Estrogen Prevents Heart Disease Part Two by Jeffrey Dach MD
In part one of this series, we discussed the history of hormone replacement regarding prevention of coronary artery disease finding a 50 percent reduction in mortality from heart disease depending on the study and the age of initiating estrogen replacement in post-menopausal women. The greatest cardiovascular benefit from HRT (hormone replacement therapy) was found in post-hysterectomy women with surgically induced menopause. Excellent cardiovascular mortality reductions of about 40 percent are obtained with HRT when started early, within 5 years of the menopausal transition. This is called the “Timing Hypothesis of Dr. Howard Hodis. Cardiovascular benefits of HRT are lost in women starting HRT more than 5 years after menopausal transition. (1)
This is part two. For part one, click here.
Header Image: Lab tech doing detection of bacterial lipopolysaccharides by electrophoresis. 2009 Author Aicomfoto CC 4.0 Courtesy of Wikimedia Commons.
How to Explain the Timing Hypothesis
The next logical question is how can we explain this “Timing Hypothesis?” What is the underlying pathophysiology that explains why estrogen replacement prevents coronary artery disease when started early, but not when started later?
Let us start by stating the obvious: the abrupt decline in estrogen levels in post-menopausal women triggers accelerated coronary artery disease, a degenerative change with calcified plaque formation in the wall of the coronary arteries. Once coronary plaque has been established, this degenerative change is difficult to reverse by starting estrogen later. This explanation doesn’t explain everything, and leaves important gaps in our understanding. Part two expands on the underlying pathophysiology of coronary artery disease in post-menopausal women and explains the “Timing Hypothesis” of Dr. Hodis.
Gut Permeability, Leaky Gut and Atherosclerosis
My 2018 book on coronary artery disease, entitled Heart Book, discusses the role of intestinal permeability, “Leaky Gut”, and low-level endotoxemia in the pathogenesis of coronary artery disease. The low-level endotoxemia arising from “leaky gut” leads to colonization of the arterial wall by polymicrobial biofilm which in turn leads to intense inflammatory reaction. The calcification within the arterial wall seen on the coronary calcium score is the body’s response to inflammation. Note: the coronary calcium score is a CAT scan test performed without IV contrast. The CT-angiogram test is a CAT scan performed with IV contrast.
In part one, we learned of two coronary calcium score studies derived from the WHI post menopausal patients showing the estrogen-treated group had lower calcium scores and reduced progression of calcium scores compared to the placebo-treated group. Coronary artery calcification is a response to polymicrobial infection in the wall of the artery, seeded from the gut microbiome and periodontal microorganisms. (2-3)
Heart Book, 2018
In my 2018 Heart Book, a mechanism was proposed to explain the train of events leading to coronary artery calcification. The originating event is “Leaky Gut”, a disruption of the mucosal barrier of the gut leading to leakage of LPS (lipopolysaccharide) and gram-negative microorganisms into the bloodstream, defined as low-level endotoxemia. Both LDL (low-density lipoprotein) and macrophages take up the LPS and whole micro-organisms, which then migrate into the arterial plaque, causing infection with polymicrobial biofilm. This incites an inflammatory reaction which leads to vascular calcification. Note: LPS is the outer coat of gram-negative bacteria, one of the most toxic substances known, and the cause of gram-negative septicemia, a dreaded complication with high mortality rate.(4)
Causes of Leaky Gut
There are many causes of “Leaky Gut.” The list includes fatty meals, high blood sugar (diabetes), dysbiosis with pathogenic bacteria, wheat gluten sensitivity which prolongs the opening of tight junctions, stress-altered permeability, etc. We can now add to this list the abrupt decline in estrogen levels which occurs at menopause. (5-6)
Menopausal Estrogen Decline Triggers Leaky Gut
Left Image: Leaky Gut: The opening of intercellular tight junctions (increased intestinal permeability) allows uncontrolled passage of substances into the bloodstream, with consequent possible development of autoimmune and inflammatory diseases, infections, allergies or cancers, both intestinal and in other organs of the body.
April 2016 Author Ballena Blanca. Courtesy of Wikimedia Commons.
