Estrogen is well-known for its role in reproductive biology, but researchers now believe it may also have effects on the immune system. This explains why women have been found to have heightened inflammatory responses compared to men. As a result, women have significantly lower rates of infection and inflammation in comparison to men. However, estrogen also contributes to an increased risk of autoimmune diseases in women (1). The effects of estrogen may seem paradoxical, on the one hand suppressing the immune system yet supporting it on the other. However, this paradox also means that estrogen may protect against some infectious diseases, but promote other autoimmune diseases and inflammatory conditions.
Estrogens and Inflammatory Disease
Estrogens are in fact a family of sex hormones, which includes estriol, estrone, and estradiol. The most potent of the estrogens is estradiol. Estrogens are metabolized or ‘detoxified’ through the formation of estrogen metabolites such as conjugated estrogen, 16-alpha-hydroxyestrone, and 2-hydroxyestrone. Estrogen metabolites are less potent and are more easily eliminated (excreted) from the body. The enzymes responsible for detoxifying estrogen include beta-glucuronidase and CYP1A1 (2, 3). As we will discuss later, lifestyle factors such as diet and supplementation may help to support estrogen detoxification.
In healthy women and men, estrogens are produced by a wide range of tissue types, including ovaries, testes, placenta, bone, and adipose (fat) tissue. In premenopausal women, the ovaries produce most of the body’s estrogens, which are released into circulation and have effects on other body systems. After menopause, however, the production of estrogens by the ovaries falls significantly and the adipose tissue takes over as the main producer of estrogens. The adipose tissue contains the aromatase enzyme which converts androstenedione produced by the adrenal glands into estrone. Estrone is then converted into estradiol, the most potent estrogen. In men, the production of estrogens is similar to that of postmenopausal women (1).
The mode of action of estrogens in premenopausal women is different to that of postmenopausal women and men. In premenopausal women, the majority of estrogens are produced by the ovaries where they are released into the circulatory system. After entering circulation, estrogens cause effects on other body systems by acting at tissue sites around the rest of the body – this mode of action is referred to as ‘endocrine’. In contrast, the estrogens that are produced by adipose tissue in postmenopausal women and men cause ‘local’ effects by acting at tissues much nearer to the site of their production – this mode of action is referred to as ‘autocrine’ if the estrogen acts on the cell that produced it, or ‘paracrine’ if the estrogen acts on a neighbouring cell (1).
Estrogens act on the immune system in an endocrine manner (estrogen produced by the ovaries act on immune cells all over the body) or in a paracrine/autocrine manner (estrogen produced by adipose tissue acts on only those cells close to the site of estrogen production). Because many of the cells of the immune system are transported throughout the circulatory system to “patrol” for infectious agents around the body, the effects of estrogens on the immune system are more striking in premenopausal women compared to postmenopausal women or men. Table 1 (on page 21) summarises the effects of estrogen on the cells of the immune system in premenopausal women compared to postmenopausal women.
Estrogens must be recognised by an estrogen receptor on a target tissue/cell to produce an effect. Receptors can be thought of as “locks” at which a specific “key” – in this case estrogen – causes an effect (i.e. opens the biological flood gates so to speak). Estrogen receptors are of two types: ER-alpha and ER-beta. And it matters which type of estrogen receptor the estrogens are recognised by. Studies have shown that a higher level of ER-beta is found in joint (synovial) tissue of patients with rheumatoid arthritis compared with healthy humans (4, 5). A higher level of ER-beta is also
found on immune cells (T cells) of patients with systemic lupus erythematosus (6), an autoimmune disease in which the immune system attacks healthy tissues in the body.
These studies suggest that estrogen may cause an inappropriate inflammatory response against the body through an increased chance for an interaction with the receptor ER-beta. This, in combination with the release of high levels of “endocrine” estrogens into the circulatory system by the ovaries, may partly explain why under certain conditions (i.e. increased ER-beta expression by immune cells) estrogen levels are associated with an increased rate of autoimmune diseases in women.
Autoimmune diseases have traditionally been explained by the theory of “autoimmunity”. Simply put, autoimmunity is an inappropriate inflammatory response against the body (“self”). In other words, the immune system attacks body tissues believing them to be infected or “foreign”, when they in fact are not. However, recent research is challenging the theory of autoimmunity as the sole basis for these inappropriate inflammatory responses. The human gastrointestinal tract contains one hundred trillion bacterial cells per gram of material (7). These infectious agents – collectively called the “microbiota” – are in fact so numerous that “at least 90% of cells in the human body are now understood to be bacterial, fungal, or otherwise non-human” (8)! Microbiologists have proposed that the normal (“commensal”) microbiota may play a role in suppressing the inflammatory response by breaking down agents that promote inflammation (i.e. hormones such as estrogen).
The collective DNA (genome) of the microbiota is referred to as the “microbiome”. The microbiome produces millions of “foreign” proteins that interact with host proteins – these foreign proteins are called the “interactome”. However, the interactome can alter the function of some of the host proteins, for example the immune response to a family of disease-causing (“pathogenic”) bacterial species, the Mycobacteria, alters a protein called PTPN22 that is associated with autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus (8). Through successive exposure to these infectious agents, an individual’s interactome may change in composition such that it begins to promote inflammatory disease (9). Or put another way, the inflammatory response is negatively altered over time by the interactome due to repeated infections.
