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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 3 835-838
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Changes in Amniotic Fluid Immunoreactive Corticotropin-Releasing Factor (CRF) and CRF-Binding Protein Levels in Pregnant Women at Term and during Labor1

P. Florio, R. J. Woods, A. R. Genazzani, P. J. Lowry and F. Petraglia

Department of Gynecology and Obstetrics, University of Pisa, Pisa; and the Department of Gynecology and Obstetrics, University of Modena (F.P.), Modena, Italy; and the Department of Biochemistry and Physiology, University of Reading (R.J.W., P.J.L.), Whiteknights, Reading, United Kingdom

Address all correspondence and requests for reprints to: Felice Petraglia, M.D., Department of Obstetrics and Gynecology, University of Modena, via del Pozzo 71, 41100 Modena, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Corticotropin-releasing factor (CRF)-binding protein (CRF-BP) modulates the activity of the hypothalamus-pituitary-adrenal axis during pregnancy, counteracting the actions of circulating or locally produced CRF. The aim of the present study was to evaluate CRF and CRF-BP levels in amniotic fluid of healthy pregnant women during the last 4 weeks of gestation and during spontaneous labor at term.

A cross-sectional study was conducted on amniotic fluid collected from pregnant women (n = 68), subdivided into two groups: 1) not in labor (n = 31), and 2) in labor (n = 37). CRF-BP was measurable in all specimens of amniotic fluid, but at 37 weeks of pregnancy the concentration in amniotic fluid was lower (10-fold) than that in maternal plasma (P < 0.01). Pregnant women at 39 and 40 weeks gestation had amniotic fluid CRF-BP levels significantly lower than those at 37 weeks (P < 0.01), and pregnant in women in labor had significantly lower levels than women at term but not in labor (P < 0.01). CRF levels in amniotic fluid and plasma collected in women at 40 weeks gestation not in labor or in labor were significantly higher than those at 37 weeks (P < 0.01). During the last 4 weeks of gestation, amniotic fluid CRF levels in women not in labor did not significantly differ from those obtained at term labor.

During the last weeks of pregnancy, amniotic fluid CRF-BP levels decrease and are inversely correlated to CRF levels. The decrease in amniotic fluid CRF-BP at term, augmenting the amount of free CRF, supports the hypothesis that labor is associated with significant changes in local autocrine and paracrine factors that may affect PG release and myometrial contractility, contributing to the mechanism of parturition.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CORTICOTROPIN-RELEASING factor (CRF) is a hypothalamic, 41-amino acid peptide modulating neuroendocrine and behavioral responses to stress (1). Human placenta is a major source of CRF, with immunological and chemical characteristics identical to those of its hypothalamic counterpart (2, 3, 4). In fact, placental CRF is active in the release of ACTH from cultured rat pituitary cells (5). Immunoreactive CRF has been found in fetal membranes (amnion and chorion) (6, 7), contributing in part to the CRF present in the amniotic fluid (8, 9). During normal healthy pregnancy, CRF levels in amniotic fluid progressively increase throughout gestation (9), with no further changes at delivery (vaginal or by cesarean section) (10).

More recently, CRF-binding protein (CRF-BP), a 37-kDa protein of 322 amino acids, has been discovered, purified, and subsequently cloned from a human liver complementary DNA library (11, 12, 13, 14, 15). Recent studies indicated that CRF-BP messenger ribonucleic acid is also expressed in human trophoblast and intrauterine tissues during pregnancy (16, 17). Because of its capacity to bind CRF with high affinity, CRF-BP modulates the ACTH-releasing activity of CRF in cultured rat pituitary cells (11) as well as in human placental cells (16). The protein is also active in blocking the effect of CRF on decidual cells as well as on myometrial contractility (18). CRF-BP is measurable in maternal circulation, and a significant decrease in its concentration has been observed in healthy women approaching labor (19, 20, 21) and in patients with preterm labor (20, 21). The presence of immunoreactive CRF-BP in amniotic fluid of healthy women has been demonstrated by Suda et al. (22), but no information is available on the reciprocal amniotic levels of CRF and CRF-BP in women at term and/or at parturition.