The next obvious question is: can the sudden menopausal decline in estrogen trigger leaky gut and subsequent low-level endotoxemia? This is not well-known and not intuitively obvious. However, the medical literature on this is overwhelming, showing the menopausal decline in estrogen does indeed trigger disruption of the mucosal barrier of the gut, and causes increased gut permeability (i.e. Leaky Gut). We can now propose the menopausal decline in estrogen as the trigger for accelerated coronary atherosclerosis. Estrogen has two mechanisms for doing so. Firstly, estrogen is anti-inflammatory and secondly, estrogen controls and restores gut integrity. Anti-inflammatory effects of estrogen are mediated through the inhibition of Nuclear Factor Kappa B (NF-KB), the inflammatory master controller, which downregulates proinflammatory cytokines IL-1, IL-6, and TNF-alpha. Control of gut barrier integrity is mediated through ER-beta (estrogen receptor beta) which regulates tight junctions between epithelial cells of the gut lining. Thus, menopausal estrogen deficiency leads to disruption of the gut barrier, low-level endotoxemia, increased pro-inflammatory cytokines, and acceleration of atherosclerotic vascular disease, all reversed by estrogen replacement. In 2020, Dr. Albert Shieh studied animal models showing menopausal estrogen deficiency leads to increased gut permeability and inflammation, two major predicates for coronary artery disease and loss of bone mineral density (BMD), writing:
Inflammation is implicated in many aging-related disorders. In animal models, menopause [estrogen deficiency] leads to increased gut permeability and inflammation…Gut permeability increases during the MT [Menopausal Transition]. Greater gut permeability is associated with more inflammation and lower BMD [Bone Mineral Density]. Future studies should examine the longitudinal associations of gut permeability, inflammation, and BMD. Note: lower bone mineral density (BMD) is also associated with increased gut permeability and inflammation. (7-12)
In 2024, Dr. Xiuting Xiang studied the role of estrogen in the digestive system, noting ER-beta signaling regulates the permeability of the intestinal barrier, writing:
Overall, estrogen influences the composition and function of the gastrointestinal barrier and also impacts inflammatory processes within the digestive system. ER-beta signaling has been shown to regulate the permeability of the intestinal barrier by increasing the integrity of tight junctions through the expression of occludin and junctional adhesion molecule A. (13)
In 2024, Dr. Qinghai Meng from Nanjing, China found menopausal women have disordered gut microbiota which amplifies intestinal tight junction damage, accelerating atherosclerosis. Dr. Meng studied both women and a mouse model before and after menopause finding estrogen deficiency promotes microbiome disturbance, intestinal barrier damage, inflammation, and accelerates atherosclerosis, writing:
This study examined aortic estrogen receptor expression, histological changes, and gut microbiota in women before and after menopause, and tested serum estrogen levels, systemic inflammation, intestinal estrogen receptor expression, histological changes, atherosclerosis, and gut microbiota in low-density lipoprotein receptor knockout (LDLR-∕-) female mice before and after ovariectomy. We demonstrated that the downregulation of estrogen and estrogen receptors after menopause promotes gut microbiota disturbance in both women and female mice. We found that gut microbiota disturbance amplifies the intestinal barrier damage and aggravates systemic inflammation, thereby promoting atherosclerosis in female mice. Note: LDL receptor knockout mice are a good animal model for the study of atherosclerosis since they spontaneously develop atherosclerotic lesions. (14-16)
In 2023, Dr. Yuanuan Li used mice to show chronic psychological stress leads to decreased estrogen levels, disruption of the intestinal barrier with increased intestinal permeability, and increased pro-inflammatory cytokines. Estrogen replacement is protective and prevents these changes, writing:
Chronic psychological stress resulted in colonic mucosal injury, pro-inflammatory reaction, and decreased the diversity and richness of the colonic microbiota in pregnant mice. It was interesting that 25 pg/mL E2 provides better protective effect on intestinal epithelial cells…In summary, chronic stress significantly induces stress responses in maternal mice, leading to reduced estrogen secretion, disruption of the intestinal barrier, increased secretion of pro-inflammatory cytokines, decreased secretion of anti-inflammatory cytokines, and dysbiosis of the gut microbiota. Moreover, 25 pg/mL E2 protected the intestine. Our research demonstrates that maintaining stable maternal estrogen levels during pregnancy can safeguard intestinal health… (17)
