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Original Studies |
Medical Research Council Group in Fetal and Neonatal Health and Development (M.Y.S., J.R.G.C.); Medical Research Council Group in Development and Fetal Health (S.J.L.); the Departments of Physiology and Obstetrics and Gynecology, University of Toronto; and the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5S 1A8
Address all correspondence and requests for reprints to: Dr. J. R. G. Challis, Department of Physiology, University of Toronto, Medical Sciences Building, Room 3205/7, 1 Kings College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail j.challis{at}utoronto.ca
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Abstract |
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Myometrial samples were collected from the lower segment (LS) in nonpregnant, preterm (32 ± 2 weeks), and term (39 ± 1.6 weeks) pregnant patients before and at labor. Fundus and LS samples were also collected from nonpregnant, pregnant, laboring, and postpartum women. FM were collected at term and at labor. We identified CRH receptors in myometrium and FM by semiquantitative RT-PCR and immunohistochemistry.
CRH-R1 messenger ribonucleic acid (mRNA) in the LS was decreased in pregnancy and increased significantly in both preterm and term labor (P < 0.05), but remained unchanged in the fundus. CRH-R2 mRNA was present in 28% of LS myometrium with no change at labor. CRH-R1 and CRH-R2 protein was localized to myometrial smooth muscle in nonpregnant and laboring patients, with lower levels at term. CRH-R1 mRNA was present in chorion and decidua, but CRH-R2 was undetectable in these tissues. We conclude that CRH-R1 is expressed preferentially in myometrium and FM. Changes in CRH receptors during labor are consistent with CRH mediating effects on myometrial activity.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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During pregnancy, the human placenta secretes increasing amounts of CRH into the maternal circulation, resulting in a progressive increase in maternal peripheral venous CRH values that reach a peak at the time of labor (12, 13). The physiological significance of high circulating levels of placental CRH, however, remains to be established. It has been reported that CRH plays an effect on myometrial tone; however, there are some apparent discrepancies with regard to these reports. Some researchers have suggested that CRH stimulates myometrial contractions by potentiating the actions of uterotonic agonists, although it has no direct stimulatory action itself (14–16). Moreover, cAMP, the second messenger that mediates CRH action, is usually associated with the relaxation of smooth muscle, including the myometrium (17). Recently mRNAs encoding CRH-R1 and CRH-R2 have been identified in the myometria of pregnant women (18). However, there is no information concerning changes in the expression of CRH receptors in the myometrium during term or preterm labor that would support their role in the regulation of labor contractions. Furthermore, although CRH has been shown to regulate PG synthesis in fetal membranes (FM) and thus contribute to the mechanisms involved in the onset of labor, the relative distribution of the CRH receptor subtypes in FM has not been established.
In previous studies using tissue from the lower uterine segment, we found increased expression of genes that probably confer relaxation on the myometrium during labor (19, 20). This led us to hypothesize that there is a functional regionalization in the myometrium during labor. Thus, the LS would activate genes involved in relaxation, whereas in the fundus the expression of genes mediating myometrial stimulation would be increased. The paradox in the role of CRH in the myometrium could be similarly explained by regionalization of expression or by differential expression of the receptor subtypes. We therefore determined the expression of CRH-R1 mRNA and CRH-R2 mRNA and their respective proteins in human myometrium in term and preterm pregnancies before and at the time of labor. To establish regional differences in CRH receptor expression, we also distinguished between myometrium collected from the fundus and that from the LS of the uterus. We examined the level of mRNA encoding CRH-R1 and CRH-R2 in the decidua and FM in term pregnancies before and at the time of labor to establish whether increased receptor expression in these tissues might contribute to the onset of labor.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Myometrial samples were collected from the lower region of the uterus of nonpregnant and pregnant women. The nonpregnant premenopausal women (mean age, 42 ± 1.5 yr; n = 4) were undergoing hysterectomy for fibroids. Tissues were collected at cesarean section from the following groups of pregnant women (mean age, 31 ± 2.4 yr): preterm no labor [mean gestational ages (MGA), 32 ± 2 weeks; n = 5], preterm labor (MGA, 32 ± 3 weeks; n = 6), term elective cesarean section (MGA, 39 ± 1.6 weeks; n = 7), and term in labor (MGA, 39 ± 1.7 weeks; n = 7). Indications for preterm cesarean section included preeclampsia and/or other maternal disease. Indications for cesarean section at term included breech delivery (n = 12), repeat cesarean section (n = 9), or failure of labor progression (n = 4). Myometrial samples were collected from the upper edge of the incision line in the lower uterine segment at cesarean section.
