Evaluating the association of hormonal contraceptive use with HPV detection in pre- and perimenopausal women in the U.

Introduction:.;Long-term and recent use of combined oral contraceptives (COCs) was suggested to be a risk factor of cervical cancer. It is unclear whether the association is driven by COC's effect(s) on carcinogenesis and/or on upstream events of HPV infection, as study findings on the association between hormonal contraceptive use and HPV infection have been inconsistent. Understanding the effect of hormonal contraceptive use on HPV detection and cervical immune milieu in women older than 35 years may provide insight into the biological mechanisms underlying the impact of hormonal contraceptive use on cervical cancer risk.;Objectives:.;A prospective cohort of pre- and perimenopausal females (age range: 35-54) who had normal cervical cytology were followed to investigate the association between cervical HPV detection and hormonal contraceptive use (n=530). The study has 3 aims: Aim 1: To determine the association of hormonal contraceptive use with HPV prevalence at baseline. Aim 2: To compare the odds of new HPV DNA detection between users and non-users of hormonal contraceptives. Aim 3: To describe and compare differences in the host cervical cytokine profiles between hormonal contraceptive users and non-users who were HPV-negative at baseline.;Methods:.;Pre- and perimenopausal women (age range: 35-54 years) were recruited from gynecologic clinics in Baltimore, MD. Information was collected on hormonal contraceptive use, HPV genotypes, history of other sexually transmitted infections, Pap smear diagnoses, sexual behavioral and reproductive characteristics. For Aim 1: associations were assessed using prevalence ratios (PRs) with 95% confidence intervals (CIs). For Aim 2: associations between hormonal contraceptive use and incident HPV detection were measured by odds ratios (ORs) with 95% confidence intervals (CIs) estimated in generalized estimating equation models. For Aim 3: baseline pairs of cervical secretion samples matched in 5-year age groups were collected from current and non-current hormonal contraceptive users who were HPV-negative. Extracted specimens from cervical secretion samples were tested for 27 cytokines, chemokines and growth factors. Comparison of individual mean cytokine levels were made between user groups of hormonal contraceptives. Profile comparison was done using Spearman's rank correlation to determine correlations for all pairwise combinations of the cytokines, chemokines, and growth factors measured in different strata of hormonal contraceptive use and type.;Results:.;For Aim 1: more than 5 years' use of progestin-only contraceptives (POCs) was associated with 3-fold increased prevalence of any HPV [adjusted prevalence ratio (aPR): 3.16 (95% CI: 1.82-5.48)] and high-risk (HR)-HPV [aPR: 4.26 (95% CI: 1.60-11.30)] as compared to never POC users. Current POC use was positively associated with prevalence of HR-HPV (aPR: 2.44 (0.99-5.99) and any HPV (aPR: 1.58 (0.94-2.65) with the estimates bordering on statistical significance. For Aim 2: Relative to never POC users, increased incident detection of HR-HPV was observed among current users of POCs [adjusted odds ratio (aOR): 3.24 (95% CI: 1.37-7.65) after controlling for sexual behavioral factors. No similar associations were observed with the duration or recency of overall hormonal contraceptive or oral contraceptive (OC) use. For Aim 3: Compared to current users of hormonal contraceptives, significantly more positive correlations were detected among proinflammatory cytokines as well as between proinflammatory and immunoregulatory cytokines in current hormonal contraceptive users. Compared to COC users, correlation coefficients were significantly lower in magnitude among immunoregulatory cytokines such as IL9, IL15 and IL17, as well as IL5, IL15, IL17 in current POC users. Relative to non-current hormonal contraceptive users, current POC users were also found to have statistically significantly lower levels of IP10 and several immunoregulatory cytokines, including IL12, IL13, IL15.;Conclusions:.;Long-term and current use of POCs may be associated with increased risk of prevalent and incident HPV infection independent of sexual behavior among older women with normal cervical cytology. Our laboratory study showed differences in cytokine profiles between current and non-current hormonal contraceptive users as well as between current POC and COC users in HPV-negative women. These findings suggest differential impacts of exogenous hormones on cervical cytokine milieu, which in turn may potentially affect host responses to local genital infections.