The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort

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.

Multilevel Analysis on the Social Determinants of Cervical Cancer in Yogyakarta

“…There are between oral contraceptive use and risk of cervical cancer. The study conducted by Vaisy et al, (2014) and Roura et al, (2016) that the duration of oral contraceptive use have a risk three times more likely to have cervical cancer.…”

Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis

“…In particular, the transformation zone of the uterine ectocervix, which serves as the site of initiation of tumorigenesis, is highly sensitive to steroid hormone stimulation (Remoue et al 2003). There is a consistent association between the degree of steroid hormone contraceptive usage, repeated fullterm pregnancies and HPV infection and an increased risk of developing CC (Moreno et al 2002, Muñoz et al 2002, Chung et al 2010, Marks et al 2011, Liao et al 2012, Roura et al 2016. Several investigators have shown that the mere presence of an HPV infection is not a mandate to develop CC.…”

“…However, the role of oestrogens in human CC has not yet been well-defined (Chung et al 2010). Currently, with the epidemiological evidence linking multi-parity and oral contraceptive usage to an increase in CC risk, oestrogens have been speculated to be involved in the development of cervical carcinogenesis (Moreno et al 2002, Muñoz et al 2002, Roura et al 2016. Nevertheless, such carcinogenic transformations due to oestrogens are not physiological and involve a synergistic combination with infection of high-risk human papilloma virus (HPV) as the strongest factor (Brake & Lambert 2005, Chung et al 2008, Marks et al 2011, Liao et al 2012.…”

Dimensions of Cooperative Cervical Oncogenesis in Abortive Infection by Human Papillomavirus

“…The full evolving spectrum of infection of basal and squamous epithelial cells is intrinsically a parameter function of the proliferative activities of cells localized predominantly within the transformation zone between the os and the squamo-columnar cell junction. High parity and hormonal contraceptives have also been related to cervical cancer [12].…”