One of the many challenges for people who suffer from symptoms of chronic fatigue and pain is determining what the root cause or causes are. This is particularly difficult because the symptomology of adrenal fatigue, chronic fatigue syndome (CFS), fibromyalgia syndrome (FMS), and myalgic encephalomyelitis (ME — the common name for CFS outside of the United States) have striking similarities. All of these conditions also have substantial overlap in symptoms with multiple sclerosis (MS), Lyme disease, and many other physiological causes for chronic fatigue and pain.
There are a huge number of possible explanations for chronic fatigue and chronic pain symptoms. A lot of them can be ruled out with tests and carefully examining symptoms. Many of these possibilities are mentioned in the article Tired All the Time for Months or Years? Here’s A Resource With Many Possible Explanations along with a link to a primary care diagnostic manual online that may help improve your awareness of the many possible causes. Before assuming that your chronic fatigue and/or chronic pain symptoms are adrenal fatigue, CFS/ME, or FMS, you should familiarize yourself with that list of possibilities and consider whether any of them may apply to you. After having done so, you may realize that your symptoms still don’t appear to be explained completely by any one of these more simple explanations. In that case, it may be that you suffer multiple conditions or that you suffer from one of the confusingly complex conditions such as adrenal fatigue, CFS/ME, and FMS.
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Often doctors jump to a conclusion that a person reporting chronic low energy and tiredness, widespread diffuse pain, difficulty sleeping, anxiety, and depression with some strong psychosocial stress factors present (job loss, divorce, death in the family, recent overseas combat duty in the military, etc.) is suffering from a mental illness such as depression or anxiety. They may assume the patient simply needs medications for these and some time for the psychosocial stress to pass. Between the pressure to pack in many patients and the tempting easy diagnostic targets that mental health disorders such as major depression and anxiety spectrum disorders make, they quickly jump to conclusions because the multitude of symptoms sounds on the surface to be yet another case of depression and anxiety. Considering adrenal fatigue, CFS, and FMS/ME would simply take to much time and effort. So to finish the appointment in the allotted 5 minutes and 13 seconds per patient, they then whip out the prescription pad, prescribe the first antidepressant, anxiety, and sleep meds that come to mind, and completely fail to adequately evaluate the possible physiological causes for the symptoms. If it doesn’t work, they figure you’ll come back for another 5 minutes and 13 seconds with them in a few weeks.
Yet many mental health disorders appear to involve biochemical factors strikingly similar to those found in adrenal fatigue, CFS/ME, and FMS. For instance, researchers studying Nazi concentration camp survivors have found that the mental health disaster of Post Traumatic Stress Disorder triggers abnormally low cortisol levels that can last for decades after the most obvious traumatic stress ended and even impact their children. The research paper Transgenerational transmission of cortisol and PTSD risk discusses how parents who suffer PTSD and low cortisol often see their children grow up to face the same kinds of health problems likely because of epigenetic transmission of the parent’s stress-related medical damage to the children.
There are other biochemical similarities between these conditions, too. The researchers behind the paper Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness noted that many people with chronic drug-resistant depression have low CoQ10 levels. Low CoQ10 levels are also common in adrenal fatigue, CFS/ME, and FMS.
While anxiolytic and antidepressant medications may sometimes help with the anxiety and depression and improve sleep somewhat, they are likely to do nothing at all for the hormonal and biochemical imbalances that often accompany supposedly “mental” illnesses. Sometimes they actually make matters worse, sapping the last bits of energy the unfortunate patient has because many of these patients are acutely sensitive to even low dosages of psychiatric drugs. If there’s a way to treat more of the root causes and biochemical imbalances rather than applying drug band-aids on the most evident “mental health” symptoms, the outcomes for patients may be much improved.
Adrenal Fatigue, CFS/ME, and FMS Have Confusingly Similar Symptoms
While there is not total overlap in the symptoms, all of the above-mentioned conditions often manifest in ways that include anxiety, depression, insomnia, low energy, digestive discomfort (often similar to irritable bowel syndome (IBS)), chronic pain, cognitive impairments such as short-term memory loss and confusion, weight changes, and more. As of yet, there is no easy test to distinguish between many of these conditions that cause similar symptoms. You can’t simply “take a blood test” that conclusively demonstrates you do or do not have any of these conditions. That’s even the case for something obviously tied to a bacterial infection as Lyme disease tests are known to be error-prone and symptoms can continue even after the bacterial infection itself is largely or entirely eradicated. Yet many of the other conditions do not have even an error-prone test available to determine their presence or absence.