We were also able to collect myometrial tissue from both the fundus and the lower uterine segment of nonpregnant patients (age, 40 ± 1.3 yr; n = 4) undergoing hysterectomy for fibroids, from pregnant patients (age, 32 ± 2.1 yr) at 38 weeks gestation undergoing elective hysterectomy for progressive cervical cancer (n = 4), and from a postpartum patient undergoing hysterectomy for disseminated intravascular coagulation (n = 1). Fundal and LS myometrial tissues were also collected from a woman (age, 35 yr; n = 1) undergoing a classical cesarean section during labor to deliver conjoined twins. All tissue samples were frozen immediately in liquid nitrogen and stored at -80 C.
Decidua (n = 8), chorion (n = 8), and amnion (n = 8) were collected from term patients in the absence (MGA, 39 ± 2 weeks) or in the presence of labor (MGA, 39 ± 1.7 weeks). The chorion and decidua were separated by gentle scraping and were immediately snap-frozen in liquid nitrogen. All tissue biopsies were collected at Mount Sinai Hospital (Toronto, Canada). Informed consent was obtained from all patients, and ethical approval for the study was obtained from the institutional human ethic committee and the University of Toronto.
To obtain positive and negative control tissues, virgin female Wistar rats (250–280 g; Charles River Canada, St. Constant, Canada) were decapitated, and pituitaries and livers were collected. Pituitary tissue was also collected from fetal sheep at term delivery (145 days gestation) after killing the animals with an overdose of pentobarbitone given via cardiac puncture. All tissue samples were frozen immediately in liquid nitrogen and stored at -80 C. The animal experimental protocols were approved by the Samuel Lunenfeld Research Institute animal care committee and the animal care committee of the University of Toronto according to the Guidelines of the Canadian Council on Animal Care.
Total RNA extraction
Total RNA was extracted from the samples of myometrium, decidua, chorion, and amnion using the methods described by Chomczynski and Sacchi (21). Briefly, frozen tissue samples (2–5 mg) were powdered under liquid nitrogen and homogenized in 1 mL of a denaturing solution [4 mol/L guanidinium thiocyanate, 25 mmol/L sodium citrate, 0.5% sodium lauroylsarcosine, and 0.1 mol/L ß-mercaptoethanol (vol/vol)]. Water-saturated phenol (1 mL) and chloroform-isoamyl alcohol mixture (49:1; 0.2 mL) were added to the tissue homogenate, and the supernatant was collected. The RNA was precipitated with an equal volume of isopropanol, and the resulting pellet was resuspended in 70% ethanol (1 mL), vacuum-dried, and redissolved in double distilled water with 0.1% diethylpyrocarbonate (DEPC) water. The total RNA purity and recovery for each sample were determined with a UV spectrophotometer (model DU-64, Beckman Instruments, Inc., Palo Alto, CA) at 260 and 280 nm.
RT-PCR
Total RNA from myometrium, decidua, chorion, amnion, rat liver, and rat pituitary was converted by RT into cDNA. An aliquot of total RNA (1 µg) was added to a RT reaction mix composed of 1 x PCR buffer (10 mmol/L Tris-HCl and 50 mmol/L KCl; Perkin-Elmer/Cetus, Emeryville, CA), 5 mmol/L MgCl2 (Perkin-Elmer/Cetus), 1 mmol/L each of deoxy (d)-NTP (dATP, dCTP, dGTP, and dTTP; Pharmacia Biotech, Piscataway, NJ), 5 ng/µL random hexamers (Pharmacia Biotech), 1 U/µL ribonuclease Inhibitor (Boehringer Mannheim, Indianapolis, IN), and 100 U Moloney murine leukemia virus reverse transcriptase (Life Technologies, Gaithersburg, MD) in 21 µL DEPC water. The reaction mixture was incubated at 25 C for 10 min, then at 42 C for 30 min, and finally at 99 C for 5 min. The resultant cDNA (RT) mixture was stored at -20 C until use.
