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Living with Lupus

Estrogen, Sex Hormones and Lupus (SLE)

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Hormones, including the hormones associated with sex and sex expression, also impact the immune system. Because of this, they can have complex interactions with SLE.

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.

One example of the important role hormones play in the body’s regulation is insulin. Insulin allows cells to absorb glucose and helps the body regulate blood sugar levels. When the body does not respond properly to it, it can result in diabetes.

Interestingly, there are also naturally occurring steroids in the body that are also a type of hormone. Based on the body’s receptors, they have been classified into five groups: glucocorticoids, mineralocorticoids, androgens, oestrogens, and progestogens. In the form of corticosteroids, are a major part of lupus treatment, and you can read more about it here.

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Hormone Levels and Roles

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.

It is well-documented that sex-related hormones are related to systemic lupus erythematosus (SLE). 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.

That said, hormones are not the only factor in SLE. The effects of hormones on the body are too complicated for treating immune system dysfunction with hormone therapy to be considered at this time. Genetics, and sex differences in chromosome expression, is thought to play a greater role than hormone levels in most cases of SLE. 

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What is the Relationship Between Hormones and Lupus?

One potential explanation for sex differences and SLE is the varying levels of sex hormones in the body. In particular, the ratio of particular hormones to one another may affect how immune cells develop and mature. And, which immune cells the body gets rid of.

B cells are a class of immune system cell that targets and marks cells for destruction. This happens at “checkpoints” in the body, including before cells are released. This process ensures the eradication of intruders like bacteria and virus-infected cells.

Estrogen and prolactin (sex hormones associated with female reproduction and development) are also involved in protecting B cells from destruction. Higher levels of these hormones can allow more B cells to circulate in the body. Next, the increased level of B cells can lead to an immune response, and may trigger symptoms of lupus.

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Estrogen Treatments

Estrogen is known to activate or encourage the activity of T cells. These cells seek out and destroy pathogens that use the body’s own cells to multiply, such as viruses, some bacteria, and tumors. T cells are a major component of lupus-related damage and symptoms, and you can read more about them, here.

When mice were treated with an estrogen antagonist (a type of medication which prevents estrogen from binding to receptors on cells) they had decreased rates of disease and milder symptoms.

One potential explanation for the reason women (females) develop SLE more frequently than men (males) is because they have more estrogen. This can be linked to two causes: 1) higher production levels of estrogen; and 2) higher levels of the natural conversion process of testosterone to estrogen (known as aromatase).

Before converting to estrogen, testosterone first becomes estradiol. A 2003 review on hormones in SLE noted estradiol levels are higher in people with SLE. This difference in estradiol levels was not found in males, though it should be noted that there are not as many large studies on SLE in men. This implies that there is a higher-than-normal conversion of testosterone to estrogen. Plus, it might amplify estrogen’s effect in the body further.

 

Testosterone Treatments

Testosterone, a male sex hormone, is known to suppress the immune system. Conversely, estrogen and other hormones in the same family push the immune system to produce and react to antibodies, leading to immune responses.

People with lupus may be more sensitive to the estrogen in their bodies due to genetics. This allows it to trigger responses more easily, and potentially allows it to accidentally target the body’s own cells. This is supported by the finding that, if a woman’s ovaries are working sub-optimally and producing low levels of estrogen, she also has a lowered risk of lupus.

Conversely, oral contraceptives, estrogen treatments, and ovulation induction as a part of fertility treatments have been known to trigger flares. When testosterone is administered, it is linked to reduced lupus symptoms.

However, estrogen also influences the development of T-cells in the organ called the thymus. The hormone is involved in activating CD3-T cells and producing cytokines. Notably, estrogen treatment can lower thymus activity, but low levels of estrogen can also lower thymus activity. This implies that normal estrogen activity is needed to keep the thymus and the immune system working at a healthy level. It is also necessary for the destruction and survival of cancer cells, a vital function of the immune system, as well.

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Estrogen is important to regulating the immune system, and the body needs a happy medium.

The estradiol levels might be a “chicken or the egg” question — which comes first?

If it a result of increased immune activity and the body attempting to combat a threat, then it would make higher estradiol and estrogen more of a symptom of SLE and potential infection than a cause. Or, it may be produced to regulate the immune response, in order to increase or decrease activity. The higher levels could even be a result of all of the above.

Supporting this idea is the fact that low levels of estrogen are linked to exacerbated symptoms of SLE. Men with SLE are not overly affected hormonally by the estradiol and estrogen. When androgens (male sex hormones) are administered that cannot be converted to estradiol, it actually disturbs immune system regulation further.

That is why one cannot say that sex hormones cause lupus – their interactions with the body are complicated. However, one fact does remain stable despite this complexity. Women and biologically female people are more likely to develop SLE than men and biologically male people.

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Females vs. Males

Females have stronger immune responses than men to both disease and to vaccines, but this is also linked to higher rates of autoimmune diseases like SLE, at a 9-1 ratio, compared to men. Notably, males with SLE, while rarer, also have different symptomatic expression of SLE with more kidney damage, skin lesions and other severe symptoms overall. Males have twice the risk of renal disease and are nearly three times more likely to have thrombocytopenia. You can read more about lupus nephritis and about tests for renal disease, here.

One possible explanation is that the differences in sex hormones changes the way that the immune system responds to infection. Women have more estrogen and prolactin than men which are heavily involved in the immune system. 

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However, hormone levels are not so different between males, pre-pubescent females, and menopausal females — suggesting that is not the primary issue. Reviews of the literature determined that SLE is more tied to genetic and epigenetic (gene regulation) differences between males and females. There are differences in how males versus females build hormones and other messenger chemicals in their cells. A difference as small as a single polypeptide or building block at the molecular level. The molecule, in these cases, more or less does the same thing, but in susceptible people, it is just different enough to lead to SLE conditions.

People susceptible to SLE have differences in their genetic blueprints that change the way certain components of the immune system behave. Genes of note include genes that affect B and T cells. These genes, including genes associated with interferons, are upregulated in females. This is why women may have more active immune systems.

Some of these genes are on the X chromosome, which can be damaged. In women, who have two of the X chromosomes, this might give them both a higher likelihood of damage and slightly diluted symptoms. Men, who only have one X chromosome, are less likely to have a damaged gene. But, if they have damage to their X chromosome, have no “healthy” X chromosome to protect them. The lower rates of SLE in males and the worse symptoms may also be because males need more genetic factors contributing to immune dysfunction before they develop SLE. These genetic factors then cause the disease to strike harder, or to strike harder at the kidneys and vital organs.

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Hormones, Pregnancy, and Lupus

Pregnancies in lupus are high-risk, with a little less than 50% having complications. However, the risk for flares during pregnancy is greater. 

SLE flares are linked to menstruation, pregnancy, and the hormone fluctuations that come with both. Pregnancy also comes along with major immune system changes that prevent the body from attacking the developing baby, a change also linked to sex hormones including progesterone.

Certain oral contraceptives can also lead to SLE flares. For women with lupus, it is a good idea to get the advice of a doctor before trying new contraceptives, becoming pregnant, or if one’s periods are unusual in some way.

Because of the potential relationship between hormones and lupus, hormone therapy has been considered as a possible treatment for lupus. However, because the interactions of hormones in the body – and hormones with the immune system, specifically – can be complex. It has been difficult to figure out how best to go about hormone treatments.

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