Sex and Liver Disease: The Necessity of an Overarching Theory to Explain the Effect of Sex on Nonreproductive Functions

The number of studies illuminating major sex differences in liver metabolic activities is growing, but we still lack a theory to explain the origin of the functional differences we are identifying. In the animal kingdom, energy metabolism is tightly associated with reproduction; conceivably, the major evolutionary step that occurred about 200 million years ago with placentation determined a significant change in female physiology, as females had to create new energy strategies to allow the growth of the embryo in the womb and the lactation of the newborn. In vertebrates the liver is the metabolic organ most tuned to gonadal functions because the liver synthesizes and transports of all the components necessary for the maturation of the egg upon estrogenic stimulation. Thus, in mammals, evolution must have worked on the already strict gonad-liver relationship fostering these novel reproductive needs. As a consequence, the functions of mammalian liver in females diverged from that in males to acquire the flexibility necessary to tailor metabolism according to reproductive status and to ensure the parsimonious exploitation and storage of energy for the continuation of gestation in case of food scarcity. Indeed, several studies show that male and female livers adopt very different strategies when confronted with nutritional stress of varied origins. Considering the role of liver and energy metabolism in most pathologies, a better focus on liver functions in the 2 sexes might be of considerable help in personalizing medicine and pharmacology for male and female needs.