Dr. Jane Yang on Estrogen and the GI Tract
In 2024, Dr. Jane Yang reviewed the entire medical literature on menopausal estrogen deficiency from 1972 to 2023. Within this larger topic, Dr. Jane Wang discusses estrogen’s importance for the gastrointestinal (GI) tract, pointing out the extensive presence of estrogen receptors throughout the GI tract. If you thought having estrogen receptors means estrogen is playing a controlling role, then you would be quite correct. ER-beta signalling controls the permeability of the gut barrier by maintaining the integrity of the tight junctions. When estrogen levels decline after menopause, this gut barrier integrity is lost, triggering leaky gut, low level endotoxemia, and accelerated atherosclerosis. Dr. Jane Wang writes:
ER-alpha, ER-beta, and GPER1 [G-protein coupled receptor 1] are found widely throughout the gastrointestinal (GI) tract…Overall, estrogen influences the composition and function of the gastrointestinal barrier and also impacts inflammatory processes within the digestive system. ER-beta signaling has been shown to regulate the permeability of the intestinal barrier by increasing the integrity of tight junctions through the expression of occludin and junctional adhesion molecule A… In multiple experimental models of colitis, estrogen has been shown to decrease intestinal inflammation and tissue damage. Note: GPER1 is the estrogen receptor on the cell membrane involved in immediate signaling. The other two receptors must enter the nucleus which takes more time. (18-26)
Menopause as an Inflammatory Event
There is considerable evidence for viewing the menopausal transition as an inflammatory event. In 2007, Dr. Toshiyuki Yasui found that serum IL-6, the main inflammatory cytokine was inversely correlated with serum estradiol levels. As estradiol decreased, the pro-inflammatory cytokines increased. In 2021, Dr. Haidong Wang found estradiol has an inhibitory effect on NF-KappaB, the inflammatory master controller. (27-29)
In 2005, Dr Serena Ghisletti studied the mechanism by which estradiol exerts its anti-inflammatory effects, finding estrogen blocks the p65 transcription factor (a member of the NF-KappaB family), inhibiting the p65 intracellular transport to the nucleus. This anti-inflammatory effect of estrogen is mediated through ER-alpha, writing:
Estrogen is an immunoregulatory agent, in that hormone deprivation increases while 17β-estradiol (E2) administration blocks the inflammatory response; however, the underlying mechanism is still unknown. The transcription factor p65/relA, a member of the nuclear factor κB (NF-κB) family, plays a major role in inflammation and drives the expression of proinflammatory mediators. Here we report a novel mechanism of action of E2 in inflammation. We observe that in macrophages E2 blocks lipopolysaccharide-induced DNA binding and transcriptional activity of p65 by preventing its nuclear translocation. This effect is selectively activated in macrophages to prevent p65 activation by inflammatory agents and extends to other members of the NF-κB family, including c-Rel and p50. We observe that E2 activates a rapid and persistent response that involves the activation of phosphatidylinositol 3-kinase, without requiring de novo protein synthesis or modifying Iκ-Bα degradation and mitogen-activated protein kinase activation. Using a time course experiment and the microtubule-disrupting agent nocodazole, we observe that the hormone inhibits p65 intracellular transport to the nucleus. This activity is selectively mediated by estrogen receptor alpha (ER-alpha) and not ERβ and is not shared by conventional anti-inflammatory drugs. These results unravel a novel and unique mechanism for E2 anti-inflammatory activity, which may be useful for identifying more selective ligands for the prevention of the inflammatory response. (30-35)
In 2020, Dr. Micheline McCarthy reviewed the menopausal transition as an inflammatory event, suggesting the menopausal decline in estrogen levels drives a systemic pro-inflammatory state, writing:
It is now known that one of the key functions of estrogen is to work as a potent anti-inflammatory factor …The presence of the inflammasome complex in the cerebrospinal fluid of post-menopausal women suggests that the decline in estrogens induces a pro-inflammatory state...There is increasing and compelling evidence showing that estrogen decline during the menopausal transition drives a systemic inflammatory state. This state is characterized by systemic pro-inflammatory cytokines derived from reproductive tissues, alteration in the cellular immune profile, increased availability of inflammasome proteins in the CNS, and a pro-inflammatory microenvironment which makes the brain more susceptible to ischemic and other stressors.