Aim: 

To explore potential sex differences in outcomes and regenerative parameters post major hepatectomies.

Background: 

Although controversial, sex differences in liver regeneration have been reported for animals. Whether sex disparity exists in human liver regeneration is unknown.

Methods: 

Data from consecutive hepatectomy patients (55 females, 67 males) and from the international ALPPS (Associating-Liver-Partition-and-Portal-vein-ligation-for-Staged-hepatectomy, a two stage hepatectomy) registry (449 females, 729 males) were analyzed. Endpoints were severe morbidity (≥3b Clavien-Dindo grades), Model for End-stage Liver Disease (MELD) scores, and ALPPS interstage intervals. For validation and mechanistic insight, female-male ALPSS mouse models were established. t, χ², or Mann-Whitney tests were used for comparisons. Univariate/multivariate analyses were performed with sensitivity inclusion.

Results: 

Following major hepatectomy (Hx), males had more severe complications (P=0.03) and higher liver dysfunction (MELD) P=0.0001) than females. Multivariate analysis established male sex as a predictor of complications after ALPPS stage 1 (odds ratio=1.78; 95% confidence interval: 1.126–2.89; P=0.01), and of enhanced liver dysfunction after stage 2 (odds ratio=1.93; 95% confidence interval: 1.01–3.69; P=0.045). Female patients displayed shorter interstage intervals (<2 weeks, 64% females versus 56% males, P=0.01), however, not in postmenopausal subgroups. In mice, females regenerated faster than males after ALPPS stage 1, an effect that was lost upon estrogen antagonism.

Conclusions: 

Poorer outcomes after major surgery in males and shorter ALPPS interstage intervals in females not necessarily suggest a superior regenerative capacity of female liver. The loss of interstage advantages in postmenopausal women and the mouse experiments point to estrogen as the driver behind these sex disparities. Estrogen’s benefits call for an assessment in postmenopausal women, and perhaps men, undergoing major liver surgery.

中文翻译：

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大肝手术后结果的性别差异：雌激素的新力量？

目标： 

探索主要肝切除术后结果和再生参数的潜在性别差异。

背景： 

尽管存在争议，但已经报道了动物肝脏再生的性别差异。人类肝脏再生是否存在性别差异尚不清楚。

方法： 

来自连续肝切除术患者（55 名女性，67 名男性）和国际 ALPPS（联合肝分期和门静脉结扎用于分期肝切除术，两阶段肝切除术）登记处（449 名女性，729 名男性）的数据) 进行了分析。终点是严重发病率（≥3b Clavien-Dindo 等级）、终末期肝病模型 (MELD) 评分和 ALPPS 期间间隔。为了验证和机械洞察力，建立了雌雄 ALPSS 小鼠模型。t、 χ ²或 Mann-Whitney 检验用于比较。单变量/多变量分析是在敏感性纳入的情况下进行的。

结果： 

大肝切除术 (Hx) 后，男性比女性有更严重的并发症 ( P = 0.03) 和更高的肝功能障碍 (MELD) P = 0.0001)。多变量分析确定男性是 ALPPS 1 期后并发症的预测因子（优势比 = 1.78；95% 置信区间：1.126-2.89；P = 0.01）和 2 期后肝功能障碍加重（优势比 =1.93；95%置信区间：1.01-3.69；P = 0.045）。女性患者表现出较短的期间间隔（<2 周，64% 女性对 56% 男性，P = 0.01），但绝经后亚组中没有。在小鼠中，在 ALPPS 第 1 阶段后，雌性比雄性再生得更快，这种作用在雌激素拮抗作用时消失了。

结论： 

男性大手术后较差的结果和女性较短的 ALPPS 期间间隔并不一定表明女性肝脏具有较高的再生能力。绝经后妇女和小鼠实验中阶段间优势的丧失表明雌激素是这些性别差异背后的驱动因素。雌激素的好处需要对绝经后女性进行评估，也许还有男性，正在接受大型肝脏手术。