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

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. Overall design: Between September 2015 and June 2017, 130 HIV negative, sexually active adolescent females aged 15-19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and product preference of contraceptives. The participants were randomized to injectable Net-En, combined oral contraceptives (COC) or NuvaRing, a combined contraceptive vaginal ring (CCVR) for 16 weeks in a 1:1:1 fashion. Cervicovaginal samples were collected at baseline and after 16 weeks of randomized HC use for RNA sequencing. Post RNAseq, low-quality samples were filtered out and the final data set includes n=13 baseline and n=96 follow-up samples.