Symptoms May Be Common Because Physiological Damage Is Similar
It is possible that many of these conditions result from dissimilar root causes that create similar damage in the body via long-term physical and psychological stress. Long-term viral and bacterial infections, chronic child abuse, living in a war-torn nation, fighting in a war and watching your friends and colleagues be blown to bits on a daily basis, chronic exposure to chemical toxins, and many similar stressors can place a huge load on the body. Organs that produce hormones and biochemicals such as the adrenals can be overdriven into exhaustion. Energy reserves needed for proper operations of the brain, heart, liver, kidneys, and hormone-producing glands can be sapped by the long-term stress. Normal repair functions go by the wayside because there is too little energy or too little of other resources (often various nutrients) to execute them. The body’s health goes into long-term decline. The resulting damage has both psychological and physical components, yet many doctors may treat such patients as if their problems are “all in their heads.”
In this article, I’m going to discuss some of the possible reasons why there is such an overlap in symptoms between these many conditions. While it is possible to differentiate between some of these conditions based upon the precise mix of symptoms and the results of many medical tests run on a patient, rather than doing that I’m going to focus on the common aspects of these conditions that may share underlying elements of impaired function of the human body. That’s for two reasons. First, it appears that each of the conditions share many common elements at a biochemical level. Secondly, it may not be possible to distinguish between these conditions. Frankly, some of them are so similar that many patients meet the criteria for multiple conditions. The sense of them being separate conditions might actually be more an artifact of how they were named than from any essential differences in their true natures.
Adrenal Hormone Imbalances
Some believe that adrenal dysfunction is a common element of all of these conditions and explains why the symptoms are so similar. Treating the symptoms with replacement cortisol via supplements such as IsoCort and drugs such as hydrocortisone can help many of these patients. Hormone supplements such as pregnenolone, DHEA, and 7-KETO DHEA are also often very helpful as often the adrenals are unable to make adequate quantities of these hormones, too. Sometimes testosterone and/or estrogen levels are also out of balance and these may need to be treated, too. While such treatments may be very helpful, they may completely miss the root causes of the adrenal dysfunction while treating an important secondary component. This is not to dissuade you from such treatments, they are probably necessary and helpful for many. However, they are probably also not sufficient to recover full health by themselves.
A paper by Dr. Kent Holtorf (abstract below) suggests that for many chronic fatigue and chronic pain patients, the low observed values of cortisol and adrenal hormones are probably not due solely to problems with the adrenal glands themselves but that low-dose cortisol replacement (in his view around 5mg to 15mg per day) appears to help significantly for these patients. It appears that the pituitary gland and/or hypothalamus are dysfunctional and cause low production of adrenal hormones in response to stress stimulation tests that are designed to simulate the mechanisms by which healthy pituitary and hypothalamus operation can increase adrenal gland production of cortisol. Hence adding small physiological dosages of replacement cortisol by medicine or supplement can help safely boost overall cortisol levels and reduce fatigue and pain symptoms in many patients.
There is controversy regarding the incidence and significance of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in chronic fatigue syndrome (CFS) and fibromyalgia (FM). Studies that utilize central acting stimulation tests, including corticotropin-releasing hormone (CRH), insulin stress testing (IST), d-fenfluramine, ipsapirone, interleukin-6 (IL-6) and metyrapone testing, have demonstrated that HPA axis dysfunction of central origin is present in a majority of these patients. However, ACTH stimulation tests and baseline cortisol testing lack the sensitivity to detect this central dysfunction and have resulted in controversy and confusion regarding the incidence of HPA axis dysfunction in these conditions and the appropriateness of treatment. While both CFS and FM patients are shown to have central HPA dysfunction, the dysfunction in CFS is at the pituitary-hypothalamic level while the dysfunction in FM is more related to dysfunction at the hypothalamic and supra-hypothalamic levels. Because treatment with low physiologic doses of cortisol (<15 mg) has been shown to be safe and effective and routine dynamic ACTH testing does not have adequate diagnostic sensitivity, it is reasonable to give a therapeutic trial of physiologic doses of cortisol to the majority of patients with CFS and FM, especially to those who have symptoms that are consistent with adrenal dysfunction, have low blood pressure or have baseline cortisol levels in the low or low-normal range.
