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Amniotic Fluid and Umbilical Cord Plasma Corticotropin-Releasing Factor (CRF), CRF-Binding Protein, Adrenocorticotropin, and Cortisol Concentrations in Intraamniotic Infection and Inflammation at Term

Department of Pediatrics, Obstetrics, and Reproductive Medicine (P.F., M.T., F.P.), University of Siena, 53100 Siena, Italy; Perinatology Research Branch (R.R., T.C., J.P.K.), National Institute of Child Health and Human Development/ National Institutes of Health/Department of Health and Human Services, Bethesda, Maryland 20814, and Detroit, Michigan 48202, and Wayne State University/Hutzel Hospital, Department of Obstetrics and Gynecology, Detroit, Michigan 48202; and School of Animal and Microbial Sciences (P.J.L.), University of Reading, Whiteknights Campus, Reading RG6 6UR, United Kingdom

Address all correspondence and requests for reprints to: Pasquale Florio, M.D., Ph.D., Chair of Obstetrics and Gynecology, Department of Pediatrics, Obstetrics, and Reproductive Medicine, University of Siena, Policlinico "Le Scotte" Viale Bracci, 53100 Siena, Italy. E-mail: florio{at}unisi.it.

	Abstract

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Context: Pregnant tissues express corticotropin-releasing factor (CRF), a peptide modulating fetal and placental ACTH and cortisol secretion. These actions are modulated by the locally expressed CRF-binding protein (CRF-BP).

Objective: The objective of the study was to determine whether CRF, CRF-BP, ACTH, and cortisol concentrations change in amniotic fluid and umbilical cord plasma in the presence of intraamniotic infection/inflammation (IAI) in women with spontaneous labor at term.

Design: This was a cross-sectional study.

Setting: The study was conducted at a tertiary referral center for obstetric care.

Patients: Patients included women in active labor at term with (n = 39) and without (controls; n = 78) IAI.

Main Outcome Measures: Amniotic fluid and umbilical cord plasma concentrations of CRF, CRF-BP, ACTH, and cortisol measured by RIA and immunoradiometric assays were measured.

Results: In patients with IAI, amniotic fluid CRF (0.97 ± 0.18 ng/ml) and CRF-BP (33.06 ± 5.54 nmol/liter) concentrations were significantly (P < 0.001) higher than in controls (CRF: 0.32 ± 0.04 ng/ml; CRF-BP: 14.69 ± 2.79 ml). The umbilical cord plasma CRF and CRF-BP concentrations were significantly (P < 0.001 for all) higher in women with IAI than in controls (CRF: 2.96 ± 0.35 ng/ml vs. 0.38 ± 0.18 ng/ml; CRF-BP: 152.12 ± 5.94 nmol/liter vs. 106.9 ± 5.97 nmol/liter). In contrast, amniotic fluid and umbilical cord plasma ACTH and cortisol concentrations did not differ between groups.

Conclusions: Amniotic fluid and umbilical cord plasma CRF and CRF-BP concentrations are increased in women with spontaneous labor at term and IAI. CRF-BP may modulate CRF actions on ACTH and cortisol secretion, playing a pivotal role in limiting the inflammatory process and thus avoiding an overactivation of the fetal/placental hypothalamus-pituitary-adrenal axis at birth.

	Introduction

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In the past decades, progress in the understanding of physiological roles and pathological influences of the placenta, fetal membranes, and decidua has accelerated. These tissues produce brain, pituitary, gonadal, and adrenocortical hormones chemically identical and biologically as active as their hypothalamic/gonadal counterparts (1). Indeed, when added to placental cell cultures, they modulate the release of both pituitary-like peptide hormones and gonadal/adrenal cortex-like steroid hormones. Thus, the placental mechanism for control of hormone secretion resembles in many aspects the organization of hypothalamus-pituitary-target organ axes (1, 2, 3). Under this perspective, the human placenta may be considered as a neuroendocrine organ because its secretion of factors analog to neurohormones, neuropeptides, neurosteroids, and monoamines have endocrine, paracrine and autocrine functions (1, 2, 3, 4). Through these substances, human placenta decisively contributes to all phases of gestation to maintain a constant equilibrium between the fetus and the mother, providing a favorable uterine environment for fetal growth but also driving the appropriate endocrine signals to escape adverse conditions (4).

