There is emerging evidence of differences in gender in the incidence and outcome of primary liver cancer (PLC). Evidence based observations have documented that hormonal factors may be responsible for gender disparity of PLC. However, whether exposure to these hormones in human can increase the risk of PLC is yet not completely understood. Thus, the current study is aimed to evaluate the association of reproductive factors and menopausal hormone therapies (MHTs) in women with PLC risk.

The study involved observational studies (cohort, nested case-control and case-control) from PubMed and EMBASE and PLC risk. The quality of included studies was evaluated based on the Newcastle-Ottawa quality assessment scale. Random-effects model was used to assess summary risk ratios (RRs). 

The authors analysed 15 peer-reviewed studies, involving 1795 PLC cases and 2 256 686 women. The results showed that although no association was reported between database. These studies provided risk estimates of reproductive factors, MHTs overall meta-analyses on parity and PLC risk, when the research was limited to studies with PLC cases ≥100, increasing parity was remarkably related to a decreased risk of PLC [RR for the highest versus lowest parity 0.67, 95% CI 0.52, 0.88; RR for parous versus nulliparous 0.71, 95% CI 0.53, 0.94; RR per one live birth increase 0.93, 95% CI 0.88, 0.99]. A J-shaped association between parity and PLC risk was discovered. The pooled RRs of PLC were 0.60 (95% CI 0.37, 0.96) for ever users of MHT, 0.73 (95% CI 0.46, 1.17) for ever users of estrogen-only therapy (ET) and 0.67 (95% CI 0.45, 1.02) for ever users of estrogen–progestin therapy (EPT) in contrast to never users. The pooled RR of PLC for the oldest in comparison to youngest category of menarcheal age was 0.50 (95% CI 0.32, 0.79). Moreover, oophorectomy was remarkably related to an increased risk of PLC (RR 2.23, 95% CI 1.46, 3.41). However, lack of any significant association was reported of age at first birth, and spontaneous or induced abortion with PLC risk. No meta-analysis was conducted for the interrelationship of age at menopause, breastfeeding, hysterectomy, menopausal status and stillbirth with PLC risk because of huge methodological heterogeneity and/or very limited studies.

Thus, it can be inferred that similarity or parity was related to PLC risk in a J-shaped dose–response pattern. Although a significant correlation existed between late age at menarche and ever use of MHT with a reduced risk of PLC, no link of ever use of ET and EPT, age at first birth, or spontaneous and induced abortion was established with PLC risk. Women with a history of oophorectomy are at an increased risk of PLC in contrast to those without a history of oophorectomy. 

Thus, the observations of this study epidemiologically supported the role of hormonal exposures in the development of PLC in women. Nevertheless, these findings need more studies with good design and large sample size for validation and should be used cautiously because of the limited number of studies and potential biases.

Source: Reproductive factors, menopausal hormone therapies and primary liver cancer risk: a systematic review and dose–response meta-analysis of observational studies. Human Reproduction Update. December 2016;23( 1):126–138.