The Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases

We hypothesize that, ancestrally, sex-specific immune modulation evolved to facilitate survival of the pregnant person in the presence of an invasive placenta and an immunologically challenging pregnancy – an idea we term the 'pregnancy compensation hypothesis' (PCH). Further, we propose that sex differences in immune function are mediated, at least in part, by the evolution of gene content and dosage on the sex chromosomes, and are regulated by reproductive hormones. Finally, we propose that changes in reproductive ecology in industrialized environments exacerbate these evolved sex differences, resulting in the increasing risk of autoimmune disease observed in females, and a counteracting reduction in diseases such as cancer that can be combated by heightened immune surveillance. The PCH generates a series of expectations that can be tested empirically and that may help to identify the mechanisms underlying sex differences in modern human diseases. There are major sex differences in human disease that cannot be explained by reproductive hormones or environmental exposures alone.Genes on the sex chromosomes exhibit differences in expression that are independent of reproductive hormones, and could contribute to sex differences in disease.We propose that the ancestral immune system was strongly shaped by the requirement to compensate for unique immune regulation during pregnancy.Dimorphism in immune function in response to placentation and pregnancy occurs via direct impact of reproductive hormones on immune function, as well as through heritable variation in sex chromosome dosage.Although evolution has shaped sex differences in immune function over millions of years, industrialized urban populations experience both exacerbated sex differences in hormonal composition as well as reduced pregnancies compared with nonindustrialized populations.