Among the neuroendocrine factors produced by human placenta, corticotropin releasing factor (CRF) has been one of the most investigated in the last decade (1, 2, 3, 4, 5). Indeed, human placenta, decidua, and fetal membranes produce CRF, the well-known hypothalamic peptide involved in the endocrine adaptations of the hypothalamus-pituitary-adrenal (HPA) axis in response to stress stimuli (6). In pregnancy, CRF has a paracrine action inducing placental ACTH release as well as an endocrine function modulating fetal pituitary-adrenal cortex axis (1, 2, 3, 4, 5). Moreover, this classical neuroendocrine axis activated by stress also works in the human placenta; thus, the existence of a placental HPA axis that functions from early to term pregnancy has been proposed and that it is up-regulated in the presence of endogenous or exogenous stress stimuli (1, 2, 3, 4, 5).

CRF-binding protein (CRF-BP) is a 37-kDa protein of 322 amino acids, expressed in human trophoblast and intrauterine tissues during pregnancy (7), which binds CRF with high affinity (8, 9), inhibiting the ACTH-releasing activity of CRF in cultured rat pituitary (10) and cultured human placental cells (7). From these sources, immunoreactive CRF-BP is secreted in the amniotic fluid and umbilical cord plasma during human pregnancy (11, 12, 13).

Because microbial invasion of the amniotic cavity is considered one of the stress stimuli able to trigger the placental synthesis and release of CRF (14), the objective of this study was to determine whether there are changes in the amniotic fluid and umbilical cord plasma concentrations of CRF, CRF-BP, ACTH, and cortisol in the presence or absence of intraamniotic infection/inflammation (IAI) in women with spontaneous labor at term.

	Subjects and Methods

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Study design and population

A cross-sectional study was conducted by searching our clinical database and bank of amniotic fluid and umbilical cord samples, including women in active labor at term with (n = 39) and without (controls; n = 78) IAI.

In all cases, gestational age was determined by the last menstrual period and by ultrasound with measurement of the biparietal diameter, head circumference, femur length, and abdominal circumference. Spontaneous labor at term was defined as the presence of regular uterine contractions with a frequency of at least one every 10 min associated with cervical changes after 37 wk of gestation. Intraamniotic infection was defined as a positive amniotic fluid culture for microorganisms, or a combination of a positive Gram stain, and a positive Limulus amebocyte lysate assay (to detect endotoxin). Intraamniotic inflammation was defined as an amniotic fluid white blood cell (WBC) count greater than 50 cells/mm³. We used the term intraamniotic infection/inflammation because publications from our group indicated that the outcome of patients with microbiologically proven intraamniotic infection is similar to that of patients with intraamniotic inflammation and a negative amniotic fluid cultures (15).

Sample collections and assays

Amniotic fluid samples were retrieved in all women by transabdominal amniocentesis under ultrasonographic guidance for clinical indications (e.g. suspected intraamniotic infection, fetal lung maturity). Immediately after collection, amniotic fluid was transported to the laboratory in a sterile capped plastic syringe and cultured for aerobic and anaerobic bacteria as well as genital Mycoplasmas. An aliquot of amniotic fluid was examined under a hemocytometer (Neubauer chamber) for the presence of WBC. The absolute WBC count was calculated by multiplying the area examined by a factor of 10 per area and expressed as number of cells per cubic millimeter. Gram stain for microorganisms was performed with commercial reagents (crystal violet, safranin, and Gram’s iodine; Difco Laboratories, Detroit, MI) under standard conditions. Stained slides were examined by trained technicians, and the presence or absence of microorganisms was noted. The result of the Gram stain examination was reported to the clinicians, and patients with a positive Gram stain received parenteral antibiotics (generally gentamicin and ampicillin). Amniotic fluid not required for clinical purposes was centrifuged at 200 x g for 10 min at 4 C to remove cellular and particulate matter. Aliquots of amniotic fluid were stored at –70C until analysis.

Umbilical cord blood was collected immediately after birth and before placental detachment in heparinized plastic tubes, which were subsequently centrifuged at 3000 x g for 10 min at 4 C.

All women provided written informed consent before the collection of amniotic fluid and umbilical cord blood samples. The use of samples for research purposes was approved by the local Ethical Committee.