Therefore, the present study investigated CRF and CRF-BP levels in the amniotic fluid of healthy pregnant women during the last 4 weeks of gestation and during spontaneous labor at term.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

A cross-sectional study was conducted in pregnant women (n = 68; age range, 22–35 yr). Specimens of amniotic fluid were collected at various gestational ages in the following groups of women: 1) healthy women not in labor (total, n = 31; at 37 weeks, n = 7; at 38 weeks, n = 6; at 39 weeks, n = 8; at 40 weeks, n = 10); the patients studied at 37 weeks of pregnancy subsequently delivered at 40 weeks gestation; and 2) healthy women in labor (total, n = 37; at 37 weeks, n = 9; at 38 weeks, n = 6; at 39 weeks, n = 11; at 40 weeks, n = 11). All specimens were collected at stage I of labor (cervical dilatation, >=4 cm).

In pregnant women not in labor, amniotic fluid was obtained by transabdominal amniocentesis for microbiologic assessment of the amniotic cavity and/or for the assessment of fetal lung maturity. When pregnant women with spontaneous active labor were studied, amniotic fluid samples were collected transvaginally by amniotomy (cervical dilatation, >=4 cm). Amniotic fluid specimens were collected in polypropylene tubes, and after centrifugation at 1000 x g for 15 min, the clear supernatant was divided in aliquots and stored at -20 C until assayed.

Informed consent was obtained, and the study was approved by the local ethical committee. In a group of healthy pregnant women at 37 weeks gestation, a specimen of maternal blood was also collected, and CRF-BP concentrations were compared between amniotic fluid and maternal serum.

Peripheral blood samples were drawn from the anticubital vein with a polypropylene syringe and a butterfly needle, and then transferred to chilled tubes containing ethylene diaminetetraacetic acid (10 mg/mL blood) and aprotinin (50 µL/tube from a solution of 20,000 IU/mL; Trasylol 100,000 UIC, Bayropharm, Milan, Italy). The tubes were immediately centrifuged at 4 C (3000 x g for 10 min). All plasma samples were kept at -80 C until assay.

CRF-BP assay

CRF-BP levels were measured by RIA. Purified recombinant CRF-BP was radioiodinated by the glucose oxidase/lactoperoxidase method and was separated on a 90 x 1-cm bed of Sephacryl S200 developed with 0.05 mL/L phosphate buffer, pH 7.4, containing 0.5% BSA and 0.1% sodium azide at a flow rate of 3 mL/h, with fractions collected every 20 min. Only a radiolabel constituting the peak eluting with a Kav of 0.46 was used as tracer for the CRF-BP RIA. Seventy-nine percent of the radioactivity from these peak fractions was precipitable by the addition of an excess of the rabbit antibody raised against recombinant CRF-BP, as used in the RIA. The immunoassay was performed essentially as previously described (23). Briefly, CRF-BP stocks (3.28 mg/L) were prepared in aliquots of 0.5 mL in sheep serum and stored frozen at -20 C. Assay standards were prepared by dilution of stock aliquots in 0.05 mol/L phosphate buffer, pH 7.4, containing 0.5% (wt/vol) BSA and 0.1% (wt/vol) sodium azide to obtain a range of concentrations from 0.9–464 mg/L. To 50 mL of the above buffer were added 50 mL standard or a column fraction, 100 mL tracer containing 20,000 cpm [125I]CRF-BP, and 100 mL rabbit anti-CRF-BP antibody diluted 4,000-fold in the same buffer. Standard and samples were prepared in duplicate, and the assay was incubated for 16 h at 4 C before separation. Separation was achieved by a precipitating antibody consisting of 10% sheep antirabbit antiserum directed against the Fc fragment containing 0.5% (vol/vol) normal rabbit serum and 4% Polyethylene Glycol 6000 (Sigma Chimica, Milan, Italy). Inclusion of human CRF (hCRF) in standards or in human plasma samples in concentrations ranging from 1.6–25 mg/liter had no effect on CRF-BP measurements (24). The assay sensitivity was 3.125 ng/mL. Samples were assayed within the same assay, and the intraassay coefficient of variation was 7%.

