Trends in Genetics
OpinionThe Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases
Section snippets
Pregnancy Compensation Hypothesis: An Explanation for Sex Differences in Human Disease Risk
Sex differences exist across a range of human diseases, but these remain understudied and largely unexplained [1]. For example, females in industrialized populations (see Glossary) exhibit a higher prevalence of most autoimmune diseases than do males (Table 1) [2]. By contrast, females have a lower risk of developing cancer, with nearly all nonreproductive cancers showing a higher incidence in males (Table 1) [3]. We present here the pregnancy compensation hypothesis (PCH), which explains both
Sex Differences in Autoimmune Disease and Cancer Incidence
Sexual dimorphism in immune function appears to be a general feature of many species, and differences are documented across vertebrates and invertebrates, although at varying magnitudes [5]. Across several vertebrate species, there is evidence of female bias in the peripheral abundance of markers of innate and adaptive immunity 5., 6.. Autoimmunity is characterized by the presence of an increased level of autoantibodies, as well as of inflammatory and mediatory cells, resulting in chronic
Industrialization Explains Increases in Autoimmunity and Cancer, but not Sex Differences
Most research on cancer and autoimmunity is conducted in urban populations, but most of human evolution took place in small-scale subsistence populations; sedentary industrialized life has resulted in major changes in human reproductive ecology and lifetime fertility [13]. There is a documented increase in the incidence of autoimmune disorders over recent decades in urban and industrialized populations [14]. The 'old friends' or hygiene hypothesis suggests that, because humans coevolved with
In Urban Industrialized Contexts, Pregnancy Compensation Explains Dimorphism in Disease Risk
Despite caloric availability to maintain a high number of pregnancies, fertility in modern urban environments has decreased [19]. In the contemporary industrialized context, the absence of repeat pregnancies may leave the immune system of an urban industrial female prone to dysregulation. Given the role of the immune system in surveying and preventing cancer 24., 25., this 'undampened' immune response should facilitate increased immune surveillance, which may be protective against some cancers
Pregnancy, and Related Hormonal Shifts, Are Directly Linked to Changes in the Maternal Immune System and the Incidence/Onset of Autoimmune Disease
The maternal immune system is alternately dampened and recalibrated throughout gestation and lactation during a successful pregnancy. Such immunomodulation is facilitated by the highly invasive nature of the eutherian placenta, that is primarily composed of fetal tissue, and is accomplished through coordinated signaling between the fetus and the mother. Early implantation by the fetal trophoblast is facilitated by innate inflammatory processes at the maternal–fetal interface [32], followed by a
Evolution of the Mammalian Sex Chromosomes and Placentation Leads to Sex Differences in Immune Function
Although eutherian mammals are commonly termed placental mammals to contrast them with marsupials, it is now understood that the development of a placenta, if even for a short time, occurs in marsupial mammals and is important for successful pregnancy [46]. Thus, although all mammals share lactation as a trait [47], placentation evolved in the common ancestor of therian mammals, after they diverged from the egg-laying monotreme mammals (Figure 3). Further, phylogenetic comparisons have been
Concluding Remarks
We present here the PCH to explain how evolution may have shaped both gene dosage on the X chromosome and reproductive hormones in response to placentation and pregnancy to mechanistically explain sex differences in disease, reflecting an ancestral mismatch with modern environments. There are both general trends and specific exceptions to sex differences in disease that can be explained by the PCH. For example, it is notable that a key exception to reduced female cancer incidence is thyroid
Outstanding Questions
Which genes escape inactivation during development, in which tissues, and do they show a sex difference?
Which classes of genes (oncogenes and/or immune genes) are specifically tied to sex differences?
Is the dosage of tumor-suppressor and immune-related genes altered in cancer, or does it reflect healthy system regulation?
What is the difference in disease risk between absolute dosage differences between sexes, or it is the relative heterozygous dosage? (i.e., is mosaicism afforded by
Acknowledgments
This study was supported by Arizona State University (ASU) Center for Evolution and Medicine postdoctoral fellowships to H.N. and A.R.G., a Marcia and Frank Carlucci Charitable Foundation postdoctoral award from the Prevent Cancer Foundation to H.N., startup funds from the School of Life Sciences and the Biodesign Institute at ASU to M.A.W., and partial support from National Institutes of Health (NIH)/National Institute on Aging (NIA) grant RF1AG054442-01 to B.C.T. This study was supported by
Glossary
- Eutherian mammal
- a classification of mammals that includes those that have fully formed placentas, often referred to as 'placental' mammals.
- Hygiene hypothesis
- this proposes that the decreasing incidence of infections in western countries is the origin of the increasing incidence of both autoimmune and allergic diseases as a result of insufficient immunomodulation caused by the lack of early exposure to parasites and pathogens.
- Industrialized population
- middle to high development index countries
References (84)
Gender differences in autoimmune disease
Front. Neuroendocrinol.
(2014)- et al.
Maternal–fetal immune tolerance, block by block
Cell
(2012) Sex as a predictor of response to cancer immunotherapy
Lancet Oncol.
(2018)Human reproduction and health: an evolutionary perspective
Lancet
(2017)Helminth and protozoal parasites of the Hadza of Tanzania
Trans. R. Soc. Trop. Med. Hyg.
(1970)- et al.
Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis
Horm. Behav.
(2012) - et al.
The basis of oncoimmunology
Cell
(2016) The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus
Immunol. Lett.
(2014)- et al.
The structural biology of oestrogen metabolism
J. Steroid Biochem. Mol. Biol.
(2013) Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis: implications for multiple sclerosis
J. Neuroimmunol.
(2004)