endometriosis, heavy menstrual bleeding HIF

Endometriosis and Heavy Menstrual Bleeding: Two Sides of the Same Molecular Coin

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For as long as I have been studying endometriosis, I have suspected that endometriosis represented a protective cascade, one that has either gone awry or was incapable of fully eliminating or adapting to an internal stressor. To me, endometriosis behaves like cancer, not the cancer of aberrant oncogenes and tumor suppressors, though they are factors, but the cancer of metabolism, of Otto Warburg and others. I think aberrant metabolism is the key to understanding endometriosis and a myriad of other disease processes, including heavy menstrual bleeding. Until recently, however, I have not had much evidence to support this hypothesis. There is a troubling paucity of research on topics related to women’s health. Of the research that exists, much of it is focused on tried and mostly untrue conventional interpretations disease. Interpretations, I would argue, that do more to serve economic or political purposes than health, but I digress.

Over the last few years, however, mitochondrial metabolism has emerged as key determinant of health or disease. Central to this work is the role of cellular hypoxia. In order for cells to function, in order for our brains to think, our hearts to pump, muscles to contract, the mitochondria, organelles within the cells, must breathe. That is, they must consume oxygen and respire. Mitochondrial oxygen consumption results in the critically important production of ATP – cellular energy. Without oxygen, no ATP. Without ATP, nothing works. Cells die. Tissues die. Organs fail. Whether and how quickly injury or death ensues is determined by a number of factors, including the totality of the oxygen deprivation, but also, the metabolic flexibility to withstand insufficient oxygenation, even at low levels. Mitochondrial metabolism can be derailed quite easily by dietpharmaceutical and environmental chemicals, and even a sedentary lifestyle. Metabolic alterations may transpire across generations when exposures are coincident with critical periods of fetal development and even result in de novo or first generation mutations in either nDNA or mtDNA. Mitochondrial metabolism is a key determinant of health and may in fact determine whether and how oxygenation is maintained at the cellular level.

Hypoxia and the HIF Survival Cascades

Adequate oxygenation in the cell involves a system of molecular adaptations that kick into gear during periods of hypoxia and remit when oxygenation returns. These survival cascades are initiated by oxygen sensors that trigger a set of proteins called hypoxia inducible factors (HIF1α and its counterparts HIF1β, HIF2α, HIF3α). HIFs are the master regulators of oxygen homeostasis, ensuring cell survival during periods of low oxygen. So far, researchers have identified at least 100 other proteins controlled by HIFs and tasked with bringing more oxygen and fuel into the cells. HIFs activate angiogenesis (formation of new blood vessels), erythropoiesis (production of new blood cells) and iron metabolism (oxygen carriers), glucose metabolism (substrate for ATP), growth factors, and other proteins. When all else fails, the HIF system signals apoptosis, cell death. In the short term, the hypoxia cascades are brilliant in their ability to forestall anoxia and death. In the long term, however, they wreak havoc.

If you have followed the endometriosis research, most, if not all of the proteins involved in maintaining and spreading endometriotic lesions, are controlled by HIF proteins. I suspect they were activated by disturbed mitochondrial metabolism, either causatively or consequently. Owing to the laws of reciprocity, once hypoxia sets in, it will disturb mitochondrial metabolism further, initiating a downward spiral that becomes difficult to unwind without full consideration of mitochondrial function. Of interest, these same cascades are active in preeclampsia and other diseases of modernity. In fact, I think many of the diseases we see in western cultures, are a result of long-term, low-level, cellular hypoxia mediated by mitochondrial dysfunction.

What precipitates the hypoxia and the mitochondrial dysfunction is not clear, but here again, I have some ideas. With endometriosis I suspect there are multiple factors that coalesce to generate cell level hypoxia.  Fetal and germ cell damage of our grandmothers and mothers mitigated by environmental (hereherehere) and/or pharmaceutical toxicants combined with our own exposures are key among them. For the heavy menstrual bleeding, however, I think the origins are almost entirely environmental, and by environmental, I mean the totality of the modern environment that includes diet, pharmaceuticals, and the ever-present industrial and environmental chemicals that pervade our existence.

