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Biomedical Research Institute, Biological Sciences and Leicester Warwick Medical School (S.T.), University of Warwick, Coventry, United Kingdom CV4 7AL; and Receptor Screening and Enzyme Technologies, Glaxo-Smithkline (M.J.A.), Stevenage, Hertfordshire, United Kingdom SG1 2NY
Address all correspondence and requests for reprints to: Dr. Steven Thornton, Biomedical Research Institute, Biological Sciences, University of Warwick, Coventry, United Kingdom CV4 7AL. E-mail: sthornton{at}bio.warwick.ac.uk.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-amidated OT. Immunohistochemistry localized OT to chorionic trophoblast, decidual stroma, and glandular epithelium. RT-PCR analysis of OTR mRNA demonstrated a significant difference between FU and LS samples, which remained unchanged with labor in all tissues. Immunohistochemistry localized OTR to amniotic epithelium, decidual stroma, and myometrium. Tissue E2 concentrations, as determined by ELISA, demonstrated a significant increase with labor in all tissues. E2 was highest in CD, followed by FU, AM, and LS, respectively. E2 correlated with OT in samples of FU and CD taken from NIL women and in FU, CD, and AM taken from LAB women. We conclude that a significant increase in both OT and E2 occurs at the myometrial decidual interface with labor, and this increase is reflected in both the fundal and lower segments of the uterus. In contrast to OT and E2 the OTR is spatially regulated, with significantly greater expression in the fundal region of the uterus. Paracrine OT production stimulated by E2 may be important in activating the uterus at term.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the rhesus monkey, the formation of estradiol (E2) by the infusion of androstenedione initiates preterm delivery with key associated features of normal parturition, such as increased fibronectin and OT and diurnal changes in myometrial activity (7). Furthermore, such changes are prevented by aromatase inhibitors and are not mimicked by estrogen infusion (8). This infers that paracrine metabolism of estrogen from fetal androgens is a critical event for the precipitation of labor, and that local uterine, rather than systemic, plasma concentrations of estrogen are more important for this process. The infusion of maternal androstenedione, but not E2, increases plasma OT, implying that at least some OT is produced in the intrauterine tissues rather than by the hypothalamus. Intrauterine OT production was first demonstrated in the rat (9) and is supported in the human by an increase in OT mRNA in the chorio-decidua (CD) with the onset of labor (10). Although intrauterine OT peptide concentrations have never been demonstrated in vivo, in explant culture, CD discs produce OT in response to E2, an effect prevented by tamoxifen (11). The aim of this study was to evaluate the temporal and spatial relationship among E2, OT peptide, and OT receptor (OTR) within the human uterus.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects were recruited into two groups, spontaneous labor (LAB) and elective cesarean section not in labor (NIL) between 38–40 wk gestation. The LAB group was undergoing cesarean section for reasons of presumed fetal distress. Spontaneous labor was defined as regular contractions (<3 min apart), membrane rupture, and cervical dilation (>2 cm) with no augmentation.
Sample collection
At cesarean section, samples were collected before OT administration, after obtaining informed consent, according to the following protocols. Fundal (FU) samples (
100 mg) were taken using ovarian biopsy forceps as described previously (12). At the same time a small (500 mg) knife biopsy was taken from the lower uterine segment incision. After delivery of placenta and membranes, 4-cm squares of amnion (AM) and CD were removed.
Sample pretreatment
Samples were washed briefly in saline and flash-frozen in liquid nitrogen for peptide/E2/mRNA analysis or fixed for 24 h in 4% paraformaldehyde/saline for immunohistochemistry. Frozen samples were pulverized in liquid nitrogen, and a small sample was analyzed for mRNA analysis. RNA was isolated by SV isolation columns according to the manufacturer’s instructions (Promega, Madison, WI). The remaining frozen sample was resuspended by mechanical homogenization in a 10x volume of ice-cold acid extraction buffer as described previously (11) and frozen (-70 C) in 1-ml aliquots for subsequent analysis.
