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Lupron, Brain Function, and the Keto Diet

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Reproductive senescence, the time in a woman’s life marked by the slowing and eventual cessation of reproductive function, frequently coincides with an increased risk of a host of neurodegenerative disorders from memory impairment to dementia and Alzheimer’s disease. Researchers have long postulated that the loss of ovarian hormones was responsible; estradiol, in particular, but likely others as well.

This begs the question, what happens to the brain when we abruptly and artificially derail ovarian hormone synthesis in young women using drugs such as Lupron (leuprolide) and the other GnRH agonists and antagonists or by removing the ovaries altogether as in surgical oophorectomy? Is it the same damage we see in aging, only expedited and perhaps magnified, or does it run a different course? Along those same lines, though perhaps a topic for another day, what happens when we chronically supplant endogenous ovarian hormone production with synthetic hormones such as those used in hormonal birth control or menopausal hormone replacement therapies? I suspect, and there is evidence to back up my suspicions, that in all cases brain function is altered, and not for the better.

Estrogens and the Brain

The mechanisms by which estradiol and other steroid hormones influence brain function are myriad and complicated. Beyond just reproduction, steroid hormones influence all aspects of neurological function, with estrogen, androgen, glucocorticoid (cortisol), and mineralocorticoid (electrolyte balance, blood pressure) receptors located throughout the brain. Steroid hormones produced in the body, because of their fat solubility, easily cross the blood-brain barrier where they bind to their receptors and regulate all sorts of processes. Perhaps even more remarkable, the brain has all of the machinery to synthesize its own steroid hormones and so when body concentrations fall, at least for a time, the brain can compensate. Eventually, however, brain synthesis declines and that is where we begin to have problems. Fortunately, natural reproductive senescence occurs later in life and the risk of neurodegenerative diseases is just that, a risk, not a foretold conclusion. This suggests that other variables are at play, ones that we may be able to modulate to improve health, offset and/or reduce the severity of the natural neurodegenerative processes. Again, however, we must ask, what happens when we induce reproductive senescence in young women? By all accounts, the effects are often devastating, leaving many to wonder if they will ever recover.

Estradiol and Mitochondrial Energy

Among the myriad of functions mitochondria control, perhaps the most important is energy production. That is, mitochondria take the nutrients supplied by diet and convert them into adenosine triphosphate (ATP), the energy currency that cells use to perform all of the functions that keep us alive. The loss or diminishment of ATP is deleterious to health and can ultimately be deadly, by invoking a series of complicated processes

Estradiol is a critical component of that process and directly impacts mitochondrial energy production. That’s right, estradiol is part of the mitochondrial bioenergetic machinery such that when estradiol wanes, so too does energy production or ATP. As one might suspect, waning ATP is deleterious to brain health. In previous posts, I detailed the research showing how the loss of estradiol deforms mitochondrial morphology essentially disabling mitochondrial membrane potential while turning the mitochondria into misshapen donuts and blobs ripe for a slow, messy necrotic death; a process that evokes all sorts of deleterious reactions.

The Lupron Brain and Ketosis

Just recently, I stumbled upon research showing yet another mechanism of damage. In the absence of estradiol, brain glucose transport diminishes significantly. This effectively starves the brain for energy inducing severe bioenergetic deficiencies with all of the concordant neuronal damage one might expect. The reduction in glucose affects the mitochondria severely. Recall that glucose is one of the major fuel substrates of the brain, particularly where the Western diet predominates. The decline of glucose transport, therefore, is significant, and alone, without any other changes to the mitochondria, elicits a cascade of deleterious reactions. Oxidative phosphorylation and associated enzymes are downregulated, ATP production wanes, and ultimately may initiate the deformation of the very shape of the mitochondria, as observed in the research cited above. The ensuing reduction of ATP starves the brain of critical energy but also induces a state of hypoxia with the mitochondria incapable of utilizing molecular oxygen. With that hypoxia, inflammatory pathways are initiated further cementing mitochondrial death spirals and associated neuronal damage.

Interestingly, this reduction in aerobic activity coincides with the emergence of a ketogenic phenotype. That is, with the loss of one fuel substrate, ketones become the dominant source of fuel and the associated enzyme machinery is upregulated. Unfortunately, the Western diet is highly dependent upon carbohydrates and so a woman experiencing this loss of estradiol is not likely to consume sufficient fats and proteins to effectively weather this shift. Nevertheless, it does provide an opportunity for recovery. What if women who have lost the ability to produce sufficient estradiol either because of surgically (oophorectomy) or chemically (Lupron and other GnRH analogs) induced menopause adopt a ketogenic diet? Could we maximize the preferred energy source of the post-menopausal brain and reduce the neurological symptoms? I do not know the answer to that question, but given the severity of the suffering with surgical and chemical menopause, it seems worth the try.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, and like it, please help support it. Contribute now.

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Image by Angelo Esslinger from Pixabay.

This article was originally published on November 15, 2018.

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Lupron, Estradiol, and the Mitochondria: A Pathway to Adverse Reactions

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Leuprolide, more commonly known as Lupron, is the GnRH agonist prescribed for endometriosis, uterine fibroids, cysts, undiagnosed pelvic pain, precocious puberty, during infertility treatments, to treat some cancers, and a host of other off-label uses. It induces a chemical castration in both women and men. In women, Lupron stops menstruation and ovulation and crashes endogenous estradiol synthesis rapidly and completely, inducing menopause and menopause-associated symptoms like hot flashes, sweats and osteoporosis, to name but a few. In men, where it is used as a treatment for prostate cancer, it prevents the synthesis of testosterone, pharmacologically castrating its users and evoking a similar constellation of symptoms.

