Multi-omics analysis of the cervical epithelial integrity of women using depot medroxyprogesterone acetate
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ABSTRACT:
PROVIDER: PRJNA761106 | ENA |
REPOSITORIES: ENA
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Project description:Depot medroxyprogesterone acetate (DMPA) is an injectable hormonal contraceptive used by millions of women worldwide. However, experimental studies have associated DMPA use with genital epithelial barrier disruption and mucosal influx of human immunodeficiency virus (HIV) target cells. We explored the underlying molecular mechanisms of these findings. Ectocervical biopsies and cervicovaginal lavage (CVL) specimens were collected from HIV-seronegative Kenyan sex workers using DMPA (n=32) or regularly cycling controls (n=64). Tissue samples were assessed by RNA-sequencing and quantitative imaging analysis, whereas protein levels were measured in CVL samples. The results suggested a DMPA-associated upregulation of genes involved in immune regulation, including genes associated with cytokine-mediated signaling and neutrophil-mediated immunity. A transcription factor analysis further revealed DMPA-associated upregulation of RELA and NFKB1 which are involved in several immune activation pathways. Several genes significantly downregulated in the DMPA versus the control group were involved in epithelial structure and function, including genes encoding keratins, small proline-rich proteins, and cell-cell adhesion proteins. Pathway analyses indicated DMPA use was associated with immune activation and suppression of epithelium development, including keratinization and cornification processes. The cervicovaginal microbiome composition (Lactobacillus dominant and non-Lactobacillus dominant) had no overall interactional impact on the DMPA associated tissue gene expression. Imaging analysis verified that DMPA use was associated with an impaired epithelial layer as illustrated by staining for the selected epithelial junction proteins E-cadherin, desmoglein-1 and claudin-1. Additional staining for CD4+ cells revealed a more superficial location of these cells in the ectocervical epithelium of DMPA users versus controls. Altered protein levels of SERPINB1 and ITIH2 were further observed in the DMPA group. Identification of specific impaired epithelial barrier structures at the gene expression level, which were verified at the functional level by tissue imaging analysis, illustrates mechanisms by which DMPA adversely may affect the integrity of the genital mucosa.
2022-04-29 | GSE183513 | GEO
Project description:Agilent 4x44k Whole Mouse Genome v1 Microarrays were used to analyze aortic transcriptome of mice substituted with medroxyprogesterone acetate, norethisterone acetate or placebo after having been ovariectomized. The aim of this experiment was to detect genes regulated in the gestagen-treated groups as compared to placebo that might be involved in thrombotic events Aortic gene expression was analyzed in ApoE-deficient mice after ovariectomy and 90 days of hormone- or placebo-treatment (medroxyprogesterone acetate or norethisterone acetate) and feeding a high-fat Western-type diet.
2014-06-30 | E-GEOD-57972 | biostudies-arrayexpress
Project description:Agilent 4x44k Whole Mouse Genome v1 Microarrays were used to analyze aortic transcriptome of mice substituted with medroxyprogesterone acetate, norethisterone acetate or placebo after having been ovariectomized. The aim of this experiment was to detect genes regulated in the gestagen-treated groups as compared to placebo that might be involved in thrombotic events
2014-06-30 | GSE57972 | GEO
Project description:Comparison between the effects of progesterone (P4) and medroxyprogesterone acetate (MPA) combined to estradiol (E2) on gene expression in normal breast cells to provide insight on their possible different impact on breast cancer risk in vivo.
2011-05-30 | GSE23500 | GEO
Project description:Injectable depot medroxyprogesterone acetate (DMPA) is one of the most popular contraception methods in areas of high HIV seroprevalence. Evidence is accumulating that use of DMPA might be associated with an increased risk of acquiring HIV-1; however, mechanisms of this association are not completely understood. We conducted a comparative whole genome transcriptome profiling of human ectocervical tissues before and after use of two hormonal contraception methods: injectable DMPA and not linked to increased risk of HIV acquisition combined oral contraceptive (COC). Microarray analysis identified 235 ectocervical genes altered in the DMPA users. The most striking effect of DMPA, but not COC, was a strong dysregulation of genes strategically involved in the maintenance of epithelial barrier function; the alterations were most likely due to the DMPA-induced estrogen deficiency. We also demonstrated inter-individual heterogeneity in gene expression profiles of the DMPA users that clustered into distinct groups. The differential response may explain divergence in reports on effects of DMPA use. We propose that impairment of the cervicovaginal epithelial integrity in response to DMPA administration is the major mechanism underlying a potential increased risk of HIV-1 acquisition in DMPA users.