With endometriosis, the hypoxia cascades are hyperactive. That is, HIF proteins are more prominent and seem not to be degraded effectively, suggesting a chronic or unremitting hypoxic threat. The ever-present HIF proteins then activate the compensatory cascades discussed above, promoting endometriotic lesion growth and the invasion into healthy cells. In contrast, with heavy menstrual bleeding researchers have found lower levels of HIF proteins. On the surface, this might suggest hypoxia is not involved, but I suspect it is. I just don’t know how exactly. There are hints to suggest I am correct. The question is why are the HIF proteins lower in women who bleed more heavily and higher in women with endometriosis? Is the bleeding another mechanism to deal with an unresolved localized hypoxia; one mediated perhaps by a different hormonal milieu?

Hypoxic Spirals and Mitochondrial Metabolism

In either case, aberrant HIF tells us that mitochondrial metabolism is altered. What it does not tell us is why or how. In many regards, however, the why and how may not matter. There are so many factors capable of affecting mitochondrial metabolism that determining THE factor is all but meaningless and perhaps a fool’s errand inasmuch as mitochondrial phenotypes even with the same genotypes are rarely consistent. More often than not, mitochondrial symptoms express with tremendous variability even among family members. This owes largely to the fact that mitochondria, as the cell danger sensors, are malleable by just about everything from nutritional status to genetics to environmental exposures and anything in between. In fact, something as simple as a nutrient deficiency, even a low-level one, can induce mitochondrial hypoxia. Carried out across time, the disease processes evoked appear identical to their genetic counterparts, and can induce de novo mutations generationally, effectively blurring the once hard and fast distinctions between genetic and environmental disease processes.

High calorie malnutrition, diets high in sugars and processed foods loaded in environmental chemicals but deficient in actual nutrients induce hypoxia. Many of agricultural, industrial and medical chemicals have been linked directly to endometriosis. Generationally, the effects are compounded. Consider DDTDioxinsPBCs, and DES. All are genotoxic, damage mitochondria and have been linked to endometriosis. Linkages to heavy menstrual bleeding are less well known, due to a complete lack of research. However, if we consider fibroids are one the most common causes of heavy menstrual bleeding, rodent research shows clear connections between long term, low level, food exposures to glyphosate, Bt toxin, and adjuvants, the chemical cocktail found in Roundup and used on genetically modified crops, to fibroid tumor growth. I suspect the accumulation of these and other toxins are keys to understanding the cell level hypoxia associated with heavy menstrual bleeding. The fibroid, like the endometriotic implant, may represent a mechanism to sequester toxicants, or in the case of heritable damage, remediate a flaw in bioenergetics with the resulting hypoxia a side-effect that then initiates its own survival cascades – the hypoxic spiral.

Hypoxic spirals are quite easy to initiate but somewhat difficult to stop, especially when resource availability is limited because of genetic or environmental liabilities. Consider the self-perpetuating cascades in iron deficiency or anemia, common in women. Anemia induces cell level hypoxia, which induces heavy bleeding. The heavy bleeding then induces or maintains the anemia. Similarly, Lupron, a medication used for both endometriosis and fibroids causes cell level hypoxia directly by damaging the mitochondria and reducing their metabolic flexibility. Hormonal contraceptives do as well. Indeed, one could argue that since all medications and vaccines damage the mitochondria by some mechanism or another, the ability to consume oxygen is necessarily impaired by modern therapeutics for all who use these chemicals. Reproductive ailments may simply be one set of manifestations among many. This begs the question, however, if cellular hypoxia can be induced so easily, in virtually anyone, why is it that some women develop endometriosis and/or heavy menstrual bleeding and others do not. In other words, why aren’t all women plagued with these disease processes? Increasingly, they are.

Damage to female reproductive function, colloquially referred to as ‘period problems’, has become almost commonplace in modern cultures affecting some 80% of the female population. Whether the issues present as endometriosis, adenomyosis, PCOS, fibroids, heavy bleeding or other menstrual or reproductive disease processes, may not matter. The nexus of each may be indicative of cell level hypoxia with the different phenotypes contingent on the individual’s cocktail of genetic, epigenetic, and environmental exposures and resources.

Treatment Possibilities

If hypoxia lay at the root of these disease processes, to the extent that the hypoxia can be resolved affords new treatment opportunities; ones that not only tackle root causes, rather than symptoms, but may also affect the totality of the individual’s health. Hypoxia, barring obstruction, is a metabolic disturbance. Whether the origins are genetic, epigenetic or environmental, metabolism resides in the mitochondria. If we support the mitochondria, provide the mitochondria with the resources, the fuel to perform the tasks they are proscribed to perform, rather than continually damaging or blocking innate signaling pathways needed for cell survival, we may just be able to, if not eliminate these disease processes, at least manage them and improve quality of life. I think this is worth looking into, don’t you?

