Cervical Mucus Of Women Research Articles

Зміни рівнів про- і протизапальних цитокінів у жінок із хронічним ендометритом та можливість медикаментозної корекції цих рівнів на преконцепційному етапі

The incidence of chronic endometritis is more than twice higher the prevalence of other clinical forms of intrauterine pathology, leading to infertility, unsuccessful attempts of in vitro fertilization and spontaneous abortion. There is a lack of data on the alteration of pro- and anti-inflammatory cytokine production in chronic endometritis and their role in the subsequent development of miscarriage. Purpose - to investigate the levels of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ), as well as the anti-inflammatory cytokine interleukin 10 (IL-10) in cervical mucus of women with chronic endometritis and to assess the impact of the developed comprehensive preconception treatment on normalizing cytokine disorders in these women. Materials and methods. The levels of pro-inflammatory cytokines TNF-α and INF-γ, as well as the anti-inflammatory cytokine IL-10, were determined using the enzyme-linked immunosorbent assay method in the cervical mucus of 426 women with chronic endometritis who were planning pregnancy. Among them, 168 patients (the Group I) received preconception comprehensive treatment, which included broad-spectrum antibacterial agents (azithromycin), hormonal estrogen-progestin therapy (Femoston 2/10) and L-arginine. The remaining 258 women (the Group II) did not receive treatment for chronic endometritis at the preconception stage. The control group consisted of 30 healthy individuals. Data analysis was performed using mathematical statistical methods, calculating the mean sample values (M), variance (σ) and standard errors of the mean (m). The Student’s t-test was applied, and probabilities were determined using the statistical program «STATISTICA» (StatSoft Inc., USA). Results. In the cervical mucus of women with chronic endometritis, an increase in the levels of pro-inflammatory cytokines INF-γ by 2.8 times (p<0.001) and TNF-α by 2 times (p<0.001) was detected, along with a 2-fold decrease in the concentration of the anti-inflammatory cytokine IL-10 (p<0.001). The shift in the cytokine balance towards pro-inflammatory cytokines is associated with a high frequency of miscarriage in these women. After the treatment of chronic endometritis, women had a 2.6 times lower level of INF-γ (p<0.05), a 2 times lower level of TNF-α (p<0.01), and a 1.7 times higher level of IL-10 (p<0.05) compared to untreated patients. Conclusions. Women with chronic endometritis experience a cytokine imbalance, characterized by an excessive increase in pro-inflammatory cytokines and a decrease in anti-inflammatory cytokines. Women with chronic endometritis who are planning pregnancy require comprehensive preconception treatment, which includes the administration of azithromycin, femoston 2/10 and L-arginine in addition to traditional preconception folate prophylaxis. This treatment, by promoting improved conditions for implantation, leads to a 15% increase in the pregnancy rate and a 1.9-fold reduction in the frequency of spontaneous abortion. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Dynamics of cervical mucus immune factors in patients with candida and mycoplasma infection before and after topical laser therapy

The article presents an analysis of the content and dynamics of indicators of humoral factors in the cervical mucus of women with inflammatory diseases of the lower reproductive tract caused by combined candida and mycoplasma infection. It has been shown that the use of topical laser therapy (wavelength 635±10 nm) with variable pulse generation leads to normalization of the sIgA, IgA production, restoration of the activity of C1, C2, C3, C4, and C5 complement components, total haemolytic complement activity, and the balance of cytokines in the cervical mucus.