CRF assay

Plasma CRF levels were measured by two-site immunoradiometric assay. The CRF two-site immunoradiometric assay design was essentially the same as previously described (23), except that the IgG for radioiodination was purified from a sheep antibody raised against the hCRF (sequence 36–41) conjugate, and the second epitope antibody was from a rabbit that had been immunized with the hCRF (sequence 1–20) conjugate. The assay sensitivity was 10 pg/mL. Samples were assayed within the same assay, and the intraassay coefficient of variation was 6%.

Statistical analysis

Results are expressed as the mean ± SEM. The statistical analysis of the results was performed using the Kruskal ANOVA and Duncan’s test for multiple comparisons.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
CRF-BP was measurable in all specimens of amniotic fluid. The concentration of the protein in amniotic fluid at 37 weeks of pregnancy (mean ± SEM, 0.89 ± 0.12 nmol/L) was 10-fold lower than that in maternal plasma (3.54 ± 0.23 nmol/L; P < 0.01; Fig. 1Go).



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  		Figure 1. Mean ± SEM CRF-BP levels in amniotic fluid (n = 11; striped bar) and maternal plasma (n = 11; pointed bar) at 37 weeks of pregnancy. *, P < 0.001 vs. maternal plasma.

 
When CRF-BP levels in amniotic fluid were analyzed in control women according to the weeks of pregnancy, they were significantly lower at 39 (0.38 ± 0.1 nmol/L) and 40 (0.34 ± 0.03 nmol/L) weeks gestation than at 37 weeks (0.89 ± 0.12 nmol/L; P < 0.01; Fig. 2Go). CRF levels in amniotic fluid collected from women not in labor at 40 weeks gestation were significantly higher (98.01 ± 3.86 pmol/L) than those at 37 weeks (48.88 ± 4.61 pmol/L; P < 0.01; Fig. 2Go). The analysis of the results of women in labor showed that CRF-BP levels in amniotic fluid at 40 weeks were significantly lower (77.7 ± 5.31 pmol/L) than those collected from women in labor at 37 weeks (35.55 ± 3.73 pmol/L; P < 0.01; Fig. 3Go).



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  		Figure 2. Mean ± SEM amniotic fluid CRF and CRF-BP levels at term pregnancy (total, n = 31; at 37 weeks, n = 7; at 38 weeks, n = 6; at 39 weeks, n = 8; at 40 weeks, n = 10). *, P < 0.01 vs. CRF-BP concentration at 37 weeks; {triangleup}, P < 0.01 vs. CRF concentration at 37 weeks.

 


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  		Figure 3. Mean ± SEM amniotic fluid CRF-BP levels in women at term not in labor (n = 31; black bars) and in labor (total, n = 37; at 37 weeks, n = 9; at 38 weeks, n = 6; at 39 weeks, n = 11; at 40 weeks, n = 11; hatched bars). *, P < 0.01 vs. women not in labor at 37 weeks; {triangleup}, P < 0.05 vs. women in labor at 37 weeks.

 
The comparison of amniotic fluid CRF-BP levels between women at labor and those not in labor did not show a significant difference at each gestational age, except at 40 weeks, when women in labor had significantly lower levels (0.34 ± 0.03 vs. 0.14 ± 0.05 nmol/L; P < 0.01; Fig. 3Go). The final comparison between CRF-BP levels in women in labor and not in labor was made in 10 and 11 subjects, respectively.

Amniotic fluid CRF levels in women in labor at 39 (62.2 ± 4.25 pmol/L) and 40 (44.7 ± 5.31 pmol/L) weeks of pregnancy were significantly higher than that at 37 weeks (35.55 ± 3.73 pmol/L; P < 0.01). No difference at each gestational age was noted between women in labor at term and those not in labor (Fig. 4Go).



