Exogenous sex steroids regulate genital epithelial barrier function in female rhesus macaques.

Nirk E Quispe Calla,Linda Fritts,Thomas L Cherpes,Christopher J Miller,Kristen M Aceves,Rodolfo D Vicetti Miguel

doi:10.1093/biolre/ioaa105

Nirk E Quispe Calla, Linda Fritts + Show 4 more

Open Access

https://doi.org/10.1093/biolre/ioaa105

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Abstract

There is concern that using depot-medroxyprogesterone acetate (DMPA) for pregnancy prevention heightens HIV susceptibility. While no clinical data establishes causal link between HIV acquisition and use of this injectable progestin, prior work from our laboratory showed that DMPA comparably lowers genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and weakens genital epithelial barrier function in female mice and women. We likewise saw DMPA increase mouse susceptibility to multiple genital pathogens including HIV. Herein, we sought to confirm and extend these findings by comparing genital epithelial barrier function in untreated rhesus macaques (RM) vs. RM treated with DMPA or DMPA and estrogen (E). Compared to controls, genital tissue from RM with pharmacologically relevant serum levels of medroxyprogesterone acetate displayed significantly lower DSG1 levels and greater permeability to low molecular mass molecules. Conversely, DMPA-mediated effects on genital epithelial integrity and function were obviated in RM administered DMPA and E. These data corroborate the diminished genital epithelial barrier function observed in women initiating DMPA and identify RM as a useful preclinical model for defining effects of exogenous sex steroids on genital pathogen susceptibility. As treatment with E averted DMPA-mediated loss of genital epithelial barrier function, our results also imply that contraceptives releasing progestin and E may be less likely to promote transmission of HIV and other sexually transmitted pathogens than progestin-only compounds.

Highlights

High rates of maternal and infant mortality and the need for affordable contraception are characteristics common to many parts of the world with large burden of HIV disease, and these conditions combine to make control of the HIV pandemic and pregnancy prevention highly interconnected public health concerns [1]
As peak serum medroxyprogesterone acetate (MPA) levels of 5.8–62 nM are detected in women IM administered 150 mg of depot-medroxyprogesterone acetate (DMPA) [25], current results established that pharmacologically relevant serum MPA levels were circulating at the time genital biopsy specimens used to evaluate gene expression and epithelial barrier function were obtained
Quantifying ectocervical gene expression in these same three groups, we found significantly lower DSG1 and DSC1 levels in rhesus macaques (RM) treated with DMPA alone, whereas treatment with DMPA and Depo-E restored DSG1 and DSC1 expression to levels seen in untreated animals (Figure 2B)

Summary

Introduction

High rates of maternal and infant mortality and the need for affordable contraception are characteristics common to many parts of the world with large burden of HIV disease, and these conditions combine to make control of the HIV pandemic and pregnancy prevention highly interconnected public health concerns [1]. Entwining the connections further still are clinical reports that indicate women using the injectable progestin depot-medroxyprogesterone acetate (DMPA) are significantly more likely to acquire HIV than women using no hormonal contraception [2, 3]. DMPA is a popular contraceptive choice in sub-Saharan Africa (SSA), the region of the world where most new HIV infections occur [4, 5]. In SSA, women 15–24 years of age are especially vulnerable, and represent about 25% of the incident infections annually [6].

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