Интерфероновый профиль мукозального иммунитета у женщин с папилломавирусной инфекцией

Papillomaviruses are a group of DNA viruses belonging to the Papillomavirida family. These viruses provoke pathological conditions manifesting with inflammation, exophytic masses, carcinogenesis, reproductive and perinatal disorders. Immune status is an essential factor de-termining the severity and duration of inflammatory diseases, the course of latent viral infections, including papillomavirus infection (PVI). The human immune system prevents the persistence, reactivation, and development of PVI clinical presentations. The cellular immune response is realized under the control of interferons (IFNs). Today, no complex studies on type 1, 2, or 3 IFNs in the cervical mucus of women with PVI associated with herpesvirus and chlamydia infec-tions are available. Aim: to compare IFN profile of mucosal immunity in women with PVI associated with herpesvirus and chlamydia infections. Patients and Methods: this study enrolled 149 women aged 25–44. Women were divided into four groups. Group 1 included women with PVI only (n=21). Group 2 included women with PVI and herpesvirus infection (n=47). Group 3 included women with PVI and chlamydia infec-tions (n=39). Group 4 included controls (n=30). Complex outpatient clinical laboratory examina-tion included clinical functional, biochemical, and immunological tests to detail pathophysiolog-ical mechanisms of urogenital PVIs. IFN (IFN-β, IFN-γ, IFN-λ1/IL-29, IFN-λ3/IL-28B) levels in the cervical mucus were measured by ELISA. Results: in all groups, IFN-λ3 and IFN-γ deficiencies were detected. In PVI, IFN-γ deficiency prevailed. In PVI associated with herpesvirus infection, IFN-λ3 deficiency prevailed. In PVI associated with chlamydia infection, a severe IFN-β deficiency was revealed. Conclusion: these patterns demonstrate a relevant role of the interferon arm of the im-mune response in the pathogenesis of isolated PVI and PVI associated with herpesvirus and chlamydia infections. These alterations in mucosal immunity support the prescription of immu-notherapy for these infections. KEYWORDS: human papillomavirus, herpesvirus infection, chlamydia infection, interferons, immune system, cervical mucus, mucosal immunity. FOR CITATION: Markelova E.V., Tulupova M.S., Nevezhkina T.A. et al. Interferon profile of the mucosal immunity in women with papillomavirus infection. Russian Medical Inquiry. 2022;6(2):67–71 (in Russ.). DOI: 10.32364/2587-6821-2022-6-2-67-71.

CHANGES IN THE ACTIVITY OF INDUCIBLE NO-SYNTHASE AND ARGINASE, THEIR RELATIONSHIP WITH THE LEVEL OF PRO- AND ANTI-INFLAMMATORY CYTOKINES IN CERVICAL MUCUS IN PREGNANT WOMEN, WHO UNDERWENT IVF AND ARE AT RISK OF PRETERM CHILDBIRTH

Introduction. Nitric oxide (NO) produces a wide range of bioregulatory effects. Imbalance in the ratio of the activity of inducible NO-synthase and arginase in favor of iNOS can lead to a pro-inflammatory reaction. At the risk of preterm childbirth, the content of proinflammatory cytokines increases both at the local and systemic levels. The aim of this work is to study the relationship between changes in the content of pro- and anti-inflammatory cytokines and the activity of inducible NO-synthase and arginase in the cervical mucus of women with in vitro fertilization (IVF), who are at risk of preterm childbirth. Materials and methods. The test group (TG) included 37 women, who underwent IVF and presented prognostic signs, indicating a high risk of preterm birth in the future. The control group (CP) consisted of 20 healthy pregnant women, who did not undergo assisted reproductive technologies. We determined the indicators of inducible NO-synthase activity and total arginase activity, as well as the level of pro- and anti-inflammatory cytokines in the mucus of the cervical canal of the participants at their 28-34 weeks of pregnancy. Results and discussion. The activity of iNOS in TG significantly increased (in 2.57 times) compared to healthy pregnant women (CP), while the activity of arginase, on the contrary, decreased significantly (in 1.91 times). There was a significant increase in the levels of pro-inflammatory cytokines INF-γ and TNF-α in the TG women, while they demonstrated the significantly reduced concentration of anti-inflammatory cytokine IL-10. In cervical mucus taken from TG women, positive correlations were found between an increase in the concentration of the proinflammatory cytokine INF-γ and an increase in iNOS activity, between a decrease in IL-10 levels and arginase activity, and a negative relationship between an increase in iNOS activity and a decrease in arginase activity. Conclusions. The detected cytokine imbalance in pregnant women, who underwent in vitro fertilization and were at risk of preterm childbirth, together with a impaired ratio of iNOS and arginase, indicates an inappropriate level of immunosuppression. These immune changes, by activating cellular responses of maternal immunity, can contribute to preterme childbirth.

