Are sex hormone differences responsible for the high prevalence of autoimmune diseases in women?

In 2016, Arushi Tandon began to fall ill several times. It started with bouts of viral fever, quickly progressing to immense fatigue, anxiety, skin issues and loss of appetite. When she went to a doctor to have her swollen lymph nodes in her neck and armpits checked, the doctor seemed convinced she had cancer.

After eight months of back and forth from doctor to doctor, Tandon was finally diagnosed with systemic lupus erythematosus (SLE). Lupus is one of more than 80 known autoimmune diseases – conditions in which the body’s immune system mistakenly begins to attack its own cells. It is widely accepted in research that autoimmune diseases disproportionately affect women. A 1997 study noted that approximately 78% of autoimmune patients in the United States were female. With no known cure and symptoms that often overlap with common conditions, these disorders remain underdiagnosed and undertreated in women.

Despite the high prevalence of autoimmune diseases in women, Maya Dusenbery, a journalist with rheumatoid arthritis, told NPR that women’s symptoms are often misdiagnosed or dismissed due to long-standing gender biases in medicine – the “systemic and unconscious bias” that is rooted in the medical curriculum. “The medical knowledge we have is simply biased towards knowing more about men’s bodies and the conditions that disproportionately affect them,” she said.

For Fiza Jha, 28, it took 5 years to be diagnosed with psoriasis – a skin condition characterized by red, scaly patches. Between the ages of 15 and 21, she saw several doctors who all said she suffered from atopic dermatitis or eczema. However, the creams and medications they prescribed did not work. Meanwhile, the red, itchy rash spread from her legs to her elbows and behind her ears. “I just gave up. It was horrible, I was very conscious when I was wearing skirts and shorts,” she says. Finally, a doctor confirmed she had developed an autoimmune disease.

According to research, a range of contributing factors can trigger autoimmune diseases, including hormonal changes during reproductive cycles.

Although hormonal changes are not the only possible cause of autoimmune disorders, knowledge of how these hormones interact with the immune system may help explain the sex bias with which they present. Understanding them can also broaden the conversation about women’s health issues that have traditionally been on the back burner.

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“There is a hormone called estrogen in our body that predisposes women to these autoimmune diseases,” says Dr. Aarti Sharma, rheumatologist and ex-professor in the department of rheumatology, All India Institute of Medical Sciences (AIIMS). Many autoimmune diseases present themselves in women of childbearing age. During this period, fluctuating estrogen levels create hormonal imbalances, especially during pregnancy, menopause, and the monthly menstrual cycle.

Additionally, polycystic ovary syndrome (PCOS), which is a common condition in women, also causes reproductive hormonal imbalances. Before Tandon was diagnosed with lupus, she didn’t have her period for about six months. She was later diagnosed with PCOS and hypothyroidism. Some studies have linked PCOS with autoimmune diseases, such as autoimmune thyroid disorders.

Another factor responsible for the gender difference in autoimmune diseases is genetics. Genes linked to the X chromosome – of which women have two – and a process known as X chromosome inactivation predispose them to these conditions.

Previous research also suggests a strong link between hormonal changes during reproductive cycles and the development of certain autoimmune diseases in women. According to a Scientific American report, sex hormones affect the expression of a number of genes involved in immunity. Testosterone, for example, decreases immune cell response – a possible reason why men are less prone to developing most autoimmune diseases.

Specifically in the case of pregnancy, estrogen levels increase in the body. “[In] In early pregnancy, there is a higher chance of developing autoimmune diseases and again, once they give birth, the chances of developing autoimmune diseases increase, due to hormonal changes,” explains the Dr Shallu Verma, Rheumatologist at Metro Heart Institute with Multispecialty, Faridabad.

Pregnancy is considered a “unique immune condition”, where women’s immunity undergoes rapid changes. “Early in pregnancy, some healthy immune responses increase, which helps the placenta grow new blood vessels; in the middle of pregnancy, immunity decreases. Then immune responses and inflammation increase again in anticipation of labor,” the Scientific American report said. Dr. Sharma adds that during pregnancy, the underlying immune system is activated due to the implantation of a “foreign body” in the uterus, potentially acting as a trigger for autoimmune diseases.

