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. Overall design: 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.

现有部分证据表明，避孕药的使用可能会对女性生殖道（female genital tract, FGT）的黏膜微环境造成影响。然而，针对当前临床最常用的激素与非激素避孕药对女性生殖道宿主基因表达谱的影响开展比较分析的相关研究，尚未在随机临床试验（randomized clinical trial）场景下得到详尽评估。本研究纳入2015年12月至2017年9月期间，在“避孕药选择与HIV感染风险（Evidence for Contraceptive Options and HIV Outcomes, ECHO）”试验（Clinicaltrials.gov注册号：NCT02550067）中入组的188名女性，采用RNA测序（RNA-Seq）转录组分析技术，评估了三种避孕方案——肌内注射型长效醋酸甲羟孕酮（DMPA-IM）、左炔诺孕酮（LNG）植入剂，以及非激素型T-380含铜宫内节育器（Cu-IUD）——在基线状态及随机使用避孕药1个月后，对宫颈内膜宿主转录组的调控作用。研究整体设计：经质量过滤流程筛选后，来自152名受试者的成对RNA测序数据（肌内注射型长效醋酸甲羟孕酮组，n=59；左炔诺孕酮植入剂组，n=45；含铜宫内节育器组，n=48）可用于后续的差异表达分析。本研究发现，被随机分配至含铜宫内节育器组的受试者，其宫颈内膜转录组受到的扰动幅度显著高于分配至肌内注射型长效醋酸甲羟孕酮组与左炔诺孕酮植入剂组的受试者，且此类转录组学变化与宿主的炎症及抗病毒应答密切相关。我们还观察到，肌内注射型长效醋酸甲羟孕酮组富集了与T细胞应答相关的信号通路，而与细胞生长及代谢相关的基因通路则呈现下调趋势；且上述结果并未显著受避孕措施启动时的生殖道微生物群组成影响。左炔诺孕酮植入剂的使用对宫颈内膜基因表达的影响最为轻微，但该组受试者的生长因子信号通路出现富集。本研究数据凸显了不同避孕方案对宿主微环境的生物学影响存在显著差异，这一发现可为新型避孕药的研发以及为寻求避孕服务的女性提供更优化的咨询指导提供重要参考。