Evaluation of the levels of secretory leukocyte protease inhibitor in the cervical mucus of women with unexplained infertility.

Secretory leukocyte protease inhibitor (SLPI) has specific effects on the immune system. SLPI is overexpressed in inflammation triggered by immune responses, which could have significant effects on the local immune responses in cervical mucosa. This over expression may be greater in women with unexplained infertility, which would increase the immune reaction in the cervical region against sperm. The aim of our study was to assess the levels of SLPI in cervical mucus in women with unexplained infertility. This prospective cross-sectional study was conducted using 50 Caucasian volunteers between 20 and 40 years old. The 50 participants were divided into two groups as unexplained infertility (n = 20) and control (n = 30). The control group comprised healthy fertile women with demographic characteristics similar to those of the infertility group. The enzyme-linked immunosorbent assay method was used to assess SLPI levels in the cervical mucus of all participants. The median SLPI level in cervical mucus was 3767 (3541-4594, 95% CI) pg/mL (25th percentile; 3139 pg/mL, 75th percentile; 5047 pg/mL) in the unexplained-infertility group and 3204 (2602-3539, 95% CI) pg/mL (the 25th percentile = 2615 pg/mL; 75th percentile = 3990 pg/mL) in the control group, which was a significant difference (P = 0.013). Our results indicated that SLPI levels in cervical mucus were remarkably higher in patients with unexplained infertility than in the control group.

Molecular detection of microbial colonization in cervical mucus of women with and without endometriosis.

Intrauterine microbial colonization and its association with the pathogenesis of endometriosis via an innate immune cascade have been reported. As a potential source of microbial transmission, information on microbial colonization in cervical mucus is unknown. We investigated pattern of microbiota in the cervical mucus collected from women with and without endometriosis using next-generation sequencing (NGS) technology. Cervical mucus samples were collected from women with (n=30) and without (n=39) endometriosis. The communities of microbiota in cervical mucus in the endometriosis group and the control group were examined by Gram staining and NGS targeting the V5-V6 region of 16S ribosomal RNA gene. Copy number of some target bacteria was detected by real-time PCR. We confirmed visual presence of bacteria in cervical mucus by Gram staining. NGS analysis showed that distribution of microbiota was similar in cervical mucus of women with and without endometriosis regardless of the phases of the menstrual cycle. In addition to predominant Lactobacilli spp., the populations of Corynebacterium, Enterobacteriaceae, Flavobacterium, Pseudomonas, and Streptococcus were increased in the endometriosis group. Of them, Enterobacteriaceae and Streptococcus were identified as the more significant candidates in the endometriosis group than in controls by real-time PCR (P<0.05 for each). Our NGS analysis of cervical mucus indicated that among a variable microbiota, two candidates (Enterobacteriaceae and Streptococcus) were more frequently detected in women with endometriosis. Further investigation is needed to elucidate a mechanistic link of these bacteria in the pathophysiology of endometriosis.

