Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection

Abstract

Depot-medroxyprogesterone acetate (DMPA) is a hormonal contraceptive especially popular in areas with high prevalence of HIV and other sexually transmitted infections (STI). While observational studies identify DMPA as an important STI risk factor, mechanisms underlying this connection are undefined. Levonorgestrel (LNG) is another progestin used for hormonal contraception, but its effect on STI susceptibility is much less explored. Using a mouse model of genital HSV-2 infection, we herein found DMPA and LNG similarly reduced genital expression of the desmosomal cadherin desmoglein-1α (DSG1α), enhanced access of inflammatory cells to genital tissue by increasing mucosal epithelial permeability, and increased susceptibility to viral infection. Additional studies with uninfected mice revealed DMPA-mediated increases in mucosal permeability promoted tissue inflammation by facilitating endogenous vaginal microbiota invasion. Conversely, concomitant treatment of mice with DMPA and intravaginal estrogen restored mucosal barrier function and prevented HSV-2 infection. Evaluating ectocervical biopsy tissue from women before and 1 month after initiating DMPA remarkably revealed inflammation and barrier protection were altered by treatment identically to changes seen in progestin-treated mice. Together, our work reveals DMPA and LNG diminish the genital mucosal barrier; a first-line defense against all STI, but may offer foundation for new contraceptive strategies less compromising of barrier protection.

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

“…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]. For example, in mice MPA at 4–7 nM decreases genital tract barrier function with an increased susceptibility to HSV-2 viral infection [59]. E x vivo data are broadly consistent with results from animal studies; MPA appears to increase HIV-1 proliferation in human immune cells at about 0.1 nM [72], dampen the function of immune cells at 0.3 nM [73], increase transcytosis of HIV-1 across the FGT epithelial cells at 1 nM [74], and decrease expression of select immunomodulators by FGT epithelial cells at 1–20 nM [74, 75].…”

“…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]. For example, in mice MPA at 4–7 nM decreases genital tract barrier function with an increased susceptibility to HSV-2 viral infection [59].…”

Dendritic cell function and pathogen-specific T cell immunity are inhibited in mice administered levonorgestrel prior to intranasal Chlamydia trachomatis infection

“…As examples, LNG-treated mice showed greater genital mucosal permeability and susceptibility to virus infection8, while multiple clinical studies identified IUSs users as most likely to develop pelvic inflammatory disease (PID) during the first 3 weeks after IUS insertion91011. Conversely, the incidence of acquiring sexually transmitted infection among women using LNG-IUS vs. no hormonal contraceptive is unexplored by prospective longitudinal study.…”

Comment on ‘Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial’

“…In mice, we showed that systemic treatment with DMPA or levonorgestrel (LNG), the progestogen released by commercially available subcutaneous implants and LNG-releasing intrauterine systems (LNG-IUSs), comparably increased genital mucosal permeability and susceptibility to herpes simplex virus type  2 (HSV-2) infection 4. This indicated that enhanced genital infection susceptibility is a class effect of exogenous progestogens, not unique to DMPA.…”

“…Conversely, we also used the mouse to show that combined administration of exogenous progestogen and estrogen restored genital mucosal integrity and abolished susceptibility to genital HSV-2 infection 4. Whether similar approaches in women would deliver contraception less compromising of genital mucosal barrier function than unopposed progestogens is uncertain.…”