Lupron for Endometriosis: Questionable Research

Lupron’s widespread use for pain-related, female reproductive disorders, such as endometriosis or fibroids is not well supported, with little research indicating its efficacy in reducing pain and no research delineating its effects on disease progression. Conversely, evidence of safety issues have long been recognized, especially within the patient communities where reports of chronic and life-altering side effects are common. We have many case reports on our site alone. Although, class-action and marketing lawsuits have arisen, Lupron continues to be mis-prescribed regularly to diagnose or treat pelvic pain disorders like endometriosis, generating over $700 million in revenue in 2010 and 2011 for the manufacturers and an array of serious and chronic health issue for its recipients.

The reported side effects of Lupron are staggering both in the breadth of physiological systems affected and the depth of symptom severity experienced (a partial list). Indeed, everything from the brain and nervous system to the musculature, skeletal, gastrointestinal and cardiac systems are affected by Lupron, sometimes irreversibly. This is in addition to  thyroid, gallbladder and pancreatic side effects. How can one drug evoke so many seemingly disparate side effects? Is it possible that the magic of chemical castration is not as safe as we were led to believe; and that hormones regulate a myriad of functions beyond reproduction? It is.

Beyond Reproduction and Reproductive Disease

A major fallacy in medical science, and indeed medical research, is the total compartmentalization of physiological systems and by association an insoluble marriage of hormones to their respective reproductive organs, functions, and gender. Lupron, and drugs like it, were developed based upon this fallacy; that somehow suppressing estradiol and the other endogenous estrogens would affect solely the reproductive system. If only human physiology were that simple.

Hormones, even those inappropriately designated sex hormones, like estradiol and testosterone, regulate all manner of physiological adaptations in every tissue and organ in the body and they do so in conjunction with other hormones and by decidedly non-linear trajectories. That is, the dose-response functions are curvilinear where both too little and too much of a particular hormone can evoke serious negative consequences in body systems totally unrelated to reproduction. Chemical and surgical castration would fall into the ‘too little’ category.

Hormone Receptors are Ubiquitous

Hormones mediate these reactions via hormone receptors. Estrogen and androgen receptors are located throughout the brain and the nervous system, on the heart, in GI system, in fat cells, in immune cells, in muscle, the pancreas, the gallbladder, the liver,  everywhere. When hormones bind to these receptors, whether they are membrane bound, nuclear, or other types, the hormone-receptor complex activates or deactivates what are called signal transduction pathways, essentially message lines. Those messaging lines tell the cell to do something. Too much or too little of any one type of hormone sends mixed messages, skewing cell behavior just slightly at first and when there are only small changes in hormone concentration, but with more chronic or more severe hormone changes, the signals become increasingly more deranged and the compensatory reactions, meant only for short term, become more exaggerated and self-perpetuating. This is where problems emerge. Even if estradiol or more appropriately, estrogens (there are many estrogens) feed endometriosis, tanking estradiol concentrations is dangerous and sets into motion complex reactions that we are only now beginning to understand.

Hormones Influence Everything

Since the hormones and receptors are broadly located throughout the body, it doesn’t take a genius to figure out that if we kill off one or more hormones completely, as Lupron does with estradiol, there are going to be negative effects globally, and they are likely to be pretty serious. So, even a surface level evaluation of the safety of drug like Lupron, would suggest a strong possibility of negative outcomes in regions of the body not associated with reproductive function. And with just a little bit of endocrinology under one’s belt, it should be clear that negative outcomes would compound over time, as additional reactions meant to compensate for short term changes in hormone concentrations, become increasingly entrenched and self-perpetuating, and in many cases, increasingly damaging to the health of the cells – but it isn’t. Despite the range of serious side effects, Lupron is a commonly and cavalierly prescribed drug and newer versions of Lupron like drugs are expected to take the market by storm.

Estradiol Is Critical to Human Health

While the pharmacological mechanism of action for Lupron and drugs like it is clear, they override pituitary control of the tropic hormones that signal the ovaries or testes to synthesize new hormones, how these drugs induce the array of side effects, many of them long term and even permanent, has not been explored as seriously as it should be. Certainly, one can hypothesize the effects of estradiol elimination on different systems based upon receptor distribution within each tissue and the signaling pathways therewith, but the effects are diverse and sometimes contradictory or highly tissue specific. One has to wonder if there might be a final common pathway by which the elimination of estradiol could disrupt multiple physiological systems in a predictably discriminate manner. Indeed, there might be.

Estradiol Regulates Mitochondrial Function: Mitochondria Regulate Everything Else

If you’ve read any of our articles over the last year, you’re aware that we have become increasingly interested in mitochondria, particularly how drugs and nutrients or nutrient deficiencies, impact mitochondrial functioning. Mitochondria take nutrients from food we eat and convert them to the biochemical energy required to power cellular life – ATP. Without appropriate cellular energy all sorts of things go wrong. Energy is fundamental to life and so functioning ATP pathways are critical for cellular and organismal health (and so is proper nutrition!). A number of disease states emerge when the mitochondria are damaged or inefficient at producing ATP, from chronic fatigue, muscle wasting and autonomic system dysregulation to name but a few. Estradiol, and likely other hormones, (most of the research focuses on estradiol), influences mitochondrial functioning and the production of ATP via a number of mechanisms.

