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

Published on March 26, 2025

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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.

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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.

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This article was first published on January 16, 2015.

Lupron: The Cycle of Negligence

by E. S.

Published on March 5, 2025

10515 views

My pelvic pain first started at age 13 with menses, but I was blacking out at 28-day intervals from the age of nine. I was told it was normal by both my grandmother and mother because they experienced the same thing. The abdominopelvic symptoms got severe after the birth of my daughter when I was 33 years old. I didn’t get a diagnosis for another 14 years at the age of 47 years. It has been nothing but a steady stream of dismissive and abusive doctors with absolutely nobody offering an explanation. The only solutions that I was offered were a hysterectomy and Lupron. Neither helped and in fact, made everything worse.

Physician Abuse

When I was 44, I had a hysterectomy, and adenomyosis was found but I was told everything was removed. Four months after my subtotal hysterectomy in December 2014, I was still having the same pelvic pain symptoms. My gynecologist didn’t know what else to do other than to use Lupron for 3-6 months to see if it would diminish my pelvic pain. If the pain persisted, she said the ovaries would have to come out. She told me she was using it as a diagnostic tool and if I didn’t try it she “would drop me as a patient.” More accurately, she screamed at me, started frantically waving her hands above her head and hit me with her pen. There were times I wish I had a witness to some of the behavior I was subjected to over the years; this was definitely one of them. I took the prescription home but didn’t fill it. I was not only shocked by her behavior but also, a little leery about being souped-up on yet another medication with horrible side effects.

Worsening Symptoms While on Lupron

I held off until Sept 2015 when I decided I couldn’t stand the pain anymore. My first injection was in October and I seemed to handle it quite well. I had relief from my pelvic pain within two days and a bit of mild dizziness that went away after about a week. The reduction in pain allowed me to go out for walks 2-3 times per day, which is something I hadn’t experienced for quite a long time—it was great to be walking again. Then I started noticing some strange symptoms every two weeks after the injection.

The first time it happened the symptoms were so mild I brushed them off as a minor cold bug: body aches and pains, sniffles, lungs slightly congested, watery eyes, my hearing was off and my eardrums felt plugged up. I thought maybe my daughter brought a cold bug home from school but these same symptoms happened exactly two weeks after the Lupron injection and every time the symptoms kept getting stronger. When I was due for my 4^th injection I knew something wasn’t right. My regular gynecologist wasn’t in and I’m glad she wasn’t. The one I did speak to about my symptoms told me to not take it anymore. He looked up my symptoms in a large pharmaceutical reference book; Lupron was listed as having “flu-like symptoms” in its trial phase but had no further information. I was told to go home and just let the effects “wear off.”

From December 2015 to February 2016, I had 11 visits to the ER for worsening flu-like symptoms that included: strong body aches and pains that felt like I had been hit by a train, congested lungs, and coughing up greenish-yellow fluid. The same gross mucous was coming out of my eyes and ears. My lungs were so congested I was gasping for air and I was terrified! They tested for bacteria, throat and nasal swabs, and full blood work—everything came back negative and it wasn’t pneumonia. I didn’t even have a fever. The last ER doctor I saw actually called the drugmaker to see what to do. He told me they have something similar to a WHMIS or Workplace Hazardous Materials Information System on all their products in case of adverse events. Well, guess what? They didn’t! The representative told him they knew about the severe flu-like symptoms in their trials with Lupron but they did not follow those patients to record their outcomes. In other words, there was no due diligence before releasing their product to the public. They don’t even know if those patients are still alive.

I was given an IV to prevent dehydration and placed on oxygen until my vitals improved; even then I was sent home without any concrete advice on how to deal with the side effects other than “it should wear off” and “if it gets worse don’t hesitate to come back”—like now isn’t worse. I asked the ER doctor if he is filing an adverse event report to Health Canada or the FDA and he said “that is for the patients to do but in your case, I wouldn’t worry about it. We don’t know if that is what is causing your symptoms. It could just be a viral thing.” I was about ready to flip my lid! He told me earlier if it was viral I would have a fever because that is what your body does to fight off infection and viral infection symptoms build up, peak and then you start feeling better. These symptoms occurred two weeks after each and every injection. I felt like I was talking to a brick wall. Do you know it took another four months for that damn Lupron to wear off? The entire time I was terrified. I was gasping for air while this green mucus is pouring out of my ears, eyes, and lungs. I would panic, cry, and then have to calm myself down because crying would congest my lungs making it harder to breathe. I have never been so scared in all my life.

Lupron Side Effects and Gynecological Ignorance

I did go back to the gynecologist that prescribed the Lupron and she had the nerve to tell me it was not her problem and to go see my GP. My GP told me since she didn’t prescribe it that it was the gyn’s problem. I went back to the gynecologist to tell her what my GP said and she threw another hissy fit because, apparently, I wasn’t on Lupron long enough to satisfy her 6-month requirement. My husband didn’t believe what I was telling him so I had him call the office to rebook an appointment so that we both could talk to her. At this next appointment, she placated my husband and refused to look me in the eye while she was speaking. I reminded her of everything she said previously; that it is her problem because she is the prescribing doctor; that my pelvic pain symptoms did improve while on the Lupron; that my adverse effects were directly related to the drug as my worsening symptoms occurred exactly two weeks after each and every injection; that I was tested at the ER and it was not viral or bacterial; that the ER doctor called the drugmaker and they had severe flu-like symptoms listed during their drug trials but never not followed up. I informed her I filed complaints with both Health Canada and the FDA.