CRF assay

Amniotic fluid and umbilical cord plasma samples were submitted to an extraction procedure as previously described (11). Briefly, cyclohexyl columns (500 mg) (Bondelut; AnalyLichem Int., Arbor City, CA) were washed with methanol (0.5 ml) and a 2-ml mixture of formic acid plus triethylamine and 0.2% B-mercaptoethanol (pH 3) and loaded slowly into the column. The peptide was finally eluted with a mixture of 75% acetonitrile, 25% triethylamine, and 0.2% mercaptoethanol (2 ml). The final recovery of the peptide evaluated with cold (100 ng) or labeled (125 liters) CRF was 85%. All extracted samples were then dried in a speed vacuum concentrator (Savant, Hicksville, NJ). All reagents were purchased from Sigma Chemical Co. (St. Louis, MO). Each dried sample was redissolved in buffer [0.1% BSA/0.05% Triton X-100, 100 PBS (pH 7.3)], and CRF concentrations were measured by RIA in duplicate at two different dilutions. Rabbit antirat CRF serum was used at a final dilution of 1:770,000. Synthetic human CRF (J. Rivier, Salk Institute, La Jolla, CA) was used to prepare the standard curve. The tracer (125 I-human CRF) was purchased from NEN Life Science Products (Boston, MA). The entire reagent was diluted in buffer. The characteristics of the RIA have been described previously. The limit of detection was 2 pg/ml, and the intraassay coefficient of variation was 4.0%. The final results are expressed as nanograms per milliliter.

CRF-BP assay

CRF-BP concentrations were measured by a specific RIA, as previously described (11, 12, 13). Purified recombinant CRF-BP was radioiodinated by the glucose oxidase/lactoperoxidase method and separated on a 90- x 1-cm bed of Sephacryl s200 developed with 0.05 ml/liter 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 k_AV 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 (11, 12). Briefly, CRF-BP stocks (3.28 mg/liter) 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/liter 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 to 464 mg/liter. To the 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 4000-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 in standards or human plasma samples in concentrations ranging from 1.6 to 25 mg/liter had no effect on CRF-BP measurement (8, 9). The assay sensitivity was 3.125 ng/ml. Samples were assayed within the assay, and the intraassay coefficient of variation was 7%. The final results are expressed as nanomoles per liter.

ACTH and cortisol assays

ACTH concentrations were measured by a sensitive and specific immunoradiometric assay, in duplicate at two different dilutions (reagents purchased by Euro-Diagnostics, Appeldoorn, The Netherlands). The sensitivity of the assay was 2 pg/tube, and the inter- and intraassay coefficients of variations were 6.0 and 4.0%, respectively. The final results are expressed as picograms per milliliter. Cortisol concentrations were measured by a commercially available RIA kit (Radim; Pomezia, Rome, Italy). The sensitivity of the assay was 2.0 ng/tube, with inter- and intraassay coefficients of variations of 5.0 and 3.6%, respectively. Cortisol concentrations are expressed as nanomoles per milliliter.

Statistical analysis

The Kolmogorov-Smirnov test was used to evaluate whether distributions of data were Gaussian. Results are expressed as the mean ± SEM. The statistical analysis of the results was performed using the Mann-Whitney U test.

Statistical analysis was performed using the GraphPad Prism version 3.00 for Windows (GraphPad Software, Inc., San Diego, CA). A value of P < 0.05 was considered statistically significant.

	Results

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Amniotic fluid and umbilical cord plasma concentrations of CRF, CRF-BP, ACTH, and cortisol were detectable in all samples. Microorganisms isolated from the amniotic fluid included Ureaplasma urealyticum (n = 5), Group B Streptococcus (n = 3), Hemophillus spp (n = 2), Klebsiella pneumoniae (n = 1), and Lactobacillus spp (n = 2).

In patients with IAI, amniotic fluid CRF and CRF-BP concentrations were significantly higher than in control women (CRF: 0.97 ± 0.18 vs. 0.32 ± 0.04 ng/ml, P < 0.001; and CRF-BP: 33.06 ± 5.54 vs. 14.69 ± 2.79 nmol/liter, P < 0.001; Fig. 1, A and B, respectively). In contrast, amniotic fluid ACTH and cortisol concentrations did not differ between patients with IAI and controls (ACTH: 53.45 ± 6.28 vs. 54.02 ± 4.31 pg/ml; and cortisol: 63.23 ± 4.31 vs. 61.31 ± 3.5 ng/ml; Fig. 2, A and B, respectively).

View larger version (7K): [in this window] [in a new window]   FIG. 1. Amniotic fluid CRF (A) and CRF-BP (B) concentrations in controls and patients with IAI. *, P < 0.001.

View larger version (7K): [in this window] [in a new window]   FIG. 2. Amniotic fluid ACTH (A) and cortisol (B) concentrations in controls and patients with IAI.

View larger version (6K): [in this window] [in a new window]   FIG. 3. Umbilical cord CRF (A) and CRF-BP (B) concentrations in controls and patients with IAI. *, P < 0.001.

View larger version (8K): [in this window] [in a new window]   FIG. 4. Umbilical cord ACTH (A) and cortisol (B) concentrations in healthy controls and patients with IAI.