The interactome contains a sub-set of proteins that are able to interact with estrogens in the body. This sub-set of proteins is called the “estrobolome”. The estrobolome is capable of metabolizing or detoxifying estrogens. An estrobolome that contains enzymes such as beta-glucuronide and beta-glucuronidase – enzymes that can attach (“conjugate”) or remove (“de-conjugate”) a molecule of glucuronic acid to/from a molecule of estrogen – which can alter the levels of estrogens in the body. Beta-glucuronide conjugates (attaches) a molecule called glucuronic acid to estrogens in the gastrointestinal tract, forming “conjugated estrogen” (i.e. estrogen with glucuronic acid attached to it). Conjugated estrogens are more water soluble and are therefore less easily absorbed from the gastrointestinal tract into circulation. The conjugation of glucuronic acid to estrogens in the gastrointestinal tract aids in the elimination (or excretion) of estrogen from the body, a process that contributes to estrogen detoxification. On the other hand, the de-conjugation (removal) of glucuronic acid from estrogens by beta-glucuronidase in the gastrointestinal tract forms “de-conjugated estrogens” (free estrogens) that are more lipid soluble. Lipid soluble estrogens are more easily reabsorbed from the gastrointestinal tract back into circulation. This process raises the levels of estrogen in the body and opposes estrogen detoxification.
Unfortunately, beta-glucuronidase is produced by bacteria such as Escherichia coli, Clostridium perfringens and Bacteroides fragilis (2). Through successive exposure to these infectious agents, an individual’s estrobolome may change in composition such that it alters the balance of beta-glucuronide and beta-glucuronidase in the gastrointestinal tract. Such changes reflect alterations to the normal composition of the microbiota – a state referred to as ‘dysbiosis’ – and may lead to inappropriate inflammatory responses due to the lack of estrogen detoxification.
Estrogen Detoxifcation and Diet/ Supplementation
Vegetarians have been found to excrete a higher proportion of estrogens compared to non-vegetarians (7). The reason for this finding is thought to be the effect of the vegetarian diet on the composition of the microbiota, which influences the function of the estrobolome leading to higher levels of estrogen detoxification. This raises the possibility that lifestyle factors such as diet, supplementation, and probiotics may influence the function of the estrobolome and reduce the risk of inappropriate inflammatory Researchers have also suggested harnessing the estrobolome to reduce the risk of estrogen-driven cancers such as endometrial cancer, estrogen receptor-positive breast cancer, and some ovarian cancers (7).
A diet rich in fats and sugar and low in calcium and fibre has been shown to increase (2.5-fold) the activity of the beta-glucuronidase enzyme compared to an energy-equivalent diet that was low in fat and high in starch, calcium and fibre (10). In contrast, the activity of beta-glucuronidase has been shown to be reduced due to the use of probiotics containing the “good” bacteria Lactobacillus acidophilus and Bifidobacterium infantis. Therefore, eating a low fat/sugar diet that is rich in fibre (i.e. cruciferous vegetables) and consuming probiotics may enhance estrogen detoxification by helping to address any imbalances caused by estrobolome dysfunction.
Research has shown that D-glucarate supplements are able to inhibit the function of beta-glucoronidase, resulting in increased estrogen detoxification (11). D-glucarate may therefore be an effective supplement for promoting estrogen detoxification. Research has also shown that the consumption of fibre from fruit, vegetables and grains may help to convert the more potent estrogen 17-beta-estradiol into the less potent form 16-alpha-hydroxyestrone (12). Similarly, the consumption of cruciferous vegetables can provide the active component indole-3-carbinol, which also plays a role in the detoxification of estrogens. Indole-3-carbinol may act on the enzyme CYP1A1, which converts 16-alpha-hydroxyestrone into an even less potent form, 2-hydroxyestrone (3). The consumption of flax seed has also been shown to play a role in the conversion of 16-alpha-hydroxyestrone into 2-hydroxyestrone (13).
Dietary fibre imbalances can be addressed through supplementation with partially hydrolyzed guar gum, a tasteless, odourless alternative to potentially allergenic wheat and corn-based fibre. However, further research is needed to evaluate the link between the consumption fibre and its effects on the estrobolome.
Our understanding of estrogens and the estrobolome provide important insights into the links between sex hormones, the gut microbiota, and inflammatory disease. These insights also offer alternative approaches for 1) improving the health of the microbiota of the gastrointestinal tract, 2) reducing sex hormone imbalances by promoting estrogen detoxification, and 3) reducing estrobolome dysfunction and inappropriate inflammatory responses. Consuming a low-fat vegetarian diet, rich in fibre combined with probiotics and D-glucarate supplementation may provide an effective strategy to support estrogen detoxification.
Table 1: The effect of estrogen on cells of the immune system in premenopausal women in comparison to postmenopausal women. The immune system is made up from immune cells that carry out the functions that support the inflammatory response: B cells (B lymphocytes) produce antibodies that help to kill infectious agents; T cells (T lymphocytes) can produce cytokines that activate B cells, and also directly kill infected host cells; Macrophages literally ‘eat’ infectious agents that become coated with antibodies, killing them once ingested; Dendritic cells (antigen presenting cells) present antigens to B and T cells, identifying which infectious agents the B and T cells should attack; Microglia perform them same task as macrophages but only in the central nervous system (the brain and spinal cord); Natral killer cells perform a similar task to T cells by killing some infected host cells. An antibody is a protein that binds to a specific infectious agent that has been identified by recognition of an antigen (a ‘foreign’ structure that is unique to a particular pathogen, i.e. not normally found in the host). Cytokines are agents (proteins) that have pro-inflammatory or anti-inflammatory effects that enhance or inhibit certain types of inflammatory response. Adapted from (1).