… The use of ER-beta-selective agonists may constitute a safer and more effective target for future therapeutic research than an ER-alpha agonist or E2 [estradiol]. ER-beta activation in the brain confers ischemic protection, stimulates mitochondrial functions, and inhibits inflammasome activation. ER-beta agonists may be safer in that ER-beta lacks the ability to stimulate the proliferation of breast or endometrial tissue. The ER-beta agonist may be able to act both on the cerebro- and cardiovascular system to reduce the ischemic burden. Thus, ER-beta signaling is a guide for future translational research to reduce cognitive decline and cerebral ischemia incidents and impact in post-menopausal women, while avoiding the side effects produced by chronic E2 [estradiol] treatment…Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. (36-38)
Low Grade Endotoxemia, LPS and Infection in Atherosclerotic Plaque
In 2023, Dr. Francesco Violi reviewed the link between gut-derived low grade endotoxemia, atherosclerosis and cardiovascular disease. Gut dysbiosis (Leaky Gut) is implicated in atherosclerosis via leakage of live bacteria and LPS into the blood stream causing low-level endotoxemia. Studies show the presence of LPS adjacent to macrophages within atherosclerotic plaques. Dr. Francesco Violi writes:
A growing body of evidence indicates that gut dysbiosis is implicated in the atherothrombotic process via increased translocation of viable bacteria or bacterial products such as lipopolysaccharides (LPS) and trimethylamine-N-oxide (TMAO) into the systemic circulation ….Support for the putative role of LPS in atherosclerosis has been provided by immunohistochemistry analysis of carotid atherosclerotic plaques from patients undergoing endarterectomy, which revealed the presence of LPS adjacent to plaque macrophages with high TLR4 levels. By contrast, LPS was not detected in atherosclerosis-free thyroid arteries from the same patients….Experimental data support the association between low-grade endotoxaemia, atherosclerosis and thrombosis, and indicate that gut dysbiosis-induced changes in intestinal permeability are a key step for LPS translocation into the systemic circulation. (39)
In 2011, Dr. Omry Koren 16s ribosomal RNA sequencing to find bacterial DNA present within atherosclerotic plaques, writing:
Using qPCR, we show that bacterial DNA was present in the atherosclerotic plaque and that the amount of DNA correlated with the amount of leukocytes in the atherosclerotic plaque. To investigate the microbial composition of atherosclerotic plaques and test the hypothesis that the oral or gut microbiota may contribute to atherosclerosis in humans, we used 454 pyrosequencing of 16S rRNA genes to survey the bacterial diversity of atherosclerotic plaque, oral, and gut samples of 15 patients with atherosclerosis, and oral and gut samples of healthy controls…Our analysis also revealed several OTUs [operational taxonomic units] shared between the atherosclerotic plaque and the gut, suggesting that bacteria present in the atherosclerotic plaque could also be derived from the distal gut as well as the oral cavity. One mechanism by which bacteria could reach the atherosclerotic plaque is phagocytosis by macrophages at epithelial linings (e.g., the oral cavity, gut, and the lung). Upon phagocytosis, the macrophages become activated, and when they reach the activated endothelium of the atheroma, they leave the blood stream to enter the atheroma and transform into cholesterol-laden foam cells. In support of this mechanism, patients with cardiovascular disease have a twofold increase of C. pneumonia-infected peripheral blood mononuclear cells compared with controls. Furthermore, bacteria are only present in atheromas and not in healthy aortic tissues in mice and have been identified in human atherosclerotic plaques. Thus, infected macrophages may specifically target bacteria to atheromas… In summary, we detected key bacterial members of dental plaque in atherosclerotic plaques in humans, as well as a novel common member, Chryseomonas, in all atherosclerotic plaques. In addition, the atherosclerotic plaques contained numerous bacteria from different phyla. Our findings strongly support the hypothesis that the oral cavity and gut can be sources for atherosclerotic plaque-associated bacteria. (40)
In 2018, Dr. Roberto Canevale found LPS from E. Coli (gram negative bacteria) within atherosclerotic plaque material. (41-42)
In 2022, Dr. Iman Razeghian-Jahromi reviewed the medical literature on the prevalence of micro-organisms within atherosclerotic plaques of the coronary arteries finding 44 studies, writing:
