The sex hormone estrogen is implicated in hastening the progression of many chronic diseases. In particular, when compared to people with testes, menstruating people with ovaries are at higher risk of developing estrogen-dependent cancers[i], autoimmunity[ii][iii], and more rapid disease progression along with poorer prognosis in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis[iv][v]. In different tissues estrogen has differing effects that include cell proliferation, immunomodulation, and stimulation of mucin secretion[vi][vii][viii]. Here I will briefly touch on what role estrogen is theorized to play in the pathogenesis of estrogen-dependent cancers and autoimmunity, but I will discuss in more depth the role that it plays in the disease progression of chronic respiratory diseases. Lastly, I will discuss the potential therapeutic effects of phytoestrogens on estrogen-related disease progression.
Estrogen plays a major role in certain hormone-dependent cancers. There are two types of estrogen receptors: estrogen receptor alpha (ER-a) and estrogen receptor beta (ER-b). It is thought that estrogen’s agonism of the ER-a causes cell proliferation indirectly through a paracrine mechanism involving non-proliferating ER-a-positive cells. In addition, the ER-b seems to repress cell proliferation and is pro-apoptotic, therefore the ER-b might generally inhibit the mitogenic activity of estrogens mediated by ER-a[ix][x]. Studies have shown that later-stage breast cancers have an over-expression of ER-a, and an under-expression of ER-b. The breast cancer drug tamoxifen is an ER-a antagonist, but may also act as an ER-b agonist[xi]. Theoretically, by agonizing the ER-b in the earlier stages of estrogen-dependent cancers, tumor growth may be inhibited.
The role of sex hormones in the development of autoimmunity is complex, and sex hormone production and its related risks to autoimmunity may even interface with the human gut microbiome[xii]. Menstruating people are on average 2.6 times more likely than males to develop autoimmunity, and in particular have a significantly higher risk of developing Hashimoto’s, Graves’, Sjogren’s, lupus, multiple sclerosis, and rheumatoid arthritis than males[xiii]. In general, it has been shown that menstruating people/those with ovaries have stronger immune responses than people with testes, and this may lead to an increased production of either auto-antibodies or inflammatory cytokines, both of which make autoimmune symptoms worse. People with ovaries tend to have both stronger cell-mediated immune responses and higher antibody production than males when immunized. The T-cell mediated immune response in females is influenced by sex hormones. A helper T-cell type 1 (Th1) response is a cell-mediated and pro-inflammatory, involving the production of IL-2, IFN-gamma, and lymphotoxin. A Th2 response is less inflammatory but is focused on the production of antibodies. Females are more likely to have a Th1 response when challenged by an infection or antigen, yet during pregnancy the Th2 response is dominant. It is thought that estrogen has a biphasic effect on the immune system, with higher levels stimulating a Th2 response (e.g. during pregnancy and ovulation), and lower levels stimulating a Th1 response (e.g. during menstruation). Progesterone promotes the development of Th2 cells and therefore antagonizes the Th1 response. In females with multiple sclerosis (MS) and rheumatoid arthritis (RA), symptoms can often become worse during menstruation, when estrogen and progesterone are low, and disease can go into temporary remission during pregnancy, when estrogen and progesterone are high. Furthermore, females with MS and RA often experience improvements in their symptoms when using oral contraceptives or hormone replacement therapy. Conversely, females with lupus can see their symptoms worsen with pregnancy or hormone therapy. Testosterone seems to have an anti-inflammatory and immunosuppressive effect on autoimmunity[xiv].