RNA analysis
Three 100-ng total RNA aliquots were reverse transcribed according to the manufacturer’s instructions using Superscript II reverse transcriptase (Life Technologies, Inc., Paisley, UK), pooled, and diluted 1:3 for PCR analysis. Two microliters of cDNA were cycled to linear amplification in duplicate in a 25-µl total reaction volume by PCR. For OT, reaction components were as described by the manufacturer for Taq polymerase (Life Technologies, Inc.), except 0.1 µCi -deoxy-GTP, 2.6 mM betaine/2.6% dimethylsulfoxide with oligonucleotide sequences (A, 5'-ATATCTGCTGCGCGGAAGAG-3'; B, 5'-GGTGTTCGGAGCCATCAAGT-3') and reaction conditions (annealing at 60 C, 33 cycles). OTR reactions were as described for OT, except for the oligonucleotide sequences (A, 5'-CTACGGCCTTATCAGCTTCA-3'; B, 5'-TTCTCGTTGAGCAGGAGGAA-3') with linear amplification at 28 cycles. Reactions for ß-actin were previously described (13). Test primers were also validated against glyceraldehyde-3-phosphate dehydrogenase, and results were comparable. Reactions were separated by electrophoresis on a 6% polyacrylamide gel as described previously (14) and dried under vacuum. Incorporated radioactivity was quantified by laser scanning PhosphorImager (Molecular Dynamics, Inc., Sunnyvale, CA).
OT peptide purification
Frozen (-70 C) aliquots of lysate were freeze-dried under vacuum, resuspended in 1 ml 0.1% trifluoroacetic acid/water, and separated by reverse phase HPLC through a C18 S50DS2 Spherisorb (Phasesep, Deeside, UK) column on an increasing gradient of acetonitrile/water. Fractions were collected, freeze-dried under vacuum, and stored at -70 C. Immunoreactive OT was quantified by specific RIA as described previously (15).
Estrogen measurements
Frozen (-70 C) aliquots of lysate were extracted by mixing in diethyl ether at a dilution of 3:7 (vol/vol). The organic phase was dried and reconstituted in zero serum for assay by ELISA (International Diagnostic Systems, Inc., St. Joseph, MO) according to the manufacturer’s instructions.
Immunohistochemistry
Detection of OTR was performed as described previously (16) using the monoclonal 2-F8 antibody (Rhoto Pharmaceuticals, Osaka, Japan), antimouse immunoglobulin M (IgM) secondary biotinylated antibody and chromogen substrate for visualization using 3,3'-diaminobenzidine tetrahydrochloride with nickel enhancer (Vector Laboratories, Inc., Burlingame, CA). Staining was compared with serial sections replacing 2-F8 with 0.1 µg/ml mouse IgM clone DAK-G08 (DAKO A/S, Copenhagen, Denmark).
Detection of neurophysin using the rabbit polyclonal NCL-NPp IgG was performed according to the manufacturer’s instructions (Novo Castra Laboratories, Newcastle upon Tyne, UK), with antirabbit IgG biotinylated antibody and chromogen substrate for visualization as for OTR. Staining was compared with serial sections, replacing NCL-NPp with 0.1 µg/ml nonimmune rabbit IgG (Vector Laboratories, Inc., Burlingame, CA). All sections were counterstained with hematoxylin.
Mass spectrometry
Freeze-dried fractions were resuspended in 0.1% trifluoroacetic acid and desalted on Zip-Tip C18 columns (Millipore Corp., Bedford, MA) according to the manufacturer’s instructions. Samples were eluted in 25% acetonitrile/1% formic acid in water and analyzed by electrospray ionization on a Q-Tof 1 mass spectrometer (Micromass, Manchester, UK).
Computer analysis and statistics
Phosphorimaged files were quantified using the Total Lab (Nonlinear Dynamics, Durham, NC) gel analysis package. Incorporation was expressed as a ratio of counts per minute of test over ß-actin. RIA and ELISA triplicate determinations were analyzed by a curve fit to a nonlinear regression algorithm for the single site competitive binding model using the PRISM program (GraphPad Software, Inc., San Diego, CA). Data are expressed as the mean and SE and were interpolated from within the 95% confidence interval of the standard curve. Statistics for LAB vs. NIL groups were calculated using the PRISM program by unpaired two-way t test. Correlation analysis of E2 and OT was performed nonparametrically by two-tailed Spearman rank test. The relationship between E2 and OT was tested by linear regression analysis.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The central hypothesis of OT production (9, 10, 11, 17, 18) within the intrauterine tissues of rats and humans is that under the control of estrogen, OT perfuses the intrauterine environment, stimulating receptors located in the uterine epithelium (rat) and decidua and myometrium (human). In samples taken from the FU, CD, and AM, there was a significant (P < 0.05) increase in OT mRNA in association with labor (Figs. 1
and 2A). In contrast, OT mRNA was not increased in paired samples from the lower segment (LS). Quantification of OT peptide (Fig. 2B) demonstrated a significant (P < 0.05) labor-associated increase in samples of FU, CD, and AM, which was consistent with the mRNA data. OT peptide levels in the LS also reflected mRNA levels, demonstrating no significant difference when comparing LAB with NIL samples.
