Once again, estrogen rears its ugly head. The evidence on a link between estrogen and RA, as well as all “autoimmune” conditions, goes back decades, yet it is still considered “controversial (read: true), and medicine now pushes for reintroduction of estrogen therapy in females. Be that as it may, there is not much information in regards to a link between estrogen and “structural” conditions such as OA. The studies below present evidence that estrogen is a causative agent in both RA and OA, and one reason estrogen has not been officially implicated so far in either condition may be that it is not estrogens such as estrone and estradiol (the major circulating estrogens measured by doctors on blood tests) that are the causative agents, but their metabolites (also highly estrogenic). Namely, hydroxylated metabolites on position C-16 of both estrone and estradiol. To my knowledge, blood tests for these metabolites are not even commercially available through major labs such as LabCorp/Quest, which makes the task of implicating conclusively estrogens in those conditions that much more difficult. However, since multiple studies have demonstrated that blood levels of estrone sulfate (E1S) are highly predictive of total body estrogenic reserves, I suspect a test for E1S can be predictive and diagnostic for these conditions. And since E1S is also not easy to order as a blood test, another good surrogate for “estrogenicity” is prolactin, which is available as a test in virtually all labs. Coincidentally, elevated prolactin has already been linked to most “autoimmune” conditions, which corroborates both the suitability of prolactin for measuring estrogenicity of an organism, as well as the role of estrogens in “autoimmune” conditions. Interestingly enough, some of the studies below suggest that it is the ability of the estrogenic metabolites to generate reactive oxygen species (ROS) that drives the immunogenicity in tissues where the ROS are generated, and thus create/drive an “autoimmune” reaction. As such, vitamin E may be the perfect substance for “autoimmune” conditions, because not only is it the major endogenous anti-oxidant, but it is also a direct estrogen receptor antagonist and an aromatase inhibitor. Adding other anti-estrogenic chemicals such as progesterone, androgens, pregnenolone, flavones/flavanones, etc would probably synergize with vitamin E for such conditions and, again “coincidentally”, multiple studies have already demonstrated benefits of progesterone, testosterone, DHEA, DHT, etc in both RA and OA, as well as many other “autoimmune” conditions such as multiple sclerosis (MS), psoriasis, inflammatory bowel diseases, etc. Another major pathway through which estrogen may cause “autoimmune” conditions is apparently by activating the synthesis of prostaglandins and leukotrienes (PUFA metabolites) and the study authors suggest synthesis inhibitors of such metabolites as viable treatments for RA/OA. Aspirin, anyone? Oh, and last but not least – the studies below openly discuss the genotoxic and mutagenic properties of estrogen, as a mechanism behind estrogen’s immunogenicity. So, the next time some guru tries to make an argument that estrogen is “beneficial” and has no link to cancer (as it happened after one of my podcasts with Dr. Mercola), please remind that person that in the scientific literature estrogen is an established genotoxic, mutagenic carcinogen.
https://arthritis-research.biomedcentral.com/articles/10.1186/ar1769
https://www.intechopen.com/chapters/39615
“…Remarkable progress have been made in understanding the role of estrogen in the etiology of RA but the role of catechol-estrogens (CE) in RA is lacking. Catechol metabolites are known to play an important role in RA but the exact patho-aetiology remain elusive. The evidence concerning the possibility of CEs in the development of RA is very limited and preliminary. It has been observed that oxidative reactions, often catalyzed by isoforms of the cytochrome P-450, can result in the formation of CEs from parent estrogen and subsequently, semiquinones and quinones derived from CEs, are capable of forming either stable or depurinating DNA adducts. Oxidation of CEs also leads to high amount of ROS that can generate extensive DNA damage. This would probably alter its immunogenicity leading to the induction and elevated levels of RA autoantibodies (Figure 4). Therefore, it is possible that the CE-modified bases of DNA might be one of the contributing factors towards production of SLE autoantibodies. In addition, estrogen not only induces DNA damage but also modulate immune response and immune mediated disease. Estrogen was found to increase IgG and IgM from PBMC, which let to elevated level of polyclonal IgG including IgG anti-ds DNA by enhancing B cell activity via IL-10. These autoantibodies could be strongly bound to DNA and serve as an immunological marker for the diagnosis of diseases. Estrogen is thought to play both pro- and anti-inflammatory role in chronic inflammatory diseases that were found to be related to low and high concentration. Increased estrogen to androgen ratio have been observed in RA patients SF, perhaps due to increase aromatase expression by inflammatory macrophages infiltrating synovial tissues. The discovery of high concentration in SF from RA patients of both sexes can also be explain by the fact that inflammatory cytokines (i.e. TNFα, IL-1, IL-6) are increased in RA cynovitis and can markedly stimulate aromatase activity in peripheral tissue. But renal excretion studies showed that enhanced estrogen metabolism observed in RA resulted in elevation of pro-inflammatory metabolites derived from estrone and estradiol such as 16-OHE1 (or 4-OHE2, 4-OHE1) which exert mitogenic effect on different synovial fibroblast. In contrast, RA SF have reduced amount of anti-inflammatory estrogen metabolites such as 2-hydroxyestrogen that inhibit the growth-promoting effect of estradiol. An unwanted shift from 2- to 4-hydroxyestrogen might be an additional pro-inflammatory signal because these 4-hydroxylated metabolites can be converted to 3,4-quinone, which lead to depurination and mutation in DNA. In conclusion, an increase in 16-OHE1 relative to the sum of all 2- and 4-hydroxylated estrogens must be considered as pro-inflammatory signal which is particularly evident in RA [60].”
https://www.nature.com/articles/ncprheum0308
“…Women with an increased urinary 2-hydroxyestrone:16α-hydroxyestrone ratio were more likely to develop incident knee OA, an association that persisted after controlling for confounding variables. Sowers et al. speculate that high concentrations of 2-hydroxyestrone in urine could reflect levels of leukotriene synthesis and modulation of lipoxygenases in the arachidonic acid pathway (which is associated with pain and inflammation), rather than estrogen-receptor-mediated effects. They suggest that the arachidonic acid pathway could provide therapeutic targets for intervention in OA.”
https://doi.org/10.1002/art.22005
“…Women who developed knee OA were more likely to have a ratio of 16α-hydroxyestrone to 2-hydroxyestrone in the highest tertile (>0.86; OR 1.86, 95% CI 1.01–3.44 compared with women with ratios in the 0.54–0.86 range), after adjustment for other covariates.”