2018-04-10 | GSE110313 | GEO
Project description:Some evidence suggests that contraceptive use may influence the female genital tract (FGT) mucosal environment. However, comparative analysis of the effects of the most commonly used hormonal and non-hormonal contraceptives on the FGT host gene expression profile have not been evaluated in detail in a randomized clinical trial setting. Among 188 women enrolled in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial (Clinicaltrials.gov ID NCT02550067) between December 2015 and September 2017, we evaluated the effect of three contraceptive methods, injectable intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implant, and a non-hormonal T-380 copper intrauterine contraceptive device (Cu-IUD), on the endocervical host transcriptome at baseline and after one month of randomized contraceptive use, using RNA-Seq transcriptomic analysis.
2023-09-13 | GSE190923 | GEO
Project description:Comparison between the effects of progesterone (P4) and medroxyprogesterone acetate (MPA) combined to estradiol (E2) on gene expression in normal breast cells to provide insight on their possible different impact on breast cancer risk in vivo. Total RNA obtained from cultures of normal human breast epithelial cells (HBE) under E2, E2+MPA and E2+P4 six hour treatments, compared to untreated HBE cells
2011-05-30 | E-GEOD-23500 | biostudies-arrayexpress
Project description:Epidemiological studies indicate that progestin-containing contraceptives may increase susceptibility to HIV and other infections; however, underlying mechanisms involving the upper female reproductive tract are undefined. To determine the effects of depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) on gene expression and physiology of the human endometrial and cervical transformation zone (TZ), microarray analyses were performed on whole tissue biopsies. In endometrium, activated pathways included leukocyte chemotaxis, attachment, and inflammation in DMPA (z>2.5) and LNG-IUS (z>3.5) users, and regulation of pattern recognition receptors and other immune mediators. In cervical TZ, progestin treatment altered expression of tissue remodeling and viability genes, but not those of immune functions. Together, these results indicate that progestins influence expression of immune-related genes in endometrium that would be expected to result in the local recruitment of HIV target cells, and thus may increase HIV susceptibility. It is important to consider the upper reproductive tract in the assessment of effects of contraceptives that may influence susceptibility to pathogens, such as HIV.
2014-11-21 | GSE60129 | GEO
Project description:The use of the hormonal contraceptive DMPA has been associated with a moderate increase in sexually transmitted infections, including HIV-1. To better understand the biological mechanisms behind this phenomenon, we report here the use of mRNA-sequencing on the Illumina HiSeq2000 of vaginal epithelial cells from women using DMPA or controls. We found that women using DMPA demonstrate over 330-fold decrease in the anti-microbial peptide human beta defensin 3 (HBD3) and massive downregulation of genes involved in structural integrity, barrier function, and wound healing. CXCL6, CXCL1, and IL-1B among other inflammatory genes were up-regulated in the tissue of DMPA users compared to controls. Overall, these results demonstrate significant differences in basic epithelial functions following DMPA use.
2016-04-23 | GSE68229 | GEO
Project description:Epidemiological studies indicate that progestin-containing contraceptives may increase susceptibility to HIV and other infections; however, underlying mechanisms involving the upper female reproductive tract are undefined. To determine the effects of depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) on gene expression and physiology of the human endometrial and cervical transformation zone (TZ), microarray analyses were performed on whole tissue biopsies. In endometrium, activated pathways included leukocyte chemotaxis, attachment, and inflammation in DMPA (z>2.5) and LNG-IUS (z>3.5) users, and regulation of pattern recognition receptors and other immune mediators. In cervical TZ, progestin treatment altered expression of tissue remodeling and viability genes, but not those of immune functions. Together, these results indicate that progestins influence expression of immune-related genes in endometrium that would be expected to result in the local recruitment of HIV target cells, and thus may increase HIV susceptibility. It is important to consider the upper reproductive tract in the assessment of effects of contraceptives that may influence susceptibility to pathogens, such as HIV. Cross-sectional study conducted at an academic medical center. Cervical transformation zone and endometrial biopsies were obtained from 3 groups of volunteers: those using no hormonal contraceptives (controls, mid-secretory phase, n=20 cervix, 11 endometrium), DMPA users (150mg, n=15, 8), or LNG-IUS users (n=17, 13). DMPA and LNG-IUS groups had used these contraceptives for at least 6 months.
2014-11-21 | E-GEOD-60129 | biostudies-arrayexpress