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-amidated and carboxyl- extended forms of OT are present within the uterus (19). Carboxyl-extended forms of OT have reduced biological potency compared with -amidated OT and can, albeit at high concentrations, cross-react with the RIA antisera. It was therefore important to ascertain which form of OT was present in the purified fractions used for RIA analysis. HPLC-purified fractions of FU lysate were analyzed by mass spectrometry to detect different OT species. Analysis of the OT-immunoreactive fraction demonstrated a singly charged ion with a mass of 1007 Da, thereby confirming fully processed -amidated OT as the immunoreactive peptide in FU samples (Fig. 2C
). No carboxyl-extended forms of OT were detected in any of the HLPC fractions analyzed over a 20-min elution period (data not shown).
Histological examination determined the cellular compositions of FU (Fig. 3A) and LS samples (Fig. 3B). LS biopsies consist almost entirely of myometrium, whereas FU contains both myometrium and decidua. FU samples taken by ovarian biopsy forceps are therefore not only reflective of myometrium taken at a different site of the uterus (i.e. FU vs. LS), but are also closer in proximity to the decidua than the more serosal LS samples.
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), decidual stroma, and glandular epithelium (Fig. 4B). Taken with the mRNA data, these results show that intrauterine OT is formed primarily in the decidua, with some production in the chorionic trophoblast, and that OT peptide concentrations are highest at the myometrial/decidual interface. To confirm that the high OT concentrations observed in the FU samples reflected the proximity of the decidua and not an FU/LS difference, LS samples were taken from NIL patients using ovarian biopsy forceps. Mean OT concentrations (8.94 ± 3.10 pg/g; n = 3) in samples taken in this manner were not significantly different from those in NIL samples from the FU.
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OTR protein and mRNA increase dramatically in myometrium and decidua over gestation in all mammalian species analyzed, suggesting an important role in parturition (9, 20, 21, 22). In this study we concurrently determined OT formation and OTR expression in the same samples to investigate their precise spatial and temporal relationships. OTR mRNA analysis demonstrated a dramatic increase in expression at term compared with nonpregnant myometrium as previously described (23), but no significant increase with spontaneous labor (Fig. 5A). There was, however, significantly higher (P < 0.05) mRNA in FU compared with LS, CD, and AM samples. Although, immunohistochemistry localized OTR expression to decidual stroma (Fig. 5B), the highest expression was in myocytes at term (Fig. 5C). Given that the OTR is principally expressed in myocytes, and the FU samples contain decidua, the actual increase in myometrial OTR mRNA in the FU at term may be higher than our data suggest.
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We measured E2 concentrations in the same samples analyzed for OT. Tissue E2 concentrations were significantly (P < 0.05) greater in all LAB samples (Fig. 6A) compared with those in NIL samples. E2 concentrations were highest in CD (NIL, 21,757 ± 2,333 pg/g; LAB, 36,019 ± 2,311), followed by FU (NIL, 11,788 ± 1,360; LAB, 24,714 ± 2,692), AM (NIL, 10,530 ± 809; LAB, 19,754 ± 4,368), and LS samples (NIL, 8,467 ± 1,960; LAB, 15,040 ± 2,509) respectively. The concentrations in CD were significantly different compared with those in FU (NIL, P < 0.01; LAB, P < 0.01), AM (NIL, P < 0.001; LAB, P < 0.01), and LS (NIL, P < 0.001; LAB, P < 0.001) samples, as determined by two-way t test. Concentrations were also significantly different when comparing FU to LS samples (NIL, P < 0.05; LAB, P < 0.05). Concentrations were not significantly different when comparing FU to AM and AM to LS in either LAB or NIL samples.