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Graphic credits: Tony Grist (Photographer’s own files) [CC0], via Wikimedia Commons

This article was originally published on May 9, 2017. 

Chandler Marrs MS, MA, PhD spent the last dozen years in women’s health research with a focus on steroid neuroendocrinology and mental health. She has published and presented several articles on her findings. As a graduate student, she founded and directed the UNLV Maternal Health Lab, mentoring dozens of students while directing clinical and Internet-based research. Post graduate, she continued at UNLV as an adjunct faculty member, teaching advanced undergraduate psychopharmacology and health psychology (stress endocrinology). Dr. Marrs received her BA in philosophy from the University of Redlands; MS in Clinical Psychology from California Lutheran University; and, MA and PhD in Experimental Psychology/ Neuroendocrinology from the University of Nevada, Las Vegas.

18 Comments

  1. I read somewhere that phthalates (eg. from fragrances and personal care products) were the main driver of fibroids.

  2. Really love your work. I’m curious what are ways that I as an individual with endo can reverse and support the effects you talk about here? Is it through diet? Working out?

  3. Endometriosis is caused by an imbalance in the prostaglandin cascade. The cascade starts from ingestion of 2 fatty acids known as alpha linoleic and alpha linolenic acids. Because they are essential, they are sometimes known, together, as vitamin F. These acids have to go through an enzyme called delta-6-desaturase to be converted to the delta 6 fatty acid called gamma linoleic acid (GLA) and the delta 3 eicosapentoic acid (EPA, also known as fish oil). The delta 6 desaturase requires several vitamins and their absence results in failure to deliver GLA and EPA. I used a combination of 1 part GLA to 8 parts EPA, an oral food supplement, for endometriosis. Just to stimulate interest, *I used 1 part GLA to 4 parts EPA for ectopic dermatitis in kids. Prostaglandins cause inflammation when out of balance. You sometimes see fish oil for treatment but a book on fatty acids contained 10 chapters by different authors, each of which stated that GLA and EPA should always be given together, never singly. The only “bone of contention” was the ratio of one to the other. GLA should always be the lesser concentration.

  4. Just wondering if oxalates could be the cause of Endometriosis? I also have Interstitial Cystitis and have been following a low oxalate diet for it with excellent results. I have a long list of symptoms like vertigo, tinnitus, lichen sclerosus that are also slowly going away on a low oxalate diet along with all the recommended supplements.

  5. But what is one supposed to do? When every supplement out there has been tried, when every diet regimen has veen tried, wgen experts has been consulted, when one avoids chemicals in food and toiletries like the plague, but nothing is working. Nothing. Not even science proven things like NAC. Not surgery. The endometriosis is spreading rapidly and viciously and is swallowing my organs as I type this.
    I have refused hormonal treatment out of fear of their side effects. Now I am afraid it is too late. I have been given gnrh agonist (not lupron) but not even my surgeon is hopeful anymore.

    What is one to do?

    • I used natural progesterone oil for Endometriosis. I also have Interstitial Cystitis (the evil twin) so I am now following a low oxalate diet along with the recommended supplements.

      • Progesterone had been tried before my original comment and I wish I never tried it because it messed me up even worse. One should be extremely cautious with hormones, bioodentical does not mean harmless.

        Low vit A and low oxalate seems to have had a positive effect, only time will tell. Pretty sure all the health foods I ate (high in oxalate) ruined my kidneys.

        I now eat mainly white rice, white bread, muscle meat, the occational Apple and some dairy, and am finally starting to notice a positive effect. Funny that doing the opposite of all recommendations and health gurus seems to be working. When following the perfect diet only made me sicker in every way possible.

  6. Dr. Marrs,
    I hope you find these research papers of interest. It seemed like this was a good way to pass them along to you. I wouldn’t expect that these would be posted, as they’re a bit off the beaten track. I only find a few papers that even come close to pointing the finger at RA. I think the dogma is too dense and the lab technology is too complex for proper identification of what’s really going on. Here’s another one where retinoic acid is found at the scene of the crime. (ALDH1A1 is a retinal dehydrogenase that catalyzes the conversion of retinal to retinoic acid in a non-reversible chemical reaction).

