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Systems analysis of the female genital tract reveals differential expression of inflammatory and epithelial barrier genes in South African adolescents randomized to injectable, oral or vaginal ring contraception

ABSTRACT: Use of hormonal contraceptives (HC) could alter the bacterial community, immune response and epithelial barrier integrity of the female genital tract (FGT) mucosal environment, leading to increased susceptibility to sexually transmitted infections (STIs), including HIV. Here, we tested whether use of three types of HCs, injectable Net-En, combined oral contraceptives (COC) and NuvaRing, a combined contraceptive vaginal ring (CCVR), led to distinct patterns in FGT host transcriptomics transcriptome in South African adolescent females. In an intention-to-treat analysis, we observed few changes in endocervical gene expression in the Net-En and COC groups. Relative to the COC and Net-En arms, samples from the CCVR arm had significant elevation of transcriptional networks driven by IL-6, IL-1 and NFKB, and lower expression of genes supporting epithelial barrier integrity. An integrated multivariate analysis of the cervicovaginal microbiome, transcriptome and cytokines demonstrated that networks of microbial dysbiosis and inflammation accurately discriminated the CCVR arm from the other contraceptive groups, while genes involved in epithelial cell differentiation were predictive of the Net-En and COC arms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171825 | GEO | 2022/07/11

REPOSITORIES: GEO

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Project description:The contraceptive effectiveness of intrauterine devices has been attributed in part to effects of a foreign body reaction on the endometrium. We performed this study to identify compare the effects on the endometrial transcriptome of intrauterine devices and combined oral contraceptives, to better understand their mechanisms of action. We collected endometrial and cervical biopsies from women using the levonorgestrel-intrauterine device, copper intrauterine device or levonorgestrel-containing combined oral contraceptives, and from women not using contraceptives (control group). Transcriptional profiling was performed with Affymetrix arrays, Principal Component Analysis and the bioconductor package limma. Pathway analysis was performed using EnrichR and Reactome 2016. In endometrial samples from copper intrauterine device users (n=13), there were no genes with statistically significant differential expression compared to controls (n=11), whereas in levonorgestrel-intrauterine device users (n=11), 2509 genes were significantly dysregulated and mapped onto several immune and inflammatory pathways. In combined oral contraceptive users (n=12), 133 genes were significantly dysregulated and mapped predominantly onto pathways involving regulation of metal ions. Both levonorgestrel-intrauterine device and combined oral contraceptive use were associated with significant downregulation of members of the metallothionein gene family. In cervical samples, none of the groups showed statistically significant differential gene expression compared to controls. In conclusion, hormonal and copper intrauterine devices differ significantly in their effects on the endometrial transcriptome, with endometrium from copper intrauterine device users being indistinguishable from luteal phase endometrium. These results suggest that the contraceptive mechanisms of intrauterine devices are unlikely to rely on a common pathway involving a foreign body reaction in the endometrium.

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Systems analysis of the female genital tract reveals differential expression of inflammatory and epithelial barrier genes in South African adolescents randomized to injectable, oral or vaginal ring contraception

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