Effects of Menopause on Autoimmune Diseases

Miranda A Farage; Kenneth W Miller; Howard I Maibach

Disclosures

Expert Rev of Obstet Gynecol. 2012;7(6):557-571. 

In This Article

Conclusion

Immunosenescence is a complex phenomenon, involving cellular, humoral and innate immunity in a downward spiral of dysregulation of the tightly interdependent responses characteristic of young adulthood, with multiple effects on hematopoiesis, immune cell proliferation and differentiation, and immune cell function. The eventual result is an immune system that is hyperactivated but defective, which sets the stage for a rise in autoantibodies and thus autoimmunity.

Unraveling the respective roles of genes, hormones, lifestyle factors and environment in autoimmunity in general and in postmenopausal women in particular has yet to be accomplished. Although the general understanding that estrogen skews immune responses toward Th2 pathways, while androgens drive the Th1 pathway explains many of the gender discrepancies and age-related peaks of disease observed, it does not explain all. There are discrepancies and it proves difficult to attach hormones to specific mechanisms.

Obviously other factors are at play. Genetic and epigenetic components need further investigation. The major autoimmune diseases of the connective tissue all have a strong predominance in women, tissue specificity for Th1 or Th2 responses may be a factor as well.

The specificity of Ig subclass may influence autoimmunity as autoimmunity is characterized by a marked increase of IgM levels produced by B cells. The role of sex hormones in autoimmunity and in the menopausal period is unmistakable but not easily understood. Estrogen, progesterone and testosterone share the same precursor: cholesterol, as well as common intermediate metabolites that are known to interact with the immune system. Levels of both estrogen and progesterone decline rapidly as menopause nears; progesterone levels drop more steeply than estrogen. Progesterone may substantially impact autoimmune development, as progesterone receptors are ubiquitous in immune organs tissues and cells. Progesterone has different immunomodulatory effects from estrogen but shares interdependent signaling pathways.

The profound female predisposition to autoimmunity as well as the fact that significant immune derangement occurs during the estrogen-infused months of pregnancy suggest the likelihood that, in general, lower physiological amounts of estrogen stimulate Th1 effects whereas higher doses stimulate Th2.

The presence of at least two different types of ERs also allows for multiple levels of control, as does the fact that at menopause, the predominant circulating form of estrogen changes. In addition, the X-chromosome, apart from female hormones, may contribute to the female predominance in autoimmune diseases. Racial differences have yet to be seriously explored; other factors implicated in autoimmunity have lacked significant research effort as well. For example, geographical differences in autoimmune disease prevalence have been note, as has level of industrialization. Increased parity has also been associated with an increased risk in autoimmunity.

With steadily expanding life expectancy, immunosenescence in general, and autoimmunity in old age in particular should be given increased medical focus. The role of menopause, with its attendant depletion of estrogen, in autoimmune disease should be an important part of that research effort, given the drastic dichotomy in incidence of autoimmune disease in women and men and the longer expected female lifespan. A better understanding of the interplay between genetic, hormonal and environmental factors that lead to autoimmunity in menopause is necessary to provide appropriate prevention and/or treatment options for older patients, preserving health into old age and providing an increased quality of life throughout those additional years.

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