PCR was performed using the resulting cDNA. The PCR mixture consisted of 10 µL of the RT mixture, 0.25 mmol/L dNTP, 50 ng of each specific PCR primer (ACGT Corp., Toronto, Canada), 2.5 U Taq polymerase (Boehringer Mannheim) in 1.25 mmol/L MgCl2, 50 mmol/L KCl, and 10 mmol/L Tris-HCl (pH 8.3) in 24.5 µL DEPC water. Each PCR reaction underwent an amplification regimen characterized by preincubation (95 C, 5 min), denaturation (94 C, 30 s), primer annealing (62 C, 30 s), extension (72 C, 30 s), and a long extension (72 C, 8 min) in a thermal cycler (MJ Research, Inc., Cambridge, MA).
Specific primers were used to identify a 333-bp product for CRH-R1 in human myometrium, decidua, and FM (22). A sense primer (5'-GCC CTG CCC TGC CTT TTT CTA-3') and an antisense primer (5'-GCT CAT GGT TAG CTG GAC CA-3') corresponding to positions 235–255 and 549–568, respectively, were used (accession no. L23332) (3). Similarly, primers were designed to identify a 781-bp product for CRH-R2 in human myometrium, decidua, and FM. A sense primer (5'-GCT GGC CCC GCA GCG CTG CC-3') and an antisense primer (5'-CTT CAC TGC CTT CCT GTA CT-3') corresponding to positions 149–169 and 911–930, respectively, were used (accession no. U34587) (9). ß-Actin gene expression (internal control) was also determined in all samples to assess the integrity of the RNA. Primers were designed to identify a 218-bp product for ß-actin in all samples. A sense primer (5'-AAG AGA GGC ATC CTC ACC CT-3') and an antisense primer (5'-TAC ATG GCT GGG GTG TTG AA-3') corresponding to positions 222–241 and 420–439, respectively, were used (accession no. M10278).
Semiquantitative PCR
To compare the levels of CRH receptor expression after different treatments, PCR methodologies were adapted to provide a semiquantitative measure of mRNA levels. We first determined the linear range of amplification of cDNA using each of the primer sets. We then chose three progressive amplification cycles within this range for each cDNA species. For CRH-R1, we used 28, 30, and 32 PCR amplification cycles for samples of myometrium. For samples of the decidua and FM, we used 31, 33, and 35 PCR amplification cycles. To obtain gene expression in the linear range of CRH-R2 cDNA in human myometrium, we used 31, 33, and 35 PCR amplification cycles. The amplification cycles used for ß-actin gene expression were 16, 18, and 20. Within these ranges, the PCR products were detectable and showed a linear increase in signal intensity. Each set of samples was electrophoresed on a 2% agarose gel stained with ethidium bromide (0.15%) in Tris-acetate/ethylenediamine tetraacetate buffer and photographed using Polaroid 665 positive/negative film (Polaroid, Cambridge, MA). The relative intensity of cDNA signals was quantified from negatives using computerized image analysis (Imaging Research, Inc., St. Catherine, Canada). Analysis of the gene expression was conducted by calculating the average ratios of the relative optical densities of CRH receptor to ß-actin at the three cycle numbers for each myometrial sample.
