Phenylacetic acid, an anti-vaginitis metabolite produced by the vaginal symbiotic bacterium Chryseobacterium gleum.

The human microbiome contains genetic information that regulates metabolic processes in response to host health and disease. While acidic vaginal pH is maintained in normal conditions, the pH level increases in infectious vaginitis. We propose that this change in the vaginal environment triggers the biosynthesis of anti-vaginitis metabolites. Gene expression levels of Chryseobacterium gleum, a vaginal symbiotic bacterium, were found to be affected by pH changes. The distinctive difference in the metabolic profiles between two C. gleum cultures incubated under acidic and neutral pH conditions was suggested to be an anti-vaginitis molecule, which was identified as phenylacetic acid (PAA) by spectroscopic data analysis. The antimicrobial activity of PAA was evaluated in vitro, showing greater toxicity toward Gardnerella vaginalis and Candida albicans, two major vaginal pathogens, relative to commensal Lactobacillus spp. The activation of myeloperoxidase, prostaglandin E2, and nuclear factor-κB, and the expression of cyclooxygenase-2 were reduced by an intravaginal administration of PAA in the vaginitis mouse model. In addition, PAA displayed the downregulation of mast cell activation. Therefore, PAA was suggested to be a messenger molecule that mediates interactions between the human microbiome and vaginal health.

In vitro anti-inflammatory potential of phloretin microemulsion as a new formulation for prospective treatment of vaginitis.

Phloretin is a promising polyphenolic compound known for its anti-inflammatory properties, but its poor solubility and low bioavailability hinder its clinical applicability. Till current date, its potential in the treatment of vaginitis has not been explored, and only very few papers reported its formulation as nanoparticles to overcome its pharmaceutical challenges. Therefore, in the current study, phloretin was formulated in microemulsion of 11 nm size, and its in vitro anti-inflammatory properties were explored using histamine and IL-6 release inhibition assays, protease inhibition assay, and membrane stabilization potential. The anti-inflammatory properties of phloretin microemulsion were compared to the drug phloretin, and the reference standard non-steroidal anti-inflammatory drugs (NSAIDs). Results proved that both phloretin and phloretin microemulsion significantly inhibited the release of the inflammatory mediators histamine and IL-6, inhibited protease action, and exhibited membrane stabilization potential. Phloretin microemulsion exhibited comparable anti-inflammatory properties to the NSAIDs diclofenac and indomethacin, and, hence, it can be delineated as a promising therapeutic tool in topical treatment of vaginal inflammation.

Deciphering the complex interplay between microbiota, HPV, inflammation and cancer through cervicovaginal metabolic profiling.

BACKGROUND: Dysbiotic vaginal microbiota have been implicated as contributors to persistent HPV-mediated cervical carcinogenesis and genital inflammation with mechanisms unknown. Given that cancer is a metabolic disease, metabolic profiling of the cervicovaginal microenvironment has the potential to reveal the functional interplay between the host and microbes in HPV persistence and progression to cancer. METHODS: Our study design included HPV-negative/positive controls, women with low-grade and high-grade cervical dysplasia, or cervical cancer (n = 78). Metabolic fingerprints were profiled using liquid chromatography-mass spectrometry. Vaginal microbiota and genital inflammation were analysed using 16S rRNA gene sequencing and immunoassays, respectively. We used an integrative bioinformatic pipeline to reveal host and microbe contributions to the metabolome and to comprehensively assess the link between HPV, microbiota, inflammation and cervical disease. FINDINGS: Metabolic analysis yielded 475 metabolites with known identities. Unique metabolic fingerprints discriminated patient groups from healthy controls. Three-hydroxybutyrate, eicosenoate, and oleate/vaccenate discriminated (with excellent capacity) between cancer patients versus the healthy participants. Sphingolipids, plasmalogens, and linoleate positively correlated with genital inflammation. Non-Lactobacillus dominant communities, particularly in high-grade dysplasia, perturbed amino acid and nucleotide metabolisms. Adenosine and cytosine correlated positively with Lactobacillus abundance and negatively with genital inflammation. Glycochenodeoxycholate and carnitine metabolisms connected non-Lactobacillus dominance to genital inflammation. INTERPRETATION: Cervicovaginal metabolic profiles were driven by cancer followed by genital inflammation, HPV infection, and vaginal microbiota. This study provides evidence for metabolite-driven complex host-microbe interactions as hallmarks of cervical cancer with future translational potential. FUND: Flinn Foundation (#1974), Banner Foundation Obstetrics/Gynecology, and NIH NCI (P30-CA023074).

