstained with hematoxylin and eosin, mounted, and covered with a glass coverslip.
Synthesis of probes
Our cloned ovine PGHS2 cDNA in pCR II vector (Invitrogen), which includes promoters for phage polymerases SP-6 to produce antisense probe and T-7 to produce sense probe, was linearized by an appropriate restriction enzyme. The antisense and sense riboprobes were synthesized using a commercial kit (MAXIscript, Ambion, Austin, TX) labeled with [-32P] uridine 5-triphosphate for Northern or [-35S] uridine 5-triphosphate for in situ (NEN Life Science Products). Recombinant ovine P450c17 hydroxylase cDNA was kindly made available to us by Dr. Mike Waterman (University of Texas Health Science Center, Dallas, TX). The cDNA probes were labeled with -32P dCTP using the random priming method (NEN Life Science Products-DuPont).
In situ hybridization image acquisition, processing, and analysis
To analyze PGHS2 mRNA abundance obtained from in situ hybridization, autoradiograph signals of PGHS2 in myometrium, endometrium, and maternal and fetal placenta were quantified by scanning densitometry using a densitometry program-Scan analysis (Biosoft, Cambridge, UK) as we described previously (12). The relative OD of the signals on autoradiographic films was quantified after subtraction of each individual background using a computerized image analysis system. The value obtained represents an average density over the area measured. Comparison between groups was performed using values obtained from six sections/animal.
Solubilized cell membrane extraction and Western blot analysis
To prepare solubilized cell extracts, approximately 1 g tissues were homogenized for 1 min (Polytorn, Kinematica AG, Littau-Lucerne, Switzerland) on ice in TE buffer (50 mM Tris and 10 mM EDTA) containing 2 mM octyl glucoside and 0.2 mM phenylmethylsulfonyl fluoride and centrifuged at 30,000 x g for 1 h at 4 C. The crude pellets (membrane, nuclei, and mitochondria) were sonicated in 1 ml TE sonication buffer (20 mM Tris and 50 mM EDTA) containing 45 mM octyl glucoside and 0.2 mM phenylmethylsulfonyl fluoride. The supernatants were centrifuged at 13,000 x g for 25 min at 4 C. The recovered supernatants (solubilized cell extract) were stored at -70 C until electrophoretic analysis. The protein concentration was determined by the method of Bradford (Bio-Rad Laboratories, Hercules, CA). The extracted protein samples from different groups in each tissue were separated on the same gel and stained with Coomassie blue to analyze IgG heavy and light chains before performing Western blot analysis. We used only protein samples that did not yield significant differences in these control proteins. The solubilized proteins (50 µg/lane) separated on 10% SDS-PAGE were electrophoretically transferred to a nylon membrane (Immobilon, Millipore Corp., Bedford, MA), using a Bio-Rad transfer blot cell. The protein bands were visualized using an enhanced chemiluminescence Western blotting detection kit (ECL, Amersham Life Sciences, Arlington Heights, IL). The molecular sizes of the proteins were determined by running standard molecular-weight-marker proteins (Bio-Rad) in an adjacent lane. Chemiluminescence signals were analyzed and quantified with the scanner and data were analyzed with a densitometry program-scan analysis and quantified against an arbitrary scale in the plot.
Immunocytochemistry
Frozen sections (4 µm) of the pregnant sheep myometrium, endometrium, maternal placenta, and fetal placenta were immunostained for PGHS2 using the avidin-biotin immunoperoxidase method as described previously (7) to localize the cellular distribution of PGHS2 protein in intrauterine tissues. Specificity of immunostaining for the PGHS2 was confirmed by two approaches: omission of the primary antibody and incubation of the slides with the normal rabbit serum instead of the primary antibody (7).
Antibodies for PGHS2 used for Western blot analysis and immunocytochemistry
A rabbit polyclonal antibody for human PGHS2 (Oxford Biomedical Research, Inc., Oxford, MI) was used at 1:1000 dilution and incubated at 4 C for 20 h. This PGHS2 antibody has been characterized previously (7, 9, 13, 14). A second antibody, horseradish peroxidase-conjugated donkey antirabbit IgG, was used for Western (Amersham Life Sciences) and a biotinylated goat antirabbit IgG (Vector Laboratories, Burlingame, CA) was used for immunocytochemistry.
Statistical analysis
Comparison of two means was made with the Student’s t test. Comparison of three or more means was made by ANOVA and multiple post hoc comparisons with Tukey’s method for 95% confidence interval of pairwise differences. Statistical significance was assumed at the 5% level. Data are presented throughout as mean ± SEM.