However, in the case of people with pre-existing autoimmune diseases, several patterns emerge during pregnancy that make disease activity much more complex. “There are few diseases that [an] inactive phase, which we call remission. Like rheumatoid arthritis, which is the most common of all, and this disease goes into remission during pregnancy. But there is another set of diseases like lupus. It’s a disease that increases its activity during pregnancy, which can trigger repeat abortions and other things as well,” she says.

These observed links between hormonal activity and autoimmune disorders also raise several questions about women’s reproductive health, including the use of oral contraceptives. Oral contraceptives – which usually contain a combination of two hormones, estrogen and progestogen – can upset the body’s hormonal balance. A report suggests that the use of oral contraceptives and hormone replacement therapy has been linked to an increased risk of lupus. Dr Sharma explains that although oral contraceptives are important and patients are not prevented from taking birth control pills, taking birth control pills could slightly increase the risk of disease activity – although this has been noticed in a very small percentage of people.

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However, changes in hormonal activity are not the only factor in the high prevalence of autoimmune diseases in women. Among other causes, environmental factors and disparity in stress load also play a role. Studies have shown that women experience more stress than men. Exhaustion from unpaid domestic work and emotional labor, which have long been responsibilities primarily undertaken by women, increases their stress levels. Added to this is women’s general neglect of their health, as they are often more focused on others than on themselves, says Dr. Verma.

“Women are only brought in by their families for regular check-ups when they are really sick. They are the ones who prepare the food at home, do the household activities. So when the men in the family or other family members think that they can’t cope because she is sick… That’s the reason why they bring them to the doctor for checkups regular. Once she gets [a] little better, and then again, they don’t follow up,” says Dr. Verma. This is why diseases do not go into remission for many patients, she adds.

These societal pressures, along with a general lack of awareness, also contribute to late diagnosis of autoimmune diseases in women compared to men, Dr. Verma says. “In all rheumatological diseases, the first three weeks are a magical rainbow period,” she says. If the disease is diagnosed early and treatment begins, there is a chance that “women can get rid of all the drugs and lead a healthy life within two years of treatment.” Instead, “they come to us maybe after three or four years of being sick,” adds Dr. Sharma.

Anshul Srivastava, 34, has ankylosing spondylitis, a rare form of arthritis that causes pain and stiffness in the spine. His diagnosis took over 5 years, during which time the condition worsened. From fever, back pain and dizziness, her symptoms progressed to such an extent that she could no longer get out of bed due to swelling in her knees.

These conditions take a heavy toll on the minds and bodies of individuals, requiring lifelong treatment, medications, and lifestyle changes to manage disease activity. “There is this particular immunosuppressant that I have to take daily and if I miss it one day, the next day will be hell for me,” says Srivastava. Tandon’s treatment for lupus, meanwhile, has involved steroids, immunosuppressants, dietary conditions and even sun avoidance due to his photosensitive skin. Some of the drugs, she adds, have also caused side effects.

Countless women’s experiences reveal how living with an autoimmune disease is a daily challenge that also profoundly affects their mental health. When a flare-up occurs, Srivastava says, “Two weeks of my life have suddenly passed. After these two weeks for me to get up, go back to work and resume the day I left…it takes a lot of effort. Many symptoms of autoimmune diseases, such as chronic pain or fatigue, are not immediately apparent to others. Patients then suffer the effects of these invisible diseases in silence.

“What we need is more awareness of autoimmune diseases [in women]says Dr. Rekha Khandelwal, a Delhi-based obstetrician-gynecologist. As one review article noted, sex-specific differences in autoimmune diseases are not only related to higher numbers of cases in females, but can also affect symptom severity, treatment options, disease progression and overall patient survival. Understanding this sex bias is essential because it can shed light on how to improve the quality of life of patients living with autoimmune diseases.

These disorders tend to “stay with you,” says Srivastava, adding that there is a need for community groups and support for people with autoimmune conditions. “It would be nice to know what other people are doing, maybe someone has figured out how to better live with it. I just live in partial denial. The community would really help,” she says.