She got up to check on my ER visit reports. While she was gone even my husband noticed she wasn’t talking directly to me, only to him and that I did meet her requirements—Lupron for at least 3 months, if the pain is relieved then it means the ovaries need to come out. My husband was ready to have it out with her when she came back. She kept trying to placate us, saying things like “I don’t know what to do”. I kept pushing for an answer—what was causing my pelvic pain if Lupron was the diagnostic tool—what was she using it to diagnose? She never mentioned “endometriosis”. I asked her if it could be cancer–no answer. I finally said, “If you don’t know what to do then send me to someone who has more experience dealing with complex gynecological issues. I want a referral to the Women’s Health Sciences Centre in Halifax.”

I hate to think of what would have happened if my husband wasn’t there to keep me centered; even he was getting frustrated by this gynecologist. She finally agreed to send a referral to Halifax. As we were leaving, she told my husband she was retiring in a couple of months so do not bother contacting her for any further concerns. I found out just a few days ago she is still working as a gyn—so she basically lied to my husband. What a piece of work!

I don’t understand how doctors can behave like this. There has to be some kind of benefit, either monetary kickbacks or endorsements, to blindly stand behind a drug like this and totally ignore what the patient is telling you to your face.

Recovering From Lupron

It took four months for the Lupron effects to “wear off” and for my lungs, ears, and eyes to return to normal. It was a terrifying experience that I don’t wish on anyone. I realize I was one of the lucky ones to walk away from this experience whereas others haven’t. To this day, I keep asking myself why I was put through this Hell in the first place. Why are doctors so ignorant in prescribing this drug as a diagnostic tool if they know about the adverse effects? We trust that drug companies are performing due diligence with regards to adverse reactions in trials and long-term follow up and they are NOT! How is it that the drug maker can get away with this? Why are there not more strict checks and balances before releasing a drug and when problems are being reported afterward? It is absolutely insane that this drug, with all its reported adverse effects and deaths, is still on the market. Why are the FDA and Canada Health dragging their heels and not banning this drug?

Two years after the hysterectomy and Lupron, I was still in excruciating pain. I had a cervical cyst removed and pathology indicated that I had endometriosis. My ovaries were removed in 2017 and both were completely “disintegrated”. Once again I had to fight to get my diagnosis. The surgeon had the nerve to try to hide the biopsy report so I wouldn’t have proof. Luckily, the medical records clerk did some searching and found it, but she also told me she could have lost her job because of what this doctor did.

My NP, although supportive in the beginning, has now resorted to telling me “this is your new normal, you’re just going to have to get used to it.” I am at my wit’s end trying to get help dealing with what is left of my health. I am not able to work or enjoy any quality of life anymore. I’ve been given the run-a-round by 5 GPs, 1 NP, 11 OBGYNs, and 35+ ER doctors. I don’t have any faith left in our health care system. My only alternative is to seek legal advice, but I really don’t know how to move forward in a system that is so dismissive and corrupt in how it treats women’s health issues. I’m beyond whatever “disgusted” is.

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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.

Yes, I would like to support Hormones Matter.

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This story was published originally on June 8, 2020.

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

by Chandler Marrs, PhD

Published on December 10, 2024

22285 views

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

Lupron, Surrogacy, and Multiple Sclerosis White Matter Lesions

by Julie Labbe

Published on October 3, 2024

15059 views

I decided to be a surrogate after watching a birth story on TV. I felt like it would be a meaningful way to give back. I was adopted as an infant and I wanted to help another couple have a baby of their own. I did some research, found an agency, met a couple, and went through reproductive screening at a fertility clinic. They explained to me that they would give me hormone injections to artificially stop my body from releasing an egg. I was a gestational surrogate, meaning I only carried the embryo. The embryo was made from a donor egg. Once they confirmed that I had not ovulated they would begin giving me estrogen to produce a uterine lining. After two weeks, it was time for the big day, the transfer of the embryo to my uterus. The embryo transfer was successful and so for twelve weeks following I took a daily injection of progesterone.

I am ashamed to say that I did not do my research and I did not know exactly what I was taking, other than “hormones”. I recall the potential side effects being listed as headache, fatigue and hot flashes and that these side effects were temporary and would dissipate after I stopped taking the medication. I remember glancing over the package insert for the leuprolide acetate (Lupron) noticing nothing was too alarming.

Post Lupron Symptoms

I went on to deliver a healthy baby boy in May of 2013, his parents were thrilled and it was time to focus on me again, get my body back in shape and move on with my life. It was August when I had my first “attack”. I was feeling extremely dizzy and had tingling in my left hand so I went to my primary care provider. She could not tell exactly what was going on but felt that the dizziness was caused by allergies and the numbness in my left arm caused by carpel tunnel. She sent me home with an antihistamine and a brace for my left arm. Eventually my symptoms subsided and I felt perfectly normal.

