According to a 2020 study published in Cureus, autoimmune diseases are two times more prevalent in women than men, with the gender gap continuing to rise for certain diseases. Rhonda Voskuhl, an NIH researcher, reported multiple sclerosis prevalence jumped from two to three times as common in women compared to men from the mid-1990s to today. While some autoimmune diseases such as ankylosing spondylitis are more common in men, the overwhelming majority strike women more often – Sjogren's, Hashimoto's thyroiditis, lupus, and rheumatoid arthritis, to name a few.
Several theories have been purported to explain this discrepancy. These include the effects of sex hormones and sex chromosomes on the immune system and lifestyle changes that have altered the timing of the immune system's exposure to sex hormones from what was typical throughout much of humans' evolutionary history.
Sex hormones influence the immune system by targeting the respective receptors on immune cells, and effects are apparent in women with fluctuating autoimmune disease symptoms as hormonal levels shift throughout pregnancy. During the first trimester of pregnancy, inflammation levels rise to allow a fertilized egg to successfully implant on the uterine wall, only to drop in the second trimester before they rise again as birth approaches in the third trimester. For instance, in pregnant patients with multiple sclerosis, 70% have a reduction in relapses in the second half of pregnancy before symptoms return after delivery, typically. At this time, it is unknown if relatively high estrogen levels, low levels of testosterone, or a combination of both are responsible for the observed fluctuation of symptoms with changing hormonal levels.
The presence of a double pair of X sex chromosomes is thought to contribute to increased autoimmune disease rates in women based on mice studies, genetic disorders, and gene studies linking certain X chromosome genes to specific autoimmune diseases. In studies where mice are genetically engineered to have the same sex organs and hormonal levels and differ only by the presence of XX and XY chromosomes, mice with XX chromosomes develop lupus more often than those with XY chromosomes. In the genetic disorder Klinefelter syndrome, where males are born with an extra X chromosome, men develop lupus and Sjogren's at higher rates, similar to women. And the TLR7 gene found on X chromosomes has been linked to an increased risk of lupus. XX chromosomes are thought to make the immune system overactive when multiple copies of genes present on these X chromosomes escape the normal deactivation process.
Lifestyle factors are also suspected to be at play. Compared to much of their evolutionary history, fewer women have children and pregnancy and motherhood are postponed. Autoimmune disease incidence rates have increased with increased contraception use and decreased pregnancy rates. A hormone produced by the placenta during pregnancy known as oestriol is a powerful anti-inflammatory and is currently being investigated as a potential multiple sclerosis treatment. The female immune system may not function as deftly without precisely-timed exposure to oestriol.
Sources: Nature
