Epidemiological studies indicate that progestin-containing contraceptives increase susceptibility to HIV, although the underlying mechanisms involving the upper female reproductive tract are undefined. To determine the effects of depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) on gene expression and physiology of human endometrial and cervical transformation zone (TZ), microarray analyses were performed on whole tissue biopsies. In endometrium, activated pathways included leukocyte chemotaxis, attachment, and inflammation in DMPA and LNG-IUS users, and individual genes included pattern recognition receptors, complement components, and other immune mediators. In cervical TZ, progestin treatment altered expression of tissue remodeling and viability but not immune function genes. Together, these results indicate that progestins influence expression of immune-related genes in endometrium relevant to local recruitment of HIV target cells with potential to increase susceptibility and underscore the importance of the upper reproductive tract when assessing the safety of contraceptive products.

Problem

The goal of this study was to investigate the phenotype and functional responsiveness of CD4(+) and CD8(+) T-cells in the upper reproductive tract of healthy premenopausal women. The lower reproductive tract is frequently studied as a site of sexually transmitted infections; however, the upper reproductive tract may also be a portal of entry and dissemination for pathogens, including HIV-1.

Method of study

Endometrial biopsy, endocervical curettage, cytobrush, and blood were collected during mid-luteal phase from 23 healthy women. T-cells were isolated and analyzed by flow cytometry.

Results

As compared with their counterparts in blood, endometrial and endocervical T-cells had enhanced CCR5 expression, and were enriched for activated, effector memory cells. Endometrial T-cells were more responsive to polyclonal stimuli, producing a broad range of cytokines and chemokines.

Conclusion

These findings underscore the responsiveness of endometrial T-cells to stimulation, and reveal their activated phenotype. These findings also suggest susceptibility of the upper reproductive tract to HIV-1 infection.