Estradiol Is Needed for the Production of ATP

Though not a component of what is called the citric acid or TCA cycle or the electron transport chain (also called the mitochondrial respiratory chain), estradiol appears to be intimately involved in up – and down-regulating the enzymes and other proteins within those energy production cycles. Estradiol directly and indirectly modifies the types fuel used to produce ATP (glucose, fatty acids or proteins) and impacts the efficiency and flexibility with which ATP is produced. Essentially, estradiol impacts the substrate inputs and keeps the cogs in electron transport chain cycles moving. When estradiol is eliminated, fuel sources shift (by tissue) and those cogs, called complexes, begin to slow, become less efficient and send off more damage signals (reactive oxygen species – ROS) than can be effectively cleaned up. Since functioning mitochondria and sufficient ATP are required for cellular health in all cells, where energy demands are greatest, symptoms emerge: the brain and nervous system, the  heart, the GI system, muscles, and bone formation/turnover.

In the brain, we see serious cognitive deficits and derangement of mood and perception with damaged mitochondria relative to estradiol elimination. We also see autonomic instability that impacts mood (flipping between depression and anxiety) but also heart rhythm and balance.

In the heart, the estradiol directly impacts mitochondrial fuel preferences and availability by regulating cardiac glucose and fatty acid metabolism. Without estradiol, the machinery within the mitochondria are not as flexible in their ability to switch between glucose, fat or proteins for precursor fuels to make ATP. The lack of flexibility, particularly during other physiological stressors, leads to impaired cardiac functioning and increased inflammation in affected tissues.

Bone formation is particularly hard hit as estradiol is required bone growth, maturation and turnover. Estradiol deficiency leads to increased osteoclast formation and enhanced bone resorption – destruction of bone or osteoporosis. Proper bone formation is also highly dependent upon vitamin D concentrations. Vitamin D deficiency leads to bone loss. Vitamin D activates estradiol synthesis, while estradiol activates vitamin D receptors. Lupron tanks estradiol and by association vitamin D, a double hit to bone health. At the level of the mitochondria, the third hit, reduced ATP, further damages bone health.

Estradiol is an Antioxidant

Antioxidants scavenge ROS. Antioxidants are needed to keep ROS concentrations at bay as too much ROS, though a natural byproduct of ATP production, will damage the mitochondria and initiate a damaging, self-perpetuating cycle. The body has a number of anti-oxidants to temper ROS. Many nutrients are included in this category: Vitamins C and E, CoEnzyme Q10 and glutathione are among the most well known. It turns out that estradiol and progesterone are potent anti-oxidants as well. So chemically or surgically eliminating estradiol reduces the body’s ability to detoxify and eliminate damaging ROS, evoking further mitochondrial damage.

Estradiol Modulates Mitochondrial Hormone Synthesis

That’s right, the mitochondrial estrogen receptors impact what is called steroidogenesis – steroid hormone synthesis – for multiple hormones, not just those pesky ‘female’ hormones. Like a thermostat that turns on or off when the temperature changes, mitochondrial estrogen (and other hormone) receptors sense hormone changes and up or downregulate the synthesis of pregnenolone (and the use of cholesterol to make pregnenolone). Pregnenolone is the precursor for all steroid hormones. So when Lupron or ovariectomy tank estradiol, not only is the synthesis of estrogens affected, but so too is the synthesis of other steroid hormones.

Estradiol Tempers Mitochondrial Ca2+ Homeostasis

Ca2+ balance is a complicated topic, a bit beyond the scope of this paper but is an important function modified by mitochondrial estrogen receptors. Ca2+ influx into cells is excitatory and turns on the cellular machinery. As one might expect, too much or too little Ca2+ activity could be damaging. Too much Ca2+ is cytotoxic or neurotoxic (if in the brain), killing the cells. The mitochondria are largely responsible for controlling the influx of Ca2+, sequestering Ca2+ when there is too much in order to save the cells. So when mitochondria become damaged or inefficient by any mechanism, Ca2+ homeostasis becomes an issue and cell death, tissue and organ damage become very real outcomes. Estradiol influences the mitochondria’s ability to sequester and temper Ca2+, so that the cells don’t become too turned on or over-active and die. (This is an interesting mechanism because estradiol itself is an excitatory hormone, increasing the activity of the cell when bound to the cell membrane or nuclear receptors but when bound to receptors on the mitochondria, estradiol tempers that excitation.)

Estradiol Regulates Immune Function

Estradiol bound to the estrogen receptors on immune and other cells activate and deactivate a number of signal transduction pathways that turn on/off inflammation and other immune responses. The mitochondria also regulate immune function via ROS signalling. Depletion of estradiol, particularly at the mitochondrial level, guarantees disrupted immune function and hyper inflammation by way of mitochondrial structural damage, derangement in function, and the loss of estradiol mediated anti-oxidant abilities. So by multiple mechanisms Lupron, drugs like it, and ovariectomy, damage mitochondria and initiate cascades of ill health.

Lupron, Maybe Not Such a Good Idea

Estradiol bound to mitochondrial receptors, controls a whole host of functions in the mitochondria, which then control cellular health throughout the brain and body. Without estradiol, the mitochondria become misshapen and dysfunctional and eventually die a messy death (necrosis), but not before inducing mutations in next generation mitochondria (mitochondrial life cycles include the regular birth of new mitochondria and the necessary death of old and damaged mitochondria). As the damage and mutations build and the ratio of healthy to damaged mitochondria shifts, cell death, tissue/organ damage and disease develop. Lupron, other drugs that tank estradiol, and ovariectomy, initiate mitochondrial damage. The mitochondrial damage represents a possible final common pathway by which Lupron induces the myriad of side-effects and adverse reactions associated with this drug.

