Hormonal contraception alters vaginal microbiota and cytokines in South African adolescents in a randomized trial

Abstract

Young women in sub-Saharan Africa are disproportionally affected by HIV infection and unintended pregnancies. However, hormonal contraceptive (HC) use may influence HIV risk through changes in genital tract microbiota and inflammatory cytokines. To investigate this, 130 HIV negative adolescent females aged 15–19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and contraceptive product preference as a proxy for HIV prevention delivery methods. Participants were randomized to injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) or etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR) for 16 weeks, then crossed over to another HC for 16 weeks. Cervicovaginal samples were collected at baseline, crossover and exit for characterization of the microbiota and measurement of cytokine levels; primary endpoints were cervical T cell activation, vaginal microbial diversity and cytokine concentrations. Adolescents randomized to COCs had lower vaginal microbial diversity and relative abundance of HIV risk-associated taxa compared to Net-En or CCVR. Cervicovaginal inflammatory cytokine concentrations were significantly higher in adolescents randomized to CCVR compared to COC and Net-En. This suggests that COC use may induce an optimal vaginal ecosystem by decreasing bacterial diversity and inflammatory taxa, while CCVR use is associated with genital inflammation.

Impact of the menstrual cycle and ethinyl estradiol/etonogestrel contraceptive vaginal ring on granulysin and other mucosal immune mediators

“…The effect of CVR use on cervicovaginal cytokines has been assessed in three previous studies, though none differentiated between follicular and luteal phase. [33][34][35] Two studies used SoftCup samples and longitudinal designs 33,34 and found similar results to ours: elevated IL-6 and IL-1β during CVR use (in addition to IFNγ and TNFα, which we did not find). The third study used cervicovaginal lavage samples and a cross-sectional design 35 and the results agreed less well with ours, in particular, their finding that IL-1β was lower in CVR users.…”

“…The effect of CVR use on cervicovaginal cytokines has been assessed in three previous studies, though none differentiated between follicular and luteal phase 33‐35 . Two studies used SoftCup samples and longitudinal designs 33,34 and found similar results to ours: elevated IL‐6 and IL‐1β during CVR use (in addition to IFN‐γ and TNF‐α, which we did not find).…”

The Effect of Exogenous Sex Steroids on the Vaginal Microbiota: A Systematic Review

“…Ten studies investigated the effect of the combined oestrogencontaining OCP on the vaginal microbiome (Borgdorff et al, 2015;Borgdorff et al, 2017;Brooks et al, 2017;Onywera et al, 2019;Wessels et al, 2019;Balle et al, 2020;Song et al, 2020;van de Wijgert et al, 2020;Ratten et al, 2021); six reported a positive effect on the vaginal microbiota, and four reported neutral findings (Tables 1 and 3).…”

“…Three studies investigated the effect of the oestrogen-containing CVR (Borgdorff et al, 2017;Crucitti et al, 2018;Balle et al, 2020). Compared to baseline specimens, Borgdorff et al (2017) found that CVR-use was associated with a non-significant decrease in the relative abundance of G. vaginalis and Crucitti et al ( 2018) found CVR-use was associated with a significant decrease in the prevalence G.vaginalis and A.vaginae (Table 1).…”

DataSheet_1.pdf

“…Eighteen studies used agematched women not using hormonal contraceptives as the comparator group (e.g. no contraceptives or condom-use) (low risk), and seven used the baseline specimen prior to contraception initiation as the comparator group (low/medium risk) (Jacobson et al, 2014;Bassis et al, 2015;Achilles et al, 2018;Crucitti et al, 2018;Tuddenham et al, 2019b;Yang et al, 2019;Balle et al, 2020). Five studies did not stratify hormonal contraceptive exposure by oestrogen-containing or progestinonly (high risk) (Gautam et al, 2015;Scott et al, 2019;Tuddenham et al, 2019a;Tuddenham et al, 2019b;Marconi et al, 2020).…”