Contraceptive microbicides offer the possibility of women-controlled contraception and HIV prevention. Serious public health concerns were raised following a report that HIV infection rates increased after multiple doses of nonoxynol-9 (N-9). This finding may be related to vaginal epithelium disruption and recruitment of HIV host inflammatory cells because of genital toxicity. Several lines of evidence support the existence of physiologic fluid movement from the vagina to the upper reproductive tract by uterine peristalsis. Therefore, the toxicity of microbicidal candidates on the endometrium and upper reproductive tract must be determined. A preliminary study performed at USC using an endometrial explant treated with three doses of N-9, showed multiple toxic effects on endometrial integrity. We demonstrated, using immunohistochemistry, a dose-related increase in early apoptosis by M30 antibody staining, and presence of late apoptosis at all doses of N-9 by DNA fragmentation. In addition, we demonstrated obliteration of the endometrial inflammatory response and a dose-dependent reduction in expression of MUC-1, a protein that creates a protective mucin layer over endometrial epithelium. The purpose of the current study is to determine the effects of N-9 on human endometrium in vivo and in vitro during both phases of the menstrual cycle. Twenty-eight women will undergo a pre-treatment cycle during which uterine lavage and endometrial biopsies will be performed. Subjects will then apply N-9 for one or three days and have a second uterine lavage and biopsy. Lavage fluids will be examined for cytokines and inflammatory cells. Endometrial biopsy tissue will be evaluated using light and electron microscopy, and stained for M30 CytoDeath antibody and MUC-1. DNA will be extracted for gel electrophoresis. Tissue from pre-treatment biopsies will be cultured as explants and parallel evaluations performed. The results of this study will provide important preliminary information on the role of microbicides on endometrial toxicity and may help guide future research priorities. ? ?
