Why do autoimmune diseases affect more females than males?

And what does it actually mean

Autoimmune diseases affect, in general, more females than males. Why is that so? Is it coded in our genes, is it our environment and the way we interact with it? Do we feel autoimmune diseases in the same way? Will our biological sex determine how protected are we from the long-lasting effects of these conditions? Are the sex-observed differences stronger than the individual differences?

Autoimmune diseases were first described a bit over 50 years ago (1), in simplest terms it is the failure of body to tolerate own cells or organs, and it results in pathological change, the destruction of the full organ or the parts of it, and the inability of that particular organ to fulfil it’s function. Autoimmune diseases are usually systemic, meaning they affect the entire body, and not only one specific organ or a tissue.

Human immune system is complex, it has many different cell types coded to execute different functions. Our immune system protects us from our environment, which is a good thing. And that same environment sometimes triggers autoimmune disease (2). How does that happen? Or when? By now it is certain that the predisposition to develop an autoimmune disease is not written in only one spot of our DNA. There are rather many places in across our DNA with tiny imperfections, mutations that together ultimately form the disease we have(3–5). We inherit our genes from our ancestors, so it is normal to see higher chance of autoimmune disease running in a family, and to be aware that our biological descendants have an increased chance of suffering from them(6–8).

Differences related to sex hormones

Prevalence

Most of autoimmune diseases seem to affect more females (9–20). It was not always like that, at least research reported equal distribution of Multiple Sclerosis (MS) cases between females and males in the 1950s, which changed to a more daring 3 in 4 MS patients being female, reported in 2013 (reviewed in (20)). Could this observed increase also be because gender is taken in a more consideration in studies than in the 1950s?

Both Hashimoto’s and Graves affect more females than males, the numbers are ranging from 7 in 10 to 9 in 10 of people having these conditions also being female (10, 20–23).

Does the severity of the condition differ between females and males?

This is for sure less easy to quantify, research states that both psoriasis and MS seem to be more severe in males (reviewed in (20)). Research has also probed into health complications, and in systemic lupus erythematosus (SLE) female patients were more likely to suffer from urinary tract infections, hypothyroidism, depression, reflux, asthma, and fibromyalgia, while male patients were more likely to suffer kidney and heart problems (24).

However, it is good to know that autoimmune conditions affect individual people, irrespective of their sex, differently. Differences in the immune response, specific organ sensitivity, sex hormones and the environment determine if one will develop an autoimmune condition, which condition will it be, how severe will it affect the individual, and it will determine individual’s long-term health prospects.

Immune systems differ, not only between the people, but within the course of person’s life. That is because, at least evolutionarily, bodies are supposed to perform different tasks: mature, grow up, become strong, reproduce and nurture the offspring (reviewed in (20)).

Interestingly, it seems that in a population of people pregnancy might be the trigger to develop the autoimmune disease (25).

Rather than sex, it might be the hormones

Sex hormones play a big role in triggering or protecting from autoimmunity. The level of certain hormones, but also the combination of hormones and their respective ratio will impact the development and the course of autoimmune condition. This goes beyond female — male division, hormonal levels are very individual, their interactions with other molecules in our body are complex, and experiences should not be grouped and averaged under two distinctgenders.

Estrogens directly impact multiple cells of the immune system, change their behaviour and function (reviewed in (20)). Role of estrogens is complex, because they do not act alone, but rather depend on other hormones or stress molecules present in the body at a specific time. As a result, estrogens might protect from an autoimmune flare-up or contribute to it’s severity(reviewed in (20)).

There are many naturally occurring chemicals in our environment that resemble estrogens (environmental estrogens) as well as some synthetic compounds resembling estrogens (xenoestrogens) (reviewed in (20)). Some of the foods we eat, detergents, plastics and pesticide contain these chemicals, and once in our body, they accumulate in our fat cells, and this is where they interfere with the immune system (26).

Progesterone, like estrogen, impacts many different cells belonging to the immune system (27), and usually it blocks inflammation (reviewed in (20)).

Androgens, including testosterone, also have an effect on the immune system. The effect depends on the type of androgen, the amount of it, and the time when the effect happened if the activity of our immune system will be blocked or activated (reviewed in (20)). Testosterone treatment showed some improvement in male patients with MS, while it did not help females with SLE (reviewed in (20)).

Prolactin can be produced by the immune cells (reviewed in (20)) and it may exacerbate flare-ups (28). Hyperprolactinemia, a state of increased prolactin levels is seen in many autoimmune conditions, including Hashimoto’s (29).

Finally, chromosomes

The X chromosome contains a lot of genes involved in immune and autoimmune system (reviewed in (20)), but even the XX chromosome individuals have one of their X chromosomes inactivated. This compensates the X-chromosome dosage in XX and makes it pretty equal to the amount of active X-chromosome in XY people. There are errors in this process too: changes in inactivation patterns of X chromosome have been found in both Hashimoto’s and Graves’s disease (reviewed in (20)).

The Y chromosome has much less genes, in comparison to the X chromosome, but research a couple of years ago found age dependent, loss of the Y-chromosome in patients with both Hashimoto’s and Graves (30).

Conclusion

As with many other research pieces on Hashimoto’s and autoimmune conditions, more research is needed to understand what exactly causes the condition, which hormones, at what dose, and in what combination may be protective or perilous.

More research will hopefully start drawing conclusion on the basis of individual differences, rather than putting us under the same averaged umbrella.

References

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19. McNally RJ, et al. Seasonal variation in the patient diagnosis of primary biliary cirrhosis: further evidence for an environmental component to etiology. Hepatology. 2011.

20. Ngo ST, et al. Gender differences in autoimmune disease. Front Neuroendocrinol. 2014.

21. Ramagopalan SV, et al. Associations between selected immune-mediated diseases and tuberculosis: record-linkage studies. BMC Med. 2013.

22. Carle A, et al. Epidemiology of subtypes of hyperthyroidism in Denmark: a population-based study. Eur J Endocrinol. 201.

23. Gaujoux S, et al. Extensive thyroidectomy in Graves’ disease. J Am Coll Surg. 2006.

24. Crosslin KL, et al. Sex differences in disease severity among patients with systemic lupus erythematosus. Gend Med. 2011.

25. Zandman-Goddard G, et al. Gender and autoimmunity. Autoimmun Rev. 2007.

26. Chighizola C, et al. The role of environmental estrogens and autoimmunity. Autoimmun Rev. 2012

27. Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev. 2012

28. Orbach H, et al. Hyperprolactinemia and autoimmune diseases. Autoimmun Rev. 2007

29. Orbach H, et al. Prolactin and autoimmunity: hyperprolactinemia correlates with serositis and anemia in SLE patients. Clin Rev Allergy Immunol. 2012

30. Persani L, et al. Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis. J Autoimmun. 2012