Detection of Human Papillomavirus in Cervical Mucus of Women with Spontaneous Abortion by Real-Time PCR

Detection of Human Papillomavirus in Cervical Mucus of Women with Spontaneous Abortion by Real-Time PCR

Abstract A57: Curcumin nanoformulation: A new therapeutic approach for cervical cancer treatment

Abstract Underserved populations such as African Americans (AA) and American Indians (AI) are experiencing increasing prevalence and mortality rates of cervical cancer (CxCa) as compared to Caucasians (CA). CxCa is one of the most common and deadly cancers among women worldwide and is associated with persistent Human Papillomavirus (HPV) infection. A persistent oncogenic HPV infection itself is not enough to immortalize and transform the epithelial host cell, as over a course of time only a small proportion of women with chronic HPV infection progress to develop disease. Additional factors are needed to acquire an immortal, malignant and invasive phenotype. In addition to HPV infection, cigarette smoking is a known risk factor. Polycyclic aromatic hydrocarbons (PAHs), such as Benzo[a]pyrene (BaP), are among the numerous carcinogens associated with cigarette smoking. The level of BaP has been found to be elevated in the cervical mucus of women who smoke. Moreover, a number of studies have implicated BaP to affect both the viral life cycle and the cellular environment. BaP has been shown to stimulate high levels of virion synthesis in cell lines prolifically infected with HPV. Furthermore, in other cancers the primary metabolite of BaP, benzo(a)pyrene diol epoxide increases the expression of oncogenic transcription factors like NFκB and oncogenic cytokines such as Interleukin-6 (IL-6). IL-6 in turn is known to activate transcription factors such as STAT3 and enhance the malignant transformation of cells. This is achieved through the transcriptional activation of oncogenic microRNAs (miRNA) like miRNA-21. MiRNAs are small non-coding RNAs that regulate gene expression and their aberrant regulation/function has been reported in a large majority of cancers. miRNA-21 has been shown to enhance chemoresistance to established regimens of chemotherapy and radiation therapy. This resistance to chemo-radio therapy with prolonged treatment, resulting in an invasive form of cancer, requires the development of novel therapeutic modalities to conquer chemo resistance and improve overall life expectancy of patients. Nanotechnology provides targeted delivery of anti-cancer drugs and indicates a new approach for cancer diagnosis and treatment. Our lab has developed PLGA (poly [lactic-co-glycolic acid]), an FDA approved polymer coated nanoparticle(s) using a well-known anti-cancer drug Curcumin (Cur) for the enhanced bioavailability and improved therapeutic efficacy of Cur, known as nano-curcumin (NC). In comparison to pure Cur, NC effectively inhibited Caski/ SiHa cell growth and also induced apoptosis as determined by staining for Annexin V/7AAD. PI staining revealed that NC treatment arrests growth cycle of Caski/SiHa cells in the G2-M phase. Additionally, NC treatment caused a marked decrease in the levels of miRNA 21, an oncomiRNA associated with chemoresistance, and enhanced by BaP, with a concomitant increase in the tumor suppressor miRNA-214 (decreased by BaP). It was found to down-regulate the expression of oncogenic proteins and cytokines such as IL-6 and enhance the expression of tumor suppressor entities as evident from Western blots. Moreover, NC formulation effectively reduced the tumor burden in Non SCID gamma mice. Furthermore, it decreased the expression of oncogenic miRNA-21 in in vivo experiments as observed through ISH. Our findings show that PLGA based NC significantly inhibits Caski/SiHa CxCa cell tumorigenicity and regulates the expression of miRNAs, associated with CxCa. In vivo experiments show that NC is efficacious in reducing the tumor burden. Therefore, NC may be a novel chemo-preventive and therapeutic modality for the overall management of CxCa. Citation Format: Mohd Saif Zaman, Neeraj Chauhan, Diane Maher, Rishi Gara, Mohammed Sikander, Murali Mohan Yallapu, Sheema Khan, Meena Jaggi, Subhash Chauhan. Curcumin nanoformulation: A new therapeutic approach for cervical cancer treatment. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A57.