In January of 2014, I began feeling dizzy again, I tried an antihistamine and it just made me tired. The tingling and numbness came back in my left hand. I went to a different doctor who told me I had vertigo. The doctor tried a few tricks, such as hanging upside down and flipping up really quickly to try to “reset” my equilibrium (that didn’t work). The tingling in my arm was thought to be a pinched nerve in my neck because I lifted weights. Several days went by and I was still feeling terrible, the numbness was also occurring in my face. I was convinced I was having a stroke or that I had brain tumor. I went back to the doctor, insisting on an MRI. I was relieved when I was told that I did not have a tumor. The doctor said that I had signs of a demyelinating disease, such as multiple sclerosis. There are six lesions on my brain.

Multiple Sclerosis or Something Else?

Obtaining the actual diagnosis was a very long process which involved a lumbar puncture to check my cerebrospinal fluid for elevated levels of antibodies and a specific group of proteins called oligoclonal bands. The findings indicated I did have elevated levels of the antibodies but that the group of proteins were not present. Still the neurologist felt that it was enough for a diagnosis for multiple sclerosis and prescribed a disease modifying drug, a three times a week injection. Multiple sclerosis cannot be cured but there are drugs designed to try to prevent the immune system from attacking the myelin sheath (protective nerve coating). I sought the opinion of another neurologist who had a specialty in multiple sclerosis. She agreed with the diagnosis of Relapsing Remitting Multiple Sclerosis, which is characterized by clearly defined attacks of new or increasing neurologic symptoms. These attacks are followed by periods of partial or complete recovery. During remissions, all symptoms may disappear, or some symptoms may continue and become permanent. However, there is no apparent progression of the disease during the periods of remission.

Another Surrogacy and Another Round of Lupron

During this process, I knew that I was going to be gestational surrogate again. I had already committed to the couple to carry a second child for them. I stopped taking my disease modifying drug and began the gestational surrogacy protocol again of Lupron, estrogen and progesterone. Thankfully we were successful on the first round as we were with the first baby. Many surrogates are not successful on the first round and go through the protocol over and over again.

I was advised by my neurologist that many women have an exacerbation of MS after birth, as it is very stressful on the body. He advised that I begin taking steroids immediately following the birth to prevent a relapse. I had a very traumatic birth, resulting in surgery and I decided I did not want to take steroids. I would take my chances with the relapse – nothing happened, I felt perfectly normal again.

I am currently not treating myself with the medication prescribed for MS. I have not had any new or worsening symptoms in three years and each MRI shows no new lesions, although I live daily with existing symptoms. I have damage to my trigeminal nerve causing constant pain and numbness in the left side of my face, I also have occasional numbness and tingling in my left arm and leg.

When I was first diagnosed, I searched for nearly every cause I could think of. There is no one in my family history with MS. I didn’t have a vitamin D deficiency. I didn’t have the Epstein-Barr virus or any of the other things thought to be linked to multiple sclerosis. I started searching though my life for anything unusual, which is when I finally researched Lupron. There have been less than 5% of adverse effects reported; however, neuromuscular conditions are listed. I have since learned that there are no clinical studies on the safety of Lupron for IVF and it is being used as an “off label” medication. This allows for it to be used for medical purposes that were not originally specified in the FDA’s approval of the drug and it is not on the labeling. I have reached out to many women online and have heard similar stories of MS, or MS like symptoms or other autoimmune conditions and the use of Lupron.

I feel that I was lucky, I only took Lupron for a short amount of time, many women take it for much longer and at higher doses, possibly causing more damage. I want women, potential surrogates, reproductive endocrinologists and fertility clinics to be aware of this. I want more research to be done on the hazards of the drug. I want to prevent the off-label use of medications.

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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.

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This article was published originally on February 13, 2018.

Short and Long Term Consequences of Lupron for Precocious Puberty

by Jody

Published on May 8, 2024

12454 views

As a child, at around age 5, I started experiencing severe pain in my legs and back. I had migraines from hell that made me feel as if my head were going to explode. I had hair in places that no five-year-old should and I needed a bra for kindergarten. I looked down on all my peers because I was a good 12 inches taller than most of them. I always had to be the mom when playing house in kindergarten. My parents struggled to find help for me because no doctor could explain why I hurt and felt the way I did. Finally, after being hospitalized for over a week my parents had answers. I was diagnosed with a hormone imbalance. The doctors in the area where I lived had no answers about how to treat me, so I was sent to a specialist in Augusta Georgia. He then called my diagnosis precocious puberty, a hormonal imbalance. After more needles and tests, he decided to start me on Lupron.

I took Lupron as a child from 1989 to 1994 for my hormone imbalance. I received a shot once a month in my thigh and sometimes in my butt cheek. I can remember the burn of the Lupron going into my body like it was yesterday. The injection always took me a week to recover from. I experienced soreness in the injection spot and redness every time I received Lupron. I could not run and play as a child. My legs either hurt or my mind would make me feel as though I had no purpose. From the outside, the Lupron shots were a success. The shots slowed my abnormal hair growth in private places and stopped my breast from growing, but on the inside, where it counts, what was the Lupron doing to me?

