The Role of Contraceptive Use in Cervical Cancer Susceptibility: A Comprehensive Review of Endocrine, Immune, and Cell-Cycle Regulatory Pathways

Cervical cancer is one of the top cancers contributing to morbidity and mortality among women in the global society, especially the low and middle income nations. Although long-term contraceptive use contributed to the development of cervical cancer, although weakly proven, it is gradually becoming apparent that a persistent infection with high-risk human papillomavirus (HPV) is the main etiological factor in conjunction with complex biological effects caused by long-term use of contraceptives. This is a review to critically assess the role of contraceptive use especially hormonal contraceptives in cervical carcinogenesis with references to endocrine disruption, immune modulation, and cell-cycle regulatory pathway. It has been demonstrated that hormonal contraceptives, in particular the ones that include estrogen and progestin, eventually impact cervical epithelial biology by modifying hormone receptor signals, enhancing cellular growth, and influencing the processes of apoptosis and DNA repair. These hormonal actions have the potential of increasing HPV persistence and integration because they alter the cell-cycle regulators including p53, pRb, cyclins, and cyclin-dependent kinases. Simultaneously, the endocrine alteration brought about by contraceptives has the capacity to regulate local and systemic immunity, such as the inhibition of cell-mediated immunity, disruption of cytokine responses and antigen presentation, leading to the reduced viral clearance and oncogenic progression. Additionally, the new findings outline the effects of contraceptives on the inflammatory pathway, oxidative stress and epigenetic changes, all of which lead to cervical microenvironment remodeling and malignant transformation. This paper summarizes the existing epidemiological, molecular and clinical evidence to explain the multidimensional nature of the relationship between the risk of cervical cancer and the use of contraceptives. The interplay of endocrine immune cells and the cell-cycle in contraceptive-related cervical cancer vulnerability can help in improving risk stratification, personalizing contraceptive counseling, and discovering new preventive and curative agents.