A question that remains, is whether this damage can be offset by supporting mitochondrial machinery by other mechanisms. This is particularly important since millions of women have been exposed to Lupron and/or have had their ovaries removed. Other hormones and a myriad of nutrient factors are necessary for the enzymes within the mitochondrial machinery to work properly. Could we offset the damage evoked by too little (or too much) hormone by maximizing the efficiency of the other reactions. I think it is possible, at least theoretically and at least partially. That will be addressed in a subsequent post. For now, however, I think we ought to reconsider the use Lupron, other GnRH agonists, antagonists and the surgical removal of women’s ovaries. The damage evoked by eliminating estradiol is likely far greater than any potential benefit in an ill-understood disease process like endometriosis.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

Photo by Mufid Majnun on Unsplash.

This article was first published on January 16, 2015. 

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A Rant about Lupron and Oophorectomy, Some Mechanisms and Clues to Recovery

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A Rant

Women who have been given Lupron (leuprolide) and the other GnRH agonists and antagonists and women who have had their ovaries removed are thrust violently into menopause. Overnight. There is no gradual decline of ovarian hormones that allows for molecular adaptations to the new state of chemical senescence. No, none of that. Just the chemical trauma of the loss of hormones.

The experience is akin to castration; something that should never be considered as a viable treatment option for any benign disease process, especially in young people. Yet millions of young women and children (Lupron for precocious puberty, gender dysphoria, and now autism) are prescribed these drugs and undergo these procedures annually without as much as the slightest recognition that there might be negative sequelae. Indeed, women are told routinely that what they experience with Lupron, its analogs, or upon oophorectomy is not real, that it does not exist, and that their symptoms are no more than some form of psychosomatic stress – the long vestige of Freudian acquiescence called hysteria. It is not. The symptoms these women experience is real and directly related to how the loss of estradiol and other ovarian hormones damage the mitochondria.

Some Mechanisms

Estradiol regulates mitochondrial energetics via multiple mechanisms both directly and indirectly. I have written about the mitochondrial damage provoked by the loss of estradiol previously, see here, here and here. In brief, the loss of estradiol fundamentally changes the shape and functionality of the mitochondria, effectively disabling not only their ability to produce ATP (cellular energy), but also, reducing their capacity to perform the myriad of vital functions for which the mitochondria are responsible. The reduction of ATP is alone sufficiently damaging and I would argue the root of all disease. Without sufficient ATP all sorts of vital functions grind to a halt, but when one considers that the mitochondria are responsible for managing immune and inflammatory signals, the production of steroids, the sequestration of Ca+ (cell excitability), the removal of toxicants, both endogenous and exogenous, and even cell life/death cycles, the logic behind using a form medically induced castration as a treatment for any disease becomes suspect.

For all the young women who suffer through the loss of estradiol, either via Lupron, its analogs or via oophorectomy, the damage is believed to be irreparable, mostly because there is neither recognition of the ill-effects nor any research into possible recovery options. Some of the damage may be permanent, unfortunately. It is impossible to tell at this point. However, and this is a big however, the human organism is remarkable in its ability to heal and sustain life despite our best efforts to the contrary. I believe strongly that the body can recover from just about anything, save except death. One just has to give it what it needs to heal. That is, if we provide the core substrates, the appropriate fuel sources and nutrients and if we remove the toxins, healing can occur. It will not be quick and it may not be complete, but it will happen. This is where basic research comes into play. Though not ideal, it can guide us. I will explain, but first, let us review some components of mitochondrial illness.

Understanding Mitochondrial Damage

Mitochondria are central to cell survival, and thus, our survival. Mitochondria take the foods we eat and through a series of enzymatic reactions convert the food into chemical energy called ATP. ATP fuels everything. Without ATP, cells struggle to function, become hypoxic, protein synthesis and repair processes falter producing aberrantly folded proteins, until the damage becomes too great, overwhelming their capacity to function. Cells die, tissues and organs die, and eventually, we die. Before we die, however, a whole host of seemingly random and complex illnesses and symptoms emerge as a direct result of the diminished ATP. That is, in an effort to keep us alive, the mitochondria and the cells in which they reside initiate survival cascades, key among them, inflammation and immune reactivity. These cascades, if left unchecked, evoke even more damage, illness, and eventually death. Yes, mitochondrial damage can precipitate death or a life so painful that death may seem preferable. The pain and suffering these women experience is real.

What Causes Mitochondrial Illness?

Mitochondrial illness can be initiated via a whole host of interacting variables. Genetics play a role, but so too do epigenetics – environmental stressors that activate or deactivate genes. Diet is a huge contributor. Too much sugar, processed food, alcohol and not enough nutrients are key variables determining mitochondrial illness or health. Nearly every, if not every, pharmaceutical damages mitochondria via one mechanism or another. All environmental and industrial chemicals damage the mitochondria. Hormones too influence mitochondria. Estradiol is top among them, but likely not the only hormone influencing mitochondria, only the most frequently studied.

Presentation of Mitochondrial Illness

Mitochondrial illness breaks all the rules of modern medicine. The symptoms are highly varied and individual. They do not fit into our discretely compartmentalized view of illness, and how could they? Mitochondria are the engines of every cell in the body, powering all life sustaining functions, from the brain and nervous system to the heart, the GI system to the musculature and everything in between. So when the mitochondria struggle, we have symptoms everywhere, in every compartment of the body, but exactly how those symptoms present is as individual as we are.

When the mitochondria are struggling, the systems that require the most energy are taxed most, but depending upon the individual’s genetic/epigenetic and nutritional liabilities, all sorts of weird symptoms may emerge due to the lack of ATP, the survival cascades initiated, and the other mitochondrial functions that now struggle. In that regard, even folks with the same constellation of genetic variables, express their symptoms differently. The wild variability in symptom expression makes mitochondrial disorders simultaneously the most difficult and the easiest to diagnose; most difficult if one subscribes to a compartmentalized, organ specific form of medicine and easiest if one looks to root causes. At the root of every disease process, whether cause or consequence, are struggling mitochondria. All disease begins and ends in the mitochondria. As such, unless and until the needs of the mitochondria are addressed, healing cannot occur. The flipside, of course, is if we support mitochondria, healing becomes possible.

