Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users
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PROVIDER: PRJNA1276099 | ENA |
REPOSITORIES: ENA
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Project description:The injectable contraceptive, depot medroxyprogesterone acetate (DMPA), is associated with compromised cervical mucosal barriers. High-resolution spatial transcriptomics is applied here to reveal the spatial localization of these altered molecular markers. Ectocervical tissue samples from Kenyan sex workers using DMPA, or non-hormonal contraceptives, underwent spatial transcriptomics and gene set enrichment analyses. Integrated systemic estradiol levels and bulk tissue gene expression data from a larger cohort enhanced the study’s scope. Unsupervised clustering unveiled four epithelial and seven submucosal layers, showcasing spatially restricted and diverse functional epithelial responses, and a less structured submucosal spatial ordering. DMPA associated with mucosal-wide immunoglobulin gene upregulation, verified by CD20+ B-cell immunostaining, and upregulated immune markers adjacent to the basal membrane. Downregulated genes represented spatially restricted disrupted epithelial barrier integrity and submucosal extracellular matrix dysfunction. The transcriptional profile was associated with markers of estrogen regulation. Collectively, our findings reveal estrogen-modulated distinct ectocervical transcriptional profiles associated with DMPA usage. While upregulation of immunoglobulin genes occurs throughout the mucosa, activation of innate immune responses and dysregulation of barrier integrity markers are spatially restricted. These results extend previous analyses using bulk transcriptomics and provide insights into the molecular landscape influenced by DMPA, shedding light on contraceptive effects and health implications.
2025-06-19 | GSE299708 | GEO
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: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:ObjectiveTo compare medroxyprogesterone acetate (MPA) concentrations between HIV-positive women on antiretroviral therapy (ART) and HIV-negative women initiating depot medroxyprogesterone (DMPA) injectable.Study designSecondary analysis of 28 HIV-positive women on non-nucleoside reverse transcriptase inhibitor-containing ART regimens and 10 HIV-negative women randomized to initiate DMPA in a clinical trial of progestin contraception in Malawi.ResultsMPA concentrations were significantly lower among HIV-positive women on ART, compared with HIV-negative women, at week 4 and week 13 (p=.03 for both), but not at day 3 or week 26 post-DMPA initiation.ConclusionsAntiretroviral medications may affect MPA metabolism in HIV-positive African women.
| S-EPMC7245365 | biostudies-literature
Project description:Multi-omics analysis of the cervical epithelial integrity of women using depot medroxyprogesterone acetate
| PRJNA761106 | ENA
Project description:ObjectivesTo characterize the relationship between serum medroxyprogesterone acetate (MPA) concentrations and ovulation suppression, and to estimate the risk of ovulation for investigational subcutaneous regimens of Depo-Provera CI (Depo-Provera) and Depo-subQ Provera 104 (Depo-subQ).Study designWe performed a secondary analysis of 2 studies that assessed the pharmacokinetics and pharmacodynamics of MPA when Depo-Provera is administered subcutaneously rather than by the labeled intramuscular route. Each woman received a single 45 mg to 300 mg subcutaneous injection of Depo-Provera, a single 104 mg subcutaneous injection of Depo-subQ, or 2 injections of Depo-subQ at 3-month intervals. We used an elevation of serum progesterone ≥4.7 ng/mL as a surrogate for ovulation and non-parametric statistical methods to assess pharmacokinetic and pharmacodynamic relationships.ResultsThis analysis included 101 women with body mass index (BMI) 18 to 34 kg/m2. Return of ovulation occurred at a median MPA concentration of 0.07 ng/mL (95% CI: 0.06-0.08) and the 90th percentile was 0.10 ng/mL (95% CI: 0.09-0.14). Neither age, race, nor BMI significantly influenced this relationship. The estimated probabilities of ovulation within 4 months of a 104 mg subcutaneous injection and within 7 months of a 150 mg subcutaneous injection (6 plus a 1-month grace) were each below 2.2%.ConclusionsThe typical MPA concentration associated with loss of ovulation suppression is substantially less than the commonly cited threshold of 0.2 ng/mL. Based on our results, MPA levels would rarely be low enough to permit ovulation if the Depo-subQ reinjection interval were extended to four months or if 150 mg Depo-Provera were injected subcutaneously every 6 months.ImplicationsExtending the three-month Depo-subQ reinjection interval by one month would result in a 25% reduction in yearly MPA exposure, with little risk of pregnancy. Off-label subcutaneous administration of 150 mg Depo-Provera every 6 months would be a highly effective repurposing of an excellent product, with a similar reduction in cumulative exposure.
| S-EPMC8907671 | biostudies-literature
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: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: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:Depot medroxyprogesterone acetate administered subcutaneously (DMPA-SC) is an all-in-one injectable contraceptive administered every 3 months, either by a trained health care provider or community health worker or by training a client to self-inject. Using a prospective cohort of family planning (FP) clients in Ghana, this study explores patterns of DMPA-SC use and mode of injection administration over a 6-month period. This study also examines the predictors of self-injection adoption 6 months after initiating DMPA-SC. Our analysis focuses on 378 women who were using DMPA-SC at the 6-month interview. Adjusted odds ratios accounting for clustering show that clients who were new FP users, never married, or attended high school/attained higher education were significantly more likely to self-inject by the third injection. Results of this study suggest that in Ghana, adding DMPA-SC to the method mix may improve access to FP, especially among new users. Results of this study may inform FP projects and programs aiming to improve access to contraceptive methods and increase contraceptive prevalence by introducing or scaling up DMPA-SC self-injection. The findings also provide a sociodemographic profile of FP clients most likely to adopt DMPA-SC self-injection over time, which could serve as an evidence base for social marketing strategies.
| S-EPMC8885352 | biostudies-literature