In vivo evaluation of safety and toxicity of a Lactobacillus jensenii producing modified cyanovirin-N in a rhesus macaque vaginal challenge model.

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) across the cervicovaginal mucosa in women is influenced by many factors including the microbiota and the presence of underlying inflammation. It is important that potential HIV preventative agents do not alter the mucosal environment in a way that enhances HIV acquisition. We examined the impact of a "live" microbicide on the vaginal mucosal environment in a rhesus macaque repeated vaginal simian-HIV (SHIVSF162P3) challenge model. The microbicide contained a human vaginal Lactobacillus jensenii expressing the HIV-1 entry inhibitor, modified Cyanovirin-N (mCV-N), and henceforth called LB-mCV-N. Macaques were colonized vaginally each week with LB-mCV-N and sampled six days after colonization for culturable bacteria, pH and cervical-vaginal cytokines during the duration of the six-week study. We show that macaques that retained the engineered LB-mCV-N strain in their vaginal microbiota, during SHIV challenge, had lower pH, when colonization levels were higher, and had no evidence of inflammatory cytokines. Indeed, Interleukin-13, a mediator of inflammation, was detected less often in LB-mCV-N colonized macaques than in controls and we found higher levels of Interleukin 1 receptor antagonist (IL-1RA) in LB-mCV-N colonized macaques during the SHIV challenge period. We noted an inverse correlation between levels of mucosal IL-1RA and peak plasma viral load, thus higher IL-1RA correlated with lower viral load in LB-mCV-N treated macaques. These data support the use of LB-mCV-N as a safe "live" microbicide and suggest that lactobacilli themselves may positively impact the mucosal environment.

Lipid peroxidation and antioxidant status in vagina microenvironment of patients with several common vaginitis.

OBJECTIVE: Oxidative stress has been suggested to play an important role in many diseases, including vaginitis. To evaluate oxidative biomarkers in the secretion of cervix samples of vaginitis, this study will illustrate the status of lipid peroxidation and antioxidant status in vaginal microenvironment. MATERIALS AND METHODS: A total of 257 patients with vaginitis, including candida vaginitis, bacterial vaginosis, and trichomonas vaginitis were involved in this study. Cervico-vaginal fluid was collected from these patients before and after treatment, and the malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), hydrogen peroxide (H2O2), and vitamin C levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The results revealed that the MDA and H2O2 levels were increased in the vaginitis patients, while there was no significant difference in MDA level among different kinds of vaginitis before treatment. The CAT and vitamin C levels in vaginitis were decreased before treatment. Moreover, the data also showed that the MDA and H2O2 levels were decreased, while the CAT, SOD, and vitamin C levels were increased after received treatment, respectively, and there was no significant difference between controls and vaginitis. CONCLUSION: This study indicated that oxidative stress played an important role in vaginitis.

Plasma and mucosal HIV viral loads are associated with genital tract inflammation in HIV-infected women.

BACKGROUND: Systemic and mucosal inflammation may play a role in HIV control. A cross-sectional comparison was conducted among women in the Women's Interagency HIV Study to explore the hypothesis that compared with HIV-uninfected participants, women with HIV, and, in particular, those with high plasma viral load (PVL) have increased levels of mucosal and systemic inflammatory mediators and impaired mucosal endogenous antimicrobial activity. METHODS: Nineteen HIV-uninfected, 40 HIV-infected on antiretroviral therapy (ART) with PVL ≤ 2600 copies/mL (low viral load) (HIV-LVL), and 19 HIV-infected on or off ART with PVL >10,000 (high viral load) (HIV-HVL) were evaluated. Immune mediators and viral RNA were quantified in plasma and cervicovaginal lavage (CVL). The CVL antimicrobial activity was also determined. RESULTS: Compared to HIV-uninfected participants, HIV-HVL women had higher levels of mucosal but not systemic proinflammatory cytokines and chemokines, higher Nugent scores, and lower Escherichia coli bactericidal activity. In contrast, there were no significant differences between HIV-LVL and HIV-uninfected controls. After adjusting for PVL, HIV genital tract shedding was significantly associated with higher CVL concentrations of IL-6, IL-1ß, MIP-1α, and CCL5 (RANTES) and higher plasma concentrations of MIP-1α. High PVL was associated with higher CVL levels of IL-1ß and RANTES, as well as with higher Nugent scores, lower E. coli bactericidal activity, smoking, and lower CD4 counts; smoking and CD4 count retained statistical significance in a multivariate model. CONCLUSIONS: Further study is needed to determine if the relationship between mucosal inflammation and PVL is causal and to determine if reducing mucosal inflammation is beneficial.