However, simply adding more cortisol via drugs or supplements may not achieve the expected effect even though measured cortisol levels do increase. That is because not all cortisol is in a free (active) form. There are studies that show highly elevated levels of Cortisol Binding Globulin (CBG) in CFS patients that result in very low levels of free (active) cortisol even though total cortisol levels may not appear to be dramatically low.
They found significantly lower evening cortisol levels in CFS patients vs. controls (3.2 ug/ml +/- 0.3 vs. 5.3 +/- 0.73) and 24-hour urinary free cortisol excretions that were 40% lower in the CFS patients (122.7 nmol/L vs. 203 nmol/L). Interestingly, the level of cortisol binding globulin CBG was also significantly higher in the CFS patients making the free cortisol index almost 70% lower in these patients (2.9 vs. 8.9). This elevated CBG is significant because it results in an overestimation of bioavailable and free cortisol levels, and if confirmed, it may be further contributing to the lack of sensitivity of both basal and dynamic testing by overestimating cortisol levels in these patients because most of the studies have utilized total cortisol levels when comparing CFS and FM patients to normals. This potential of overestimation of serum cortisol levels would be additive to the overestimation of actual cortisol levels by commonly used immunoassays discussed earlier (147,149).
Energy Production Deficit Due to Mitochondrial Dysfunction
It is likely that many of these long-term stressors tied to adrenal fatigue, CFS/ME, and FMS damage the essential systems the body needs to function properly by depleting reserves in the organs and cells on which a heavy functional load has been placed for extended periods of time. In Dr. Jacob Teitelbaum’s paper The Use of D-Ribose in Chronic Fatigue Syndrome and Fibromyalgia: A Pilot Study, he points out that CFS and FMS patients often show signs of abnormal cellular energy production and utilization:
Many of the clinical symptoms found in FMS/CFS may be related to a decrease in tissue energy levels with altered energy metabolism. Previous reports claim that abnormal muscular energy metabolism frequently can be reflected in pain because of chronic muscle shortening, postexertional fatigue, and low exercise tolerance associated with decreased cardiac output and stroke volumes. In addition, it has been postulated that decreased energy production in these syndromes also may result in hypothalamic dysfunction, which can be reflected clinically as disordered sleep, hormonal imbalances, and autonomic dysfunctions. Causes and mechanisms for this mitochondrial dysfunction are unknown; however, an alteration in muscle adenine nucleotide metabolism is found, mainly in lower adenosine triphosphate (ATP) levels and depleted energy reserves.
Given that about 95% of the body’s energy supply is derived from the mitochondria, microscopic power plants found inside every cell, it may be that mitochondrial dysfunction and resulting low energy production cause systemic impairments that result in a wide variety of common symptoms. These symptoms may all be unified by the observation that the organs and cells that are heavily loaded for months or years may simply start to falter as their mitochondria break down, ATP energy reserves are depleted, and the stress continues. As a result, more and more functional impairments appear. For instance, the adrenal glands that may have been busily pumping out vast stores of cortisol for months or years simply do not have enough energy and nutrition to keep up the struggle and repair themselves. Eventually, their function collapses. And with that collapse comes many of the symptoms that adrenal fatigue, CFS, FM, ME, PTSD, and other illnesses have in common. However, many other cells and organs are probably also similarly stressed by sagging numbers of mitochondria, low ATP reserves, and little ability to repair themselves and rebuild their stores of nutrients needed for good function. The body may try to compensate for the widening disaster by robbing Peter to pay Paul in an effort to shore up the function of badly damaged other areas by taking nutrients from less stressed areas of the body, thus subjecting them to more stress. This could explain symptoms such as the widespread chronic pain in FMS and CFS/ME patients.
Reducing the Energy Deficit Helps Reduce Symptoms
Teitelbaum’s paper discusses a small study on 41 patients run with a nutritional supplement D-Ribose in patients with CFS and FM. The idea behind how this supplement functions comes from how D-Ribose is a central component of a variety of important compounds used to build, operate, and utilize the energy output of mitochondria. These include DNA, RNA, ATP (adenosine triphosphate), FADH (flavin adenine dinucleotide), and NADH (Nicotinamide adenine dinucleotide hydrogenase). Every one of these compounds is important to mitochondrial energy production.
