Dr. Holtorf’s

From: 'A Confounding Condition Treating chronic fatigue syndrome and fibromyalgia requires addressing the underlying problems.' <a href="https://www.holtorfmed.com/a-confounding-condition/">https://www.holtorfmed.com/a-confounding-condition/</a>

When it comes to treating patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM), doctors are often at a loss. Because they can’t figure out what’s wrong, many consider CFS and FM “waste basket” diagnoses. Others simply dismiss the symptoms as psychiatric in nature.1-3This certainly is a disservice to the estimated 4 percent to 7 percent of the population that suffers from these conditions. These disorders, which strike women four times as much as men,1-3are consistently associated with a unique set of physiologic abnormalities.4-71

Physicians need to employ a multi-system approach, instead of resorting to single-drug modalities for each symptom.12,16,72-87This comprehensive approach is largely becoming the standard of care and is effective in 80 percent of patients with these conditions.

What is Fibromyalgia?

To be diagnosed with FM, patients must experience pain for at least three months. They also must feel pain upon palpation at 11 out of 18 tender points.88This criteria, however, is criticized for not taking into account the essential elements of FM, such as fatigue, sleep disturbance and cognitive dysfunction.89-93

For a CFS diagnosis, patients must experience fatigue that doesn’t improve with bed rest. This fatigue should impair average daily activity levels by more than 50 percent for at least six months. People also must experience four or more of the following symptoms: cognitive dysfunction, sore throat, joint pain, muscle pain, headaches, nonrefreshing sleep and post-exertional malaise.94The diagnostic criteria for FM and CFS are limited. Furthermore, there’s no accepted laboratory marker to define these conditions. Consequently, physicians have difficulty properly diagnosing FM and CFS. But despite different modes of diagnosis (physical exam vs. history), CFS and FM coexist 50 percent to 70 percent of the time, depending on the study. Therefore, from a clinical standpoint, we will consider these illnesses together. The range of symptoms in these conditions includes fatigue, sleep disturbances, muscle pain, cognitive dysfunction, gastrointestinal dysfunction, headaches and postexertional malaise.

Note that the unique physiologic hallmarks of CFS and FM don’t exist in other fatiguing illnesses.4-71These syndromes are complicated, involving pituitary and hypothalamic dysfunction, immune dysfunction, sleep stage disorder, mitochondrial dysfunction, hormonal deficiencies, coagulation defects and chronic infections.

In addition, each physiologic abnormality can cascade into other problems. For example, chronic stress can produce hypothalamic, pituitary and immune dysfunction-signature signs of fibromyalgia. Immune dysfunction can reactivate viral and intracellular bacterial infections. This can further suppress hypothalamic and pituitary function, causing mitochondrial dysfunction and coagulation dysregulation.

The hypothalamic and pituitary dysfunction produces hormonal deficiencies. In a vicious cycle, the chronic infections can further suppress mitochondrial function and produce global cellular dysfunction and a subsequent immune activation that causes a coagulation defect. This, in turn, worsens cellular function. This cascade produces multisystem illness that causes a broad range of often perplexing symptoms.

The Multisystem Approach

CFS and FM diagnoses often frustrate physicians because there’s no clear cause or treatment. Doctors typically treat the problem with NSAIDS, antidepressants and muscle relaxants. But these drugs are largely ineffective because they fail to address the underlying roots of the problem.95-109 n addition, they have a high incidence of significant side effects, including anxiety and insomnia.95,69Muscle relaxants, too, can be addictive. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants may offer some benefit (Pregabalin is the first medication that is FDA approved to treat FM), but they’re often ineffective. In addition, the majority of patients don’t tolerate the medication well.108-110Given these facts, physicians should take the following multisystem approach to address both diagnoses.

Component One: Stabilize the patient. Physicians commonly address the pain and sleep disturbances of CFS and FM with medications. These drugs can help some patients, but the overwhelming majority needs further treatment. Sadly, this first stage of treatment is the only course many doctors prescribe.

Component Two: Mitochondrial enhancement. The mitochondria are the energy factories for the cells where sugar is burned and energy is produced in the form of adenosine-triphosphate (ATP). When the mitochondria are not working properly, the cells and tissues of the body are starved for energy. This abnormality may be the common endpoint for all the dysfunctions in CFS and FM.