In this systematic review and meta-analysis, the existence of pathogens in atherosclerotic plaques of coronary arteries was investigated in CAD patients…44 studies were selected…Infection of vascular cells, detection of the microbes within the atherosclerotic plaque, and the development of atherosclerotic lesions after microbial infection in animal models reinforce the direct association of infection with atherosclerosis….Our studies show the presence of different pathogens (bacteria and virus) in the atherosclerotic plaques of coronary arteries...This may show the implication of a microbial center for the initiation and development of atherosclerotic plaque…Several studies reported the presence of more than one pathogen in atherosclerotic plaques. The simultaneous existence of some bacteria synergistically enhances their virulence. Virulence factors of bacteria including fimbriae, degradative enzymes, exopolysaccharide capsules, toxins, and atypical lipopolysaccharides trigger the process of inflammation and affect vital organs like the cardiovascular system. These adverse effects will be more detrimental in mixed infections…Atherosclerosis may be originated from bacterial infection in terms of microbial symbiosis and inflammatory stimulus]. Microbial agents contribute to the atherosclerosis process directly by infecting the vascular cells or indirectly by activation of inflammatory cytokines. … It seems that the entry of bacteria and other microbiome populations into the bloodstream is a continuous flow which inevitably leads to a surge in the expression of inflammatory cytokines and chemokines. These factors could be drivers of CAD [71]. For example, it was shown that bacterial lipopolysaccharide (LPS) upregulates LDL levels, increasing the risk of CAD. Indeed, the remnants of bacteria like DNA or membrane phospholipids provoke CAD via modulating adipose or vascular tissues. However, it was reported that the development of atherosclerotic lesions is largely accelerated by live organisms rather than heat-killed ones or their LPS. Reports on successful culturing of pathogens after their isolation from atheroma only existed about C. pneumoniae and E. hormaechei. (43-57)
Conclusion: When one begins to understand the role of leaky gut, low level endotoxemia and microbial colonization of atherosclerotic plaque, one begins to realize the role of estrogen in prevention of coronary artery disease. Firstly. estrogen is an anti-inflammatory agent, and secondly, estrogen maintains the gut barrier. Menopausal loss of estrogen increases systemic inflammation, disruption of the gut barrier, low level endotoxemia and atherosclerosis. It becomes clear these two roles of estrogen are in fact what is preventing the acute onset of coronary artery disease in the post menopausal time frame. It also becomes clear why lowering serum cholesterol with statin drugs fails in primary prevention. Although statin drugs are anti-inflammatory, and antimicrobial, two pleiotropic effects, statin drugs do not address the gut membrane barrier, while menopausal estrogen replacement does. Another difference is the well-known adverse side effects of statins which are not shared by hormone replacement, namely, muscle pain, cognitive dysfunction, and neuropathy.
The above proposed mechanism of leaky gut and low level endotoxemia also explains the timing hypothesis of Dr. Howard Hodis. Promptly starting estrogen replacement at the onset of menopausal symptoms prevents the detrimental effects on the gut barrier, prevents low level endotoxemia, and microbial infiltration of the atherosclerotic plaque. This is true prevention for coronary artery disease. The most casual observer can see the overwhelming evidence for the infection theory of coronary artery disease, yet the cholesterol theory is too entrenched and the financial stakes are too high for mainstream medicine to make the paradigm shift. Mainstream medicine clings to the old dogmas, and ignores and refuses to accept all the studies listed here that prove microbial infection is the over-riding pathology in the coronary artery plaque which causes calcification seen on the Calcium Score, a CAT scan test. Instead of prescribing hormone replacement, the menopausal woman is handed out statin drugs nonchalantly by the primary care and cardiologist, oblivious to the fact statin drugs are ineffective for primary prevention of coronary artery disease, and are associated with the horrendous adverse side effects of muscle pain, cognitive dysfunction, and neuropathy. For more on this see the Heart Book (2018) by Jeffrey Dach MD. (4)
My book is called: Heart Book
If you liked this article, you may like my book, entitled Heart Book on Amazon. See cover image at left.
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Articles with Related Interest:
Estrogen Prevents Heart Disease Part One
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References for Chapter 10 Estrogen Prevents Heart Disease Part Two
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