The lack of an overall association between HC use and HPV detection is in agreement with several other large published studies. [4
] In a systematic review that included 19 epidemiological studies, there was no association found between HC use and the detection of any HPV types, including HR or LR HPV types overall. [4
] In addition, duration of HC use did not impact the probability of HPV detection. Similarly, in a pooled analysis of HPV surveys among 15,145 women conducted by the International Agency for Research on Cancer (IARC), HPV detection was similar in long term OCP users and non-users[7
]. Neither of these studies evaluated specific HPV types. A longitudinal study of incident HPV infections among 1997 women reported an association between current OCP use and the diagnosis of any incident HPV infection. Although no type-specific association with HC use was reported, HPV-16 was the most frequently detected type accounting for 10.3% of all incident infections.[5
In our study, although there was no overall association between HR or LR HPV types, we found an intriguing type-specific association between HPV-16 and HC use. HPV-16 is the most common HPV type that causes cervical cancer in women. [11
] There are several biological mechanisms that could explain an association between HPV-16 detection and HC use. Glucocorticoid-responsive elements (GREs) that regulate HPV viral transcription respond to progesterones by increasing the transcription of E6
genes of certain HPV types- including HPV-16 (reviewed by de Villiers [12
]). However, not all HR HPV GREs respond to the same degree. These data suggest type-specificity and provide a biological mechanism to account for the increased detection of HPV-16 and its greater oncogenic potential; they cannot, however, completely explain our findings as GREs from the HR type HPV-18 and low-risk type HPV-11 are also thought to respond to progesterone. In addition to increased viral replication, recent data also suggest that other biological mechanisms may be important. Sex hormones significantly alter the immune responses to HPV-16 virus-like particles.[13
] This raises the possibility that HC may also affect the host’s susceptibility to HPV-16 infection. Other data suggest the possibility of progesterone-mediated persistence of HPV-16 infection thereby increasing the likelihood of its detection.[14
]Of note, there was no association between Clade A9 (which includes HPV type 16) and HC use, suggesting that the association between HPV-16 and HC use is type-specific and not clade-specific. Clade-specificities in GRE hormone-responsiveness, immune responses, and persistence, to our knowledge, have not been studied.
From our data, there was no short-term impact of HC use on cervical dysplasia as measured by Pap smear, even in the subset of women who had detectable HPV-16 DNA. This finding mirrors the results of two case control studies which assessed the impact of HC use on cervical intraepithelial neoplasia. [15
] Dysplastic changes, however, develop over time so a cross-sectional design is not ideal to study this association. Several other studies, however, including a systematic review [2
] and a multicenter case control study [1
] suggest an association between HC use and the development of cervical cancer. Whether the increased detection of cervical cancer among HC users may be mediated, in part, by a type-specific interaction between HPV-16 (and possibly other HR HPV types) and HC is not known.
This study has several limitations. The cross-sectional design introduces the potential for selection and information biases. The large number of women recruited and the variety of settings from which they were recruited may help limit some of these. We had limited data on the type, timing and duration of HC use so no causal link between HC use and type-specific HPV detection can be inferred. Despite our large sample size, the low prevalence of some HPV types may have limited the power of this study to detect other type-specific associations with HC use. However, the lack of an overall association between HC use and HR HPV overall, LR HPV overall, and HPV clades (all of which had a higher prevalence than HPV-16) suggests that the type-specific association described with HPV-16 is not due to its higher prevalence. Finally, we cannot completely discount the possibility that our finding is the result of behavioral changes or chance alone.
Over 300 million women worldwide use HC. Defining the impact of HC use on HPV infection is critically important. This study suggests a type-specific association between HPV-16 detection and HC use. Longitudinal studies are needed to better define this association and determine its clinical significance.