Not only do the reduced amounts of metabolized glucose produce weight gain, reduced aerobic energy production requires the body to rely on anaerobic metabolism. This causes fatigue, muscle pain, poor concentration, gastrointestinal dysfunction, headaches and postexertional malaise.

Mitochondria can be poisoned by numerous substances, including environmental toxins; pesticides; chronic bacterial, viral and fungal infections; neurotoxins; and nutritional and hormone deficiencies. Mitochondria dysfunction has the greatest impact on the most active tissues, including the hypothalamus, pituitary, muscle, nerve and immune cells. These are the major dysfunctions of these conditions and can significantly explain the symptoms of CFS/FM. Supplying mitochondrial intermediates and nutrients, such as magnesium, carnitine, D-ribose, CoQ10 and glutathione, can improve mitochondrial function and alleviate symptoms of CFS and FM.111-116

Component Three: Balance the hormones. An overwhelming amount of peer-reviewed medical literature documents pituitary and hypothalamic dysfunction in CFS and FM patients. As a result, patients often have multiple hormonal deficiencies,4-21including thyroid and cortisol. Physicians often miss these hormonal deficiencies because standard blood tests lack sufficient sensitivity to detect such centrally mediated deficiencies.4-7,17-21However, they need to pay close attention to the following hormones:

Thyroid. Numerous studies have demonstrated that central hypothyroidism, as well as cellular resistance to thyroid hormone, exists in the overwhelming majority of patients with FM and CFS. This persists, despite patients having normal thyroid function tests (TFTs).6,11-16For instance, a study published in the Journal of Rheumatology looked at the incidence of central hypothyroidism in patients with FM.6Through thyrotropin releasing hormone (TRH) testing, all of the patients with FM had central hypothyroidism, despite having baseline TFTs in the normal range. More than 90 percent of the time, standard TSH and T4 testing misses central medicated hypothyroidism.117

merging evidence, however, shows free T3/reverse T3 (rT3) ratios can be a useful indicator of tissue thyroid levels. This may, in fact, help physicians assess tissue thyroid effect with central hypothyroidism and chronic physiologic stress.118-120 nstead of T4 normally converting intracellularly to the active T3 in peripheral tissue, T4 is preferentially converted to reverse T3. Therefore, increasing levels of rT3 and diminishing levels of T3 are indicators of low tissue thyroid effect. Free T3 and rT3 tests can be ordered at most major clinical laboratories. A free T3/rT3 ratio that’s less than 2 pg/ng is consistent with low tissue thyroid activity.

Because T4 to T3 conversion in these conditions is diminished, it’s not surprising that T4 supplementation has little effect, but that treatment with T3 is significantly effective.16,121-123In a double-blinded, placebo-controlled trial by Lowe et al., T3 therapy was safe and effective for treating euthyroid (TFTs in the normal range). Patients reported a highly significant improvement in pain, fatigue, stiffness, headache, sleep disturbance, bowel disturbance, depression, cognitive dysfunction, anxiety, cold intolerance, paresthesias and exercise endurance. They noted no significant adverse effects, despite having TFTs that would normally indicate hyperthyroidism, with a suppressed TSH, low free T4 and high free T3 levels. No adverse effects were reported on heart, bone, muscle and liver function, which were monitored every two months for eight months.121

n a small, double-blinded, placebo-controlled crossover study of four patients, T3 was administered and withdrawn in two T3 phases and two placebo phases over nine months.118All patients had normal baseline TFTs. All significantly improved in the T3 phases and deteriorated during placebo phases. No adverse target tissue effects were seen and all patients chose to continue treatment after the study’s end. This study did not demonstrate any adverse cardiac or bone effects.123T3 is available as the brand Cytomel or as a compounded timed-released preparation, which has the advantage over Cytomel in minimizing serum fluctuations of T3. Optimal doses can vary significantly among patients and should be slowly titrated with careful monitoring for signs of excess, such as palpitations, rapid heart rate and anxiety.

Cortisol. Most patients with CFS and FM suffer from clinically significant adrenocortical dysfunction due to hypothalamic and pituitary dysfunction. The hypothalamic and pituitary function in these conditions (potentially due to mitochondrial function) results in inadequate cortisol production.4All studies that have used central acting stimulation testing in CFS and FM have shown hypothalamic-pituitary-adrenal (HPA) axis dysfunction.4However, physicians often believe a normal serum cortisol level or ACTH stimulation test generally rules out significant HPA axis dysfunction. These tests are more useful for primary hypoadrenalism. They, however, lack sufficient sensitivity to detect the central HPA axis dysfunction.4

The current evidence supports using physiologic doses of cortisol as an appropriate component of a multisystem treatment protocol for CFS and FM. Specialists should consider a therapeutic trial of cortisol in the majority of these patients, especially those with signs or symptoms consistent with adrenal dysfunction, low blood pressure and/or serum levels that are low or in the low-normal range.

