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, chi(2), 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.
