Lower concentrations of chemotactic cytokines and soluble innate factors in the lower female genital tract associated with the use of injectable hormonal contraceptive

Abstract

Progesterone-based injectable hormonal contraceptives (HCs) potentially modulate genital barrier integrity and regulate the innate immune environment in the female genital tract, thereby enhancing risk for STIs or HIV infection. We investigated the effects of injectable HC use on concentrations of inflammatory cytokines and other soluble factors associated with genital epithelial repair and integrity. The concentrations of 42 inflammatory, regulatory, adaptive, growth factors and hematopoetic cytokines, five matrix metalloproteinases (MMPs), and four tissue inhibitors of metalloproteinases (TIMPs) were measured in cervicovaginal lavages (CVLs) from 64 HIV negative women using injectable HCs and 64 control women not using any HCs, in a matched case-control study. There were no differences between groups in the prevalence of bacterial vaginosis (BV; nugent score ≥7), or common sexually transmitted infections (STIs). In multivariate analyses adjusting for condom use, sex work status, marital status, BV and STIs, median concentrations of chemokines (eotaxin, MCP-1, MDC), adaptive cytokines (IL-15), growth factors (PDGF-AA) and a metalloproteinase (TIMP-2) were significantly lower in CVLs from women using injectable HCs than controls. In addition, pro-inflammatory cytokine IL-12p40 and chemokine fractalkine were less likely to have detectable levels in women using injectable HCs compared to those not using HCs. We conclude that injectable HC use was associated with an immunosuppressive female genital tract innate immune profile. While the relationship between injectable HC use and STI or HIV risk is yet to be resolved, our data suggest that injectable HCs effects were similar between STI positive and STI negative participants.

Live attenuated varicella-zoster virus vaccine does not induce HIV target cell activation

“…DMPA use was inversely associated with BV incidence in our cohort, with DMPA users at 7.7 times lower risk for testing positive for BV than women using other contraceptives during the study period. Additionally, we observed a less-proinflammatory profile, as evidenced by a lower PC1 score in DMPA users' CVS than in CVS from women using implants or IUDs as contraceptives, in agreement with previous observations showing that injectable hormonal contraceptives were broadly associated with an immunosuppressive FGT innate immune profile (66). With respect to HSV-2 target cells to the mucosa (60,61).…”

Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood

“…The clinical significance of these findings on HIV acquisition is unclear. Further, while there were minimal changes in soluble immune markers in the lower genital tract, these changes suggest a slight increase in local immune suppression with reduced concentrations of proinflammatory cytokines, a finding similarly noted with DMPA [54]. As we observed some shifts in T-cell populations in the genital tract https://doi.org/10.1371/journal.pone.0230473.g004…”

“…The results of our study highlight few changes in the lower genital tract inflammatory environment following Eng-Implant initiation. While several studies have evaluated genital tract immune changes after use of other hormonal contraceptive methods [17][18][19][20][21][22][23][48][49][50][51][52][53][54][55][56][57][58][59][60][61], to our knowledge, no published study has evaluated Eng-Implant. We report an increase in the proportion of CD4 T-cells expressing the co-receptor CCR5 at the genital mucosa with Eng-Implant use that could be associated with increased risk of HIV infection; however, not all our findings relate a clear picture of increased susceptibility.…”

Is a lower-dose, subcutaneous contraceptive injectable containing depot medroxyprogesterone acetate likely to impact women's risk of HIV?

“…DMPA-IM has been shown in some clinical studies to increase surface levels of CCR5 on peripheral and female genital tract (FGT) target T cells [55, 56], increase the frequency of CCR5 + T cells in the FGT mucosa [56], decrease the production of several immune modulators by immune cells [57, 58], increase FGT mucosal permeability and expression of barrier function proteins [59] and alter cervicovaginal levels of select secreted immunomodulators [57, 60–66]. Several of these studies are consistent with results from animal studies where MPA serum concentrations are similar to those of human DMPA-IM users [59, 67–71].…”