Abstract 182: Smoking Carcinogen (BaP) enhances tumorigenic phenotypes of cervical cancer cells by modulation of HPV oncogenes and microRNA profiles

Abstract Cervical cancer (CxCa), one of the most common and deadly cancers among women worldwide, is associated with persistent Human Papillomavirus (HPV) infection. An importunate oncogenic HPV infection itself is not enough to immortalize and transform the epithelial host cell. Additional factors are needed to acquire an immortal, malignant and invasive phenotype. In addition to HPV infection, cigarette smoking is a known risk factor. Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, is among the numerous carcinogens associated with cigarette smoking. BaP levels have been found to be elevated in the cervical mucus of women who smoke. BaP has been shown to stimulate high levels of the viral oncoproteins E6 and E7 besides enhancing virion synthesis in cell lines prolifically infected with HPV. Furthermore, mixtures containing BaP, such as cigarette smoke condensate, have been shown to induce dramatic microRNA (miR) alterations in rodent lungs and in vitro human bronchial models. MiRs, small non-coding RNAs, regulate gene expression and their aberrant regulation/function has been reported in a large majority of cancers. Additionally, previous studies have shown the role of BaP in modulating miR profiles in different cancers. In this study we examine the effects of the carcinogen BaP on miRs and their related pathways in CxCa. In vitro treatment of CxCa cells with BaP resulted in an increase of expression of oncogenic miR-21 and decrease in tumor suppressor miR-214. MiR-21 has been shown to enhance chemoresistance to established regimens of chemotherapy and radiation therapy. In addition BaP also modulates the downstream pathways that these miRs regulate. BaP treatment increased the expression of oncogenic transcription factors such as NFkB-65, pSTAT-3, pSTAT-5 (transcription factors promoting miR-21 expression) and oncogenic cytokine IL-6, besides decreasing tumor suppressor PTEN (a target of miR-21). IL-6 is known to increase miR-21 expression through pSTAT-3 and pSTAT-5. Moreover, BaP in combination with IL-6 enhanced the migratory properties of CxCa cells. BaP also increased the nuclear translocation of β-catenin as observed through confocal microscopy. β-catenin is a direct target of miR-214. Natural or synthetic compounds that can mitigate BaP induced tumorigenic effects can have tremendous clinical significance. Herein, we report that curcumin (C) or its PLGA (poly [lactic-co-glycolic acid]) based nanoformulation (NC) effectively suppresses BaP induced tumorigenicity, regulates the expression of miRs and nuclear translocation of β-catenin associated with BaP in Caski/SiHa CxCa cells. In vivo experiments show that C/NC efficaciously reduced the tumor burden in xenograft mouse model. These data suggest a potential role of smoking in CxCa progression via regulating miR profiles and C/NC may effectively attenuate smoking induced CxCa progression. Citation Format: Mohd Saif Zaman, Neeraj Chauhan, Rishi K. Gara, Diane Maher, Sonam Kumari, Mohammed Sikander, Sheema Khan, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Smoking Carcinogen (BaP) enhances tumorigenic phenotypes of cervical cancer cells by modulation of HPV oncogenes and microRNA profiles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 182. doi:10.1158/1538-7445.AM2015-182

Cervical mucus properties stratify risk for preterm birth.

BackgroundAscending infection from the colonized vagina to the normally sterile intrauterine cavity is a well-documented cause of preterm birth. The primary physical barrier to microbial ascension is the cervical canal, which is filled with a dense and protective mucus plug. Despite its central role in separating the vaginal from the intrauterine tract, the barrier properties of cervical mucus have not been studied in preterm birth.Methods and FindingsTo study the protective function of the cervical mucus in preterm birth we performed a pilot case-control study to measure the viscoelasticity and permeability properties of mucus obtained from pregnant women at high-risk and low-risk for preterm birth. Using extensional and shear rheology we found that cervical mucus from women at high-risk for preterm birth was more extensible and forms significantly weaker gels compared to cervical mucus from women at low-risk of preterm birth. Moreover, permeability measurements using fluorescent microbeads show that high-risk mucus was more permeable compared with low-risk mucus.ConclusionsOur findings suggest that critical biophysical barrier properties of cervical mucus in women at high-risk for preterm birth are compromised compared to women with healthy pregnancy. We hypothesize that impaired barrier properties of cervical mucus could contribute to increased rates of intrauterine infection seen in women with preterm birth. We furthermore suggest that a robust association of spinnbarkeit and preterm birth could be an effectively exploited biomarker for preterm birth prediction.