After being on the Lupron for half a year, I had lumps in my thighs where I received the injections (which I still have today). One time it crippled my legs, leaving me on crutches for two months when I was 7 years old. Yet still, I guess my doctor felt it would be more beneficial for me to continue my treatment with the Lupron because I received injections for 3 to 4 more years.

While on Lupron, I struggled daily to focus. I had blurred vision. I battled depression and I hurt daily. I couldn’t be active in sports due to my low bone mass and what kid feels like playing ball when her body feels like it’s been beaten with the bat already? By age 11, I finished up my treatment. I saw my doctor a handful of times after and then I was written off as cured, and I did feel good and enjoyed life for a few years.

At age 15, I began to battle depression. I struggled to remember things. I was diagnosed with asthma. My sight was getting worse and I had an eating disorder where I never wanted food due because my stomach felt like someone was squeezing it with all their might. I fainted several times because I was dizzy. I struggled to stand and I would walk holding onto things. My legs, arms, fingers, and toes would tingle and go numb. My doctor at the time seemed to always just prescribe me Lortabs for the pain and never dug any further to figure out why I felt the way I did. At age 17, I overdosed on Lortabs not trying to hurt myself but only trying to find relief from the pain. I didn’t realize that my body couldn’t handle all the medicine I was putting into it. My mom found me in my room and rushed me to the hospital where my stomach was pumped and I had to drink this disguising chalky drink. My pain seemed to decrease shortly after I turned 20. I looked and felt like the average healthy person. I had my first baby at 21 and my second at age 22. I had healthy pregnancies and healthy babies. I had my third baby at age 32 and again I was a healthy mama and had a healthy baby.

For the past two years, however, I have been experiencing a pain that is all too familiar. I feel as though my body and mind are failing me. I cannot pinpoint why all of this is happening to me. I am now 34 years old and experiencing horrific body aches and pains. I’m searching for answers as I struggle to hold my baby and even get out of bed due to the pain I feel. I hurt in all my joints, my back, my neck and I have leg pains that put me on my knees and unable to walk. My feet and ankles swell, my arms, fingers, and toes tingle with pain. I sometimes drop things because I can’t squeeze my fingers together to hold them. I am experiencing night sweats, hot flashes, nausea, and abnormal weight loss. I have dropped 90 pounds in 15 months. My stomach hurts every day and I never feel hungry. I have so many other symptoms, I feel as though I’m falling apart. I am working with my doctor now to try and find answers. I want to find quality in my life again. I want to feel good when I wake up and not have to lay in bed for at least an hour (waiting for pain meds to kick in) before I can move. Most importantly, I want to be able to pick my baby up out of her crib and hold her and not cry because it hurts my body so bad.

I am in the beginning stages of trying to figure out why I feel this way. I have had blood work drown which was good and I have a CT scan this week. It never even crossed my mind that all of this could be the side effects of taking Lupron as a child until I started reading other people’s stories. Please help?? What test do I need to take to help find answers? What meds are helping restore bone mass? What are other past Lupron patients experiencing and what is working to help them find quality in life again? Thanks in advance for your help!

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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.

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This story was published originally on June 18, 2018.

Lupron Induced Osteoporosis?

by Samantha Bowick

Published on May 1, 2024

15385 views

Women who suffer with endometriosis do not have many options for treatment. As a result, many women try Lupron because they are desperate to be pain and symptom free. I was one of these women. In 2011 and 2013, I tried Lupron for a total of three doses and wish I knew then what I know now.

In 2010, I was diagnosed with endometriosis laparoscopically. After that, I tried everything from many different types of birth controls and pain medications to depression medications that can also be used to treat pain. Nothing worked. My doctor at the time suggested Lupron to me and I was desperate. I felt like I had already put my life on hold long enough because of this disease and just wanted to be out of pain. However, now I feel like I am suffering the consequences and it didn’t even get rid of my pain.

In 2015, I was diagnosed with osteoporosis. Prior to this, I had never had a bone scan done, not even before being administered Lupron. In 2009, I was diagnosed with Vitamin D deficiency and have been taking a supplement ever since. Three months before being diagnosed with osteoporosis, I stress fractured my knee and was told at my age, it should not have happened. In 2014, I had a hysterectomy because of endometriosis; I couldn’t take the pain anymore and had disease on both ovaries.

Before this, I had never had bone problems or been told that I could. I blame Lupron and strongly believe using it as a treatment for endometriosis led to me having osteoporosis. At 27 years old, I am still trying to work with doctors to determine if there are any treatments I can do because people my age having osteoporosis is rare. Many medications women use for osteoporosis could negatively impact my bones even more because of my age. If I don’t use any treatment, I could suffer from even more fractures or bone breaks the older I get. Right now, my average T-score for my left hip is -3.6 and was -3.3 when I was first diagnosed. I have no idea when my bones became so brittle. In my case, I wish I would have never tried Lupron as now I know this is one of the many side effects of this terrible treatment for endometriosis and something I will have to deal with for the rest of my life.

