Estradiol may mediate the relationship between cortisol and the vaginal microbiome in adolescent girls and young women: results of an exploratory longitudinal cohort study

Introduction Estradiol helps maintain a Lactobacillus crispatus dominant vaginal microbiome (VMB), which is protective against Bacterial vaginosis (BV). Cortisol can suppress estradiol production and function, and may therefore negatively affect VMB. We estimated the influence of cortisol on VMB composition via estradiol. We hypothesized that adolescent girls and young women (AGYW) with dysregulated cortisol would have decreased estradiol and, in turn, reduced vaginal L. crispatus . Methods We assessed psychosocial measures, cortisol, estradiol, and VMB composition every 6 months over 2 years among 51 AGYW. We measured salivary cortisol via ELISA in a single-day, 6-time point protocol; serum estradiol via ELISA, and VMB from self-collected vaginal swabs via 16S rRNA gene amplicon sequencing. Associations were estimated using adjusted longitudinal mixed effects models and mediation analysis. Models were adjusted for sociodemographics, recent menstruation, menstrual material, and hormonal contraception. Results At cohort entry, participants were median age 20.9 years; mean relative abundance (RA) of L. crispatus was 23.5%; 42.5% had normal cortisol awakening response (CAR); 50% reported feeling sad or depressed most days in the past year; and mean estradiol was 62.3 pg/mL. In longitudinal adjusted modeling: (1) normal CAR was associated with higher mean L. crispatus RA among AGYW without depressive symptoms (β=13.3, p=0.048) but not those with depressive symptoms (β=5.53, p=0.198); (2) estradiol trended higher with normal CAR among AGYW without depressive symptoms (β=26.5, p=0.091) but not those with depressive symptoms (β=6.86, p=0.664); (3) estradiol was positively associated with L. crispatus RA among AGYW without depressive symptoms (β=0.106, p=0.008) but not those with depressive symptoms (β=0.040, p=0.227). In mediation analysis, 19.9% (p=0.098) of the association between normal CAR and L. crispatus was mediated via estradiol, though the mediating effect was observed specifically among AGYW without depressive symptoms. Conclusions Normal CAR was associated with increased relative abundance of vaginal L. crispatus , possibly partially mediated through its relationship with estradiol, among AGYW who did not report depressive symptoms. If replicated in larger studies, we hypothesize this could have clinical implications for prevention or treatment of VMB dysbiosis and BV: hormonal contribution to non-optimal VMB could undermine antibiotic and biotherapeutic treatment effectiveness and durability.