    Stemness marker ALDH1A1 promotes tumor angiogenesis via retinoic acid/HIF-1α/VEGF signalling in MCF-7 breast cancer cells. PMID:30541574

      • Dr. Marrs – I’m basically archiving hundreds of abstracts and full papers on retinoic acid, in the process of looking for any involvement of RA in cancer, autoimmune, chronic disease, etc. The idea is that it is playing a much greater role in causation of illness than most would suspect. If it is the case, then the supplementation of our food-supply with retinyl palmitate, since the early 1970’s, is a gigantic blunder.

        There is much in the literature which indicts RA, at least indirectly, and some research does so very directly; the implications of which are being almost universally ignored, outside a handful of epidemiologists. I surmise that the pursuit of therapeutics is the foundation of that unfortunate reality.

        The simplest way to approach the potential toxicity of excess retinol and retinoic acid, is to study their teratogenic effects, as well as the acute form of excess known as Hypervitaminosis A. Extrapolate those destructive effects to what might happen over decades of accumulation of these molecules in all tissues of the body. Those of us studying this have differing opinions on how accurate consensus science is about the need for these molecules. That is relatively moot compared to the damage they are capable of doing, and it is the lack of warning that concerns us greatly.

        Professionals in fields other than medicine are collectively applying their skills to develop and prove a new hypothesis about so-called Vitamin A; using the existing research of the last 100 years or so. We’re doing our own mice trials and overturning the botched animal-experiments that supposedly proved retinol was a vitamin, and that its deficiency was causing rat-deaths in less than 10 weeks; rat-deaths that were preceded by a curiously long-list of autoimmune symptoms (chapter 5 of Grant’s book). We’re scrubbing papers for clues that exist within them. We think this sub-clinical toxicity has been well-known among some circles since at least the 1940’s.

        Many of us have suffered “autoimmune” and know others who are similarly afflicted. Some of us have been through the doctor-mill for decades. Most of us have lost family members to bad dietary and medical advice. We know much of modern medicine and most of the research that supports it has failed miserably, in not discovering cures for any of these inflammatory and chronic conditions. It seems like applying a name and a band-aid is all these geniuses are capable of accomplishing. Grant posted the other day that there are now over 80-named “autoimmune” diseases. Sheesh!!

        Those of us who spend hundreds of hours reading papers know full-well what is driving research, and it is certainly not the quest for cures. Thus, we take it upon ourselves to experiment, read, learn, hypothesize, and share our experience. Many of us are finding a variety of beneficial results by keeping our intake of retinol and carotenoids and retinyl palmitate very, very low.

        One of the subjects on which I’ve focused is retinoic acid metabolism and whenever I see a paper with Aldh1a1 in the title, I dive into it. I find the use of language in medical research quite interesting, particularly the manner in which simple results are obscured by various linguistic ‘wrappers’ (my term for it), whereby a toxic-truth takes a bit of unnecessary decoding; unnecessary in the sense that when things can be stated clearly, they should be. I always recall what Marcia Angell, editor of The New England Journal of Medicine said about some huge percentage of medical research being junk and not the least bit scientific. There’s likely a corollary to that observation in the field of jargon-istic obfuscation. Having come from a highly technical field, where there was no room for error, when I occasionally see the same names on 20-plus papers in one year, it reminds me of what’s wrong with a puppy-mill.

        I’m following multiple retinoic acid ‘threads’, and the more I read, the more I realize it is being studied in relation to practically everything one could imagine. It’s amazing the things being claimed for it, especially in that until fairly recently it was only “inferred”. The things science doesn’t know about it have to be as great as the ones they say they do. I can’t even guesstimate the number of genes it is said to transcribe, the numbers keep changing depending on which study one is reading. It’s somewhere between hundreds and thousands. Whatever the case on that, I think the modern problem with retinoids is one of serious over-consumption; and since the sub-clinical toxicity angle is not even on the establishment’s radar, there’s few researchers making the obvious connections that we’re able to deduce, due to the fact that we’re actually looking for them.

        If we end-up finding a quicker way to relieve the body of its excess-retinoid burden, it will really be helpful. Presently it’s a very slow and bumpy process, although one to two years generally provides significant progress in the form of symptom relief and blood-work. We have people whose facial and spinal bone-structure has changed dramatically. That’s simply mind-blowing, even though it makes sense to us in that osteoporosis (and its deformations) is a comorbidity of “autoimmune”, we think due to the necessity of buffering RA in the bloodstream with calcium from the bones. There’s a reason that cells in organs other than the liver make binding-proteins for RA and retinol. That appears to have perturbed the old “transport” idea, but there’s surely much more to know about it.