There are not studies done on medications for osteoporosis in my age group because there are not enough people with the disease to study. The medications my current doctor wants me to try would be a daily injection I would give myself in the abdomen for two years. They are known to possibly cause osteosarcoma, a bone cancer. Based on my history, I don’t like my odds. At this time, I don’t know how I will try to treat osteoporosis. I am planning on looking into natural ways of treating the disease and see how that goes.

As a result from my knee injury two years ago, I had to have an arthroscopic surgery. My doctor repaired my torn meniscus and removed scar tissue. It is taking me longer to heal than I anticipated and I wonder if it is because I have osteoporosis.

If doctors use Lupron for patients, they should be required to give these patients bone scans before their first dose and do follow ups yearly. It is a known fact that Lupron should not be administered in more than 12 doses over a patient’s LIFETIME. I wonder why this is?

I hope my story helps someone make a decision that is best for their body and raise awareness about Lupron. I am not a doctor, nor do I claim to be, but I am a patient that continues to live with the outcomes of having endometriosis.

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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.

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Image credit: Laboratoires Servier, CC BY-SA 3.0, via Wikimedia Commons.

This article was published originally on December 13, 2017.

Lupron, Thyroid Disease, and the Broken Scales of Justice

by Lynne Millican, RN, BSN, Paralegal

Published on December 5, 2023

28880 views

Even though women being prescribed Lupron (leuprolide) have, understandably, no clue about its adverse thyroid effects, it is no secret that Lupron adversely affects the thyroid gland. (The same could be said for adverse effects from Lupron on many other organs and bodily systems, but the focus here will be on the thyroid.) For decades, a wide variety of adverse thyroid effects during or following this drug have been reported to the FDA: according to RxISK.org’s compilation of Lupron FDA Adverse Event Reports (‘AERS’, for the years 2004 – 2014), Thyroid cancer, Hypothyroidism, Thyroid disorder, Thyroidectomy, Hyperthyroidism, Thyroid neoplasm, Thyroid function test abnormal, Autoimmune thyroiditis, Thyroid cyst, Blood thyroid stimulating hormone increased, Blood thyroid stimulating hormone abnormal, Blood thyroid stimulating hormone decreased, Anti-thyroid antibody positive, Thyroid cancer metastatic, Biopsy thyroid gland abnormal, Follicular thyroid cancer, Thyroiditis, and Thyroiditis subacute have all been reported (search “thyroid” in “Side effects reported” here; also Open Vigil, which contains FDA AERS for the years 2003 – 2013, can be searched.)

Different Warnings for Different Countries

For decades foreign labels for Lupron have identified “thyroid enlargement” as an adverse event ( i.e. 1998 Australian label for “Lucrin [Lupron]”, MIMS Annual 1998, Australian Edition, page 9-804; also 2010 Danish label – Danish Medicines Agency, Product Resume for “Procren [Lupron] Depot”). As early as 1986 the US product label for the initial formulation of Lupron (5 mg/mL vial, administered as 1 mg daily subcutaneous injections) identified “thyroid enlargement” as an adverse event (1986 Package Insert No. 3626, “Lupron/leuprolide acetate 5 mg/mL. Manufactured for TAP Pharmaceuticals by Abbott Laboratories, Rev[ised] Nov. 1986”; 1992 Physicians’ Desk Reference [PDR] , “Lupron/leuprolide acetate 5 mg/mL”, p. 2310). The US product label for the intramuscular injection of monthly Lupron Depot 3.75 mg (and other depot dosages) likewise identified warnings for thyroid enlargement (i.e., 1995 PDR, “Lupron Depot 3.75 mg.”, p. 2506; 1996 PDR – “Lupron Depot 3.75 mg”, p. 2558.) Between 2004 and 2012, there were 22 reported cases of thyroid cancer, and Lupron was considered “highly suspect” by a number of physician opinions, and according to RxISK.org’s FDA AERS database, there’s been 6 more cases (search “thyroid cancer” in “Side effects reported” here).

But, despite this history, all thyroid adverse events have been removed from the current labels of US Depot formulations of Lupron, and no thyroid warnings have been identified since the mid-2000’s – i.e., the current Lupron 3.75 mgs product label as well as the current labels for other depot dosages no longer contain any mention of thyroid adverse effects. The daily 1 mg formulation of leuprolide continues to identify warnings of thyroid enlargement and thyroid nodule, and foreign labels for Lupron continue to identify adverse thyroid effects, but the labels for US Lupron Depot formulations (which are prescribed the most for women with endo and fibroids) are devoid of any warning.

In the Courts

It is worthwhile here to revisit the atrocities committed during the only Lupron lawsuit to make it to trial (Karin Klein v. TAP/Abbott, Case 2:08-cv-00681-RLH-RJJ, 2011) – many prior lawsuits having been quietly settled with secrecy agreements. Karin Klein, at age 17, was prescribed Lupron Depot 3.75 mgs in 2005 when Lupron’s label no longer contained the prior-listed warnings about adverse thyroid events. Karin developed, among others, chronic autoimmune Hashimoto’s thyroiditis. Belatedly learning of Lupron Depot 3.75 mgs’ prior US label warnings of adverse thyroid effects, as well as the prior and current similar warnings in foreign labels, Klein sued for failure to warn.