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In the FU, E2 was significantly correlated with OT in samples taken from NIL patients (rs = 0.8857; P < 0.05) and LAB patients (rs = 0.9856; P < 0.05), as determined by nonparametric Spearman rank test (Table 1). However, the correlation was not significantly linear in NIL samples (r2 = 0.564; P > 0.05) or LAB samples (r2 = 0.395; P > 0.05; Fig. 6b). There was no significant correlation observed in samples taken from NIL LS (rs = 0.7143; P > 0.05) or LAB LS (rs = 0.7714; P > 0.05). In the AM, no correlation was observed in NIL samples (rs = 0.7143; P > 0.05) in contrast to LAB samples, which demonstrated a significant (rs = 0.8857; P < 0.05) and linear (r2 = 0.755; P < 0.05) correlation. A significant (rs = 0.9429; P < 0.05) and linear (r2 = 0.830; P < 0.05) correlation was also observed in CD samples taken from LAB patients, which was in contrast to a significant (rs = 0.9429; P < 0.05), but nonlinear (r2 = 0.423; P > 0.05) correlation in NIL samples.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-amidated OT. Mass spectrometry analysis failed to demonstrate any carboxyl-extended forms of OT, suggesting that the majority of synthesized hormone is rapidly converted to bioactive OT. It is possible, however, that pro-forms of OT may not have been detected by mass spectroscopy because they had poor ionization efficiency relative to -amidated OT. In the rat uterus, carboxyl-extended forms of OT are the predominant translated gene product and are present in increasing concentrations from d 13 of gestation to term (18). The poor conversion of translated OT mRNA to mature -amidated OT is similar to that observed in the neurohypophysis of the fetal rat (24) and the umbilical plasma of the ovine and human term fetus (25, 26). Our data imply that the posttranslational processing of OT in human CD may be more efficient than that observed in the rat. OT peptide increased significantly (P < 0.05) in FU, CD, and AM, but not LS, myometrial samples in LAB compared with NIL patients. In FU samples, OT increased 2-fold with labor and represented the highest concentration detected in the four tissues. Immunohistochemistry located neurophysin-1, the OT carrier protein, to the chorionic trophoblast and decidual stroma of the CD samples and the decidual stroma and glandular epithelium of the FU samples. RT-PCR analysis further confirmed this distribution, with a significant increase in mRNA for OT with labor in the FU, CD, and AM. Interestingly, the mRNA levels in CD and FU were very similar, supporting the immunohistochemistry determination that the site of intrauterine OT synthesis was primarily the decidua. However, the immunohistochemistry data do not explain why higher peptide levels of OT were detected in the FU compared with the CD when mRNA levels were comparable between the two tissues. In addition to this, OT peptide levels were significantly higher in the LS samples compared with the CD despite the fact that there were no detectable OT-producing cell types present. The observed concentration differences in OT peptide in myometrial tissues relative to fetal membranes may reflect a difference in the metabolism of OT. OT is degraded in term human decidua and chorion with similar efficiency to the placenta (27). In LAB and NIL samples of these tissues, amino peptidase activity in microsomal fractions and postproline endopeptidase activity in cytosolic fractions degrade OT with a Km of 8–20 µM. However, it is not currently known whether these degrading enzymes are present in myometrium.
As OT peptide is rapidly degraded in human CD, steady state levels of bioactive OT, as determined here, are largely reflective of de novo synthesis. Therefore, transcriptional regulation and/or mRNA stability are central to the control of OT levels. In contrast, in myometrial tissues, our data suggest that OT may not be rapidly degraded, and as such, levels may be influenced by paracrine OT from the CD and OT from endocrine sources such as the neurohypophysis. This hypothesis is supported by the close correlation observed between OT peptide and mRNA in CD and AM samples. Although such explanations may account for the higher levels observed in myometrial samples, it is ultimately not possible to determine the precise origin of OT in the tissue peptide measurements used in this study. These interesting observations should therefore be the subject of further study.
The onset of nocturnal myometrial activity at term in the rhesus monkey (8) and baboon (28) is closely correlated to a diurnal surge in maternal E2 production. The overall plasma levels of estrogens in human and nonhuman primates are known to increase in maternal plasma throughout gestation (6). This is largely because primate placenta is dependent on the C19 androgen precursor dehydroepiandrosterone sulfate, which is derived from fetal and maternal adrenals for the synthesis of estrogen (6). The gestational rise in maternal estrogens is associated with the hypertrophy and increased steroidogenic activity of the inner cortical compartment of the fetal adrenals, which provide the placenta with increased dehydroepiandrosterone sulfate substrate (29). The nocturnal uterine activity that correlates with the diurnal increase in estrogens in the nonhuman primate is closely associated with maternal OT concentrations and is prevented by OT antagonist infusion (30). Furthermore, the nocturnal increase in plasma OT in androstenedione-infused monkeys is prevented by aromatase inhibitors, but is not mimicked by estrogen infusion (8). Taken together these data suggest that in nonhuman primate species OT may be stimulated by estrogens that are synthesized in a diurnal rhythm by the placenta and metabolized specifically in the intrauterine environment.