Associations between genital tract infections, genital tract inflammation, and cervical cytobrush HIV-1 DNA in US versus Kenyan women.

Cervical shedding of HIV-1 DNA may influence HIV-1 sexual transmission. HIV-1 DNA was detected in 250 (80%) of 316 and 207 (79%) of 259 cervical cytobrush specimens from 56 US and 80 Kenyan women, respectively. Plasma HIV-1 RNA concentration was associated with increased HIV-1 DNA shedding among US and Kenyan women. Kenyan women had higher cervicovaginal concentrations of proinflammatory interleukins (IL)-1ß, IL-6, IL-8, and anti-inflammatory secretory leukocyte protease inhibitor compared with US women (all P < 0.01). HIV-1 DNA shedding was associated with increased concentrations of IL-1ß and IL-6 and lower secretory leukocyte protease inhibitor among US women but not Kenyan women.

Cervicovaginal inflammatory cytokines and sphingomyelinase in women with and without bacterial vaginosis.

INTRODUCTION: The objective is to analyze proinflammatory cytokines [interleukin-1ß (IL-1ß), interleukin-6 and tumor necrosis factor-α] and sphingomyelinase in women with bacterial vaginosis (BV), cervicitis and vaginitis. METHODS: From January 2009 to June 2010, human immunodeficiency virus (HIV)-negative, nonpregnant, married women, living with husband, aged 20 to 40 years were recruited from a slum at Hyderabad, India, after taking written consent. One hundred forty-six women including 61 women with BV, 47 women with intermediate flora and 38 women with normal vaginal flora were evaluated for local proinflammatory cytokines and sphingomyelinase. Cervicitis and vaginitis were also analyzed by scoring white blood cells in the cervix and vaginal smears, respectively. RESULTS: Of the 146 women, 50.7% had cervicitis and 19.5% had vaginitis. IL-1ß, tumor necrosis factor-α and interleukin-6 levels were significantly high in women with cervicitis (P < 0.001) and vaginitis (P < 0.001) and IL-1ß in BV (P < 0.005), intermediate flora (P < 0.05) when compared with normal women. High vaginal pH was associated with IL-1ß. Neutral sphingomelinase showed an inverse association (P < 0.05) with cervicitis. Acid sphingomelinase directly correlated with IL-1ß although not significantly. CONCLUSIONS: This study shows proinflammatory response not only in BV but also in women with vaginitis and cervicitis. These conditions are likely to be important in promoting the transmission of HIV-1 and should be the focus of HIV prevention strategies.

Genital tract inflammation during early HIV-1 infection predicts higher plasma viral load set point in women.

BACKGROUND: The biggest challenge in human immunodeficiency virus type 1 (HIV-1) prevention in Africa is the high HIV-1 burden in young women. In macaques, proinflammatory cytokine production in the genital tract is necessary for target cell recruitment and establishment of simian immunodeficiency virus (SIV) infection following vaginal inoculation. The purpose of this study was to assess if genital inflammation during early HIV-1 infection predisposes women to rapid disease progression. METHODS: Inflammatory cytokine concentrations were measured in cervicovaginal lavage (CVL) from 49 women 6, 17, 30, and 55 weeks after HIV-1 infection and from 22 of these women before infection. Associations between genital inflammation and viral load set point and blood CD4 cell counts 12 months after infection were investigated. RESULTS: Elevated genital cytokine concentrations 6 and 17 weeks after HIV-1 infection were associated with higher viral load set points and, to a lesser extent, with CD4 depletion. CVL cytokine concentrations during early infection did not differ relative to preinfection but were elevated in women who had vaginal discharge, detectable HIV-1 RNA in their genital tracts, and lower blood CD4 counts. CONCLUSION: Genital inflammation during early HIV-1 infection was associated with higher viral load set point and CD4 depletion, which are markers of rapid disease progression. Strategies aimed at reducing genital inflammation during early HIV-1 infection may slow disease progression.

Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis.

