Progesterone-Based Intrauterine Device Use Is Associated with a Thinner Apical Layer of the Human Ectocervical Epithelium and a Lower ZO-1 mRNA Expression1

Abstract

Currently, whether hormonal contraceptives affect male to female human immunodeficiency virus (HIV) transmission is being debated. In this study, we investigated whether the use of progesterone-based intrauterine devices (pIUDs) is associated with a thinning effect on the ectocervical squamous epithelium, down-regulation of epithelial junction proteins, and/or alteration of HIV target cell distribution in the human ectocervix. Ectocervical tissue biopsies from healthy premenopausal volunteers using pIUDs were collected and compared to biopsies obtained from two control groups, namely women using combined oral contraceptives (COCs) or who do not use hormonal contraceptives. In situ staining and image analysis were used to measure epithelial thickness and the presence of HIV receptors in tissue biopsies. Messenger RNA levels of epithelial junction markers were measured by quantitative PCR. The epithelial thickness displayed by women in the pIUD group was similar to those in the COC group, but significantly thinner as compared to women in the no hormonal contraceptive group. The thinner epithelial layer of the pIUD group was specific to the apical layer of the ectocervix. Furthermore, the pIUD group expressed significantly lower levels of the tight junction marker ZO-1 within the epithelium as compared to the COC group. Similar expression levels of HIV receptors and coreceptors CD4, CCR5, DC-SIGN, and Langerin were observed in the three study groups. Thus, women using pIUD displayed a thinner apical layer of the ectocervical epithelium and reduced ZO-1 expression as compared to control groups. These data suggest that pIUD use may weaken the ectocervical epithelial barrier against invading pathogens, including HIV.

Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility

“…ϩ T cell population differences during the menstrual cycle with increased levels during menstruation (51), while others did not find increased CD4 ϩ T cell numbers in cervical explant tissues collected from the luteal phase or in progesterone-based contraceptive users (10,50). Although cell populations were not assessed in our study, our data suggested that neutrophil and CD4 ϩ T cell signatures were associated with the luteal phase by GSEA.…”

“…This time of potentially increased epithelial barrier disruption may be a key feature contributing to HIV susceptibility since both in vivo macaque models and ex vivo human explant tissues show enhanced viral diffusion when the cellular junctions were compromised (16). Furthermore, the use of progesterone-based intrauterine devices has been associated with ectocervical epithelial thinning and decreased mRNA levels of important tight-junction proteins (50). This provides further evidence of the impact that progesterone levels can have on the physical barrier of the genital tract whether expressed endogenously during the luteal phase or through exogenous application.…”

Understanding mucosal and microbial functionality of the female reproductive tract by metaproteomics: Implications for HIV transmission

“…A key feature of these observations was simplified in a multivariate model, which showed that DMPA users were clearly distinguished by an inverse relationship of increasing skin inflammatory proteins, including zonulin, with decreasing wound repair factors, such as trefoil factor 3, which may contribute to increased tissue permeability due to their known functions in tight junction disassembly and tissue repair . This is similar to observations at the mRNA level of where progesterone‐based intrauterine devices associate with ectocervical epithelial thinning and decreased tight junction transcripts . Therefore, progestin‐based hormonal contraceptives use alters inflammatory, barrier, and repair mechanisms in the cervicovaginal proteome, which may increase HIV susceptibility.…”

Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood

“…The results of our study highlight few changes in the lower genital tract inflammatory environment following Eng-Implant initiation. While several studies have evaluated genital tract immune changes after use of other hormonal contraceptive methods [17][18][19][20][21][22][23][48][49][50][51][52][53][54][55][56][57][58][59][60][61], to our knowledge, no published study has evaluated Eng-Implant. We report an increase in the proportion of CD4 T-cells expressing the co-receptor CCR5 at the genital mucosa with Eng-Implant use that could be associated with increased risk of HIV infection; however, not all our findings relate a clear picture of increased susceptibility.…”