The Contribution of Cervicovaginal Infections to the Immunomodulatory Effects of Hormonal Contraception

Abstract

Particular types of hormonal contraceptives (HCs) and genital tract infections have been independently associated with risk of HIV-1 acquisition. We examined whether immunity in women using injectable depot medroxyprogesterone acetate (DMPA), combined oral contraceptives (COC), or no HCs differs by the presence of cervicovaginal infections. Immune mediators were quantified in cervical swabs from 832 HIV-uninfected reproductive-age Ugandans and Zimbabweans. Bacterial infections and HIV were diagnosed by PCR, genital herpes serostatus by enzyme-linked immunosorbent assay (ELISA), altered microflora by Nugent score, and Trichomonas vaginalis and Candida albicans infection by wet mount. Generalized linear models utilizing Box-Cox-Power transformation examined associations between levels of mediators, infection status, and HCs. In no-HC users, T. vaginalis was associated with broadest spectrum of aberrant immunity (higher interleukin 1β [IL-1β], IL-8, macrophage inflammatory protein 3α [MIP-3α], β-defensin 2 [BD2], and IL-1 receptor antigen [IL-1RA]). In women with a normal Nugent score and no genital infection, compared to the no-HC group, COC users showed higher levels of IL-1β, IL-6, IL-8, and IL-1RA, while DMPA users showed higher levels of RANTES and lower levels of BD2, both associated with HIV seroconversion. These effects of COC were blunted in the presence of gonorrhea, chlamydia, trichomoniasis, candidiasis, and an abnormal Nugent score; however, RANTES was increased among COC users with herpes, chlamydia, and abnormal Nugent scores. The effect of DMPA was exacerbated by lower levels of IL-1RA in gonorrhea, chlamydia, or herpes, SLPI in gonorrhea, and IL-1β, MIP-3α, and IL-1RA/IL1β ratio in trichomoniasis. Thus, the effects of HC on cervical immunity depend on the genital tract microenvironment, and a weakened mucosal barrier against HIV may be a combined resultant of genital tract infections and HC use.

Importance: In this article, we show that in young reproductive-age women most vulnerable to HIV, hormonal contraceptives are associated with altered cervical immunity in a manner dependent on the presence of genital tract infections. Through altered immunity, hormones may predispose women to bacterial and viral pathogens; conversely, a preexisting specific infection or disturbed vaginal microbiota may suppress the immune activation by levonorgestrel or exacerbate the suppressed immunity by DMPA, thus increasing HIV risk by their cumulative action. Clinical studies assessing the effects of contraception on HIV susceptibility and mucosal immunity may generate disparate results in populations that differ by microbiota background or prevalence of undiagnosed genital tract infections. A high prevalence of asymptomatic infections among HC users that remain undiagnosed and untreated raises even more concerns in light of their combined effects on biomarkers of HIV risk. The molecular mechanisms of the vaginal microbiome's simultaneous interactions with hormones and HIV remain to be elucidated.

FIG 1

Distribution of number of sexual acts (A) and clinical signs and symptoms of cervicovaginal infections (B) among women who chose not to use hormonal contraception (no-HC) and women with majority use of combined oral contraceptives (COC) or DMPA. P values indicate differences among the HC groups.

FIG 2

Combined effects of cervicovaginal infections (CVIs) and hormonal contraception (HC) on markers of cervical immunity. Women were stratified by CVI status and HC use within each CVI stratum, and levels of immune biomarkers were compared by multivariable analysis via generalized linear models and Wilcoxon tests after adjustment for other individual CVIs. Bars represent the differences between the average concentrations calculated for each of the combined CVI-plus-HC category listed on the left and the average concentration calculated for the physiologic CVI-free no-HC baseline (15 women who were infection free, had a normal Nugent score, and who did not use any HC). Consequently, the CVI-free, no-HC baseline average was set to 0 in each bar plot. P values with asterisks (*, P < 0.05; **, P < 0.01; and ***, P < 0.001) signify differences between no-HC and combined oral contraceptive (COC) or DMPA users within each CVI stratum. P values with plus signs (+, P < 0.05; ++, P < 0.01; and +++, P < 0.001) signify differences between each CVI-positive group and the CVI-free group matched by HC (e.g., no-HC, COC, and DMPA). The P values for the two comparisons and the number of women in each group are shown in Tables S1 and S2 in the supplemental material.