In this open-label, randomized, multiple-dose, two-treatment crossover study, 24 postmenopausal women with moderate to severe atrophic vaginitis received 0.3 mg conjugated estrogens daily for 14 days: 7 days orally (0.3 mg tablet) and 7 days vaginally (0.5 g cream). Steady-state plasma concentrations of E2 and estrone were one-third lower after vaginal versus oral administration of conjugated estrogens.

Measurement of nitric oxide in the vagina.

OBJECTIVE: Local measurement of nitric oxide (NO) gas has been used to detect and monitor inflammatory processes in the airways, the colon and in the urinary bladder, but so far NO has not been studied in the lower female genital tract. The objective of this study is to measure NO gas directly in the vaginal lumen of healthy women and in patients with vaginitis. SETTING: The outpatient clinic of a university hospital. METHODS: Eighteen non-pregnant women from 19 to 65 years of age with symptoms of vaginitis, eight healthy women in reproductive age with regular menstrual cycles and nine healthy postmenopausal women were enrolled in the study. NO levels were measured in air incubated for five minutes in a catheter balloon in the vagina. RESULTS: In patients with symptoms of vaginitis, NO concentration was almost 100-fold increased compared to healthy controls (p<0.001) with no individual overlap. Vaginal NO levels were uniformly low among healthy women, both in reproductive age and in menopause. CONCLUSIONS: NO gas can be measured directly in the vagina with a fast, simple and safe method. The levels of NO are increased in patients with vaginitis.

Differential expression of oestrogen receptor isoforms and androgen receptor in the normal vulva and vagina compared with vulval lichen sclerosus and chronic vaginitis.

BACKGROUND: Although the expression of the oestrogen receptor (ER) alpha isoform and androgen receptor (AR) has been examined in vulval lichen sclerosus (VLS), the distribution pattern of ERalpha, ERbeta and AR has not been described in chronic atrophic vaginitis nor correlated with markers of proliferation (Ki-67) in either of these diseased tissues. OBJECTIVES: To measure the levels and distribution of ERalpha, ERbeta and AR immunoreactivity in relation to Ki-67 in normal and diseased vulva and vagina. METHODS: The expression of ERalpha, ERbeta and AR in relation to the proliferation marker Ki-67 in VLS, squamous hyperplasia of the vulva and chronic atrophic vaginitis was determined by immunohistomorphometric analysis and compared with that in normal vulva and vagina. RESULTS: VLS showed similar ERalpha and ERbeta expression in the 'epidermal' and 'dermal' tissue layers to that of normal vulvae, whereas AR expression appeared to be absent in most cases. ERbeta and Ki-67 expression was correlated with ERalpha expression but only in the 'fibrovascular' layer of the vulva. ERalpha expression was absent from the 'fibromuscular' layer of diseased vulvae, while ERbeta expression was absent in normal tissues but was highly expressed in diseased vulvae. ERalpha expression was significantly correlated with AR expression in the fibrovascular layer of the vagina and inversely correlated with Ki-67 staining in the parabasal cells of the epidermis in patients with chronic atrophic vaginitis. CONCLUSIONS: These data suggest that ER expression and levels may be implicated in the aetiopathology of VLS and chronic atrophic vaginitis.

Human neutrophil peptides in vaginitis/cervicitis of different etiology.

Development of female genito-urinary infections depends on many factors, such as immune system activity, virulence of microorganism and production of factors inhibiting the growth of microorganisms. Taking into account the possibility of relapses or severe complications, it is very important to appropriately diagnose and treat infections. Because of recently observed increase of microbial resistance to antibiotics, researchers are looking for alternatives. In our study we evaluated and compared the concentration of human neutrophil peptides (HNP 1-3) in cervico-vaginal lavages (CVL), obtained from women with vaginitis/cervicitis. Swabs from the posterior vaginal fornix and from the endocervical canal as well as CVL samples were obtained from 32 patients with vaginitis/cervicitis and 29 healthy women (control group). Supernatants of CVL were used for determination of concentration of HNP by ELISA. The difference between concentrations of HNP 1-3 in studied and control groups was statistically significant (p = 0.018). The maximal concentration was determined in patients with mixed infections (28.41 ng/ml), and Group B Streptococci, GBS, (28.06 ng/ml), the minimal concentrations in cases of C. trachomatis (mean concentrations did not differ from those in the control group: 16.93 ng/ml and 16.39 ng/ml, respectively). Maximal correlation was determined for control-studied group with isolation of GBS (r = 0.79), and very high negative correlation for group of GBS - C. trachomatis (r = -0.98).

