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. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD047322-01
Application #
6809370
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Kaufman, Steven
Project Start
2004-09-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$81,250
Indirect Cost
Name
University of Southern California
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089