Mitochondria, Estradiol and the Problem with Medically Induced Menopause

As mentioned previously, when the mitochondria are deprived of estradiol, the membranes surrounding the mitochondria become deformed. The increased permeability of these membrane causes all sorts problems, but top among them, the transfer of nutrients is less efficient. Mitochondria require at least 24 vitamins and minerals to efficiently convert the food we eat into ATP.  Though it is not clear what happens first, whether the enzyme machinery responsible for processing ATP diminishes heralding the increased permeability and deformation of the mitochondrial membranes or whether the loss of estradiol deforms the membranes first and that then results in a loss of ATP, it is clear that the loss of estradiol severely constricts mitochondrial functioning. In both cases, the loss of functionality initiates the survival cascades, and what many call the death spiral, begins.

Clues to Recovery

The easy answer would be to replace the lost estradiol. The problem with that, however, is that the ovaries synthesize a whole host of hormones, not just estradiol, and our ability to replicate those hormones in the appropriate concentrations is just not there yet. Nevertheless, working with a physician or pharmacist experienced in bioidentical hormone replacement may be helpful, at least in the transition period while the body is adapting to the new state of chemistry. The use of synthetics, however, are likely to do more damage than they are worth.

I believe a more prudent approach would be to tackle the health and efficiency of the mitochondria themselves; an approach that had it been undertaken prior to the use of Lupron or oophorectomy may have been able to reduce the impetus for these procedures in the first place. In fact, these recommendations are not specific to Lupron or oophorectomy, but carryover to any type of mitochondrial illness.

Vitamins, Minerals, and Diet

Considering the mitochondrion’s primary purpose is to convert the food we eat into life sustaining ATP, the simplest and most often ignored component of recovery, is to feed the mitochondria what they need to function and avoid the stuff they do not. In other words, eat well and avoid chemical toxicants. In practice, however, this seems to be exceedingly difficult for most of us. Decades of processed food marketing has skewed our preferences away from ‘real food’, and in many ways, disconnected us from the purpose of eating – to fuel our bodies.

Mitochondrial Nutrients to Rescue Mitochondria

There are 24 of vitamins and minerals required to power the mitochondrial machinery responsible for converting food into ATP. Ensuring an adequate supply of nutrients is critical to repairing mitochondrial damage, perhaps more important than any other aspect of recovery. Top among them are thiamine and magnesium. We have written about this extensively on Hormones Matter and in our book. Thiamine is the gatekeeper to the mitochondrial factory, involved in the initial enzymatic reactions required to convert consumed carbohydrates, fats and proteins into ATP and just about every enzyme reaction throughout the process. More so than any other nutrient, thiamine is critically important to mitochondrial functioning, but its deficiency is least likely to be recognized, even though it causes a host of serious disease processes including death. Magnesium is an essential cofactor for thiamine. Deficiencies in thiamine and magnesium may well account for the vast majority of modern illnesses.

The other B vitamins are also important, as are a variety of minerals. Which ones and in what doses are required for recovery is individual, but often, the dosages are far higher than what is proposed by the RDA and in combinations that are not typically found in standard, over-the-counter (OTC) supplements or even in marketed mitochondrial cocktails, though some of these products are considerably better than the OTCs. In the case of mitochondrial recovery, vitamins and minerals are used at pharmacological doses in order to kick start, and in many cases, compensate for the increased nutrient demands caused by the damage and/or by genetic or epigenetic variables. For individuals with severe deficiencies and/or poor absorption, repeated intravenous vitamins/minerals may be warranted. The details of dosing are covered in our book.

The Mitochondria Diet: Eat Real Food

The second component of healing mitochondria involves diet more broadly. That’s right, what we eat can harm or heal us. Processed foods must be eliminated, as should alcohol and other toxicants. Diets should be high in protein and good fats and low in carbohydrates, and to the extent feasible, organic. Why proteins and fats? Chemistry. Health demands that protein synthesis outpace protein breakdown. That requires a ready supply of protein from the diet and the appropriate nutrients listed above to process them. There is much debate about how much protein, but broadly, and depending upon level and type of illness, one must consider.08 – 1.5kg of protein per kg of weight per day. In research of critically ill patients, higher protein consumption (~1.5kg/kg/day) is associated with better outcomes. With our current predilection for excess carbohydrates, most folks are nowhere near even the lower end of these requirements and that creates a barrier to healing.

The integrity of mitochondrial and all cellular membranes require fatty acids. For women recovering from the loss of estradiol, and the subsequent deformation of mitochondrial membranes, a diet poor in essential fatty acids would be doubly debilitating. Indeed, for most people, an increase in fatty acids would improve health considerably. Fatty acids are also a key fuel substrate for mitochondrial ATP (which just so happens to be thiamine dependent as well).

In general, lower carbohydrate intake is warranted. High carbohydrate intake exacerbates thiamine deficiency and in fact, by itself, with no other risk variables, can induce thiamine deficiency. Researchers from USC have shown that immediately following the loss of estradiol, brain glucose transporters begin to downregulate forcing the brain into ketosis.  That is, at least in mice, the loss of estradiol forces a metabolic shift towards using ketones as the primary fuel source to produce ATP. This means that our traditionally carbohydrate dense diets may not meet the brain’s energetic demands when estradiol is absent. Granted, this research used mice and is preliminary, but it suggests an additional route to healing post Lupron and oophorectomy would be to increase dietary fat. Ketosis may be an option to repair mitochondrial damage.