Our data are consistent with the tissue-specific metabolism of E2 because CD samples consistently demonstrated the highest concentrations of E2, followed by FU, AM, and LS. It is highly unlikely that these differences are reflective of plasma-borne E2 alone, as the most vascular specimens were the FU samples, and yet E2 concentrations were not significantly different from the AM, which is avascular. It has long been established that the fetal membranes and decidua are capable of steroidogenesis (31, 32). The activities of sulfohydrolase and 17ß,20-hydroxysteroid dehydrogenase enzymes increase in these tissues at the time of labor (33, 34). Sulfohydrolase uses estrone sulfate to produce free estrone, whereas 17ß,20-hydroxysteroid dehydrogenase interconverts E2 with estrone and progesterone with 20-dihydroprogesterone. The authors of these studies speculated that the net effect at term would be an increase in the most biologically active estrogen E2 and a concomitant increase in the most inactive progestagen 20-dihydroxyprogesterone. These studies were undertaken using a biochemical assay that detects enzyme activity that can now be attributed to at least seven different enzymes (35). It remains to be determined whether the observed changes are the result of a gestational change in any of these enzyme isoforms.
The potential in vivo relationship between E2 and OT was examined in our study by Spearman rank analysis and scatterplots of concentrations determined from the same tissue lysates. E2 was significantly correlated with OT peptide in the CD, AM, and FU, but not the LS, samples. These were the same tissues that were demonstrated to produce OT, and this provides further indirect support for the hypothesis that E2 mediates paracrine OT production. Closer analysis of the relationship between OT and E2 concentrations demonstrated that the correlation becomes significantly linear with labor in the AM and CD. The change in relationship between OT and E2 observed with labor in these tissues may be mediated by the estrogen receptor (ER). ER mRNA is significantly increased in LAB CD tissues compared with NIL samples (11). In addition, an E2-dependent increase in OT production in in vitro cultured CD explants is prevented by coadministration of the ER antagonist tamoxifen (11). There is therefore functional evidence that ER is required for estrogen-mediated OT synthesis in human CD, and that the expression of ER with labor correlates with a change in the relationship of E2 and OT concentrations.
The lack of linear correlation between E2 and OT in the FU samples supports the hypothesis that the myometrium does not degrade OT rapidly. It is difficult to draw definitive conclusions, however, because the precise cellular origins of the E2 and OT peptide measured in this study cannot be confirmed, and correlation data alone do not demonstrate cause and effect. Although we acknowledge this caveat, we believe that the correlation, immunohistochemistry, and mRNA data of this study combined with the in vitro data from human CD explants (11) support a role for estrogen mediating intrauterine OT synthesis in human labor.
The sensitivity of the uterus to OT is mediated in all eutherian mammals by a gestational increase in the OTR. In humans a gestational increase in OTR is well documented and is spatial, with higher expression in the FU (36). Such spatial distribution, as confirmed in our study, would allow an increase in contractile force from the FU region of the uterus during the second stage of labor, forcing the fetus downward through the relatively relaxed LS. Our data imply that this effect is mediated entirely by the spatial expression of the receptor and not the ligand. The expression of OTR within the decidua also supports the well established hypothesis that OT is an important stimulant of prostaglandins at term in this tissue (21).
In conclusion, our study demonstrates that OT and E2 increase significantly at the myometrial decidual/interface with labor in the FU and LS of the human uterus. OT within intrauterine tissues would have paracrine and autocrine effects on OTRs expressed within the AM epithelium, decidua, and myometrium. This study and others indicate that intrauterine OT, under the control of estrogen, may play a role in eliciting spontaneous labor at term.
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Acknowledgments |
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Footnotes |
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Abbreviations: AM, Amnion; CD, chorio-decidua; E2, estradiol; ER, estrogen receptor; FU, fundus; Ig, immunoglobulin; LAB, with labor; LS, lower segment of myometrium; NIL, without labor; OT, oxytocin; OTR, oxytocin receptor.
Received August 1, 2002.
Accepted April 9, 2003.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxyprogesterone, 17-hydroxyprogesterone, 20-dihydroxyprogesterone, 
5-pregnenolone, 5-pregnenolone sulfate, and 17-hydroxy 5-pregnenolone. J Clin Endocrinol Metab 48:133–138[Medline]
proteins in the upper and lower segments of the human uterus during pregnancy and labor. J Clin Endocrinol Metab 84:1705–1710-hydroxysteroid dehydrogenase activity supporting an increase in the estrogen/progesterone ratio of human fetal membranes at parturition. Am J Obstet Gynecol 168:1377–1385[Medline]
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; n = 6) and NIL (
; n = 6) patients; B, peptide concentrations (mean ± SEM) in samples taken from LAB (