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Results |
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Increased estradiol level in maternal plasma in estradiol-treated animals
Maternal plasma estradiol concentration measured in conscious animals at the end of the study before necropsy was significantly increased in the estradiol-treated group (P < 0.01, Fig. 1
). Estradiol concentration in maternal plasma was undetectable in the control group (Fig. 1). There was no difference in fetal plasma estradiol concentrations in two groups. There were no differences in fetal or maternal plasma progesterone concentrations between control and estradiol-treated groups (7.9 ± 1.43 and 5.16 ± 0.61 ng/ml for fetus; 22.48 ± 2.05 and 25.22 ± 6.26 ng/ml for maternal, respectively). Progesterone concentration in maternal plasma was significantly higher than fetal plasma. Fetal plasma cortisol levels were similar in baselines in two groups (5.36 ± 0.52 and 7.06 ± 0.71 ng/ml for controls and estradiol-treated animals), and there was no change after vehicle and estradiol treatment (5.14 ± 1.52 and 7.06 ± 1.21 ng/ml, respectively). Maternal plasma cortisol levels also stayed the same in baselines (13.88 ± 2.58 and 20.32 ± 4.85 for controls and estradiol-treated animals) and remained the same after vehicle and estradiol treatment (13.5 ± 1.75 and 20.02 ± 4.66 ng/ml, respectively).
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level in maternal plasma in estradiol-treated animals measured at the end of the study in the maternal plasma in estradiol-treated animals was significantly elevated, compared with their own baseline concentrations and the PGF2 concentration at the end of the study in control ewes that received vehicle treatment only (Fig. 2).
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) and in situ hybridization and PGHS2 protein analyzed by Western blot analysis (Fig. 4) in myometrium, endometrium, and maternal placenta but not in fetal placenta in all six estradiol-treated ewes. In our preliminary study, we validated our cloned PGHS2 riboprobes by Northern blot analysis before we applied them to our experiments. It was only the PGHS2 antisense probe that generated the specific signals at the expected molecular weight (about 4.5 kb, data not shown). PGHS2 protein was expressed as two bands about 70 and 72 kDa (Fig. 4) in all four intrauterine tissues on Western blot analysis. Both immunoreactive bands of PGHS2 increased after estradiol treatment (Fig. 4). This observation is consistent with the report that PGHS2 is partially N-glycosylated, and all known PGHS-2 enzymes have consensus N-glycosylation sites at an analogous position (13 , reference provided by the vendor, 14).
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and 6). No positive immunostaining or in situ signals for PGHS2 was found for endometrial or maternal placental stromal cells (Figs. 5 and 6). In the myometrium the myometrial cells were the major cell type containing PGHS2 mRNA and protein as shown in Figs. 5 and 6. Trophoblast cells were the only cell type, which was stained positively for PGHS2 mRNA (Fig. 5) and protein (Fig. 6) in the fetal placenta. When the sections were hybridized with the PGHS2 sense riboprobe or reacted with normal rabbit serum as a replacement for PGHS2 antisense probe or the primary PGHS-2 antibody, the positive signals for PGHS2 mRNA (Fig. 5) and protein (Fig. 6) were abolished.
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hydroxylase mRNA expression hydroxylase mRNA was completely absent in control and estradiol-treated ewes but was elevated in cortisol-induced labor and spontaneous term labor animals (Fig. 7).
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Discussion |
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This is the first study to examine the effect of exogenously administered estradiol on the physical and molecular changes in the uterus of pregnant sheep before the normal late-gestation rise in fetal plasma cortisol. Estradiol administration induced myometrial contractions, cervical dilation, and delivery of the fetus in five of six animals. In the sixth animal, myometrial activity switched from contractures to contractions, but delivery did not occur. Several previous studies have determined estradiol’s effect on the control of the onset of labor at maturities ranging from 108 dGA to term (22, 23). Delivery could not be achieved at gestations earlier than 135 days (22), in which a single sc injection of stilbestrol-in-oil 20 mg was used. However, none of these studies reported the estradiol concentration achieved in maternal or fetal plasma at the dose of estradiol used in their studies. In a pilot study, we found that infusion of estradiol at a rate of 2 mg/d only raised fetal or maternal plasma estradiol up to 20–25 pg/ml (data not shown), well below the level observed in maternal plasma at spontaneous labor (10, 24, 25). At the dosage used in the present study, we were able to produce maternal plasma estradiol concentrations of about 350 pg/ml (Fig. 1
), a value within the range observed in dexamethasone-induced premature labor (26) and spontaneous term labor (10).
Several previous studies have demonstrated that estradiol increases myometrial contractility in sheep (23, 27); however, the molecular mechanisms associated with increased myometrial contractility are not clear. PGs are a powerful stimulant of myometrial contractility. Our data clearly showed that estradiol administration stimulated PGHS 2 expression in three major intrauterine tissues, myometrium, endometrium, and maternal placenta, leading to increased PGF2 in maternal plasma. This increased capability of PG production reflected by increased PGF2 in maternal plasma may play a major role in the switch of the contracture pattern of activity that exists throughout pregnancy to the strong coordinated myometrial contraction activity necessary to deliver the fetus. Our data indicate that induction of the PG synthetic pathway in maternal uterine tissues is strongly dependent on stimulation by estrogen. However, there may be many other factors induced by estradiol to mediate estradiol’s stimulation on intrauterine PG synthesis.
