Abstract
Hormonal contraceptives (HCs) are vital in managing the reproductive health of women. However, HC usage has been linked to perturbations in cervicovaginal immunity and increased risk of sexually transmitted infections. Here, we evaluated the impact of three HCs on the cervicovaginal environment using high-throughput transcriptomics. From 2015 to 2017, 130 adolescent females aged 15–19 years were enrolled into a substudy of UChoose, a single-site, open-label randomized, crossover trial (NCT02404038) and randomized to injectable norethisterone–enanthate (Net-En), combined oral contraceptives (COC), or etonorgesterol/ethinyl–estradiol–combined contraceptive vaginal ring (CCVR). Cervicovaginal samples were collected after 16 weeks of randomized HC use and analyzed by RNA-Seq, 16S rRNA gene sequencing, and Luminex analysis. Participants in the CCVR arm had a 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 demonstrated that networks of microbial dysbiosis and inflammation best 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. Collectively, these data from a randomized trial represent the most comprehensive “omics” analyses of the cervicovaginal response to HCs and provide important mechanistic guidelines for the provision of HCs in sub-Saharan Africa.
Highlights
Young women in sub-Saharan Africa are at a high risk of unintended pregnancies [1, 2], which are associated with maternal and infant mortality and morbidity, especially in developing countries [3]
The impact of varying Hormonal contraceptives (HCs) on the mucosal immune environment has not been studied in detail using randomized designs, which overcomes biases introduced by observational data
We examined the effects of three HCs with different hormones and delivery strategies, including both combined and progestin-only methods, on endocervical gene expression of South African adolescents within a prospective randomized trial using high throughput transcriptomics
Summary
Young women in sub-Saharan Africa are at a high risk of unintended pregnancies [1, 2], which are associated with maternal and infant mortality and morbidity, especially in developing countries [3]. Several recent studies have indicated that HCs, in particular regimens utilizing the intramuscular progestin-only injection depot medroxyprogesterone acetate (DMPA-IM), can alter the epithelial barrier function. In nonhuman primates (NHPs), DMPA treatment has been associated with a decrease in the vaginal epithelial thickness [28–30], more so than estrogen-containing combined oral contraceptives (COCs) [30, 31]. Physiological levels of medroxyprogesterone acetate (MPA) reduced epithelial barrier integrity in the genital tract epithelial cells in vitro [32–34], whereas estradiol treatment led to enhanced barrier function [33, 34]. Rodents and NHPs treated with DMPA had reduced genital levels of the cell–cell adhesion molecules and weakened epithelial barrier function that could be reversed by treatment with exogenous estrogen [35, 36]. Vaginal epithelial thinning in humans using DMPA–IM has not been demonstrated at the dose administered [6, 37–39]
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