Having said that, there are disorders of fatty acid metabolism which make lower carbohydrate diets very difficult and sometimes even dangerous. Full blown manifestations of these disorders usually occur in infancy or childhood, but more subtle manifestations brought on by single nucleotide polymorphisms (SNPs) in key genes may remain somewhat latent until triggered. Anecdotally, the inability to metabolize fats seems relatively common among the folks who interact with us, manifesting in what can only be described as energetic collapse post ingestion of fats and proteins. In the cases where SNP analyses are available, the difficulties are related to what have been traditionally considered ‘rare’ variances in key enzymes. Nevertheless, the parameters of these recommendations hold true for most people. Eat real, nutrient dense foods. The specifics of the diet, like the specifics of the nutrient replacements is all that varies.

Avoid Toxicants

Finally, with poorly functioning mitochondria, taxing these organelles further by ingesting the chemically laden foodstuffs produced by conventional agriculture and livestock practices makes healing that much more difficult. To the extent dietary toxicants can be avoided, they should. Similarly, since most, if not all medications damage mitochondria and deplete vital nutrients by one mechanism or another, medication use should be evaluated thoughtfully assessing potential benefits against likely risks.

Is it Really That Simple?

Yes and no. In many ways, it is very simple. Feed the mitochondria and they will do the rest, but in other ways, it is not so simple. Diet is absolutely critical, but mitochondrial recovery also includes using supplements at pharmacological doses, sometimes intravenously, to rescue damaged mitochondria and induce a more favorable mitochondrial replication process. This is difficult for some folks to access. Few physicians have any background in this and many simply do not believe that mitochondrial damage exists or evokes illness. Worse yet and despite evidence to the contrary, many physicians are steadfast in their belief that pharmaceuticals have no bearing on mitochondrial function, and thus cannot possibly be responsible for these illnesses. This means that to the extent pharmaceuticals do not treat and often make matters worse in these cases, fuel to the ‘it-must-be-hysteria-or-psychosomatic’ fire is added. In many ways, the biggest stumbling block is the notion that mitochondrially-mediated disease processes exist at all. A close second, is that nutrients can be used to recover mitochondria and in many cases, override even genetic defects.

Making matters even more complicated, there is no one-size-fits-all diet or supplement protocol. While it is true that thiamine is critical and must be addressed if there is any hope of recovery, everything else downstream must be considered on an individual basis. We each carry a host of unique genetic, epigenetic and environmental exposures that combine to make a complicated chemistry; one that no one wants to untangle and few have the skills to do so. As a result, it is much easier to dismiss the symptoms as psychosomatic and prescribe an antidepressant or other pharmaceutical. I would also mention, even among those of us who have a background in this stuff, we do not know everything and cannot know everything. Untangling these patterns takes time, effort from the patient, lots of research from both parties, and a fair degree of trial and error. Finally, recovery is neither a straight line nor an absolute. There are setbacks, sometimes serious ones, and health has to be actively managed from this point forward. Even with all of these complications, however, better health is possible if one tends to the mitochondria.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

This article was published originally on August 6, 2018. 

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Tank Estradiol and Lose Metabolic Flexibility: Pitfalls of Lupron and Oophorectomy

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Lupron mitochondrial damage

Over the last several weeks, I have been looking at the role of estradiol in mitochondrial health. In the first post Hormones, Hysterectomy and the Aging Brain, we learned that estradiol depletion wreaks havoc on brain mitochondria turning them into misshapen donuts and blobs. Digging a little deeper, the next post (Lupron, Estradiol and the Mitochondria) pondered the connection between estradiol-depleting drugs such as Lupron, other Lupron-like drugs, and the devastating side effects that often follow suit. Could Lupron-mediated mitochondrial damage be at the root of these side effects? Quite possibly?  A question that remains is how. In this post, I will be digging even deeper into the role of estradiol in mitochondrial functioning, especially its role in something called metabolic flexibility.

A note of caution, while I focus on estradiol, the mitochondria, and what happens to health when we remove estradiol pharmaceutically via Lupron or surgically via oophorectomy, it is important to remember that estradiol is not the only hormone synthesized in the ovaries nor are the ovaries the only hormone-producing tissues. Moreover, the chemical castration induced by Lupron and other medications or via ovary removal disrupts and diminishes the synthesis of a myriad of hormones. Estradiol is simply where most of the research is focused, and so, it is where I too must focus, at least for the time being.

Steroid Hormones and Metabolic Flexibility: A Critical Factor in Post Lupron and Post Oophorectomy Ill Health

Steroid hormones regulate metabolic flexibility at the level of the mitochondria. Estradiol, the most frequently studied among the steroid hormones, plays a pivotal role in determining how food fuel is converted into cellular fuel or ATP.  When we eliminate estradiol with medications such as Lupron and other GnRH agonists or antagonists, or when we remove a woman’s ovaries, depleting her primary source for estrogen synthesis, metabolic flexibility diminishes significantly.  With the lack of metabolic flexibility comes several health issues, some noticeable, like weight gain, and others less noticeable, at least initially, like cardiac and neurodegenerative diseases. A common component of each of these conditions is mitochondrial dysfunction. Mitochondrial dysfunction can be initiated and accumulated via a number of mechanisms and over time, so estradiol is not the only variable, but it is a key factor that is often ignored.

