Sex and disease: the necessity of an overarching theory to explain the effect of sex on non-reproductive functions.

The number of studies underlying 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 millions of 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 mother womb and the lactation of the new-born. 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 the novel reproductive needs. As a consequence, the functions of mammalian liver had to diverge from males to acquire the flexibility necessary to tailor metabolism on the reproductive status and to ensure the parsimonious exploitation and storage of energy supplies 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 origin. Considering the role of liver and energy metabolism in most pathologies, a better focus on liver functions in the two sexes might be of considerable help in personalizing medicine and pharmacology on male and female needs.