Autoimmune Disease in Women: Endocrine Transition and Risk Across the Lifespan

Abstract

Women have a higher incidence and prevalence of autoimmune diseases than men, and 85% or more patients of multiple autoimmune diseases are female. Women undergo sweeping endocrinological changes at least twice during their lifetime, puberty and menopause, with many women undergoing an additional transition: pregnancy, which may or may not be accompanied by breastfeeding. These endocrinological transitions exert significant effects on the immune system due to interactions between the hormonal milieu, innate, and adaptive immune systems as well as pro- and anti-inflammatory cytokines, and thereby modulate the susceptibility of women to autoimmune diseases. Conversely, pre-existing autoimmune diseases themselves impact endocrine transitions. Concentration-dependent effects of estrogen on the immune system; the role of progesterone, androgens, leptin, oxytocin, and prolactin; and the interplay between Th1 and Th2 immune responses together maintain a delicate balance between host defense, immunological tolerance and autoimmunity. In this review, multiple autoimmune diseases have been analyzed in the context of each of the three endocrinological transitions in women. We provide evidence from human epidemiological data and animal studies that endocrine transitions exert profound impact on the development of autoimmune diseases in women through complex mechanisms. Greater understanding of endocrine transitions and their role in autoimmune diseases could aid in prediction, prevention, and cures of these debilitating diseases in women.

Keywords: autoimmne disease; gender differences; menopause; puberty; women.

Figure 1

Sex differences in prevalence ratio of autoimmune diseases. Autoimmune diseases are significantly more prevalent in women than men.

Figure 2

Factors that contribute to increased incidence and prevalence of autoimmunity in women. In women (46XX) with genetic susceptibility to autoimmune states, external environmental stimuli affect modifying factors as well as endocrine transitions via epigenetic mechanisms. Additionally, there are interactions between estrogens, androgens, leptin and prolactin on one hand and the interplay between Th1 and Th2 immune responses on the other. Both (endocrine and immune response) these phenomena are influenced in varying ways during the female transition states depending on the circulating concentrations of different hormones and immune cytokines, which in turn may be determined by epigenetics. Thus, hormonal fluctuation, immune polarization and transition states together drive susceptible women over the autoimmune “tipping point” leading to manifestation of overt clinical disease.

Figure 3

Three-fourths of all patients suffering from autoimmune disease are women. Based on the source of information, it is estimated that 5–8% (NIH, 2005) to 20% (American Autoimmune Related Diseases Association, 2017) of all Americans suffer from at least one autoimmune disease, of which ~78% or three-fourths patients are female, and the rest are male. Despite this, autoimmune diseases are rarely discussed as a women's health issue.