Lupron mitochondrial damage

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

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

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.


  1. Dr. Marrs,

    I have a question about a young woman, about 15 years old, who has been diagnosed with PANDAS and autoimmune encephalitis. Her story parallels my children’s stories to a great degree, and both of my children have been helped tremendously by allithiamine and several of the other supplements mentioned here by Dr. Lonsdale and Elliott Overton. The mother has written several blog posts about her difficult journey with her daughter, who was perfectly normal and healthy in 4th grade. But after a strep infection, their world turned upside down. Seizures, catalonia, severe fatigue, a total inability to concentrate, hallucinations. PANDAS, while suspected by one doctor, was deemed to “not be a real diagnosis” by the neurology department they were sent to, and they began a merry-go-round of scores of specialists in many states with minimal improvement. They currently have their daughter on IVIG infusions, with variable results, and a diagnosis of autoimmune encephalitis. But, the doctors have noted problems with mitochondrial function as well. Here is a clip from a blog post:

    “A curious piece to Gracie’s health is a mitochondrial condition that has yet to be named. Though it is treated symptomatically, her body is a prisoner to it. She can only sustain so much activity before she crashes. The challenge is that level of activity varies, so it can’t always be predicted.

    A mitochondrial crash is akin to hibernation. Her body just stops working to conserve energy. Sometimes she’ll seize, other times she’ll sleep for days on end and vital organs like her heart and liver won’t function right, creating high alert and fear. During this time she won’t communicate with us at all, and it’s brutal. But always at the end of it, she wakes singing. And it’s the most beautiful sound.“

    My question…do you have any information about a possible link between thiamine and PANDAS? I understand that a chronic infection alone could cause the kind of stress that might severely deplete thiamine. I would like to forward information from Hormones Matter to her, but after her very long road of a million specialists and chasing interventions that did not help, I was hoping to find some specific information that might link thiamine to strep, PANDAS, autoimmune encephalopathy (could it actually be Wernicke’s?) and damaged mitochondrial function. Her general symptoms, including heart involvement and an inability to walk most days, seem to echo symptoms of beriberi. I have searched the archives but hoped you might be able to suggest some articles here that would be most helpful.

    Thank you for this web site! I read and reread the archives here on almost a daily basis, and your book with Dr. Lonsdale is an incredible resource.

  2. An addendum to my previous post:

    Someone asked Ray Peat about the idea that estrogen might protect brain tissue. Here is part of his response:
    “…since estrogen activates lipid peroxidation, glutamate and calcium excitotoxicity, and DNA damage, it isn’t likely; women have, at middle age, 2.8 times the incidence of Alzheimer’s disease as men do, and in extreme old age, the ratio is over six to one. The cause of menopause is nerve damage produced by estrogen.”
    The newsletter is titled: Estrogen and brain aging in men and women: Depression, energy, stress. It is a very interesting read. The list of references included is extensive.

    The tragedy of the destruction of research by the pharmaceutical industry is appalling. They pay researchers to prove what they want proven. Estrogen is a multi-billion dollar enterprise.

  3. Welp…. From my personal experience estrogen dominance is a killer. Estrogen causes inflammation. Thiamine has been a life saver for me because it (and B2) lower estrogen.

    The studies you are relying on are using Medroxyprogesterone acetatone, not bio-identical progesterone. These two things are not interchangeable. Politics and the massive power of the Estrogen Industry have contaminated the research. Their handiwork has caused massive confusion and hopelessly damaged the research/knowledge base. Progestins are NOT bio-identical progesterone. Progestins have estrogenic qualities; bio-identical progesterone does not. It protects the body and reduces the body’s load of estrogen.
    “…Medroxyprogesterone acetate is considered a progestin (though it is not supportive of gestation), because it modifies the uterus in approximately the way progesterone does, but it is luteolytic, and lowers the ovaries’ production of progesterone while progesterone itself has a positive effect on the corpus luteum, stimulating progesterone synthesis. Defining “progestin” in a narrow way allows many synthetics to be sold as progestogens, though some of them are strongly estrogenic, allowing them to function as contraceptives–it is odd that contraceptives and agents which suppress progesterone synthesis should be officially called “supported of pregnancy.” It is probably partly the acetate group in the medroxyprogesterone acetate molecule which makes it bind firmly to receptors, yet causes it to block the enzymes which would normally be involved in progesterone metabolism. (I think testosterone, even, might be a safer progestin than medroxyprogesterone acetate.) Pregnenolone acetate similarly blocks the enzymes which normally metabolize pregnenolone. (12) In aspirin, it has been found that it is the acetyl group which (by a free radical action) blocks an enzyme involved in prostaglandin synthesis.”

    additional suggested reading:

    Thank you for your work on thiamine; it has given me my life back. I am most grateful!

  4. I was put on Lupron for 2 1/2 years straight when I was in my 20’s. I was never told the dangers, only that I would get hot flashes. It has given me serious health issues, but what I am dealing with now is uncontrollable weight gain ( 5 lbs a week and growing regardless of a heavy labor job and eating clean) and Cushing’s symptoms. Is there anyway to reverse the mitochondria damage?? Is there any way to control our metabolic systems any more? I get no answers from the doctors. I just want to know if we can stop or limit the damage, or do any repair?

  5. Excellent article Chandler! Some doctors tell women to try Lupron for 6 months or so and if the symptoms aren’t debilitating, they should consider an oophorectomy and hysterectomy. I always cringe when I hear / read that. Oophorectomy is as bad as or worse than taking Lupron permanently and Lupron is not supposed to be used for more than 6 months or so due to its harmful effects. And we know from numerous studies that oophorectomy causes more harm than good.

    • Thanks. I cringe too, especially when they put young women on Lupron. I feel like screaming at these docs – ‘what the hell are you thinking?’ But, of course, we know that is precisely the problem. They are not thinking.

      • What about in the case of hormone receptor positive breast cancers? If your cancer is highly estrogen/progesterone positive, reducing the levels of hormones has been shown to reduce the risk of cancer re occurrence. What would you recommend to women in this situation?

    • Short answer – it’s complicated. May increase risk for breast cancer, but b/c these are all dynamic/networked/cascade reactions, intricately tied to a number of factors it is difficult to tell. From :

      “Inverse associations between CYP1A2 activity and percentage free estradiol are consistent with previous reports that female sex hormones have an inhibitory effect on CYP1A2 activity. CYP1A2 activity is lower in women [6], reduced by 35–50% during pregnancy [7], inhibited by oral contraceptives [6] and hormone replacement therapy [43], and may be lower during the late luteal phase of the menstrual cycle, when estradiol concentrations peak [44].” So it is lower during periods of high estradiol b/c of the feedback loops. If it is inhibited already, and the individual has other variables associated with elevated estrogens (OCs, HRT, environmental estrogens, etc.) then this effect might be magnified. The question, what is the time frame of the FQ mediated inhibition? Is it temporary relative to the intake of the meds or is there a more chronic down regulation of these enzymes?

  6. This is a brilliant piece of work. It may be part of the explanation why a number of common diseases that occur in children are male dominated. It has been said that all disease is is a reflection of mitochondrial dysfunction and the relationship between estradiol and thiamine is very real. I was surprised at the statement that glucose is not the primary fuel of the heart since the heart is one of the organs most affected in the thiamine deficiency disease, beriberi. But now that we know that thiamin affects fat metabolism, this makes sense. The wonderfully intricate design of the human body makes the idea of that happening by chance extremely questionable in the process of evolution.

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