Women and Lupus: The Impact of Genetics & Hormones

Genetics and hormones both contribute to the development of autoimmune diseases. And, women are nine times more likely than men to be battling autoimmune diseases like lupus.

Autoimmune diseases are a broad collection of over 100 diseases characterized by autoimmunity — a condition where the body’s immune system attacks the body’s own healthy cells. These conditions are known to be complicated to diagnose and multifaceted in their presentation. They also disproportionately impact women and particular racial and ethnic groups. In fact, 78% of people with autoimmune disease are female. 

Both of these disproportionate prevalences are even more pronounced when looking at lupus. 9 out of 1o people diagnosed with lupus are women. African-American, Hispanic, Asian, and Native American women are also 2x to 3x more likely to develop lupus as compared to Caucasian women.

But why?

Lupus and the Genetic Connection

During the diagnosis process, a rheumatologist will often ask if anyone in your family has been diagnosed with any autoimmune disease. This is because genetics is known to be a major factor for the diseases. Genes are the blueprints of the body, and all of our cells use these blueprints. However, we each have different versions of these blueprints, which we inherit from our parents. Even identical twins have differences in how the body uses these blueprints, which is called gene expression. Differences in gene expression can come about due to changes in the environment (including smoking or exposures).

Essentially, your genes make your susceptible to a host of diseases. Then, in response to triggers, the symptoms of the disease may begin to manifest. Triggers can include:

• medications and drugs
• pollutants or environmental exposures
• stress
• infection

The chain reaction begins, which leads to the development of lupus and the build-up of symptoms.

Genetic Variations

Over 30 genetic variations have been linked to lupus.  Unsurprisingly, most seem to involve the regulation of the immune system or specific proteins found in the immune system. It is thought that many of these immune system genes might be on the X chromosome, and this could be why men generally have more genetic markers of lupus. Men only have one copy of the X chromosome, while women have two copies. If both copies have vulnerable genes, she could get a “double dose” of the vulnerable gene, or simply have more chances to have that gene expressed.

Calcineurin

For women, calcineurin seems to be one of the key proteins that are different in women with lupus compared to men and healthy women. Calcineurin activates T-Cells, one of the parts of the immune system that causes the symptoms of lupus. Calcineurin inhibitors are medications that treat lupus very well because of this connection, but they are also regulated naturally in the body by the hormone estrogen. One reason that calcineurin might be less regulated in women is because of the higher presence of estrogen in their bodies. Women who are predisposed to lupus might have different blueprints for calcineurin that have unusual estrogen receptors and make their immune system more likely to misbehave in the presence of the hormone.

However, estrogen is not the only sex-related hormone involved in autoimmune disease.

What are Hormones?

Hormones are chemicals that different cells in the body use to communicate with each other. By communicating, cells are able to work together to perform the many tasks that our bodies need to function. The body regulates everything from mood, to metabolism, to the immune system’s response with hormones.

Hormone levels are essentially consistent from one person to another. A person’s environment, mental state, and health can cause fluctuations. However, the family of hormones that control sexual function, reproduction, and development are different between the sexes. These hormones include:

• estradiol
• estrogen
• testosterone
• progesterone

The same hormone can fill many different roles, triggering different responses depending on the cell. The “sex hormones” are responsible for sex differentiation and reproductive behaviors. They also control a wide range of effects throughout the body. One of these effects is immune system regulation.

Some researchers think that sex hormone levels, and in particular high levels of the hormone estrogen, might be the reason that females have higher rates of SLE and other autoimmune disease.

Estrogen, Progesterone, and Lupus

Women have higher levels of estrogen, prolactin, and progesterone in their bodies. Estrogens are hormones thought to be involved with SLE. Some of the understanding of how these hormones work in lupus comes from research conducted in mice. Mouse models show that the way estrogen regulates progesterone may be impaired in people with lupus. Both estrogen and prolactin effect the production and regulation of B-cells,  one of the other immune system cells that misbehaves in lupus. In particular, estrogen and prolactin effect “tolerance,” the process through which the immune system gets rid of B cells that target the body.

For women who are already at risk of lupus due to their genetics, their sex-linked hormones, along with stress, may push them over the edge into developing lupus. Interestingly, this same vulnerability to autoimmune disease may also be responsible for the stronger immune systems found in women.

Could the genetic vulnerability to lupus turn this advantage into a disadvantage?

Social Determinants of Health, Women, and Lupus

African American and Hispanic people have symptoms of lupus begin at a younger age. They may have access to specific genes that make them more vulnerable to lupus. However, they also face additional challenges that increase their risks.

Some of the disproportionate impact of lupus on women may be related to social determinant of health. Women, especially BIPOC women, bear heavy societal and stress-related burdens in our society. In measures of economic stability, education access and quality, healthcare access and quality, women often face serious inequalities. These inequalities and difficulties limit access to resources, cause stress, and can seriously effect health – all factors that contribute to lupus. 

However, for women, biological factors are also involved.

Pregnancy and Lupus

Does lupus effect pregnancy? Yes. One of the challenges for managing lupus is maintaining fertility and ensuring safe pregnancies. The hormone and physical changes that occur in pregnancy can cause flares, which can in turn cause pregnancy complications.

However, most people with lupus are able to carry to term successfully, and the baby is generally healthy. While all lupus pregnancies are considered high risk, less than 50% have complications.

Risks of miscarriage and preeclampsia are increased for people with lupus. Preeclampsia is elevated blood pressure, swelling, and improper kidney function (resulting in protein in the urine, or proteinuria). Research has shown that the worse the lupus symptoms, the more challenging the pregnancy and outcomes.

Having the right people on your treatment team can help – and sometimes lupus symptoms even decrease during pregnancy.

Tips for Women with Lupus

Exercise is important for all people with lupus, and it has many benefits. Women are advised to drink plenty of water, eat a healthy diet, and maintain a healthy weight.

During pregnancy, folic acid prenatal vitamins are recommended, and all SLE medications should be maintained – even hydroxychloroquine. These have been shown to help prevent lupus flares. Discontinuing medications can lead to increased fatigue and joint pain. Azathioprine is considered the safest immunosuppressant as  fetuses cannot process the drug. Note: As with all medications, speak with your lupus treatment team and ensure that all specialists are aware of your active medications.

Hormone replacement therapy might be a potential treatment for lupus because of the effects of hormones on the immune system, though people with lupus presently undergoing hormone replacement therapy should be aware of this risk. For people already diagnosed with lupus HRT and birth control pills (oral contraception) have not bene linked to an increased risk of severe flares.