The gender gap in autoimmune diseases
The different types of hormonal contraception
The science of how hormones and immunity interact - estrogen receptors in immune cells
Advantages and disadvantages
References
Further reading
Immunity is modulated by sex hormones and thus has an important role in the sex bias commonly seen in autoimmunity. Hormonal contraceptives are widely used by women, different studies show an association between their use and an increased risk of developing several autoimmune diseases.
Contraceptive hormones. Image Credit: Pixel-Shot/Shutterstock.com
The gender gap in autoimmune diseases
The incidence and prevalence of autoimmune disorders are higher in women than in men. Approximately 78% of patients suffering from these pathological conditions are women.
It is known that hormones modulate the immune system. As an example, cortisol controls the immune response via the circadian rhythm, regulating T cell-mediated inflammation.
In the case of sex hormones, emerging evidence shows that the gut microbial composition influences sex hormone levels in a non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D), modifying its progression towards autoimmunity.
Men and women are known to differ in terms of energy consumption and nutritional requirements, which in turn are influenced by interactions between environmental factors and sex hormones.
Studies conducted in the past century confirmed that females exhibit an enhanced capacity for producing antibodies, giving them a greater ability to mount effective responses against infections.
As a result, women are generally less susceptible to viral infections than men. However, there is also a potential risk of hyper-immune responses leading to pathogenic effects and a predisposition to autoimmunity.
The immunomodulatory function of female hormones in autoimmune diseases depends on their concentration in the bloodstream, levels of other hormones, and the age of the host. This is explained by cyclical hormonal changes in the menstrual cycle, beginning from puberty up until menopause.
This cycle facilitates pregnancy and is characterized by hormonal fluctuations that have a long-lasting impact on women's health. Menopause, on the other hand, represents a state of reproductive senescence that marks the end of a period of irregular reproductive function known as the perimenopausal transition.
This period is characterized by differential regulation of the inflammatory response and a decline in the expression of genes involved in bioenergetics.
There is evidence suggesting that the fluctuating hormonal environment during the menopausal transition increases women's susceptibility to autoimmune diseases during the peri- and post-menopausal periods.
Among peri-menopausal women, there is an increased risk of lymphocyte-mediated autoimmunity; their neutrophil percentage drops, while lymphocytes rise. These differences in immune response can lead to variability in disease phenotypes, with women more susceptible to autoimmune diseases and men to specific types of cancers.
The thyroid. Image Credit: Emily frost/Shutterstock.com
The different types of hormonal contraception
It was established that sex hormones influence the immune systems and can lead to autoimmunity affecting mostly females. It is also known that 65% of women, in the United States, use contraceptives according to the collected data in 2017-2019; the report shows that 14% of them were using long-lasting reversible contraceptives (LARCs), while 10.4% were using oral contraceptives.
A high proportion of these methods are hormonal contraceptives, emphasizing the importance of studying their effect on autoimmunity development.
Hormonal contraceptives can be divided into: combined hormonal contraceptives, and progestin-only contraceptives. Combined hormonal contraceptives contain both estrogen and anti-androgenic progestin, which blocks the effect of androgens in the body.
They include birth control pills, contraceptive skin patches, and contraceptive vaginal rings. Progestin-only contraceptives, on the other hand, include Progestin-only pills, contraceptive injections, contraceptive implants, and hormonal intrauterine devices (IUDs).
To study the association between hormonal contraceptive use and autoimmunity, William V. William (2017) made a systematic review of the literature collecting different case-control and cohort studies in which the prevalence and incidence of autoimmune diseases and hormonal contraceptive exposure were studied. Some meta-analyses were taken into account.
The study found some evidence associating hormonal contraceptive use with an increased risk of developing autoimmune diseases like multiple sclerosis (MS), Crohn's disease, systemic lupus erythematosus (SLE), ulcerative colitis, autoimmune thyroid disease (hypothyroidism), immune skin diseases and rheumatoid arthritis (RA), with a higher risk in groups characterized by the presence of antibodies against citrullinated proteins.
It was suspected that the resemblance of a pregnancy state caused by hormonal contraceptives had a protective role against some pathologies like RA, since pregnancy provokes its remission. However, more recent studies showed an increased risk of disease development. Other studies showed no decrease or increase risk of developing this pathology. Regarding hyperthyroidism, a decreased risk was suggested.
Another source of exogenous estrogens is post-menopausal hormone replacement therapy, based on the administration of very low doses of estrogens (1/6 the dose in oral contraceptives).
It was considered protective against cardiovascular diseases, but clinical trials have now shown that it is not beneficial as it increases rates of thromboembolism, coronary artery disease, and stroke. Additionally, the incidence of SLE in hormone replacement therapy users was higher compared to non-users.
The science of how hormones and immunity interact - estrogen receptors in immune cells
The brain, gut epithelial cells, lymphoid tissue cells, and immune cells all express estrogen receptors (ERs), which are the main route by which estrogen affects physiological processes.
There are different forms of exogenous and endogenous estrogens and their effects are exerted by their binding ERs, occurring via two mechanisms. The classical mechanism involves estrogen diffusing into the cell and binding to the ER in the nucleus to regulate gene expression. Estrogens can stimulate cells through "nongenomic" mechanisms by binding to ERs in the plasma membrane or endoplasmic reticulum to stimulate immediate responses such as changes in Ca2+ levels or kinase activity. The downstream functions of estrogens depend on which receptor is activated and its cellular localization.
It has been demonstrated that estrogen controls immunological response by reducing the ability of high-affinity auto-reactive B cells to undergo negative selection, altering B cell activity, and inducing a Th2 response. Estrogen also promotes CCR5 expression, which causes T cell homing.
Advantages and disadvantages
Hormonal contraceptives can effectively prevent unwanted pregnancies and help to manage menstrual-related symptoms. However, some studies have linked the use of these hormonal treatments to an increased risk of developing autoimmune diseases, including SLE, MS, and RA.
References
- Desai MK and Brinton RD (2019) Autoimmune disease in women: Endocrine transition and risk across the lifespan. Frontiers in Endocrinology, 10. doi: 10.3389/fendo.2019.00265.
- Harding AT and Heaton NS (2022) The impact of estrogens and their receptors on immunity and inflammation during infection. Cancers, 14(4). doi: 10.3390/cancers14040909.
- Lateef A and Petri M (2012) Hormone replacement and contraceptive therapy in autoimmune diseases. Journal of Autoimmunity, 38(2–3). doi: 10.1016/j.jaut.2011.11.002.
- Markle JGM et al. (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science, 339(6123). doi: 10.1126/science.1233521.
- Taneja V (2018) Sex hormones determine immune response. Frontiers in Immunology, 9. doi: 10.3389/fimmu.2018.01931.
- Williams WV (2017) Hormonal contraception and the development of autoimmunity: A review of the literature.The Linacre Quarterly, 84(3). doi: 10.1080/00243639.2017.1360065.
Long-term use of certain progestogen drugs may raise risk of intracranial meningioma