The identity of the PCR product for CRH-R1 was confirmed by digestion using 10 U of the restriction enzymes AluI (Life Technologies) and BsrI (New England Biolabs, Inc., Beverley, MA) in the appropriate buffer (10 µL REACT 1 buffer; 50 mmol/L Tris-HCl and 10 mmol/L MgCl2, pH 8.0; Life Technologies) and buffer 3 (50 mmol/L Tris-HCl, 10 mmol/L MgCl2, 100 mmol/L NaCl, and 1 mmol/L dithiothreitol, pH 7.9, at 25 C; New England Biolabs, Inc.). The PCR product (0.5–2 µg cDNA) was incubated at 37 C (AluI) or at 65 C (BsrI and TaqI) for 2–3 h. The AluI enzyme digest was inactivated at 65 C for 10 min, then products were run on a 2% agarose gel to allow visualization. The identity of the PCR product for CRH-R2 was confirmed using 10 U TaqI (Boehringer Mannheim) in SuRe Cut Buffer B (10 µL; 10 mmol/L Tris-HCl, 5 mmol/L MgCl2, and 100 mmol/L NaCl, pH 8.0, at 37 C; Boehringer Mannheim). The CRH receptor cDNA was sequenced (ABI Prism 377 sequencer, Big Dye Terminator cycle sequencing). The sequences of the 333-bp CRH-R1 product and the 781-bp CRH-R2 product were identical to those reported in the GenBank (3, 9).
Immunohistochemistry
Myometrial samples from nonpregnant patients (n = 4) and term pregnant patients in the absence (n = 4) and the presence of labor (n = 4) were removed and fixed in 4% paraformaldehyde and 0.2% glutaraldehyde for 24 h after tissue collection. The samples were then washed twice daily in phosphate-buffered saline (0.01 mol/L, pH 7.4) and stored in 70% ethanol at 4 C. The samples were embedded in paraffin (Toronto General Hospital, Toronto, Canada). Sections (5 µm) were cut on a microtome (RM 2035, Leica Corp., Nussloch, Germany), placed on glass slides coated with 2% aminopropyltriethoxy-silane (Sigma Chemical Co., St. Louis, MO) in acetone, and dried for 24 h at 37 C. Immunohistochemistry was conducted essentially as described previously (23).
The slides were incubated with the primary antibodies for CRH-R1 and CRH-R2 at 4 C overnight. The primary antibody for CRH-R1 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was a polyclonal antibody raised in a goat against a peptide corresponding to amino acids 425–444 of human and rat CRH-R1 (3). The primary antibody for CRH-R2 (Santa Cruz Biotechnology) was a polyclonal antibody raised in a goat against a peptide corresponding to amino acids 47–66 of rat CRH-R2 (8). The CRH-R1 antibody cross-reacts with CRH-R2 (same affinity for CRH-R1 and CRH-R2). Therefore, we preabsorbed the CRH-R1 antibody with an excess of CRH-R2 peptide (1 µmol/L; Santa Cruz Biotechnology) to determine specific CRH-R1 staining. The primary antibodies were diluted to 1:175 in antibody dilution buffer (1 g BSA and 0.02 g sodium azide in 100 mL phosphate-buffered saline, pH 7.5). After 16 h of incubation with the primary antibody, a biotinylated secondary antibody (1:500; Vectastain ABC kit, Vector Laboratories, Inc., Burlingame, CA) was spotted on the sections, followed by the avidin-biotin-peroxidase complex (ABC; Vectastain). Immunostaining was continued as described previously (23). Sheep pituitaries were used as positive controls for CRH-R1 immunostaining. For negative controls, the primary antibody was preabsorbed with synthetic receptor peptide (1 µmol/L; Santa Cruz Biotechnology).
Statistical analysis
To correct for differences in the initial amount of RNA used for RT-PCR, we determined ß-actin mRNA expression in all samples. The ratio of the optical densitometry reading measurements for the expression of CRH-R1 mRNA or CRH-R2 mRNA (at three progressive amplification cycles) to those for ß-actin mRNA expression (at three progressive amplification cycles) was determined for each sample. The mean ratio was then determined for all samples within that group. A Mann-Whitney rank sum test was performed to assess the change in CRH receptor expression at the time of labor at term and then in preterm pregnancies. To determine the difference among all the treatment groups (preterm no labor, preterm in labor, term no labor, and term in labor), a Kruskal-Wallis one-way ANOVA on ranks was performed followed by an all pairwise multiple comparison procedure (Dunn’s method) to isolate the group(s) that differed from the others.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sequencing of the PCR product and enzyme digestion of CRH-R1 cDNA
(Fig. 1a
) with BsrI (Fig. 1b)
and AluI (Fig. 1c) and digestion of CRH-R2 cDNA (Fig. 1d)
with TaqI (Fig. 1e) were used to confirm the identity of the
receptors and yielded fragments of the expected size. CRH-R1 mRNA and
CRH-R2 mRNA were expressed in the myometrium of nonpregnant patients
(Fig. 2). We identified the expected band
of 333 bp representing CRH-R1 and the expected band of 781 bp
representing CRH-R2. CRH-R1 mRNA was present at consistently high
levels in all samples studied, whereas CRH-R2 mRNA expression was
variable. When using primers designed to identify CRH-R2 we also
observed a second band at 500 bp. The identity of this band is unknown.