The judge at trial refused to allow the jury to learn of Lupron Depot’s pre-2005 US labels warning of adverse thyroid effects; the judge refused to allow the jury to learn of Lupron’s past and current foreign labels identifying adverse thyroid events; and the judge refused to allow the jury to learn of published medical literature identifying Lupron’s adverse thyroid effects (See Judge’s rulings, “Document 265, filed 07/25/11, page 13 of 40”, which can be found on p. 101 in this document). The judge would only allow the jury to learn of the 2005 US label. Moreover, Abbott’s mendacious defense medical “expert” stated under oath that “it was absolutely biologically impossible for Lupron to affect the thyroid gland. No textbook, no article has ever supported that contention. It’s simply biologically impossible.” (See “Page 20 of 131” here). A simple PubMed search shows this “expert statement” to be absolutely false – and this is without-a-doubt perjury (here, here, here and here). The first published report that “demonstrate[d] the association of thyroid disorder with leuprolide” occurred in 2000 – five years prior to Klein’s Lupron Depot prescription. Rhetorically speaking, exactly how does a paid “medical expert” get away with outright perjury concerning Lupron Depot’s – or any other drug’s – known risks?

This court’s curious restriction of limiting disclosure to only the 2005 Lupron Depot label (devoid of any thyroid warning) created the illusion for the jury that there were NO thyroid adverse effects from Lupron Depot for Klein to have been warned about — and so by a legal sleight of hand, Klein’s claim of “failure to warn” was made to disappear. The jury, unknowingly dis-informed and ‘educated’ in misinformation only, believed that it was ‘biologically impossible for Lupron to affect the thyroid gland’, and the jury found against Klein and found in favor of the drug company.

An appeal – bewilderingly – resulted in the Circuit Court making false statements and misstating facts. As argued on appeal by Klein’s attorneys:

“[Klein was] entirely shackled in the evidence she was allowed to present. It is particularly galling to have qualified (and expensive) expert witnesses on hand to testify, only for them to be shut down before the jury and precluded from offering competing expert opinions. The pattern shown by the record [of the Klein trial] is deeply disturbing. Virtually every discovery and evidentiary ruling, and other orders of significance, went for one party [TAP/Abbott and never for Klein]. … Such a one-sided proceeding was not the fair trial our system demands.” The multitude of rulings against Klein’s request for admission of evidence can be found delineated the afore-mentioned in “Document 265, filed 7-25-11”.

But the Circuit Court, in a 2-day deliberation, concluded: “… The district court did not abuse its discretion in excluding the challenged Lupron labels because they all contained information regarding the side effects of different formulations of Lupron, rendering them insufficiently relevant, unduly prejudicial, and likely to confuse the jury.” Here the Circuit Court misstates facts and conveys the opinion that “the pre-2005 US Lupron Depot 3.75 mg label for endometriosis” is a “different formulation” from “the 2005 US Lupron Depot 3.75 mg label for endometriosis”. This is utter hogwash from a high court – “Lupron Depot 3.75 mgs” is identical to “Lupron Depot 3.75 mgs” regardless of the year of the label. And it should not be terribly difficult for anyone (including the Court) to comprehend that the drug comprising the initial 1 mg. daily-injected subcutaneous Lupron was subsequently put into a “depot” (“long-acting”) ‘delivery form’, allowing one intramuscular injection to slowly deliver the same drug — Lupron – over the course of one (or three) month(s). The courts had access to the 2010 Danish label (Klein v. TAP/Abbott, Document 175, filed 06/12/11) in which it is stated “Leuprorelin [leuprolide] acetate is released at a constant rate over a period of 4 weeks (3.75 mg) or 12 weeks (11.25 mg) … which is equivalent with what is seen with a daily injection of 1 mg leuprorelin acetate.” (To date, I have not located that same statement in a US Lupron label.) This appellate court concludes that “Klein has not even remotely established that the district court exhibited such a high degree of favoritism or antagonism as to make fair judgment impossible.”

Denied her right to a fair trial a second time, Klein petitioned the US Supreme Court. One would (and should) assume the Supreme Court would inherently recognize the serious ramifications and public health impact of a case (any case) where perjury of the known dangers of a drug was committed by a defense expert (effectively hiding this information from the jury and ensuring a defense ‘win’), and where a Circuit Court completely misstated facts (upon which it had relied to deny Klein’s appeal). But, in fact, the denial of a plaintiff’s right to a fair trial, the denial of a jury’s right to truthful and accurate expert medical testimony, and the denial of society’s right to expect that court rulings will be based on authentic factual information were all issues the US Supreme Court deemed unworthy of review.

Broken Justice: Precedent for Medication Adverse Events Cases

These circumstances resulted in a devastating miscarriage of justice – not just for Karin Klein, but for all Lupron victims – and to society at large as well. What kind of precedence could this Klein verdict have upon future litigation – with this or any other drug? In fact, lawyers throughout the US, with potential plaintiffs seeking redress post-Lupron, were closely following the Klein case, and had Klein prevailed the floodgates of litigation were poised to spring open. But by securing a defense ‘win’ via, in my opinion, a multitude of highly questionable actions, those floodgates were slammed shut. (In May 2015 an RN disabled post-Lupron filed a lawsuit, and this case is presently making its way through the court system.) At least a few ethical and powerful legal experts should be examining the events in the Klein case – it could (and should) become renowned as a classic case of injustice personified. (Links to additional court documents and further details on the Klein case can be found at bottom of page, left column).