The study found that 62.9% of the patients reported “much better” or “somewhat better” symptoms after a month of using D-Ribose at approximately 15 grams per day divided into three doses per day. Symptoms were reported as self-ratings on scales of 1 to 10 for energy, sleep, mental clarity, pain, and overall well-being. Overall, energy, sleep, and overall well-being were most improved. The effects on mental clarity and pain appeared to be somewhat less. Side effects were relatively minor and included mostly a few elevated anxiety and digestive discomfort complaints.
Teitelbaum reasons that the D-Ribose helps by replenishing reserves of of ATP (adenosine triphosphate):
Adenosine triphosphate (ATP) is the primary energy source of all living cells. In tissues subjected to metabolic stress, such as hypoxia, ischemia, or known conditions of mitochondrial dysfunction, ATP is catabolized with compromised metabolic recovery. With ATP catabolism, adenosine diphosphate (ADP) levels accumulate, forcing the cell to try to balance ATP/ADP ratios in order to maintain energy stasis. However, these reactions ultimately lead to an increased intracellular concentration of adenosine monophosphate (AMP). In an effort to try to control energy balance, the cell catabolizes AMP, ultimately forming inosine, hypoxanthine, and adenine. These catabolic end products are washed out of the cell, resulting in a net loss of purines and an ultimate reduction in the total pool of adenine nucleotides. Potentially, up to 90% of these produced catabolites can be biochemically salvaged and recycled.
Low CoQ10 Levels Tied to Fibromyalgia and CFS/ME
New research is also tying other mitochondrial problems to fibromyalgia. Low CoQ10 levels, poorly functioning mitochondrial membranes, and increased oxidative damage to various biochemicals are among the markers found in the blood of fibromyalgia patients.
CoQ10 levels, determined in BMCs [blood mononuclear cells] isolated from 20 FM patients, were found to be about 40% lower than those in control cells (Figure 1a). To examine further the mitochondrial dysfunction in BMCs from FM patients, we determined the mitochondrial membrane potential (ΔΨm) with flow cytometry. Mitochondrial membrane potential was significantly reduced by about 36% in BMCs from FM patients (Figure 1b).
Similar findings apply to chronic fatigue syndrome and myalgic encephalomyelitis:
Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder
Plasma CoQ10 was significantly (p=0.00001) lower in ME/CFS patients than in normal controls. Up to 44.8% of patients with ME/CFS had values beneath the lowest plasma CoQ10 value detected in the normal controls, i.e. 490 microg/L. In ME/CFS, there were significant and inverse relationships between CoQ10 and the total score on the FF scale, fatigue and autonomic symptoms. Patients with very low CoQ10 (<390 microg/L) suffered significantly more from concentration and memory disturbances.
CoQ10 is an important antioxidant and enzyme crucial to the operation and health of mitochondria. It appears that a lack of adequate CoQ10 and resulting oxidative damage and inability to generate adequate energy is connected with many of the symptoms of adrenal fatigue, CFS/ME, FMS, treatment-resistant depression, and possibly many similar conditions.
Consequently, the use of supplementation CoQ10 (particularly more effective forms such as ubiquinol) or synthetic analogues such as idebenone is likely to help people suffering from these disorders. Some of the research also suggests that supplementing with multiple antioxidants, particularly those that are lipophilic (fat soluble), is likely to help lessen the widespread oxidative damage.
Statins, Depleted CoQ10, and Elevated Mortality Risk
One particular note of caution for people with chronic fatigue and chronic pain symptoms is to avoid the use of statin drugs. Statins as a type of drug that deplete CoQ10 levels by blocking the mevalonate pathway that creates precursor biochemicals to both cholesterol and CoQ10. It is well known that statins can cause chronic pain problems in some patients. It is believed that they cause this by depleting CoQ10 levels and causing muscle tissues, particularly the heart and other frequently used muscles, to suffer degeneration and pain. It may be particularly important that researchers have found that death by cardiovascular diseases such as congestive heart failure is more common in statin users and far more common for people diagnosed with CFS, ME, and FMS at ages two or more decades sooner than those without CFS, ME, and FMS. In my view, these observations can be explained by the impact of low CoQ10 levels upon long-term health. Bottom line is that anybody with a chronic fatigue or chronic pain condition would be well-advised to avoid statin drugs or at the very least to carefully monitor CoQ10 levels with frequent blood tests.
Mitochondrial Health Boosters May Improve Chronic Fatigue and Chronic Pain
D-Ribose and CoQ10 are just two of the many nutrients that can help mitochondrial function.
