BACKGROUND A striking gender disparity in the incidence and outcome of primary liver cancer (PLC) has been well recognized. Mounting evidence from basic research suggests that hormonal factors may be involved in the gender disparity of PLC. Whether hormonal exposures in human subjects are associated with PLC risk is largely unknown. OBJECTIVE AND RATIONALE Whether reproductive factors and use of menopausal hormone therapies (MHTs) in women are associated with PLC risk remains controversial. We conducted this study to clarify this issue. SEARCH METHODS PubMed and EMBASE were searched to July, 2016 for studies published in English or Chinese. Observational studies (cohort, nested case-control and case-control) that provided risk estimates of reproductive factors, MHTs and PLC risk were eligible. The quality of included studies was determined based on the Newcastle-Ottawa quality assessment scale. Summary risk ratios (RRs) were calculated using a random-effects model. Dose-response analysis was conducted where possible. OUTCOMES Fifteen peer-reviewed studies, involving 1795 PLC cases and 2 256 686 women, were included. Overall meta-analyses on parity and PLC risk did not find any significant associations; however, when restricting to studies with PLC cases ≥100, increasing parity was found to be significantly associated with 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 relationship between parity and PLC risk was identified (Pnon-linearity < 0.01). Compared with never users, 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). The pooled RR of PLC for the oldest versus youngest category of menarcheal age was 0.50 (95% CI 0.32, 0.79). Oophorectomy was significantly associated with an increased risk of PLC (RR 2.23, 95% CI 1.46, 3.41). No significant association of age at first birth, and spontaneous or induced abortion with PLC risk was found. No meta-analysis was performed for the association of age at menopause, breastfeeding, hysterectomy, menopausal status and stillbirth with PLC risk owing to huge methodological heterogeneity and/or very limited studies. WIDER IMPLICATIONS Parity is associated with PLC risk in a J-shaped dose-response pattern. Late age at menarche and ever use of MHT are associated with a reduced risk of PLC, whereas there is no association of ever use of ET and EPT, age at first birth, or spontaneous and induced abortion with PLC risk. Compared to women with no history of oophorectomy, those with a history of oophorectomy are at an increased risk of PLC. Our findings provide some epidemiological support for a role of hormonal exposures in the development of PLC in women. However, these findings should be interpreted with much caution because of the limited number of studies and potential biases, and need to be validated by studies with good design and large sample size.

中文翻译：

---

生殖因素，更年期激素疗法和原发性肝癌风险：观察性研究的系统评价和剂量反应荟萃分析。

背景技术在原发性肝癌（PLC）的发病率和预后中存在明显的性别差异。来自基础研究的越来越多的证据表明，荷尔蒙因素可能与PLC的性别差异有关。在人类受试者中激素暴露是否与PLC风险相关尚不清楚。目的和理由女性生殖因子和更年期激素疗法（MHTs）的使用是否与PLC风险有关仍存在争议。我们进行了这项研究以澄清此问题。搜索方法搜索PubMed和EMBASE直至2016年7月，以英文或中文发表的研究。观察性研究（队列研究，嵌套病例对照研究和病例对照研究）能够提供生殖因子，MHT和PLC风险的风险估计。根据纽卡斯尔-渥太华质量评估量表确定纳入研究的质量。使用随机效应模型计算汇总风险比（RRs）。在可能的情况下进行剂量反应分析。结果纳入了15项经同行评审的研究，涉及1795例PLC病例和2 256 686名女性。关于均价和PLC风险的总体荟萃分析未发现任何显着相关性。但是，当仅限于PLC≥100的研究时，发现奇偶校验的增加与PLC风险的降低显着相关[最高与最低奇偶校验的RR为0.67、95％CI 0.52、0.88；宫内和原胎的RR为0.71，95％CI 0.53，0.94; 每活产婴儿的RR增加0.93，95％CI 0.88，0.99]。奇偶校验和PLC风险之间呈J形关系（非线性<0.01）。与从未使用过的用户相比，对于曾经使用过MHT的用户，PLC的合并RR为0.60（95％CI 0.37，0.96），对于仅使用雌激素（ET）的用户为0.73（95％CI 0.46，1.17）和0.67（95）雌激素-孕激素疗法（EPT）的使用者的百分比CI 0.45，1.02）。对于月经年龄的最大年龄段和最小年龄段，PLC的合并RR为0.50（95％CI 0.32，0.79）。卵巢切除术与PLC风险增加显着相关（RR 2.23，95％CI 1.46，3.41）。初生年龄，自发性流产或诱发流产与PLC风险均无显着相关性。由于方法学的巨大异质性和/或研究非常有限，因此没有进行荟萃分析来分析绝经年龄，母乳喂养，子宫切除术，绝经状态和死产与PLC风险之间的关系。对婴儿的影响奇偶校验与J型剂量反应模式下的PLC风险相关。初潮年龄晚和经常使用MHT与降低PLC的风险有关，而永远使用ET和EPT，初生年龄，或自然流产和人工流产与PLC风险均无关联。与没有卵巢切除术史的女性相比，具有卵巢切除术史的女性患PLC的风险增加。我们的发现为激素暴露在女性PLC发展中的作用提供了流行病学支持。但是，由于研究数量有限和潜在的偏倚，应谨慎地解释这些发现，并且需要通过具有良好设计和大样本量的研究进行验证。而没有使用过ET和EPT，初生年龄，自然流产和人工流产与PLC风险之间没有关联。与没有卵巢切除术史的女性相比，具有卵巢切除术史的女性患PLC的风险增加。我们的发现为激素暴露在女性PLC发展中的作用提供了流行病学支持。但是，由于研究数量有限和潜在的偏倚，应谨慎地解释这些发现，并且需要通过设计良好且样本量较大的研究加以验证。而没有使用过ET和EPT，初生年龄，自然流产和人工流产与PLC风险之间没有关联。与没有卵巢切除术史的女性相比，具有卵巢切除术史的女性患PLC的风险增加。我们的发现为激素暴露在女性PLC发展中的作用提供了流行病学支持。但是，由于研究数量有限和潜在的偏倚，应谨慎地解释这些发现，并且需要通过具有良好设计和大样本量的研究进行验证。我们的发现为激素暴露在女性PLC发展中的作用提供了流行病学支持。但是，由于研究数量有限和潜在的偏倚，应谨慎地解释这些发现，并且需要通过设计良好且样本量较大的研究加以验证。我们的发现为激素暴露在女性PLC发展中的作用提供了流行病学支持。但是，由于研究数量有限和潜在的偏倚，应谨慎地解释这些发现，并且需要通过设计良好且样本量较大的研究加以验证。