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

Abstract

BackgroundExogenous sex steroids within hormonal contraception and menopausal hormone therapy (MHT) have been used for family planning and management of menopausal symptoms, without consideration of their effects on the vaginal microbiota. This is largely because their use predates our understanding of the importance of the vaginal microbiome on human health. We conducted a systematic review (PROSPERO: CRD42018107730) to determine the influence of exogenous sex steroids, stratified by oestrogen-containing or progestin-only types of contraception, and MHT on the vaginal microbiome, as measured by molecular methods.MethodsEmbase, PubMed and Medline were searched for relevant literature published through to December 1st 2020. Eligible studies reported on the effect of specific exogenous sex steroids on the vaginal microbiome using a molecular method. Data regarding the ‘positive’, ‘negative’ or ‘neutral’ effect of each type of contraceptive or MHT on the vaginal microbiome was extracted and summarised. A positive effect reflected sex steroid exposure that was associated with increased abundance of lactobacilli, a change to, or maintenance of, an optimal vaginal microbiota composition, or a decrease in bacterial diversity (specifically reflecting a low-diversity optimal microbiota state), relative to the control group. An exogenous sex steroid was designated as having a negative effect on the vaginal microbiome if it resulted in opposing effects (i.e. loss of lactobacilli, a non-optimal microbiota state). When no significant change was found, this was considered neutral/inconclusive.ResultsWe identified 29 manuscripts reporting on the effect of exogenous sex steroids on the vaginal microbiome; 25 investigating hormonal contraceptives, and 4 investigating MHT. Oestrogen-containing contraception, particularly reflecting the combined oestrogen and progestin-containing contraceptive pill, had a positive effect on the composition of the vaginal microbiota. Progestin-only contraception, particularly reflecting depo-medroxyprogesterone acetate, had mixed effects on the microbiota. Among post-menopausal women using MHT, exogenous oestrogen applied topically was associated with increased prevalence of lactobacilli.ConclusionOur findings suggest that oestrogen-containing compounds may promote an optimal vaginal microbiota, which could have clinical applications. The impact of progestin-only contraceptives on the vaginal microbiota is less clear; more data is needed to determine how progestin-only contraceptives contribute to adverse reproductive and sexual health outcomes.

Lactobacillus-dominance and rapid stabilization of vaginal microbiota in combined oral contraceptive pill users examined through a longitudinal cohort study with frequent vaginal sampling over two years

“…Our results for COCs are consistent with multiple studies that demonstrated a reduced risk of incident and prevalent BV among those using combined estrogen and progestin contraceptive methods. 29 , 30 , 31 , 64 , 65 Our results are also similar to other studies evaluating the effect of COCs on the composition of the vaginal microbiota characterized using molecular approaches (16S rRNA gene amplicon sequencing or qPCR), including a cross-sectional study (N = 682) comparing the vaginal microbiota of women on HC to those who used condoms for contraception. 34 That study found that those using COCs (N = 206) were more likely to be colonized by Lactobacillus spp.…”

“… 41 To further corroborate this, a recent systematic review found that estrogen containing compounds overall seemed to promote an optimal vaginal microbiota, but the effect of progestin only contraceptives was much less clear, with some concerns for potential negative effects. 65 In our study, when participants using all forms of HC were included, the results did not change, participants remained more likely to be stable and more likely to be dominated by Lactobacillus spp. if they were using HC.…”

“…While our study and others support COC use as a contributor to promoting Lactobacillus dominance and stability, emerging data suggest that progestin-only contraceptives (POCs) may not have the same beneficial effects. 65 An early systemic review and meta-analysis 29 found that POC (based on N = 6 studies) was associated with decreased prevalent and incident BV. However, of the six included studies reporting on prevalent BV, only two reported a statistically reduced prevalence, and of the six included studies reporting on incident BV, only one reported a statistically reduced incidence.…”

Menopausal Changes in the Microbiome—A Review Focused on the Genitourinary Microbiome

“…The vaginal pH and Lactobacilli levels were restored to premenopausal levels in patients who underwent hormone therapy, though no significant changes were observed in the other groups [ 39 ]. In a systematic review of four clinical trials investigating the effects of percutaneous estrogen administration on the vaginal microbiome in postmenopausal women, Ratten et al [ 40 ] found that topical estrogen administration increases vaginal Lactobacillus . In a randomized, double-blind, placebo-controlled study conducted by Petricevic et al, when probiotic capsules containing L. rhamnosus GR-1 and L. reuteri RC-14 were administered daily for 14 days, there was a significant improvement in the Nugent score compared with that in the placebo group.…”

Effects of Depot Medroxyprogesterone Acetate Intramuscular Injection, Copper Intrauterine Device and Levonorgestrel Implant Contraception on Estradiol Levels: An Ancillary Study of the ECHO Randomized Trial

“…Estrogens have multiple physiological effects such as on metabolism, menstruation, coagulation, bone health, the cardiovascular system ( 1 ) and the vaginal microbiome ( 2 ), and are also associated with adverse effects such as increasing susceptibility to candida albicans infection ( 3 , 4 ). In addition, sex steroid hormones have important neuropsychological and behavioral effects.…”