Mitochondria

Mitochondria are the cellular powerhouses that consume oxygen and transform the foods we eat into a currency that cells can use (ATP) to perform all of the intricate tasks needed for survival and health. Mitochondria are also the site of steroidogenesis (steroid synthesis), immune signaling, and all sorts of other functions that determine cellular life and death. When you think about it, how well the mitochondria perform these tasks affects health at every level of organismal physiology. Without the appropriate amount of mitochondrial energy/ ATP, cell function becomes deranged, and ultimately, grinds to a halt. When that happens, disease is imminent. Indeed, genetic perturbations of mitochondrial function are some of the most devastating diseases known to medicine.

One has to wonder, what happens when we perturb mitochondrial function from the outside in – via toxicant exposure or by eliminating critical hormones or other co-factors such as nutrients that are necessary to mitochondrial operations? Worse yet, what if an individual with unrecognized genetic defects in mitochondrial functioning faces additional mitotoxicant exposures; what then? Complex, multi-system disease – that’s what. I would argue that mitochondrial dysfunction represents the final common pathway, a convergence point, connecting an array of seemingly disparate disease processes. Mitochondrial metabolism, and specifically, metabolic flexibility, may be at the heart of the derangement, with estradiol, and likely other hormones, in the driver’s seat.

Metabolic Flexibility: Adapt and Survive

When we think of stress and flexibility in general terms, it is easy to recognize that the more flexible one is in his/her behaviors or coping mechanisms, the easier it is for one to respond to, and survive stressors. Flexibility means that options exist for when everything hits the fan. Imagine if there were no options or if you had to respond to each and every stressful event in your life using exactly the same behaviors or response patterns. You would not get very far. The same holds true for cell behavior, and more specifically, mitochondrial behavior. The mitochondria need options to respond to the differing needs of the cells that they supply with energy. If those options become limited in any way, the mitochondria become less effective. They produce less energy, scavenge fewer oxidants (toxicants), and when stressors present, cannot easily adapt. In fact, the more inflexible the mitochondria are forced to become, the less likely they, and the cells, tissues, organs, and organism within which they reside, will survive. Estradiol is integral to mitochondrial flexibility. Remove the estradiol and the mitochondria become less metabolically flexible and less able to respond to the demands of a changing environment.

Estradiol Equals Increased Mitochondrial Efficiency and Decreased ROS

Estradiol maintains metabolic flexibility via two important mechanisms: increased mitochondrial efficiency and ROS management. With the former, estradiol regulates metabolic flexibility by altering the expression of genes that control the enzymes within the fuel conversion pathways. It is a complex algorithm of responses, with some proteins upregulated and others downregulated. The net result, however, favors increased efficiency in ATP production by maximizing metabolic flexibility or adaptability to the environment.

With the latter, estradiol, along with progesterone, manage the clean-up tasks inherent to any energy production process. In effect, estradiol manages ROS both on the front end and the back end of mitochondrial ATP production. On the front end, increased metabolic efficiency and flexibility equals fewer ROS byproducts. On the backend, estradiol cleans up the byproducts of processing -ROS – and tempers the damage these byproducts can cause.

Estradiol, Pyruvate, and ATP

Of particular interest to our work here at Hormones Matter, estradiol upregulates a set of enzymes called the pyruvate dehydrogenase complex, PDC. The PDC, responsible for converting glucose into pyruvate, is the first step in the long process that nets multiple units of mitochondrial ATP. The PDC is key to carbohydrate metabolism and more recently has been linked to fatty acid metabolism, making this enzyme complex central to mitochondrial energy production. Diminished PDC derails mitochondrial functioning, producing serious diseases. Children born with genetic pyruvate dehydrogenase deficiency suffer serious neurological consequences and rarely live to adulthood.

Importantly, the PDC (like all of the enzymes within these cascades) is highly dependent upon nutrient co-factors to function properly. Thiamine and magnesium, are critical to the PDC complex. Since PDC function demands thiamine, children and adults with thiamine deficiency also suffer significant ill-health, ranging from fatigue and muscle pain, to disturbed cognitive function, disrupted autonomic function affecting multiple organs, psychosis, and even death if not identified. Thiamine deficiency is most well known as a disease associated with chronic alcoholism but has recently begun re-emerging in non-alcoholic populations relative to medication and vaccine reactions.  Many medications and environmental variables deplete thiamine and magnesium, diminishing mitochondrial function significantly, by way of pyruvate.

Along with nutrient co-factors, estradiol is critical for pyruvate. Estradiol upregulates the expression of the enzymes that make up the PDC (in the brain). If estradiol is reduced or blocked, mitochondrial ATP production will take a hit. If estradiol is blocked in an already nutrient-depleted woman, the first step in mitochondrial fuel conversion would take a double hit. One can imagine the consequences.

In light of the direct role that thiamine, magnesium, and other nutrients play in the cascade of reactions required to produce ATP, can we maximize mitochondrial functioning with nutrients to compensate for the mitochondrial damage or deficiencies likely to occur post oophorectomy or as a result of GnRH agonist or antagonist drugs, like Lupron? I can find no research on the subject, but it is certainly a topic to explore given the millions of women already suffering from the mitochondrial damage induced by Lupron and/or pre-menopausal ovary removal. Even without the necessary research, correcting nutrient deficiencies and dietary issues should be undertaken for general health.

Another question in need of exploration, if we maximize mitochondrial functioning, does that then increase steroidogenesis in other endocrine glands? A section of the adrenal glands called the zona reticularus, for example, produces a complement of hormones similar to those of the ovaries. In postmenopausal women androgens, precursors for estradiol, produced by the adrenals account for a large percentage of total estradiol production. Could we take advantage of that to help stabilize circulating hormones?

Finally, beyond the nutrient requirements for mitochondrial ATP production, enzymes throughout the body, even those involved in post-mitochondrial steroid metabolism, require nutrient co-factors to function properly. Could we maximize those enzymes for more efficient steroid metabolism to net sufficient estradiol to maintain mitochondrial function?