Physiologic replacement of cortisol at doses of 5 mg to 15 mg a day are safe, with little or no associated risk. Such physiologic doses don’t carry the risk of adrenal and immune suppression or bone loss, which are well known risks of pharmacological doses of corticosteroids. Cortisol treatment carries significantly less risk and a greater potential for benefit than standard treatments, such as antidepressants, muscle relaxants, anticonvulsants and narcotics.4

Growth hormone. Studies also show CFS and FM patients have diminished secretion of growth hormone, a single-chain polypeptide produced in the pituitary gland with a wide range of metabolic and cellular effects. Growth hormone stimulates the production of insulin-like growth factor-1 (IGF-1) in the liver. Both play an important role in regulating body composition, lipid profiles, tissue repair, cardiac and neuronal functioning and bone mineral density. A great deal of peer-reviewed research, including long-term randomized control trial data, has demonstrated that growth hormone replacement can improve energy, strength, cardiac function, cognitive function, immunity and psychological well-being. It also decreases body fat, increases lean muscle and improves quality of life. In addition, it significantly improves symptoms in these conditions with little or no side effects.7-21,124

Because of the pulsatile nature of growth hormone production and short half-life (20 to 50 minutes), routine serum growth hormone levels cannot be used to determine overall production. However, IGF-1 levels correlate with overall growth hormone production and are relatively stable in the serum. While a normal IGF-1 level doesn’t rule out a significant growth hormone deficiency, the IGF-1 level is the best estimate of growth hormone production and effect. Low-normal IGF-1 levels are consistent with a relative growth hormone deficiency.

Titrating the dose of growth hormone to achieve IGF-1 levels in the upper limit of normal is safe, well tolerated and offers significant clinical benefits. Typical doses are 0.5-2 iu injected subcutaneously daily. Patients can start with a three-month therapeutic trial. We must monitor for water retention, which can produce joint pain and carpal tunnel syndrome. Insulin sensitivity may temporarily decline as well. Such treatment is generally well tolerated and if such side effects do occur, they usually resolve with a reduction in dose.

Because of the synergistic nature of hormones, small doses of multiple hormones are generally superior to large doses of any one hormone. Each hormone, however, should be started one at a time so we can best monitor for potential side effects.

Component Four: Treat the infectious components. A great deal of medical literature documents the multiple infections that may either cause or contribute to CFS and FM.39-48,125-128Likely, this is due to the immune dysfunction seen with these conditions, which allows opportunistic organisms and other infections to flourish. This includes a variety of viruses such as Epstein Barr (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV6) and intracellular bacterial infections, such as mycoplasma, Chlamydia pneumonia and Borrelia burgdorferi (Lyme disease). Various antimicrobial treatments directed at such infections are significantly beneficial.

Component Five: Address unique etiologies. Several cycles of dysfunction occur in these conditions that can produce unique pathological etiologies. For instance, chronic infections can cause an abnormal immune activation of coagulation. This produces a fibrin coating on the lumen of the vessel, causing impaired oxygen and nutrient transfer.2,57-62

If suspected, the diagnosis can be made by testing a coagulation panel of soluble fibrin monomer, thrombin-antithrombin complex, D-dimer and plasminogen activator-inhibitor-1.57-62Heparin can help such patients.12,58

Evidence also suggests that neurotoxins are a potential cause or contributing factor to CFS and FM symptoms.129-131Visual contrast sensitivity testing and serum C3(a) and C4(a) can help us assess the potential for such exposure.

Component Six: Maintenance. We need to adjust therapies and wean patients to minimal core treatments. With improvement, medications can be discontinued, generally one at a time. During this phase, patients can be seen less often. We generally wean patients off medications before supplements. We also can successfully take patients off narcotic pain relievers. Symptomatic improvement usually correlates with improved cortisol, growth hormone and thyroid levels. So we can adjust hormones as well. However, most patients feel better with the optimal supplemented thyroid levels. Continued thyroid supplementation also appears to prevent relapses.