Biomarkers of leukocyte traffic and activation in the vaginal mucosa.

Development of novel vaginal spermicides and anti-human immunodeficiency virus (HIV) microbicides requires careful assessment of their potential to recruit and activate CD4+ HIV-1 host cells in the female genital tract mucosa, two events that facilitate HIV-1 infection. Leukocyte traffic and activation are mediated by proinflammatory cytokines and chemokines, e.g. interleukin (IL)-1, IL-6 and IL-8, which have been detected in vaginal secretions in association with epithelial damage and infections. These proinflammatory mediators, however, have bidirectional, destructive as well as beneficial, effects on the mucosal barrier, and may be counterbalanced by endogenous inhibitors. Here we propose additional biomarkers for the evaluation of compound-induced cervicovaginal mucosal inflammation. Displaying different temporal patterns of detection, the levels of soluble E-selectin, vascular adhesion molecule-1, CD14 and myeloperoxidase in vaginal secretions reflected the mucosal leukocyte reaction to proinflammatory compounds being evaluated for safety in an improved rabbit vaginal irritation model. These biomarkers, which were also detected in human vaginal secretions, may be used to enhance the characterization of mucosal safety of vaginally applied compounds, both in animal as well as clinical studies.

Effect of induced expression of an antimicrobial peptide melittin on Chlamydia trachomatis and Mycoplasma hominis infections in vivo.

A plasmid construct was designed in which the gene of antimicrobial peptide melittin is controlled by the tetracycline-responsive promoter of human cytomegalovirus, aided by a constitutively expressed trans-activator protein gene. Its vaginal administration and induction of melittin gene transcription with doxycycline markedly suppressed subsequent genital tract infection of mice by Mycoplasma hominis and Chlamydia trachomatis. At least half of the melittin-protected animals proved free of either pathogen within 3-4 weeks. Recombinant plasmids expressing genes of antimicrobial peptides hold much promise as agents for prevention and control of urogenital latent infections.

Comparison of dermatopharmacokinetic vs. clinicial efficacy methods for bioequivalence assessment of miconazole nitrate vaginal cream, 2% in humans.

PURPOSE: To compare the dermatopharmacokinetic vs. clinical trial methods for bioequivalence assessment of two miconazole nitrate vaginal cream, 2% products. METHODS: The dermatopharmacokinetic method determined the bioequivalence of two products simultaneously in 24 healthy subjects, as a function of Cmax and AUC(0-1) parameters using miconazole nitrate content in harvested volar forearm stratum corneum. The clinical trial method determined bioequivalence as a function of clinical, mycological culture and therapeutic cure(s) after 7 days of product use and 30 days after therapy cessation in 106 female subjects with positive signs and symptoms of vaginitis, KOH vaginal smears and Candida cultures, randomly assigned to test or reference product. RESULTS: The dermatopharmacokinetic method demonstrated that the two products were not bioequivalent, while the clinical trial method concluded bioequivalence. CONCLUSION: The dermatopharmacokinetic method allowed simultaneous evaluation of both products in the same subject, within the same study period, and was more sensitive and discriminating in the assessment of bioequivalence between the two miconazole nitrate vaginal cream, 2% products than the clinical trial method.

Vaginal fluid pH as a screening test for vaginitis.

OBJECTIVE: To assess how effective the pH test can detect infectious vaginitis. METHODS: Ambulatory gynecological patients attending the gynecological out-patient department of Srinagarind Hospital from May 1 to July 31, 1997 were assessed for vaginitis by history, overall physical examination and vaginal examination. Specimens were collected for microbiological examination and measurement of pH level. RESULTS: Among 422 women recruited, a vaginal fluid pH level greater than 4.5 was found in 149 (35.3%) cases. The vaginal fluid pH as a screening test for infectious vaginitis showed a sensitivity of 49.7% (95% C.I.: 42.6-56.9). When using vaginal fluid pH combined with clinical symptoms and signs to screen for vaginitis the sensitivity was 67.5% (95% C.I.: 60.4-73.9). If a pH test was used to screen for BV, its sensitivity was 73.4% (95% C.I.; 60.7-83.3). Using a pH test in combination with clinical symptoms and signs of vaginitis to screen for BV, its sensitivity was 81.3% (95% C.I.: 69.2-89.5). CONCLUSION: Vaginal fluid pH combined with clinical symptoms and signs had a considerably high sensitivity to screen for BV.