	Discussion

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Increasing evidence indicates that during pregnancy the secretion of CRF from intrauterine sources may be influenced by maternal and/or fetal physiological and pathological stress conditions (1, 2, 3, 4, 5). Microbial invasion of the amniotic cavity is a stress situation associated with a significant CRF elevation in placenta extracts, in both maternal plasma and amniotic fluid (14). However, the findings of increased CRF concentrations in umbilical cord plasma in patients with IAI, as well as on the lack of the expected ACTH and cortisol rise both in amniotic fluid and umbilical cord plasma, are novel. In fact, it is well known that CRF triggers ACTH and cortisol secretion and that CRF-BP can completely reverse CRF-induced responses, in both human placenta (16) and nonpregnant individuals (6). CRF-BP binds CRF in vitro with great affinity: on a perfused pituitary cell column system, the bioactivity of CRF is reduced by coincubation with CRF-BP (8), whereas, in vivo, the presence of the binding protein shortens the half-life of immunoreactive CRF (8, 9, 16). With respect to pregnant tissues, CRF-BP is effective in regulating CRF actions on target sites (17, 18). Taken together, the findings presented herein suggest that the increased concentrations of CRF-BP in maternal-associated infection may prevent the CRF-induced stimulation of ACTH and cortisol, even in the presence of elevated CRF concentrations in amniotic fluid and umbilical cord plasma. Another interpretation may be that infection/inflammation may affect cortisol synthesis by decreasing 11β-hydroxysteroid dehydrogenase 2 expression and activit (19, 20). Therefore, because 11β-hydroxysteroid dehydrogenase 2 inactivates cortisol to cortisone, in the absence of changes in cord and maternal cortisol levels, there would be less placental metabolism of cortisol and more effective cortisol stimulation of placental CRF (1, 2, 3) and, probably, CRF-BP (21).

To date, this is the first study reporting increased concentrations of both CRF and CRF-BP at term gestation because levels of these proteins in amniotic fluid and maternal plasma have been found to be inversely correlated (11, 13, 22). A possible explanation for the elevated amniotic fluid and umbilical cord plasma CRF-BP concentrations may be found in the genomic characterization of CRF-BP, which has revealed acute phase response elements. One of them is known to bind the transcription factor nuclear factor-B, which regulates immunoglobulin and interleukin transcription and is thought to play a role in response to inflammation (23). Consequently, a role for proinflammatory cytokines can be suggested in the mechanisms regulating CRF-BP synthesis and secretion. This hypothesis is supported by the evidence that CRF-BP (and CRF) concentrations are increased in synovial fluid of patients affected by arthritis and septicemia (24) and that IAI is associated with a significant increase of cytokine concentrations in amniotic fluid (25). On the other hand, cytokines stimulate CRF expression and secretion (26, 27); thus, the increased concentrations of CRF-BP in the presence of IAI may play a role in regulating inflammatory responses evoked by CRF. Indeed, CRF production is an early event in the cellular inflammatory response and plays a role in the initiation and propagation of the inflammatory reaction in concert with other local factors (28). Taken together, the present findings and the evidence that CRF and CRF-BP concentrations are increased in amniotic fluid and cord plasma in the presence of IAI suggest a role for CRF-BP in limiting the inflammatory process. Furthermore, because severe and prolonged stress is known to cause perinatal damage through ACTH and cortisol (29, 30), the rise of CRF-BP may avoid an overactivation of the fetal HPA axis at birth.

Whatever the role of CRF-BP, the source of its elevated concentrations in presence of IAI merits further discussion. Indeed, the findings that CRF-BP levels are higher in fetal (12) than maternal plasma (13, 22), together with the evidence that stressful events of pregnancy, like parturition, are not associated with changes in placental CRF-BP mRNA expression (31) would suggest that the fetus is the main source of such a neuropeptide and that through its secretion the fetus may protect itself from an overactivation of the HPA axis hormones.

	Footnotes

 
The work was partially supported by grants from the Italian Ministry of University and Scientific Research and the University of Siena (to F.P.). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.

Disclosure Statement: All authors have nothing to declare.

First Published Online June 17, 2008

Abbreviations: CRF, Corticotropin-releasing factor; CRF-BP, CRF-binding protein; HPA, hypothalamus-pituitary-adrenal; IAI, intraamniotic infection/inflammation; WBC, white blood cell.

Received December 26, 2007.

Accepted June 9, 2008.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Florio, P. Articles by Petraglia, F. Search for Related Content PubMed PubMed Citation Articles by Florio, P. Articles by Petraglia, F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Bacterial Infections Hazardous Substances DB HYDROCORTISONE Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology Female Endocrinology