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  		Figure 4. Mean ± SEM amniotic fluid CRF levels in women at term not in labor (n = 31; black bars) and in labor (total, n = 37: at 37 weeks, n = 9; at 38 weeks, n = 6; at 39 weeks, n = 11; at 40 weeks, n = 11; hatched bars). *, P < 0.01 vs. women not in labor at 37 weeks women not in labor; {triangleup}, P < 0.01 vs. women in labor at 37 weeks.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study shows for the first time the changes in CRF-BP levels in amniotic fluid according to the week of gestation at term and in labor. In a previous study it was shown that amniotic fluid CRF-BP has the same mol wt as maternal plasma CRF-BP (22). In fact, the apparent mol wt of the cross-linked CRF-BP-[125I]Tyr-hCRF complex is approximately 43,000, and subtracting the mol wt of [125I]Tyr-hCRF, amniotic fluid CRF-BP has a mol wt of approximately 38,000, which is identical to that present in normal human plasma (22).

The present finding of amniotic levels 10-fold lower than those in maternal plasma confirms previous observations conducted with a different assay (22) and suggests that amniotic fluid and maternal plasma CRF-BP may have a different production and/or metabolic rate; a high maternal plasma/amniotic fluid ratio exists for other hormones (i.e. CRF, hCG, GH, somatostatin, and activin B) (24, 25), thus suggesting autonomous sources for various peptide hormones in the fetus (skin, kidney, lungs, and intestinal tract) and the mother (trophoblast, amnion, chorion, and decidua). Supporting amniotic epithelium as a putative local source for amniotic CRF-BP (18), it has been shown by in situ hybridization that hCRF-BP messenger ribonucleic acid probe positively hybridized to cells in human amnion (18).

Similarly to maternal plasma (19, 26), amniotic fluid CRF-BP levels decrease during the last weeks of pregnancy and are inversely correlated to the free CRF levels. Therefore, the present finding indicates that at the end of gestation, CRF-BP and CRF levels are inversely correlated in both maternal plasma and amniotic fluid. These reciprocal changes and the evidence that infusion of synthetic CRF in normal male volunteers causes a decrease in CRF-BP levels (27) suggests that an increase in CRF concentrations may be the cause of the decreased CRF-BP levels in amniotic fluid. However, the possibility that the decrease in amniotic fluid CRF-BP may be due to the conversion of CRF-BP to an isoform that is not immunoreactive in the current assay cannot yet be excluded.

The decrease in amniotic fluid CRF-BP levels in the last weeks of gestation and at labor and the high CRF levels strongly support that the CRF/CRF-BP pathway may play a role in the mechanism of parturition. The changes in CRF/CRF-BP observed in amniotic fluid and maternal plasma may reflect local changes in CRF/CRF-BP activities in intrauterine tissues. Indeed, CRF stimulates the release of PGs from fetal membranes (17) and potentiates PG-induced myometrial contractility (28), whereas CRF-BP is able to counteract these effects (18). Therefore, the decrease in amniotic fluid CRF-BP at term allows the occurrence of local autocrine/paracrine actions of CRF, which may participate in the mechanisms of parturition. A clinical model supporting this hypothesis is preterm labor. High levels of plasma CRF in patients with preterm labor have been reported (29, 30, 31), and maternal CRF increases early in pregnancies complicated by preterm labor (29), suggesting CRF as a predictive marker (29). In another study in women delivering preterm, low levels of maternal serum CRF-BP have been found (20), thus allowing higher plasma levels of free CRF (32).

The present study for the first time revealed the reciprocal changes in CRF and CRF-BP in the amniotic compartment at term gestation and in spontaneous labor, which mimics in large part the changes occurring in the maternal circulation.


   Footnotes
 
1 This work was supported in part by the Italian National Research Council-targeted project Prevention and Control Disease Factors, subproject Maternal-Infant Diseases (Contract 95.00887.PF41). Back

Received June 24, 1996.

Revised September 26, 1996.

Accepted November 11, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Vale W, Rivier C, Brown MR, et al. 1983 Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res. 39:245–270.
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