Estrogen affects the respiratory tract in multiple ways. Chronic respiratory diseases such as certain types of asthma, COPD, and cystic fibrosis often involve mucus hypersecretion and bacterial colonization of the lungs. Cystic fibrosis (CF), a genetic disease that results in a thickening of the mucus in the respiratory tract, is typified by chronic Pseudomonas aeruginosa lung infections. Bacterial colonization and mucus hypersecretion in CF, COPD, and non-CF bronchiectasis results in an immune response where neutrophils are over-recruited and inefficient at cleaning up infection, and thus die in large numbers, leaving behind inflammatory cytokines and proteolytic enzymes, such as neutrophil elastase, which cause further airway damage[xv]. Females with CF experience more pulmonary exacerbations during the follicular phase of the menstrual cycle, when estrogen is high[xvi]. Estrogen affects CF pulmonary exacerbations in at least two ways. First, exposure to estrogen causes Pseudomonas aeruginosa (PA) to mutate from its non-mucoid, planktonic form to its mucoid, biofilm-mediated form. PA in its mucoid form is more virulent and more resistant to antibiotics, making it harder to treat. Females with CF are colonized with PA at an earlier age and more often culture mucoid strains than males. Mucoid PA is cultured more often in females during the follicular phase (when estrogen is high) than during menstruation (when estrogen is low)[xvii]. Secondly, the epithelium of the airways changes when exposed to estrogen. When airway tissue is exposed to estrogen, the expression of mucin-producing goblet cells in the epithelium increases by about 635%, while the expression of ciliated cells decreases by about 64%. Furthermore, estrogen increases goblet cell mucin production by about two-fold[xviii].
Phytoestrogens, such as the soy isoflavone genistein, agonize ER-a less strongly than estrogen (estradiol) yet agonize ER-b more strongly than estradiol. In fact, the ER-b has a 30-fold greater binding affinity for genistein than ER-a. By preferentially agonizing the ER-b, which is anti-mitogenic, phytoestrogens may have a role preventing the formation and proliferation of estrogen-dependent cancers, and may even provide a safer alternative to hormone replacement therapy in menopausal women[xix]. While there has been preliminary research on the impacts of phytoestrogens on autoimmunity[xx], more research must be done to determine whether they can be used to reduce disease progression in estrogen-affected autoimmune diseases. The use of phytoestrogens in chronic respiratory diseases like asthma and CF may have beneficial effects in multiple different ways. For example, one study showed that females with CF using oral contraceptives had less frequent pulmonary exacerbations than those not using contraceptives[xxi]. In bronchial epithelium, the ER-b is the predominant type of ER expressed[xxii]. Therefore, phytoestrogens may be a preferential analogue to exogenous estradiol in its effects on the lung. Herbs containing phytoestrogens include red clover, licorice, shatavari, and black cohosh.
However, research on the use of phytoestrogens such as genistein in people with CF has mainly focused on their ability to correct and potentiate mutant CFTR channels in the epithelium, addressing the fundamental cellular defect that leads to CF disease expression. One animal study showed that the expression of CFTR channels in the uterine epithelium is upregulated by genistein supplementation, possibly via agonism of the ER-b, and this results in an increase in luminal fluid accumulation[xxiii]. Several in vitro studies have shown that genistein potentiates gating in wild-type and mutant deltaF508 CFTRs, allowing chloride to flow out of the cell[xxiv][xxv], which in humans would increase water outflow into the mucus lining outside of epithelial cells, ameliorating the fundamental disease process of CF. These studies show that genistein and other isoflavones can have epigenetic effects that may rescue faulty CFTR expression in people with CF. Furthermore, when paired with curcumin, a well-documented corrector of mutant CFTR function, genistein can have a significant potentiating effect on CFTR gating in G551D mutations[xxvi]. Therefore, the epigenetic effects of phytoestrogens may prove very useful in the treatment of CF, and may even be synergistic with pharmaceutical CFTR correctors and potentiators[xxvii].
The use of other herbs that balance menstruation and sex hormone production may also be helpful in minimizing estrogen's negative impact on lung health. Vitex berry (Vitex agnus-castus) is an excellent herb for balancing estrogen and progesterone in people with ovaries, and can alleviate dysmennhorea. Several other herbs may also help female hormone imbalances such as shatavari, black cohosh, licorice, and others. Consult a clinical herbalist to discuss which of these herbs may be most suitable for your constitution and to check for possible herb-drug interactions.
In conclusion, estrogen has a harmful effect on the progression of chronic disease in many people who menstruate. Estrogen can have mitogenic, inflammatory, and mucus hypersecretory effects in certain conditions. Supplementation with phytoestrogens or herbal hormone modulants may have beneficial effects on these mechanisms of disease, and may cause epigenetic changes that result in improved prognosis for people with cystic fibrosis.
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[xviii] Tam, Anthony, et al. 2014.
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[xxii] Tam, Anthony, et al. 2014.
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Mica McDonald (they/he) is a clinical herbalist, nutritionist, ecologist, and writer living in Abenaki territory (Vermont).