450: Permeability properties of cervical mucus in women at high risk for preterm birth

Receiver-operating characteristics (ROC) curve and logistic regression analysis were used for statistical analysis. RESULTS: The prevalence of a positive AF culture was 45.9% (34/74). Univariate analyses showed that both all the cytokines tested in cervicovaginal fluids and gestational age had a significant relationship with intra-amniotic infection. Stepwise multivariate regression analysis yielded a model using cervicovaginal IL-6 and gestational age with the area under the ROC curve (AUC) of 0.829 for predicting intra-amniotic infection. The AUC for this model was significantly higher than either parameter retained in this model, but no differences were observed between the AUC of this model and AF WBC for the prediction of intra-amniotic infection. CONCLUSION: In women with PPROM, a model combining cervicovaginal IL-6 and gestational age provides a better prediction of intraamniotic infection than either variable alone. Overall, this non-invasive model performed as well as AF WBC count for predicting intraamniotic infection.

Anti-Helicobacter pylori antibodies in cervical mucus: a new cause of infertility

ObjectiveThe aims of our study were to determine on the one hand a correlation between the presence of anti-Helicobacter pylori (anti-H. pylori) IgG antibodies in serum and cervical mucus of women with idiopathic infertility, and on the other hand the effect of these antibodies on cervical mucus quality, in particular related to the ability of spermatozoa to penetrate it. Study designWe analysed anti-H. pylori IgG antibodies in the serum and cervical mucus of 67 patients diagnosed with idiopathic infertility using the Quanta Lite H. pylori IgG test. The penetration of normal sperm, in 15 cervical mucus samples positive for anti-H. pylori antibodies and in 15 negative samples, was assessed using the simplified slide test. ResultsA significant positive correlation emerged between anti-H. pylori IgG antibody concentrations in the serum and in the cervical mucus (r=0.9275; p<0.00001). In the 15 anti-H. pylori IgG mucus-positive samples the slide test showed abnormal penetration by the spermatozoa. ConclusionsOur study demonstrated that the presence of anti-H. pylori antibody in the cervical mucus can be involved in female infertility, interfering with sperm progression. Considering the close correlation found between serum and cervical mucus anti-H. pylori antibody titres, measuring serum antibodies could become an additional test, in particular in couples with unexplained infertility.

Scanning electron and light microscopy study of the cervical mucus in women with polycystic ovary syndrome

Two types of cervical mucus are recognized, oestrogenic and gestagenic. These are constituted by different subtypes, and their characteristics change depending on variations in the hormonal levels and on the existence of several pathologies. Our aim was to identify the ultrastructure and crystallization characteristics of the cervical mucus in women suffering from polycystic ovary syndrome, and to compare these characteristics with those of normal control women. Cervical mucus samples were taken from 10 women, 4 control group women (with normal ovulatory menstrual cycles) and 6 suffering from polycystic ovary syndrome (2 with ovulatory and 4 with anovulatory cycles). This mucus was characterized according to its ultrastructure and crystallization. The type of mucus obtained was related to the levels of oestradiol and progesterone present when the samples were taken. As regards mucus ultrastructure, differences were found between the control women and those with polycystic ovary syndrome and anovulatory menstrual cycles. Such variations were evident in the type of mesh and the average diameter of the mucus pores. Mucus crystallization in control women showed the usual oestrogenic disposition: fern-like (L, P2), rectilinear (S) or a hexagonal structure (P6). On the other hand, in women with polycystic ovary syndrome, indefinite mucus crystallizations were found, as well as crystallization patches resembling oestrogenic and gestagenic-like mucus. This study shows that the ultrastructure and crystallization characteristics of the cervical mucus in polycystic ovary syndrome women are different from those of control women. The latter would be dependent on their levels of oestradiol and progesterone.