What does it mean when a young woman’s health and life are irreparably damaged and there is no recourse? How does a disabled victim fight against a system that has clearly indicated it is obfuscating and is the antithesis of justice? How does a society ensure that truth prevails, and harmful effects of drugs are exposed rather than shielded?

Recently, in attempts to achieve transparency in clinical trial data, many drug companies have put their clinical trial data online. The endometriosis clinical trial data for Lupron 3.75 mgs remains under a court seal – ensuring this data will never see the light of day.

There are many, many questions, and many, many victims, but as of yet – there are no substantive answers.

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.

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If you have a Lupron story to share, send us a note: Write For Us.

This article was published originally on January 20, 2016.

Image by jessica45 from Pixabay.

Post Lupron Mitochondrial Collapse: A Case Story

by Derrick Lonsdale MD, FACN, CNS

Published on April 3, 2023

7479 views

Dr. Marrs and I became aware of the symptoms and some of the laboratory results in a 38 year old woman. We wish to describe the case because it represents what should be an entirely new approach to medicine in general.

Before Lupron

The patient had been an active 38-year-old woman caring for her home and two children, ages 7 and 9 that were her focus, prior to Lupron. She had walked her dog daily, worked out at the gym twice a week and she had renovated her home in the summer of 2017. She had had her gallbladder removed in 2016, said to be because of a polyp. She had received allergy shots once a month for a couple of years. She took birth-control pills. Her history revealed that she had had a severe reaction to penicillin as a child, resulting in a rash and joint swelling causing inability to walk for a short time. She also had a history of frequent sinus infections and antibiotic treatment. In 2017, she began experiencing heavy menstrual bleeding and hysterectomy was recommended. She refused this and a second doctor recommended Lupron in an attempt to change her hormonal balance before hysterectomy.

After Lupron

She had received an injection of Lupron into her left hip and side effects, beginning within a few days, included:

Fatigue
Skin redness
Severe weakness in the legs, and tingling in the left side of the head and right leg.
A few days later she developed severe headaches and vomiting.

An initial estradiol patch caused no improvement, so another one at double the dose was prescribed with some improvement (presumably in menses). By November 2017 the patches were discontinued. She began to experience

Joint pain
Pain throughout her body
Nervousness
Shaking
Panic attacks
Changes in personality.
In December she experienced cyclic vomiting and weight loss.

The estrogen patches were prescribed again. She saw an endocrinologist and some laboratory tests were abnormal, including what was described as a borderline high blood glucose.

These symptoms continued and in February 2018, three drugs were prescribed (Celexa, Neurontin, Ambien). They were discontinued two weeks later because there was no relief of symptoms.

In March, she experienced severe fatigue and had episodes of difficulty in walking which were intermittent and described as “almost like being paralyzed”.

In April, she saw a geneticist and some lab tests were performed that I will comment on shortly. A diagnosis of fibromyalgia and possible chronic fatigue syndrome were each entertained. The endocrinologist said that test results indicated that she was not producing estrogen or progesterone.

Based upon conversations with us, she began supplements of thiamine, fish oil, alpha lipoic acid, B complex, folinic acid, ferrous sulfate and methyl B12. Estradiol patches were resumed. We suggested the use of intravenous water-soluble vitamins, since Dr. Marrs and I agreed that giving the nutrients by mouth probably could not reach the necessary concentration of vitamin therapy needed. This was not followed through on by her current physician.

Discussion of Symptoms and Side Effects

The patient’s medical history indicated that she had experienced many different symptoms throughout her life. These included a severe reaction from penicillin and multiple sinus infections. The side effects from Lupron were fatigue, leg weakness, headaches, general body pain, panic attacks and cyclic vomiting. In other words, she had been a classic “problem patient” to her physicians. Since the symptoms could not be defined by usual and customary laboratory evidence the general conclusion was repeatedly that this was evidence of psychosomatic disease. Curiously, this common diagnosis in modern medical circles appears to be that the patient is thought of as inventing her symptoms neurotically without ever considering an underlying mechanism. Even worse, polysymptomatic disease of this nature is usually experienced by the brightest and the best. This is because high intelligence is developed within a brain which is more energy consuming than that of a less intelligent person. Such individuals are much more prone to unforeseen stress events, making them more susceptible to side effects from medication and inoculations. A car engine uses more energy to climb a hill. Stresses that we meet in life are like “hills to be climbed” and involve a commensurate supply of energy.

Laboratory Results: Low Amino Acids, Vitamin Deficiency and Defective Energy Metabolism

Many tests were performed on this patient. Two amino acid tests were performed, one measuring the amino acids found in blood plasma, the other measuring those excreted in urine. A word of explanation is necessary. Amino acids are the building blocks of proteins in the body and finding a given amino acid in very low or unusually high concentration can be used to define important aspects of body chemistry. Of 34 amino acids recorded in the plasma of this patient, aspartic acid, serine, ethanolamine, and tyrosine were severely decreased, while glutamine, histidine, alanine, ethanolamine and tyrosine were severely decreased in urine. All the others were in their expected normal concentration.

