Abstract
BackgroundIn addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).Methods and FindingsWe followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4–0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).ConclusionsEven though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.
Highlights
Cervical cancer (CC) is the fourth most common cancer among women worldwide with an estimated 528,000 new cases and the fourth most common cause of female death from cancer with an estimated 266,000 deaths in 2012 [1]
Even though Human papillomavirus (HPV) is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis
Even though these associations are generally consistent across studies, it must be noted that the evidence for a role of hormones in cervical carcinogenesis is mostly derived from retrospective case-control studies that did not always take into account HPV
Summary
Cervical cancer (CC) is the fourth most common cancer among women worldwide with an estimated 528,000 new cases and the fourth most common cause of female death from cancer with an estimated 266,000 deaths in 2012 [1]. Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) showed that circulating levels of sex steroid hormones testosterone and possibly estradiol were positively involved in the etiology of CC [9]. Even though these associations are generally consistent across studies, it must be noted that the evidence for a role of hormones in cervical carcinogenesis is mostly derived from retrospective case-control studies that did not always take into account HPV. In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC)
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