Detection of cervical immunoglobulin A in normal pregnancy

The aim of our study was to evaluate a feasible method to quantify the immunoglobulin A concentration in the cervical mucus of women with a normal singleton pregnancy. In 60 immunologic healthy pregnant women cervical mucus samples were taken at a random time in pregnancy using an absorbing cylindrical cotton-swab stick. In this cervical mucus immunoglobulin A concentration was measured by radial immunodiffusion. A vaginal bacterial swab was taken from each woman. Concentration of immunoglobulins in maternal serum was estimated. There was no statistically significant difference of cervical immunoglobulin A concentration between the investigated groups (p = 0.952): 18-24 gestational weeks (gw): 52.8 (6.6-258.4) mg/l; 25-29 gw: 89.3 (4.8-193.8) mg/l; 30-34 gw: 55 (1.4-326) mg/l; 35-40 gw: 59.2 (4-400.9) mg/l. Women with a normal vaginal flora showed a significantly higher cervical immunoglobulin A concentration than those with a pathological colonization: 92.2 (6.6-400.9) mg/l vs. 42.5 (1.4-326) mg/l (p < 0.05). The serum levels of immunoglobulins A, A1, A2, M and G do not correlate to cervical immunoglobulin A levels nor to gestational age. In normal pregnancy, cervical immunoglobulin A concentration does not change with advancing gestational age, but a pathological vaginal colonization seems to be associated with decreased immunoglobulin A levels.

CGMP-dependent ADP depolymerization of actin mediates estrogen increase in cervical epithelial permeability.

Estrogen increases secretion of cervical mucus in women, and the effect depends on fragmentation of the cytoskeleton. The objective of the present study was to understand the molecular mechanism of estrogen action. Treatment of human cervical epithelial cells with 17beta-estradiol, sodium nitroprusside (SNP), or 8-bromoguanosine 3', 5'-cyclic monophosphate (8-Br-cGMP) increased cellular monomeric G-actin and decreased polymerized F-actin. The effects of estradiol were blocked by tamoxifen, by the guanylate cyclase inhibitor LY-83583, and by the cGMP-dependent protein kinase inhibitor KT-5823. The effects of SNP were blocked by LY-83583 and KT-5823, while the effects of 8-Br-cGMP were blocked only by KT-5823. Treatment with phalloidin decreased paracellular permeability and G-actin. Treatment with 17beta-estradiol, SNP, or 8-Br-cGMP attenuated SNP-induced phosphorylation of [(32)P]adenylate NAD in vitro: tamoxifen blocked the effect of estrogen; LY-83583 blocked the effect of SNP but not that of 8-Br-cGMP, while KT-5823 blocked effects of both SNP and 8-Br-cGMP. These results indicate that estrogen, nitric oxide (NO), and cGMP stimulate actin depolymerization. A possible mechanism is NO-induced, cGMP-dependent protein kinase augmentation of ADP-ribosylation of monomeric actin.

Secretory leukocyte protease inhibitor (SLPI) concentrations in cervical mucus of women with normal menstrual cycle.

Secretory leukocyte protease inhibitor (SLPI) is a potent inhibitor of human leukocyte elastase. SLPI transcripts in the cervical tissue were detected during the menstrual cycle by reverse transcription-polymerase chain reaction (RT-PCR). Western blot analysis revealed that the intensity of SLPI protein in cervical tissue in the ovulatory phase was stronger than in other phases. Immunohistochemistry using an anti-SLPI polyclonal antibody revealed positive staining in the epithelial cells of the endocervix. Western blot analysis also revealed that SLPI protein was present in the cervical mucus. Again the intensity of SLPI protein in the ovulatory phase was stronger than that in the follicular phase. The SLPI concentrations and SLPI/elastase ratios in the cervical mucus of women in the ovulatory phase were significantly higher than in the follicular and luteal phases. The SLPI and elastase concentrations in the cervical mucus were positively correlated. No significant difference was found in the SLPI serum concentrations of women during the menstrual cycle. These results suggest that production of SLPI from cervical epithelial cells during the ovulatory phase may be important for protection from the effects of elastase.

