title: 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). Although 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 herpes simplex virus type 2 (HSV-2) infection, we herein found that 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 that 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 that 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.
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Quispe Calla
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Vicetti Miguel
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA.
authors.forename: P N
authors.initials: PN
authors.lastname: Boyaka
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hall-Stoodley
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: W
authors.initials: W
authors.lastname: Trout
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Pavelko
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.|Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Cherpes
mesh_terms: D000818:Animals; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006558:Herpes Genitalis / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D016912:Levonorgestrel / Q000494:pharmacology*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D051379:Mice; D009092:Mucous Membrane / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D010539:Permeability / Q000187:drug effects; D014621:Vagina / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology
chemical_list: D003271:Contraceptive Agents, Female; D004967:Estrogens; D016912:Levonorgestrel; D017258:Medroxyprogesterone Acetate