What about Natural Declines in Estradiol?

It is not clear how menstrual cycle changes in estradiol affect mitochondrial functioning or how the postpartum decline in pregnancy hormones affects mitochondria. One would suspect there are compensatory reactions to prevent damage, but this has not been investigated. In natural menopause, however, researchers have noted that some form of compensation occurs as estradiol declines and, at least for a time, and in rodents, mitochondria maintain efficient production of ATP. In contrast, no such changes are noted with premature menopause or oophorectomy.

Also not investigated sufficiently, is the impact of chronic synthetic estrogen exposure on mitochondrial functioning. In other words, what are the effects of oral contraceptives, HRT, and the growing list of environmental endocrine disruptors, on mitochondrial ATP production? Since these compounds bind to estrogen receptors and displace the endogenous estrogens like estradiol, some evidence suggests endogenous production of estradiol is reduced. Do the mitochondria respond also by downregulating estrogen receptors or by some other mechanism?  Short-term, animal research suggests that supplementing 17B estradiol post oophorectomy reduces mitochondrial damage. In research in humans, where synthetic estrogens are used, results are less clear and longer-term studies do not exist beyond the broad brush strokes of epidemiology.

Metabolic Flexibility and Tissue Type

One of the more interesting aspects of estradiol’s role in metabolic flexibility is that it is site or tissue-specific and may point to novel therapeutic opportunities. Since different cell types, in different parts of the body, prefer different fuels for power to survive, when we eliminate estradiol from the equation, mitochondria from different tissues or organs respond differently to the lack of flexibility. Perhaps, we can utilize the information about fuel requirements to design diets that compensate for diminished metabolic flexibility.

Heart Cells. I’ve written about this research previously, not fully understanding the implications. Estradiol allows cardiomyocytes (heart cells) to switch from their preferred fuel of fatty acids to glucose during stressors such as heart attacks (and theoretically during any stressor like exercise). That ability to switch fuel types is protective and allows the cells to survive and heal. It may explain why women are more susceptible to heart damage post-menopause when endogenous estradiol declines. This may also point to a pathway for post oophorectomy and post Lupron declines in normal heart function.

Brain Health. Declining estradiol affects brain mitochondria differently. As I noted in a previous post, without estradiol, brain mitochondria become progressively less functional and misshapen. These structural changes impair mitochondrial ATP production. Unlike the heart, however, the brain prefers glucose as its primary fuel source. Estradiol appears to enhance glucose uptake from the periphery and across the blood-brain barrier. When estradiol is absent, brain glucose uptake diminishes significantly (in rodent studies), leaving the brain perpetually starved for glucose.

We know from brain cancer research, that with declining brain glucose, secondary fuels can kick in, but only when the mitochondria have sufficient flexibility to switch. For example, mitochondrial fuel flexibility is critical to battling brain tumors. Under conditions of stress and when brain glucose concentrations are low, healthy mitochondria can readily transition to ketone bodies for energy, at least in vivo. The transition from glucose to ketone bodies is believed to be an evolutionary adaptation to food deprivation allowing the survival of healthy cells during severe shifts in the nutritional environment. Estradiol appears to be key in maintaining that flexibility.

Weight Gain and Fat Accumulation. Post-menopausal, post-hysterectomy, and oophorectomy weight gain are well established research findings. Anecdotal complaints of Lupron weight gain are also common. These findings may be related to derangements in metabolic flexibility mediated by the relationship between estradiol and mitochondrial functioning. The increased lipid or fat accumulation in skeletal muscle though associated with impaired insulin-stimulated glucose metabolism may be related to the reduced capacity to adjust to a changing fuel environment. More specifically, weight gain may represent a declining ability to utilize fats effectively as a mitochondrial fuel source, possibly via a derangement in a mitochondrial channel responsible for shuttling fats and cholesterol into the mitochondria for processing. When the mitochondria become less flexible, a channel called the TSPO, shuts down, disallowing fats that would normally be shuttled into the mitochondria and processed for ATP (and steroid hormones), from entering. Instead, they are stored peripherally in adipocytes. I wrote about this in detail here: It’s All about the Diet: Obesity and Mitochondrial Dysfunction. It is possible in estradiol-depleted women that TSPO downregulation is a compensatory reaction to diminished metabolic flexibility.

It is also conceivable that the lack of brain glucose, as discussed above, leads to overeating and, more specifically, cravings for sugary foods. This would be a logical compensatory reaction to bring more fuel to the brain; one likely meant only for the short term and that when held chronically begins the cascade of other metabolic reactions known as obesity, diabetes, and heart disease. Perhaps, just as fat storage becomes a survival mechanism when mitochondria can longer process it effectively, the craving for sugar in estradiol-deprived women is also a survival mechanism.

Finally, adipocytes can synthesize estradiol. It is conceivable that in response to declining estradiol concentrations, the body stores fat to produce more estradiol.

Final Thoughts

Central to mitochondrial dysfunction, whether by genetic predisposition or environmental influence, is the inability to efficiently produce ATP (the fuel that all cells need to survive) and to effectively manage the by-products of fuel production and other toxicants. Estradiol plays a huge role in both of these processes. Eliminate estradiol and mitochondrial functioning becomes less efficient and less flexible initiating cascades of chronic and life-altering conditions. This suggests the ready application of medications like Lupron that deplete estradiol or the prophylactic removal of women’s ovaries is misguided at best, and dangerous at worst.

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Image by Triggermouse from Pixabay.

This post was published originally on Hormones Matter on February 11, 2015. 

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