        In the meantime, resolution of dozens of long-term problems are being reported. Among my many improvements is the disappearance of bone-pain in my heels in less than a year, improved eyesight, reduced joint inflammation, cognitive enhancement, better sleep, healthier skin, and regrowth of hair and it’s coming in dark.

        As with your work with Thiamine, the proof is in the pudding, as well as the scientific literature. We’re accumulating extensive positive results among a growing cohort, as well as the kind of papers that add to our knowledge of what’s really going on and how retinoic acid does its damage, particularly to epithelial tissues and stem cells. The immune-response to a poisonous-level of RA concentration is understandable. The thickening of tissue, whether in eczema or crohn’s, is a common feature due to replacement-signaling at the point of cell death. There’s a lot we don’t know, but what we do is growing. Enough people are getting better that we know we’re on to something real.

        Quite a few of the pathways, proteins and molecules I see in papers referencing retinoic acid, are ones I have encountered before, while studying Chronic Inflammatory Response Syndrome and the cytokine-storms induced by biotoxins of all sorts. I’ll link a very good lecture series on CIRS and the treatment protocol for it. I read Dr. Shoemaker’s books, after a serious (hospitalized) bout of mold-illness a few years ago, and I was very pleased to see how far these folks have come when I discovered the videos recently. Hopefully, one day something similar can be presented regarding retinoid toxicity, once we have all of our ducks in a row.

        https://www.youtube.com/watch?v=31Ftaa_PBRk

        Take care Dr. Marrs, thanks for reading and thanks again for your excellent work. I’ve got your book on the way and I’m looking forward to learning more about Thiamine.

        • Having had RA for 12 years, IMO insulin resistance comes 1st & it’s the primary factor behind most chronic diseases. Low carb/keto has made a huge difference for me and many others – likely through changes in inflammation and glycation. See Stephen Phinney, Jeff Volek and Ben Bikman’s work.

        • I just listened – fascinating talk. Will listen to the others in the series. Find it interesting that he states that the mitochondria are not involved. How could they not be? I like his approach though, particularly his view that detox too early creates problems for these patients. That has been a common finding of mine too. Everyone jumps on the ‘detox’ bandwagon, only to decompensate rapidly. From a mitochondrial standpoint, when there are impaired or stressed mitochondria, the added stress of detox protocols exacerbates rather than helps.

  7. Hello Dr. Marrs,

    Fantastic site. I’ve been reading almost non-stop since yesterday when a forum member at ggenereux.blog posted a link to an article from 2015. Hopefully I’ll have some useful information from PubMed on a connection between retinoic acid and hypoxia for you after I dig through my archive. I found one a few weeks ago showing retinoic acid causing folate deficiency, an Alzheimer’s associated marker. I’ve been looking into a retinoic acid and thiamine connection lately and will dig further now that I see how important this subject is. I had no idea. I have at least 2000 hours of PubMed reading verifying Grant Genereux’s work on the toxicity of retinoic acid and its association to chronic and autoimmune disease. I’d highly recommend reading at least chapters 3 and 5 of his second book – Poisoning for Profits – if you have time. His books are free downloads at his website. Best regards, John

    • Retinoic Acid-Induced Protein 14 (RAI14) Promotes mTOR-Mediated Inflammation Under Inflammatory Stress and Chemical Hypoxia in a U87 Glioblastoma Cell Line. PMID:30554401

  8. I’m curious if you’ve explored iodine supplementation? The hormonal balancing affects of iodine can sometimes be nothing short of amazing. Not to mention the antimicrobial properties and the halogen balancing aspects. I have direct experience Of women turning fibrocystic breast disease into normal breast tissue and heavy bleeding return to more normal volume. For over four years I was actively involved in a forum on http://www.curezone.com regarding iodine supplementation. Members of that forum reported disappearance of uterine fibroids, disappearance of ovarian and thyroid cysts, healing of endometriosis, improved energy level and numerous other benefits. Dr. David Brownstein, Dr. Jorge Flechas, Dr. guy Abraham, Charles Hakala and Lynne Farrow‘s book the iodine crisis are all useful resources for those not familiar with this work.

  9. very interesting. I got the asherman syndrome after d&c and was operated 7 times. Unfortunately, the surgeon has overlooked some adhesions. behind these adhesions there is a new adenomyosis.

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