Characterization of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones

Mucosal immunity in the female reproductive tract is influenced by immunoglobulins (Igs), cytokines, and reproductive hormones. Previous studies of reproductive-aged women demonstrated that IgA and IgG increases in cervical mucus corresponded to elevated levels of IL-1 β which occurred 1 day before the peak of endogenous estradiol production prior to ovulation. We sought to determine the effect of exogenous hormones on reproductive tract immunity in women on oral contraceptive pills (OCPs) and to compare the results with respect to naturally cycling women. Twelve women of reproductive age who had negative cervical cultures, a normal pap smear, and agreed to abstain from sexual intercourse during the study initiated OCPs. Cervical mucus and vaginal washes were collected at six intervals (2–3 days apart) throughout the treatment cycle. Fifteen naturally cycling women had similar samples collected prior to, during, and subsequent to ovulation. Cervical mucus samples were assayed for IgA, IgG, IL-1 β, IL-6, and IL-10 by enzyme-linked immunosorbent assay (ELISA). IgA, IgG and IL-1 β levels in women on OCPs paralleled increasing levels of norethindrone. Mean values of IgA increased from a low of 14.4±3.1 to 41.1±9.4 mg/dl and decreased significantly after the cessation of the pills ( P<0.001). In naturally cycling women, the largest quantities of Igs were detected prior to ovulation. By comparison, mean values of IgA in the cervical mucus of women on OCPs (24.4 mg/dl) exceeded peak levels of IgA in the cervical mucus of naturally cycling women (14.6 mg/dl). IgA was the predominant Ig detected in cervical mucus of women on OCPs. Both immunoglobulins in each group exhibited changes relative to their hormonal status. The increased levels of IgA in the cervical mucus of women on OCPs may explain the clinical observation of a lower incidence of sexually transmitted diseases.

Increased interleukin-1 and interleukin-1 receptor antagonist levels in cervical mucus in the ovulatory phase in comparison with the follicular phase.

Interleukin-1 (IL-1) receptor antagonist (IL-1ra) levels in the cervical mucus of women in the ovulatory phase are significantly higher than those in the follicular phase. IL-1 titers of women in the ovulatory phase are also significantly higher than those in the follicular phase. A positive correlation between IL-1ra and IL-1 levels in the cervical mucus was observed. Immunohistochemistry using an anti-IL-1ra monoclonal antibody revealed positive staining in the epithelial cells of the endocervix. These results suggest that IL-1ra from cervical epithelial cells protects the reproductive system from the toxicity of IL-1 produced in the endocervix.

The frequency of antisperm antibodies in the cervical mucus of women with poor postcoital tests and their effect on pregnancy rates.

To determine the impact of the presence of antisperm antibodies (ASAs) in the cervical mucus of female partners in couples with unexplained poor postcoital tests (PCT). Furthermore, the efficacy of intrauterine insemination (IUI) in these same patients was determined by pregnancy rates (PRs). Pregnancy rates following IUI in patients with infertility and poor postcoital tests, whether the cervical mucus was positive or negative for ASAs, were evaluated. The 6-month PRs were similar in the ASA negative (40.5%) versus the positive (42.4%) group. It appears that the antifertility effect of ASA may be mainly the immobilization of sperm in the cervical mucus, and thus, performing IUI may effectively correct the problem.

Mutagenic Cervical Mucus in Women With Cervical Intraepithelial Neoplasia

Mutagenic Cervical Mucus in Women With Cervical Intraepithelial Neoplasia