ß-Actin mRNA (218 bp) expression was present at similar levels in all
patients.
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, a and b) than that of CRH-R2 (Fig. 3, d and e). CRH-R1 and CRH-R2 staining was eliminated from the uterine
smooth muscle (Fig. 3, c and f, respectively) and from the smooth
muscle of the vasculature when the antibody was preabsorbed with
synthetic peptide.
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We identified CRH-R1 mRNA expression in myometrium from the LS of
women in term and preterm pregnancies. Levels of CRH-R1 mRNA were
significantly lower in samples of myometrium from pregnant than in
those from nonpregnant women (Fig. 4).
Compared to levels during pregnancy, CRH-R1 mRNA expression was
significantly up-regulated (P < 0.05) at the time of
labor in term pregnancies (Fig. 5a).
CRH-R1 mRNA expression was also significantly up-regulated
(P < 0.05) at the time of labor in preterm pregnancies
(MGA, 32 weeks; Fig. 5b) compared to that in age-matched controls. Mean
CRH-R1 mRNA levels showed an increasing trend between 32 and 39 weeks
gestation in the absence of labor (P < 0.05; Fig. 5).
We could not detect CRH-R1 protein in human myometrium at term before
the onset of labor (Fig. 6a), but
immunoreactive CRH-R1 was detected in uterine smooth muscle (Fig. 6b)
and vascular smooth muscle of myometrial vessels at the time of
labor.
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), but was faintly detectable in
the myometrium of patients in labor (Fig. 6d).
Immunoreactive CRH-R1 was present in the sheep pituitary (Fig. 6e), and
the staining was preabsorbed with CRH-R1 peptide (Fig. 6f). CRH-R2 was
not detected in the pituitary (not shown), as previously reported
(11).
Regional expression of CRH-R1 in myometrium from nonpregnant, pregnant, laboring, and postpartum patients
We observed gestational-age dependent changes in the regional
expression of CRH-R1 in myometrium from the fundal and the lower
myometrial segment. Thus, in myometrium from nonpregnant and pregnant
women before the onset of labor, CRH-R1 mRNA levels were similar in
fundus and LS. However, in a paired sample obtained at the time of
labor, the expression of CRH-R1 mRNA was markedly higher in the LS
compared to the fundus or to fundal and LS samples before labor.
This differential expression of CRH-R1 mRNA was lost postpartum,
when mRNA levels were low in both fundus and LS (Fig. 7).
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CRH-R1 mRNA expression was present in decidua and
chorion, but was not altered significantly at the time of labor (Fig. 8). CRH-R1 mRNA expression was
undetectable in the amnion. CRH-R2 mRNA expression was undetectable in
the chorion, amnion, or decidua.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The presence of CRH receptors in the myometrium is in accordance with results of Hillhouse et al. (24). These researchers identified specific CRH-binding sites in myometrium from nonpregnant and pregnant women. However, these researchers did not identify the distribution of the receptors subtypes. Most previous studies failed to differentiate between CRH receptor subtypes in the myometrium (6, 16, 24). However, the presence of heterogeneous CRH receptors in the myometrium is not a novel concept. Grammatopoulos et al. (25) have identified previously, by isoelectric focusing, at least five populations of CRH receptors in the human myometrium.