Acetyl-L-Carnitine (ALC or ALCAR) and L-Carnitine help to transport nutrients for energy production into the mitochondria. ALA (alpha lipoic acid) helps potentiate ALCAR and to recycle antioxidants such as vitamins C and E. N-acetylcysteine (NAC) helps to boost the liver’s production of the important endogenous antioxidant glutathione, reducing oxidative damage throughout the body.
Shilajit helps to potentiate CoQ10 variants, increasing CoQ10 levels and allowing more rapid recycling of used CoQ10 into active CoQ10.
One of the most interesting mitochondrial nutrients is PQQ. This nutrient, being considered as a possible new vitamin, is both a potent antioxidant and one of the few substances shown to help grow new mitochondria. For a patient with long-term mitochondrial damage, helping to grow new mitochondria may be particularly important.
Antioxidant Boosting and Lipid Replacement Therapy May Boost Mitochondrial Function
In the paper Lipid Replacement and Antioxidant Nutritional Therapy for Restoring Mitochondrial Function and Reducing Fatigue in Chronic Fatigue Syndrome and other Fatiguing Illnesse, Garth Nicolson and Rita Ellithorpe contend that people with CFS and other conditions involving impaired mitochondrial function tend to have a lot of oxidative damage, particularly to lipids in cellular membranes. As a result, they recommend using therapies that boost antioxidant levels and replace essential damaged lipids. They discuss in particular a product called Propax with NTFactor which is essentially a proprietary mixture of commonly needed nutrients similar to those you would get in high quality multivitamins such as Life Extension Mix Multivitamin tablets plus separate lipid supplements including omega 3 fatty acids such as fish oils and phosphatidylcholine sources such as lecithin. I’ve included a link to a source for the NTFactor product for those interested, but suspect that you could get similar benefits at lower cost by using Life Extension’s multivitamin product combined with one or more fish oil and lecithin products.
Evidence in the literature indicates that diminished mitochondrial function through loss of efficiency in the electron transport chain caused by oxidation occurs during aging and in fatiguing illnesses. Lipid Replacement Therapy (LRT) administered as a nutritional supplement with antioxidants can prevent oxidative membrane damage, and LRT can be used to restore mitochondrial and other cellular membrane functions via delivery of undamaged replacement lipids to cellular organelles. Recent clinical trials using patients with chronic fatigue have shown the benefit of LRT plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue. These studies indicate the benefits of LRT plus antioxidants in reducing fatigue and preventing loss of mitochondrial function, most likely by protecting mitochondrial and other cellular membranes from oxidative and other damage and removing damaged lipids by lipid replacement. In one clinical study we determined if mitochondrial function is reduced in subjects with mild to severe chronic fatigue, and if this can be reversed with NTFactor®, a nutritional supplement that replaces damaged cellular lipids. Using the Piper Fatigue Scale there was a significant time-dependent reduction in overall fatigue in moderately or severely fatigued subjects while on the dietary supplement for 4-8 weeks. Analysis of mitochrondrial function indicated that four and eight weeks of the dietary supplement in moderately or severely fatigued subjects significantly increased mitochondrial function. Similarly, chronic fatigue syndrome patients administered antioxidants plus LRT also show reductions in fatigue. The results indicate that LRT plus antioxidants can significantly reduce moderate to severe chronic fatigue and restore mitochondrial function. Dietary use of unoxidized membrane lipids plus antioxidants is recommended for patients with moderate to severe chronic fatigue.
Anti-Aging Benefits from Mitochondrial Health Boosting
Those who have read previous articles on mitochondrial health probably are aware that damaged mitochondria are one of the suspected causes for the symptoms and diseases associated with aging. If you are not sure you have adrenal fatigue, CFS/ME, fibromyalgia, or another severe condition but do feel a general lack of energy along with frequent pain and fatigue and are in your 40s or older, the odds are strong that you would benefit to some degree from a healthy diet and nutritional supplements focused on improving your mitochondrial health. As medical research advances, mitochondrial dysfunction is being increasingly tied not just to fatigue and aging but also to many other aging-related diseases such as Parkinson’s and Alzheimer’s. It may be that many of those who suffer chronic fatigue and chronic pain conditions in their 20s to 40s are experiencing symptoms of accelerated aging as if their mitochondria function like those of people in their 70s or older. If that is so, then many anti-aging research findings may apply to chronic fatigue and chronic pain conditions, too.
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