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In Vivo Effects of Nonoxynol-9 on Endometrial Immune Cell Populations

INTRODUCTION Vaginally applied microbicides are being evaluated for efficacy in the prevention of sexual HIV transmission. These studies are based on a model in which the vagina and ectocervix are the anatomic sites of HIV transmission; whether transmission can also occur in the upper genital tract (UGT: endocervix and endometrium) is not known. Vaginally administered gels and creams rapidly gain entrance into the UGT. Nonoxynol-9 (N-9) is a nonionic detergent that failed to protect against HIV transmission in clinical trials and was associated with increased acquisition of HIV in high prevalence settings. This latter finding was attributed to N-9– associated lower genital tract irritation and genital ulceration. Various subsequent microbicides were associated with no protection or potential increased risk of HIV acquisition, despite the apparent absence of inflammatory effects on the lower genital tract; microbicide-induced effects on the UGT may explain these findings. We undertook a pilot study of inflammatory effects of N-9 on the UGT using paired endometrial biopsy (EMB) specimens from women in the luteal phase of the menstrual cycle before and after vaginal exposure to N-9. METHODS The study protocol was approved by the University of California San Francisco Committee on Human Research. Inclusion criteria were as follows: age 18–40 years; HIV negative; 21–35 day menstrual cycles; and agreement to avoid use of extraneous intravaginal products for the study duration. Exclusion criteria included the following: pregnancy or attempting to conceive; abnormal Pap test within the past 12 months; recent use of intravaginal or intrauterine contraceptives; use of exogenous sex hormones; and immunocompromised status. Participants were tested for HIV, pregnancy, and sexually transmitted infections and were instructed in the use of luteinizing hormone (LH) surge predictor kits (ClearBlue Easy Ovulation Test, Inverness Medical Innovations, Delaware, DE). Subjects returned 8–10 days after the LH surge for the first (pre–N-9) EMB. Participants were then provided with intravaginal N-9 [4% N-9 contraceptive gel (Conceptrol, Ortho, Raritan, NJ)] and instructed to apply it intravaginally every night, beginning after their next menses, and continuing until their next study visit resulting in usage of approximately 2–3 weeks depending on cycle length. Participants returned 8–10 days after the next LH surge for post-N-9 EMB. Standard hematoxylin and eosin-stained slides were prepared from formalin-fixed paraffin-embedded EMB samples for endometrial dating by 2 independent board-certified pathologists; in cases where the results were discordant, a third pathologist was consulted. Immunohistochemistry was used to identify T cells (CD4, CD8), macrophages (CD68), B cells (CD20), natural killer cells (CD56), and regulatory T cells (FoxP3+) using published techniques. Image analysis software was used to measure the area of stromal regions of interest (excluding epithelium, glands, and vessels). The number of stained cells (counted visually) was divided by the area of the region of interest to determine stromal density of each cell type.