We have shown that levels of CRH-R1 mRNA are higher in myometrium from the lower uterine segment compared to levels of CRH-R2 mRNA. The presence of CRH receptor mRNA was extended to the localization of CRH-R1 and CRH-R2 protein in uterine smooth muscle and in association with the smooth muscle layer of the uterine vasculature in the myometrium from nonpregnant patients. CRH is a potent vasodilator in the placental vasculature (26), suggesting that CRH may be involved in the regulation of myometrial blood flow in nonpregnant and pregnant women. However, from the present studies we cannot determine the relative contributions of vascular vs. smooth muscle CRH receptor to the RT-PCR results. This issue will require further examination using in situ hybridization. Further, we recognize that tissue collected at preterm cesarean section or with uterine atony may not be reflective of normal physiology.
Low levels of CRH-R1 mRNA were found in the myometrium of pregnant women before the onset of labor in term and preterm pregnancies, but we failed to detect CRH receptor protein at this time. The failure to detect CRH-R1 or CRH-R2 protein despite measuring CRH-R1 mRNA and CRH-R2 mRNA levels may reflect the lack of sensitivity of the immunohistochemical staining method. We observed an increase in CRH-R1 mRNA in myometrium at the time of labor that was associated with detectable levels of immunoreactive CRH-R1 protein in the myometrium. CRH-R2 was expressed in only a subset of patient samples, and there was no consistent change in expression with the onset of labor. Our results suggest that CRH-R1 might be more important than CRH-R2 in mediating the effects of CRH in the human myometrium at the time of labor. Moreover, we suggest that the variability in CRH-R1 expression between different laboring patients probably reflects variation in the stage of labor and/or the duration of labor before surgery. It has been proposed that urocortin and not CRH is the major ligand for CRH-R2 (10), suggesting that CRH-R2 is not directly involved in mediating the effects of maternal plasma CRH at the time of labor.
The expression pattern of CRH-R1 at the time of labor supports previous suggestions (14, 15) that CRH could act to potentiate the contractile action of uterotonic agonists. However, we found no increase in CRH-R1 expression in fundal myometrium with the onset of labor. The fundus is the most highly contractile region of the uterus, and we would have expected expression of stimulatory systems to be markedly up-regulated. In contrast, increased expression of CRH-R1 during labor was restricted to the lower uterine segment, a region that is less contractile and has been shown to relax in response to some uterotonic agonists (27). As CRH-R1 increases the generation of cAMP (an inhibitor of myometrial contractility), we suggest that the role of CRH-R1 in the lower uterine segment is to promote relaxation of this region during labor and thus facilitate descent of the fetus during labor. Our data also suggest that there are mechanisms to differentially regulate CRH-R1 expression in the fundus and LS during labor, although the nature of these mechanisms remains unknown. Differential regulation of the CRH receptor subtypes has been reported previously by others (28, 29), suggesting that within a tissue, CRH receptor subtypes may mediate different functions.
We identified the presence of CRH-R1 expression in the decidua and the
chorion, supporting studies that have indicated that CRH may stimulate
the output of PGs from human FM at term (30). Alvi et al.
(31) reported that the addition of CRH to explants of full thickness
membranes resulted in increased concentrations of PGE2 in
the culture medium and increased levels of PGHS-2 mRNA in the tissues.
Our finding of CRH-R1 mRNA in decidua but not in amnion is consistent
with the decidua as a major site of CRH action in these explant
cultures (30). The PGHS-2 gene contains a putative cAMP response
element (32), raising the possibility that CRH-induced cAMP synthesis
could mediate the increase in PG synthesis in the decidua. The human
decidua also expresses CRH mRNA (33) and produces CRH peptide in
vitro (33, 34). Hence the CRH receptor subtype(s) within the FM
and/or decidua could be activated by CRH synthesized locally and acting
in a paracrine/autocrine fashion. Furthermore, it is evident that
PGE2 or PGF2
produced by FM/decidua locally
in response to CRH (31) could have stimulatory effects on the fundus of
the uterus, even if CRH itself inhibited contractility in the lower
uterine segment.
