title: Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study.
abstract: Intravaginal anti-HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract might contribute to the lower-than-expected efficacy of HIV microbicides. Our objective was to study the effects of intravaginal gels on the immune microenvironment of the cervix and uterus. In this randomized crossover study, 27 healthy female volunteers used a nightly application of intravaginal nonoxynol-9 (N9) gel as a "failed" microbicide or the universal placebo gel (UPG) as a "safe" gel (intervention cycles), or nothing (control cycle) from the end of menses to the mid-luteal phase. At a specific time-point following ovulation, all participants underwent sample collection for measurements of T-cell phenotypes, gene expression, and cytokine/chemokine protein concentrations from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention effects, for N9 and UPG relative to control. Exposure to N9 gel and UPG generated a common "harm signal" that included transcriptional up-regulation of inflammatory genes chemokine (C-C motif) ligand 20 (macrophage inflammatory factor-3alpha) and interleukin 8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor, and transcriptional up-regulation of inflammatory mediators glycodelin-A and osteopontin in the endometrium. These results need to be replicated with a larger sample, but underscore the need to consider the effects of microbicide agents and gel excipients on the upper female reproductive tract in studies of vaginal microbicides.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Smith-McCune
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Chen
authors.affiliation: Departments of Clinical Pharmacy and Internal Medicine, University of California San Francisco, San Francisco, California, United States of America; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Greenblatt
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Uma
authors.initials: U
authors.lastname: Shanmugasundaram
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Shacklett
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Joan F
authors.initials: JF
authors.lastname: Hilton
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Brittni
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Irwin
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Giudice
mesh_terms: D000282:Administration, Intravaginal; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D060833:Cellular Microenvironment / Q000187:drug effects / Q000276:immunology; D002584:Cervix Uteri / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D018592:Cross-Over Studies; D005260:Female; D005782:Gels; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D017137:Nonoxynol / Q000008:administration & dosage / Q000009:adverse effects*; D010641:Phenotype; D010919:Placebos; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D059467:Transcriptome / Q000187:drug effects; D014599:Uterus / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D005782:Gels; D010919:Placebos; D017137:Nonoxynol