TY - JOUR
T1 - Exogenous sex steroids regulate genital epithelial barrier function in female rhesus macaques
AU - Quispe Calla, Nirk E.
AU - Vicetti Miguel, Rodolfo D.
AU - Fritts, Linda
AU - Miller, Christopher J.
AU - Aceves, Kristen M.
AU - Cherpes, Thomas L.
N1 - Funding Information:
This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Award Number R01HD094634) and the California National Primate Research Center Pilot Program. Authors are solely responsible for the content of this publication, which does not necessarily represent official views of the National Institutes of Health. Serum steroid concentrations were quantified by the Endocrine Technologies Core at the Oregon National Primate Research Center (Award Number P51OD011092).
Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - Estrogen
KW - Genital epithelial barrier function
KW - Nonhuman primate
KW - Progestin
UR - http://www.scopus.com/inward/record.url?scp=85089162291&partnerID=8YFLogxK
U2 - 10.1093/biolre/ioaa105
DO - 10.1093/biolre/ioaa105
M3 - Article
C2 - 32542371
AN - SCOPUS:85089162291
SN - 0006-3363
VL - 103
SP - 310
EP - 317
JO - Biology of Reproduction
JF - Biology of Reproduction
IS - 2
ER -