In contrast to the observed changes in PGHS2 within maternal uterine tissues, we were unable to demonstrate an increase of PGHS2 in sheep fetal placenta. Although our data support a role for estradiol in the regulation of PG synthesis by intrauterine, nontrophoblast tissues, we cannot exclude the regulatory function of estradiol on trophoblast tissues because administered estradiol was increased only in the maternal plasma. However, in light of the observation that fetal placental PGHS2 increases in late gestation (7), well before the rise in maternal plasma estradiol at the end of gestation, we and others have proposed that in late gestation fetal adrenal cortisol induces fetal placental PGHS2 expression and PG production (4, 5). Indeed, we recently reported that fetal cortisol at concentrations seen in late gestation, independent of any other steroids of fetal origin, are able to stimulate fetal placental PGHS2 expression (5). Therefore, it is likely that the increase in placentome PGHS2 in late gestation is under the control of late gestation rise of fetal cortisol, whereas estradiol may control PGHS2 expression in maternal intrauterine tissues associated with the onset of labor in pregnant sheep.
Increased maternal plasma estradiol was able to produce cervical dilation in five of six treated animals. These data indicate that cervical dilation is mainly, although possibly not completely, under the control of estradiol. The mechanism(s) by which estradiol mediates cervical changes merits further study. Oxytocin is a possible candidate because oxytocin is capable of increasing the production of PGE2 in the cervical mucosa and softening of the cervix (28).
The retention of the placenta in all estradiol-induced premature fetal deliveries at the stage of gestation studied indicates that estradiol alone is not able to complete the process of labor. Other mechanisms have to interact with estradiol to carry labor to completion. We have hypothesized that progesterone may play a key facilitating role in the separation of the placenta and fetal membranes. Separation of the fetal membranes and placenta has some similarity to menstruation in the nonpregnant uterus. Estrogen can produce a clear shedding of the endometrium in the nonpregnant uterus only after progesterone priming (29, 30). Estradiol administered to ovariectomized sheep after a period of progesterone treatment caused a much larger increase in uterine PGF2 output than occurred in the absence of progesterone priming (30). In addition, Liggins (22) reported that progesterone alone given to the pregnant sheep increased PGF2 concentration in the maternal cotyledons and myometrium. Progesterone is a potent stimulator of endometrial PGHS2 in the nonpregnant sheep uterus (9). Taken together, these data suggest that a period of sufficient progesterone priming is required to facilitate the separation of endometrium in the nonpregnant uterus and the fetal membrane and placenta in the pregnant uterus. However, the molecular mechanisms associated with these physical changes are not fully understood. PGs produced by fetal membranes and placenta might be of importance in regulating this process. Further study is needed to address these important fundamental actions of progesterone, which have received very little attention in parturition research.
In the present study, failure of fetal cortisol to rise in the estradiol-treated groups, compared with controls, indicates that the increased PG production by maternal intrauterine tissues is regulated by an estrogen-dependent pathway (4, 5). However, other factors, such as oxytocin, recruited by estradiol may play a role in mediating estradiol’s effect on induction of PG synthesis. Oxytocin has been shown to cause accumulation of PGHS2 in the uterus of pregnant and parturient cows (31). Whereas placental P450c17 hydroxylase mRNA is highly expressed in placentas obtained from ewes in spontaneous term labor and cortisol-induced labor, its expression was undetectable in estradiol-treated animals. These data further support our hypothesis that the myometrial contraction and cervical dilation observed in the current study most likely result from the stimulation by estradiol. Further studies including fetal adrenalectomy are required to address the possibility that basal levels of fetal cortisol play a permissive role in mediating the ability of estradiol to induce labor.
The onset of parturition is regulated by the complex interactions of endocrine, neural, and mechanical factors. Among these factors, a distinction should be drawn between those factors that have a permissive role and predispose the uterus to the development of parturient activity and those that act more acutely on the uterus and cervix to trigger the onset of parturition. Our data indicate that estrogen is one of the acute triggers because in the current study physiological increases in plasma estradiol was sufficient to trigger labor in absence of perturbations of maternal progesterone or fetal cortisol concentrations.
Conclusions
We conclude that maternal administration of estradiol is able to precipitate fetal delivery associated with increased uterine PG production. Estradiol stimulated PG production mainly in maternal uterine tissues. Failure of placental delivery after estradiol treatment suggests that estradiol alone is insufficient to produce complete delivery at the gestation studied.
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Footnotes |
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Abbreviations: dGA, Days of gestational age; DTT, dithiothreitol; EIA, enzyme immunoassay; PG, prostaglandin; PGHS, PG H synthase; SSC, saline sodium citrate.
1 X.H.M. is recently deceased. 
Received September 2, 2003.
Accepted for publication November 19, 2003.
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in the control of ovine parturition. J Reprod Fertil Suppl 16:85–103
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) and fetal (
) plasma from controls (Cont) and estradiol (E2)-treated animals at necropsy. There was a significant increase of maternal plasma estradiol concentration after E2 treatment (*, P < 0.01). There was no change in fetal plasma estradiol concentrations in E2 group. Values are presented as mean ± SEM.
