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Estradiol-mediated enhancement of the human ectocervical epithelial barrier correlates with desmoglein-1 expression in the follicular menstrual phase

ABSTRACT: Introduction: Structural integrity of the cervical epithelial barrier is crucial for defending the female reproductive tract against sexually transmitted infections, including HIV. Female sex hormones, estradiol and progesterone, play an important role in modulating this epithelial barrier. However, the influence of fluctuating estradiol and progesterone on ectocervical tissue gene and protein expression in naturally cycling women at high risk for sexually transmitted infections is not well understood. Methods: Ectocervical biopsies, cervicovaginal lavage fluid, and venous blood samples were collected from naturally cycling Kenyan female sex workers at two time points, separated by 2 weeks. The first time point represented the luteal phase of the menstrual cycle and the second time point represented the follicular phase. Plasma estradiol and progesterone levels were measured at each time point. Ectocervical tissues were analyzed by RNA-sequencing and in situ immunofluorescence staining. Cervicovaginal lavage samples were evaluated using antibody-based protein profiling. Results: Employing a systems biology approach, we demonstrated that high plasma estradiol levels enhanced ectocervical epithelial integrity. These findings were more pronounced in samples from the follicular phase (when progesterone and estradiol levels were significantly lower) and included increased expression, and more intact distribution, of the desmosomal cadherin DSG1. The effects of progesterone on gene and protein levels, as well as on intact tissue (as visualized by in situ staining), were modest throughout the menstrual cycle. Both estradiol and progesterone levels had limited influence on mucosal immune factors. Conclusion: Estradiol levels were associated with modulation of cervical epithelial barrier integrity, including the expression and distribution of DSG1, during the follicular phase of natural menstrual cycles in Kenyan sex workers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273823 | GEO | 2025/01/17

REPOSITORIES: GEO

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Project description:Roblitz2013 - Menstrual Cycle following GnRH analogue administration The model describes the menstrual cycle feedback mechanisms. GnRH, FSH, LH, E2, P4, inbibins A and B, and follicular development are modelled. The model predicts hormonal changes following GnRH analogue administration. Simulation results agree with measurements of hormone blood concentrations. The model gives insight into mechanisms underlying gonadotropin supression. This model is described in the article: A mathematical model of the human menstrual cycle for the administration of GnRH analogues. Röblitz S, Stötzel C, Deuflhard P, Jones HM, Azulay DO, van der Graaf PH, Martin SW. J. Theor. Biol. 2013 Mar; 321: 8-27 Abstract: The paper presents a differential equation model for the feedback mechanisms between gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), development of follicles and corpus luteum, and the production of estradiol (E2), progesterone (P4), inhibin A (IhA), and inhibin B (IhB) during the female menstrual cycle. Compared to earlier human cycle models, there are three important differences: The model presented here (a) does not involve any delay equations, (b) is based on a deterministic modeling of the GnRH pulse pattern, and (c) contains less differential equations and less parameters. These differences allow for a faster simulation and parameter identification. The focus is on modeling GnRH-receptor binding, in particular, by inclusion of a pharmacokinetic/pharmacodynamic (PK/PD) model for a GnRH agonist, Nafarelin, and a GnRH antagonist, Cetrorelix, into the menstrual cycle model. The final mathematical model describes the hormone profiles (LH, FSH, P4, E2) throughout the menstrual cycle of 12 healthy women. It correctly predicts hormonal changes following single and multiple dose administration of Nafarelin or Cetrorelix at different stages in the cycle. This model is hosted on BioModels Database and identified by: BIOMD0000000494 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:<p>The Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center [<a href="www.komentissuebank.iu.edu" target="_blank">www.komentissuebank.iu.edu</a>] (KTB) was established expressly for the prospective collection of normal, healthy breast tissue from volunteer donors. Blood is also obtained from donors at the time of donation and is processed for serum, plasma and peripheral blood leukocyte DNA. Specimens are annotated and data includes age, race, ethnicity, personal health history, family cancer history, medication usage at the time of donation, and breast cancer risk factors.</p> <p>Premenopausal donors to the KTB were identified by a query of the Bank's database. Hematoxylin and eosin stained sections of the formalin-fixed paraffin-embedded tissue of the identified donors were reviewed and tissue was graded on the basis of the abundance of epithelium within the section. Only tissue containing abundant epithelium was considered for this study. Based on dates, the specimens of nine women in the follicular phase of the menstrual cycle and five in the luteal phase were chosen. Six donors using hormonal contraception at the time of donation were also included. Whole blood obtained from 19 of the 20 donors at the time of tissue donation was available and it was processed for serum. Estradiol, estriol, luteinizing hormone and progesterone concentrations were determined by the Indiana University Health Pathology Laboratory using a Beckman Unicel DxI 800 Immunoassay System. The phase of the menstrual cycle was verified by serum progesterone concentration. The epithelium of these 20 specimens was microdissected from multiple 8 micron frozen tissue sections. Total RNA extracted from the tissue was subsequently depleted of rRNA via locked nucleic acid probes. This enabled profiling of both poly-A and non-poly-A RNA species. Barcoded cDNA libraries from the 20 normal breast epithelia were prepared and sequenced on an Applied Biosystems (AB) SOLiD3 or SOLiD 4 platform. RNA-seq reads for each sample were then mapped to the human genome (hg19) using the LifeScope software version 2.5.1 (Life Technologies, Foster City, CA) and BAM (Binary Alignment/Map) files generated. Read counts for each gene were derived from the output BAM files using the RefSeq database (UCSC Genome Brower) as the gene model.</p>

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Estradiol-mediated enhancement of the human ectocervical epithelial barrier correlates with desmoglein-1 expression in the follicular menstrual phase

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