Reduced Desmosomal Cadherin Levels in Genital Epithelium of Postmenopausal Women Also Develop in Ovariectomized Mice with Increased Susceptibility to Viral and Bacterial Genital Pathogens

Abstract

Background: The genitourinary syndrome of menopause affects about half of all women in menopause and includes symptoms of vaginal burning, dyspareunia, and urinary urgency. These symptoms stem from lower serum estrogen levels in postmenopausal women that cause reduced tissue elasticity and other genital tract changes. While the hypoestrogenemia induced in reproductive age women using the progestin-only contraceptive depot-medroxyprogesterone acetate (DMPA) decreases genital levels of the cell-cell adhesion molecules desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and impairs genital epithelial barrier function, relevance of these findings to postmenopausal women is uncertain. Methods: We compared ectocervical DSG1 and DSC1 levels in premenopausal vs. postmenopausal women. Using ovariectomized mice to model the hypoestrogenic state in postmenopausal women, we explored effects of reduced ovarian function on genital epithelial integrity barrier function and genital pathogen susceptibility. Findings: Compared to premenopausal women, ectocervical tissue from women in menopause had significantly lower levels of DSG1 and DSC1. Likewise, Dsg1 and Dsc1 levels were significantly reduced in OVX mice vs. estrus-stage mice. Consistent with these data, DMPA-treated and OVX mice displayed significant compromise of genital epithelial barrier function and compared to estrus-stage mice or OVX mice treated with estrogen, were more susceptible to genital herpes simplex virus type 2 infection and less effectively cleared genital Chlamydia trachomatis infection. Interpretation: Our studies identify analogously reduced genital epithelial integrity in postmenopausal women and OVX mice and indicate that reduced ovarian function alters host response to bacterial and viral pathogens. Our results also spotlight the need to resolve if weakened genital epithelial integrity in postmenopausal women represents an important risk factor for genital infection. Funding Statement: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD094634) and Stanford University School of Medicine. Declaration of Interests: Authors have no conflicts of interest to declare. Ethics Approval Statement: Prior to induction, all proposed mice studies were approved by the Stanford University Institutional Animal Care and Use Committee.