Use of contraceptive depot medroxyprogesterone acetate is associated with impaired cervicovaginal mucosal integrity
Irina A. Zalenskaya, … , Andrea R. Thurman, Gustavo F. Doncel
Irina A. Zalenskaya, … , Andrea R. Thurman, Gustavo F. Doncel
Published September 17, 2018
Citation Information: J Clin Invest. 2018;128(10):4622-4638. https://doi.org/10.1172/JCI120583.
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Clinical Research and Public Health AIDS/HIV Reproductive biology Article has an altmetric score of 7

Use of contraceptive depot medroxyprogesterone acetate is associated with impaired cervicovaginal mucosal integrity

Abstract

BACKGROUND. Injectable depot medroxyprogesterone acetate (DMPA) is one of the most popular contraception methods in areas of high HIV seroprevalence. Evidence is accumulating that use of DMPA might be associated with an increased risk of HIV-1 acquisition by women; however, mechanisms of this association are not completely understood. The goal of this study was to gain insight into mechanisms underlying the possible link between use of DMPA and risk of HIV-1 acquisition, exploring transcription profiling of ectocervical tissues. METHODS. Healthy women received either DMPA (n = 31) or combined oral contraceptive (COC), which has not been linked to an increased risk of HIV acquisition (n = 32). We conducted a comparative microarray-based whole-genome transcriptome profiling of human ectocervical tissues before and after 6 weeks of hormonal contraception use. RESULTS. The analysis identified that expression of 235 and 76 genes was significantly altered after DMPA and COC use, respectively. The most striking effect of DMPA, but not COC, was significantly altered expression (mostly downregulation) of many genes strategically involved in the maintenance of mucosal barrier function; the alterations, as indicated by Ingenuity Pathway Analysis (IPA), were most likely due to the DMPA-induced estrogen deficiency. Furthermore, IPA predicted that transcriptome alterations related to ectocervical immune responses were in general compatible with an immunosuppressive effect of DMPA, but, in some women, also with an inflammatory-like response. CONCLUSION. Our results suggest that impairment of cervicovaginal mucosal integrity in response to DMPA administration is an important mechanism contributing to the potential increased risk of HIV-1 acquisition in DMPA users. TRIAL REGISTRATION. ClinicalTrials.gov NCT01421368. FUNDING. This study was supported by the United States Agency for International Development (USAID) under Cooperative Agreement GPO-A-00-08-00005-00.

Authors

Irina A. Zalenskaya, Neelima Chandra, Nazita Yousefieh, Xi Fang, Oluwatosin E. Adedipe, Suzanne S. Jackson, Sharon M. Anderson, Christine K. Mauck, Jill L. Schwartz, Andrea R. Thurman, Gustavo F. Doncel

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Figure 10

Model of cervicovaginal mucosal changes in DMPA users plausibly linked to an enhanced HIV-1 susceptibility.

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Model of cervicovaginal mucosal changes in DMPA users plausibly linked t...
Use of DMPA results in altered expression of many genes involved in barrier functions of cervicovaginal mucosa. (A) Decrease in markers of differentiating keratinocytes (such as KRT10, KRT1, KRT6B) indicates a compromised epithelial differentiation. Downregulation of the molecules involved in the SC organization (FLG, RPTN, LCE3D, ALOX12B, TGM3, LOR, and CDSN) and cell junctional proteins in all layers (DSG1 and DSC2) leads to breaches in the epithelial barrier, which is exacerbated by an untimely activation of KLK peptidases due to a decreased production of peptidase inhibitors (specifically SPINK6 and SERPINB7). Decrease in GYS2 expression implicates a drop in the glycogen level and, therefore, lower abundance of Lactobacillus spp. (B) In more expanded responses, molecular changes in the cervicovaginal epithelium are intensified: alterations in the barrier-supporting genes dramatically increase in magnitude, which results in more spacious epithelial breaches and production and release of proinflammatory chemokines that attract more HIV target cells (such as CD4+ T cells, dendritic cells, macrophages) and damage-related neutrophils. In A and, on a larger scale, in B, the cervicovaginal epithelium of the DMPA users is characterized by loss of epithelial integrity, which allows HIV virions to penetrate and/or transverse the epithelium and reach HIV-1 target cells for productive infection or be transferred to the draining lymph node or circulating blood. See the legend to Figure 9 for more details.