Amino acids are used in the body to create proteins, and this is an energy consuming mechanism. One of the deficient amino acids was aspartic acid whose metabolism is important in a mechanism known as transamination. The enzyme that carries out this function requires vitamin B6.

Two of them, ethanolamine and serine, play an important part in transmethylation, a mechanism that is dependent on folate and B12.

The fourth one was tyrosine and it is involved in the synthesis of thyroid hormone.

These low levels suggested that their respective vitamin dependent mechanisms were at fault. Since all the vitamins involved are water-soluble, it invited their administration by intravenous infusion. However, because they were energy dependent reactions, it is likely to construe the possibility that the underlying common fault was energy synthesis.

Was there any evidence from these laboratory results for defective energy metabolism? Yes.

Isocitric and citric acids were reported to be low in the urine and they are vital metabolites in the citric acid cycle, the “engine” of the cell. Also, there was a deficiency of pyruvic acid and this is the fuel that enables the citric acid cycle to function. This constituted strong evidence for energy deficiency with its major effect on the brain and nervous system.

Mitochondrial Energy Synthesis

Our bodies consist of 70 to 100 trillion cells that are being broken down and reconstructed throughout life. Relatively simple molecules are acted on by enzymes in a series of chemical reactions known by biochemists as “pathways”. Each enzyme requires a vitamin and/or essential mineral that assists the action of the enzyme and are known as cofactors to the enzyme. Several pathways reflect the synthesis of energy that is stored in the cell as ATP (adenosine triphosphate). ATP is a little like a battery that is being continuously charged and discharged and most of this occurs in the mitochondria. All the other pathways consume energy, either in enabling function or rebuilding cells. They might be compared loosely to the transmission in an automobile. In other words, the healthy body functions because energy synthesis meets energy demand. The abnormally low amino acids each could be used to suggest a defect in the energy consuming pathways and possibly a reflection of missing cofactors, making the “transmission” defective.

Vitamin Cofactors, Energy Deficiency, and Symptomology

The symptoms expressed by this unfortunate patient pointed strongly to cofactor deficiencies derived from diet that could easily be tested by their administration and clinical effect. The net effect is produced by a gap between energy synthesis and its utilization to meet the stresses of life in general. The administration of cofactors does not necessarily answer the underlying question because of the possibility of unknown genetically determined factors. However, it is safe, non-toxic, may have an epigenetic effect and is relatively cheap. It therefore should be the first approach. The greater the urgency or the severity of symptoms, the stronger the indication for intravenous administration of all the water-soluble vitamins. I have successfully treated many polysymptomatic patients this way, suggesting that mitochondrial function is as much an acquired disease as well as being genetically determined.

A Note About Oxidants and Antioxidants

Think of the body as a machine that consumes fuel by uniting it with oxygen to produce energy. This combination is called oxidation. Like a fire or any form of burning, it can be slow or fast and cellular oxidation seeks an intermediate level. If the oxidation is too slow, energy production is imperiled. If it is too fast or too vigorous, oxygen atoms are “thrown out” of the oxidation process like sparks are thrown out of a vigorously burning fire. These are referred to as “free oxygen radicals”. Like sparks from a fire, they can do damage. Some vitamins act to assist or accelerate oxidation, an example being B complex. They are known as oxidants. Others quench the free oxygen radicals (sparks) and are known as antioxidants. Vitamins C and E are examples.

Without going into the highly technical details, thiamine acts as an oxidant and an antioxidant, thus increasing its importance in metabolism. From this it is easy to see the essential importance of these substances that are obtained from naturally occurring foods and why their deficiency causes disease. Of course, we have known this for a long time, but current medical belief is fixed in the concept that “vitamin deficiency disease has been conquered and the resultant diseases are only of historical interest”. For example, this patient had “borderline high glucose”, something that would occur in the thiamine deficiency disease beriberi. She also had frequent “infections”, now known to be related to free oxygen radical production, indicating that her regulation of metabolism was extremely inefficient. The amino acids that were extremely low in the plasma and urine could be used to interpret the possibility of missing cofactors, reflecting a chaotic state of metabolism. I must end this by saying that the use of vitamins and minerals in this manner is not (repeat not) simple vitamin replacement. We believe that the vitamin/mineral combination used in high-doses is resuscitating the activity of the corresponding enzyme and it is therefore acting as a drug. Identifying the underlying biochemical lesion is the essential nature of future diagnosis.

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Image Credit: Image by Steve Buissinne from Pixabay

This article was published originally on July 25, 2018.

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Before Lupron

After Lupron

Discussion of Symptoms and Side Effects

Laboratory Results: Low Amino Acids, Vitamin Deficiency and Defective Energy Metabolism

Mitochondrial Energy Synthesis

Vitamin Cofactors, Energy Deficiency, and Symptomology

A Note About Oxidants and Antioxidants

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