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Depot-medroxyprogesterone acetate reduces genital cell-cell adhesion molecule expression and increases genital herpes simplex virus type 2 infection susceptibility in a dose-dependent fashion.

Abstract

OBJECTIVE

Analyzing ectocervical biopsy tissue from women before and after they initiated use of depot-medroxyprogesterone acetate (DMPA), we previously reported this progestin reduces levels of the cell-cell adhesion molecule (CCAM) desmoglein-1 and increases genital mucosal permeability. We likewise saw treating mice with 1.0 mg of DMPA reduced vaginal CCAM expression and increased genital pathogen susceptibility. Herein, we used dose-response studies to delimit DMPA doses and serum MPA levels in mice associated with impaired genital mucosal barrier function and enhanced susceptibility to low-dose herpes simplex virus type 2 (HSV-2) infection.

STUDY DESIGN

We compared genital CCAM expression, genital mucosal permeability, and susceptibility to genital inoculation with 103 plaque-forming units of HSV-2 among mice in estrus vs. after treatment with 0.01 mg, 0.1 mg, 0.3 mg, or 1.0 mg of DMPA.

RESULTS

Compared to mice in estrus, DMPA treatment in a dose-dependent fashion significantly reduced desmoglein 1α (Dsg1a) and desmocollin-1 (Dsc1) gene expression, reduced DSG1 protein levels, and increased genital mucosal permeability to a low molecular weight molecule. While no mice infected with HSV-2 in estrus died, we respectively saw 50% and 100% mortality in mice administered 0.1 mg or 0.3 mg of DMPA. At time of infection, mean serum MPA levels in mice administered the 0.1 mg or 0.3 mg doses were 3.8 nM and 13.0 nM respectively (values comparable to trough and peak MPA serum levels in women using DMPA).

CONCLUSIONS

Mice with pharmacologically relevant serum MPA concentrations display significant changes in genital CCAM expression, genital mucosal barrier function, and HSV-2 susceptibility.

Authors+Show Affiliations

Department of Comparative Medicine, Stanford University School of Medicine. Stanford, California, USA. Electronic address: nirk.quispe@stanford.edu.Department of Comparative Medicine, Stanford University School of Medicine. Stanford, California, USA. Electronic address: rodolfo.vicetti@stanford.edu.Department of Comparative Medicine, Stanford University School of Medicine. Stanford, California, USA.Midwestern University College of Veterinary Medicine, Glendale, AZ, USA.Department of Comparative Medicine, Stanford University School of Medicine. Stanford, California, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31302121

Citation

Quispe Calla, Nirk E., et al. "Depot-medroxyprogesterone Acetate Reduces Genital Cell-cell Adhesion Molecule Expression and Increases Genital Herpes Simplex Virus Type 2 Infection Susceptibility in a Dose-dependent Fashion." Contraception, 2019.
Quispe Calla NE, Vicetti Miguel RD, Aceves KM, et al. Depot-medroxyprogesterone acetate reduces genital cell-cell adhesion molecule expression and increases genital herpes simplex virus type 2 infection susceptibility in a dose-dependent fashion. Contraception. 2019.
Quispe Calla, N. E., Vicetti Miguel, R. D., Aceves, K. M., Torres, A., & Cherpes, T. L. (2019). Depot-medroxyprogesterone acetate reduces genital cell-cell adhesion molecule expression and increases genital herpes simplex virus type 2 infection susceptibility in a dose-dependent fashion. Contraception, doi:10.1016/j.contraception.2019.07.003.
Quispe Calla NE, et al. Depot-medroxyprogesterone Acetate Reduces Genital Cell-cell Adhesion Molecule Expression and Increases Genital Herpes Simplex Virus Type 2 Infection Susceptibility in a Dose-dependent Fashion. Contraception. 2019 Jul 11; PubMed PMID: 31302121.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Depot-medroxyprogesterone acetate reduces genital cell-cell adhesion molecule expression and increases genital herpes simplex virus type 2 infection susceptibility in a dose-dependent fashion. AU - Quispe Calla,Nirk E, AU - Vicetti Miguel,Rodolfo D, AU - Aceves,Kristen M, AU - Torres,Angelo, AU - Cherpes,Thomas L, Y1 - 2019/07/11/ PY - 2018/12/18/received PY - 2019/07/02/revised PY - 2019/07/03/accepted PY - 2019/7/16/pubmed PY - 2019/7/16/medline PY - 2019/7/15/entrez KW - DMPA KW - Desmoglein-1 KW - Genital HSV-2 infection KW - Genital mucosal barrier function JF - Contraception JO - Contraception N2 - OBJECTIVE: Analyzing ectocervical biopsy tissue from women before and after they initiated use of depot-medroxyprogesterone acetate (DMPA), we previously reported this progestin reduces levels of the cell-cell adhesion molecule (CCAM) desmoglein-1 and increases genital mucosal permeability. We likewise saw treating mice with 1.0 mg of DMPA reduced vaginal CCAM expression and increased genital pathogen susceptibility. Herein, we used dose-response studies to delimit DMPA doses and serum MPA levels in mice associated with impaired genital mucosal barrier function and enhanced susceptibility to low-dose herpes simplex virus type 2 (HSV-2) infection. STUDY DESIGN: We compared genital CCAM expression, genital mucosal permeability, and susceptibility to genital inoculation with 103 plaque-forming units of HSV-2 among mice in estrus vs. after treatment with 0.01 mg, 0.1 mg, 0.3 mg, or 1.0 mg of DMPA. RESULTS: Compared to mice in estrus, DMPA treatment in a dose-dependent fashion significantly reduced desmoglein 1α (Dsg1a) and desmocollin-1 (Dsc1) gene expression, reduced DSG1 protein levels, and increased genital mucosal permeability to a low molecular weight molecule. While no mice infected with HSV-2 in estrus died, we respectively saw 50% and 100% mortality in mice administered 0.1 mg or 0.3 mg of DMPA. At time of infection, mean serum MPA levels in mice administered the 0.1 mg or 0.3 mg doses were 3.8 nM and 13.0 nM respectively (values comparable to trough and peak MPA serum levels in women using DMPA). CONCLUSIONS: Mice with pharmacologically relevant serum MPA concentrations display significant changes in genital CCAM expression, genital mucosal barrier function, and HSV-2 susceptibility. SN - 1879-0518 UR - https://www.unboundmedicine.com/medline/citation/31302121/Depot-medroxyprogesterone_acetate_reduces_genital_cell-cell_adhesion_molecule_expression_and_increases_genital_herpes_simplex_virus_type_2_infection_susceptibility_in_a_dose-dependent_fashion L2 - https://linkinghub.elsevier.com/retrieve/pii/S0010-7824(19)30230-6 DB - PRIME DP - Unbound Medicine ER -