Systems analysis reveals differential expression of endocervical genes in African women randomised to DMPA-IM, LNG implant or Cu-IUD

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. After quality filtering, paired RNA-Seq data from 152 participants (DMPA-IM, n = 59; LNG-implant, n = 45; Cu-IUD, n = 48) were considered suitable for downstream differential expression analysis. We found that participants randomized to Cu-IUD showed a larger perturbation to the endocervical transcriptome than those assigned to DMPA-IM and LNG implant and that these transcriptomic changes were associated with inflammatory and anti-viral host responses. We found that DMPA-IM enriched for pathways associated with T cell responses while gene pathways associated with growth and metabolism were downregulated, and that these results were not strongly dependent on the microbiota composition at the time of contraceptive initiation. LNG implant initiation had the mildest effect on endocervical gene expression but was associated with enrichment of growth factor signalling. Our data highlight the varying biological impact of different contraceptives on the host environment, which is relevant for development of novel contraceptive methods and for improved counselling of women seeking contraception.