Desquamative inflammatory vaginitis: a new subgroup of purulent vaginitis responsive to topical 2% clindamycin therapy.

OBJECTIVE: Desquamative inflammatory vaginitis is an uncommon clinical syndrome of unknown cause characterized by diffuse exudative vaginitis, epithelial cell exfoliation, and a profuse purulent vaginal discharge. The purpose of this report is to describe 51 patients with desquamative inflammatory vaginitis, the majority of whom were treated with 2% topical clindamycin in an open observational study. STUDY DESIGN: A retrospective chart review found 51 patients seen in a referral university vaginitis clinic between 1987 and 1993 who met the case definition of desquamative inflammatory vaginitis. All patients had diffuse exudative purulent vaginitis, signs of epithelial cell exfoliation (increased parabasal cells), elevated vaginal pH, and Gram stain findings of complete or relative absence of the normal long gram-positive bacilli and their replacement by gram-positive cocci. RESULTS: No consistent microbiologic pathogen was identified except for the absence of lactobacilli and an overall increase in prevalence of group B streptococci. Intravaginal treatment with 2% clindamycin suppositories resulted in clinical improvement in > 95% of patients and, although relapse occurred in 30%, overall antimicrobial cure was accomplished in all patients. Postmenopausal patients with desquamative inflammatory vaginitis occasionally required supplementary estrogen therapy to maintain remission. CONCLUSION: Desquamative inflammatory vaginitis responsive to topical clindamycin 2% therapy represents an uncommon cause of purulent vaginitis with unique clinical and laboratory characteristics. Evidence suggests a microbial, possibly gram-positive coccal, cause for this syndrome, although a specific bacterial species responsible for all cases has not been identified. The majority of cases occurred in patients in whom estrogen deficiency may have played a role in pathogenesis.

Interleukin-1 beta, -1 alpha, and -6 and prostaglandins in vaginal/cervical fluids of pregnant women before and during labor.

Interleukin-1 beta (IL-1 beta) is not detected in the amniotic fluid of normal human pregnancies before the initiation of parturition, but during labor, both at term and preterm, this cytokine is present in the amniotic fluid of 25-40% of pregnancies. A critical question, however, is whether this finding is indicative of a role for IL-1 beta (directly or indirectly) in the initiation of parturition or is the result of IL-1 beta formation and entry into amniotic fluid as a natural sequela of normal labor. The forebag of the amniotic sac is formed during labor in response to cervical dilatation, and on the decidual surface, the tissues of this structure become exposed and bathed by vaginal fluids as the cervix opens. Microorganisms and bacterial toxins are present in vaginal fluid before labor begins; these agents should act upon the exposed tissues of the forebag to cause inflammation and evoke an inflammatory response. This study was conducted to examine the likelihood that the inflammatory mediators found in amniotic fluid in increased amounts at parturition are produced in forebag tissues after the onset of labor because of obliged inflammation in these tissues. Vaginal/cervical fluids were collected by lavage from nonpregnant women and from pregnant women at term before and during labor. The amount of immunoreactive IL-1 beta in vaginal/cervical fluids of pregnant women during labor (mean +/- SEM, 91.5 +/- 16.9 ng; n = 17) was significantly greater (P < 0.001) than that in fluids collected before labor (7.8 +/- 3 ng; n = 14). The in vivo rate of IL-1 beta secretion directly from the decidua lining the forebag during labor was brisk (1.71 +/- 0.88 ng/cm2.min; n = 4), consistent with previous observations of higher levels of pro-IL-1 beta mRNA in decidual tissues adherent to the forebag compared with those in decidua adherent to chorion laeve of the upper compartment of the amnionic sac. The vaginal fluid content of prostaglandins (PGs) during labor [PGE2, 82.1 +/- 16.4 ng; PGF2 alpha, 141.5 +/- 30.5 ng; PGFM, 35.2 +/- 5.8 ng (mean +/- SEM; n = 13)] was significantly greater for PGE2 and PGF2 alpha (P < 0.05 and 0.004, respectively) than that before labor (PGE2, 42.6 +/- 9.4 ng; PGF2 alpha, 35.3 +/- 8.5 ng; PGFM, 21.7 +/- 4.6 ng; n = 12). In addition, there was a significant increase in the ratio of PGF2 alpha to PGE2 (P < 0.03) in vaginal fluids during labor.(ABSTRACT TRUNCATED AT 250 WORDS)