Association between sex steroid hormones and natural history of anal high-grade squamous intraepithelial lesions among people living with HIV

Division Of Cancer Epidemiology And Genetics

Investigators

Abstract

Persistent infection with one of 12 high risk human papillomavirus (hrHPV) genotypes is the causative agent in several cancers, including squamous cell carcinoma of the anus. People with HIV (PWH) are at higher risk of acquiring hrHPV and hrHPV-related disease, including anal cancer, than members of the general population. Despite the high prevalence of anal HSIL, only a proportion of these lesions progress to anal cancer, meaning that the majority of anal HSIL will regress or persist without progression for unknown reasons. A growing body of research demonstrates the importance of sex steroid hormones in immune function. Estradiol plays a significant role in cell-mediated and humoral immunity with physiological levels of estradiol increasing the Th1 response and supraphysiological levels increasing Th2 activity. Androgens may suppress immune cell activity, reduce pro-inflammatory responses, and inhibit antiviral cytokines. However, the relationship between individual sex hormones and disease is likely not linear. Higher levels of estradiol from oral contraceptive use (supraphysiological levels) have been shown promote cervical carcinogenesis. On the other hand, increasing testosterone and decreasing estrogen levels are associated with HSIL risk in males with HIV. Understanding how sex steroid hormones impact the risk of progression or regression/clearance of anal HSIL among males is important as this group is likely to experience alterations to endogenous sex hormones. Males with HIV are more likely than males without HIV to experience premature decreases in testosterone and may supplement with exogenous androgens as a result. Given the high risk of anal cancer among PWH and the increased use of endogenous hormones, it is vital to understand how sex steroid hormones influence HPV-associated disease progression. The results of this study can be used to inform anal cancer screening and treatment timing, as well as informing HPV-associated disease risk. The goal of this study is to understand how sex steroid hormones influence the natural history of high-grade squamous intraepithelial lesions (HSIL) to anal cancer among people living with HIV (PLWH) at highest risk for anal cancer. We aim to estimate the association between sex steroid hormone levels (estradiol, estrone, progesterone, testosterone, dehydroepiandrosterone [DHEA], androstenedione, dihydrotestosterone [DHT], and sex hormone binding globulin [SHBG]) and anal HSIL progression to cancer, regression of HSIL to LSIL or normal tissue, of HSIL persistence among males with HIV.