In conclusion, CRH-R1 mRNA and CRH-R2 mRNA have been detected in myometrium from nonpregnant women and during pregnancy. CRH-R1 mRNA was present at higher levels than CRH-R2 mRNA in both groups of women and was up-regulated significantly at the time of labor in myometrium from the lower uterine segment. Our finding of CRH receptors in myometrium from pregnant women is in accordance with a role for CRH in regulating uterine contractility. However, we suggest that contrary to earlier reports (14, 15), CRH may act in a dual function. Acting through cAMP-coupled CRH-R1 receptors, it promotes relaxation of the lower uterine segment during labor and helps set up regionalization of uterine activity patterns. In the FM and decidua it may contribute to the stimulus of PG release, which, in turn, stimulates contractility of the uterine body. Hence, CRH may have divergent contributions to uterine activity, but through these may promote the coordinated pattern of uterine activity that leads to birth.
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Acknowledgments |
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Footnotes |
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Received May 13, 1998.
Revised July 7, 1998.
Accepted August 3, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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activity on human myometrium in vitro. Am J Obstet Gynecol. 171:126–131.[Medline]
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Y. Muramatsu, N. Sugino, T. Suzuki, K. Totsune, K. Takahashi, A. Tashiro, M. Hongo, Y. Oki, and H. Sasano Urocortin and Corticotropin-Releasing Factor Receptor Expression in Normal Cycling Human Ovaries J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1362 - 1369. [Abstract] [Full Text]
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B. Sehringer, W. R. Schäfer, B. Wetzka, W. R. Deppert, R. Brunner-Spahr, E. Benedek, and H. P. Zahradnik Formation of Proinflammatory Cytokines in Human Term Myometrium Is Stimulated by Lipopolysaccharide But Not by Corticotropin-Releasing Hormone J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4859 - 4865. [Abstract] [Full Text]
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 J. R.G. Challis, S. G. Matthews, W. Gibb, and S. J. Lye Endocrine and Paracrine Regulation of Birth at Term and Preterm Endocr. Rev., October 1, 2000; 21(5): 514 - 550. [Abstract] [Full Text]
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 A. Slominski, J. Wortsman, T. Luger, R. Paus, and S. Solomon Corticotropin Releasing Hormone and Proopiomelanocortin Involvement in the Cutaneous Response to Stress Physiol Rev, July 1, 2000; 80(3): 979 - 1020. [Abstract] [Full Text] [PDF]
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V. Jain, M. Longo, M. Ali, G. R. Saade, K. Chwalisz, and R. E. Garfield Expression of Receptors for Corticotropin-Releasing Factor in the Vasculature of Pregnant Rats Reproductive Sciences, May 1, 2000; 7(3): 153 - 160. [Abstract] [PDF]
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A. J. Pollard, C. Sparey, S. C. Robson, A. R. Krainer, and G. N. Europe-Finner Spatio-Temporal Expression of the Trans-Acting Splicing Factors SF2/ASF and Heterogeneous Ribonuclear Proteins A1/A1B in the Myometrium of the Pregnant Human Uterus: A Molecular Mechanism for Regulating Regional Protein Isoform Expression in Vivo J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1928 - 1936. [Abstract] [Full Text]
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E. P. Spaziani, W. F. O'Brien, R. R. Benoit, and S. F. Gould Corticotropin-Releasing Hormone Increases the Expression of the Prostaglandin E2 Receptor Subtype EP1 in Amnion WISH Cells Biol Reprod, January 1, 2000; 62(1): 23 - 26. [Abstract] [Full Text]
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D. K. Grammatopoulos and E. W. Hillhouse Basal and Interleukin-1{beta}-Stimulated Prostaglandin Production from Cultured Human Myometrial Cells: Differential Regulation by Corticotropin- Releasing Hormone J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2204 - 2211. [Abstract] [Full Text]
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C. Sparey, S. C. Robson, J. Bailey, F. Lyall, and G. Nicholas Europe-Finner The Differential Expression of Myometrial Connexin-43, Cyclooxygenase-1 and -2, and Gs{alpha} Proteins in the Upper and Lower Segments of the Human Uterus during Pregnancy and Labor J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1705 - 1710. [Abstract] [Full Text]
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E. Aggelidou, E. W. Hillhouse, and D. K. Grammatopoulos Up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotropin-releasing hormone but not urocortin II or urocortin III in cultured human pregnant myometrial cells PNAS, March 5, 2002; 99(5): 3300 - 3305. [Abstract] [Full Text] [PDF]
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