Multisystem Efficacy

A multisystem approach is becoming the standard of care for patients with CFS and FM. And studies are backing this approach. For example, Teitelbaum et al. performed a randomized, double-blinded, placebo-controlled, intent-to-treat study on 72 FM/CFS patients. The goal was to assess the effectiveness of an integrative treatment approach that simultaneously treated the nutritional deficiencies, chronic infections and hormonal dysfunctions that exist with these conditions.72Overall, 90 percent of patients had significant improvements vs. placebo in visual analog scores (p < 0.0002), the Fibromyalgia Impact Questionnaire (p < 0.0005) the tender point index (p < 0.0001) and ovezrall response (p < 0.0001) with no significant reported side effects.

The Journal of Chronic Fatigue Syndrome recently reported our center’s novel use of a computerized symptom assessment that evaluated the multisystem treatment protocol for more than 500 consecutive patients with CFS and FM.4Ninety-four percent of patients had overall improvement by the fourth visit, with 75 percent noting significant overall improvement and 62 percent reporting substantial overall improvement. In subsequent visits, the majority of patients continued to improve. The average energy level more than doubled by the fourth visit, going from an average of 2.98 at baseline to 6.39, and then to 6.77 and 7.67 at the seventh and ninth visits, respectively.

The average sense of well-being more than doubled by the fourth visit, increasing from a baseline average of 3.03 then to 6.29, 7.45 and 6.83 on the fourth, seventh and ninth visit, respectively.

Subsequently, more than 40 physicians were trained to use a simplified treatment algorithm at 17 centers across the country. This multicenter study included more than 4,000 consecutive CFS and FM patients who were treated with this simplified algorithm and tracked via the same computerized patient assessment system. Eighty-five percent of patients improved by the fourth visit. By the seventh visit, 62 percent of patients reported significant improvement, and 46 percent indicated substantial improvement.87 By addressing the multiple physiologic abnormalities that occur with CFS and FM, we can give our patients hope for dealing with these debilitating disorders.

For a list of references, go to www.advanceweb.com/healthyaging and click on the references toolbar.

Kent Holtorf, MD, is an expert in treating chronic fatigue syndrome, fibromyalgia, complex endocrine dysfunction and chronic infections (including EBV, HHV6 and Lyme disease). Dr. Holtorf received his doctorate of medicine from St. Louis University with residency training at UCLA. He has personally trained numerous physicians across the country to effectively treat chronic fatigue syndrome, fibromyalgia and chronic infectious diseases. Additionally, Dr. Holtorf was the founding medical director and developed the protocols for Fibromyalgia and Fatigue Centers and other facilities across the country.

From: http://www.hormoneandlongevitycenter.com/

Component One:

Stabilize the Patient This is a component in which pain and sleep disturbances are addressed. This may include the use of sleep medications, pain medications and antidepressants. This is in general a temporary "stop gap" phase because as the treatment progresses and the underlying problems are addressed, the medications that "mask the symptoms" are no longer needed. Unfortunately, the overwhelming majority of patients are never brought past this stage by their doctors. This is because this component is the limit of training for most doctors, but it really should only be the first step.

Component Two:

Mitochondrial Enhancement This component is actually integrated throughout the treatment program and tapered as the patient returns to normal functioning. The mitochondria are the energy producers of the cells and are critical for normal functioning. But they are shown to be poisoned in these conditions, leaving the cells starving for energy. Many things can poison the mitochondria including hormonal deficiencies, toxins and infections. Mitochondria dysfunction may be the common denominator and underlying mechanism that explains the symptoms of CFIDS/FM. In addition to the treatments above to rid the body of the offending agents, specific nutrients can be given to jump start the mitochondria and get the body functioning again. These can also be administered orally or via an intravenous route.

Component Three:

Balance the Hormones There are a number of hormonal deficiencies with these conditions that must be addressed to assure successful treatment. Unfortunately, these hormonal deficiencies are often missed or poorly treated because doctors have come to rely on standard blood tests that require an intact pituitary and hypothalamus for diagnosis and dosing of hormone levels. There is, however, severe hypothalamic and pituitary dysfunction with these conditions, making the standard blood tests inadequate. Some typical hormones functions, not just levels, that need to be evaluated include thyroid function, growth hormone, testosterone, aldosterone, cortisol, DHEA, pregnenolone, estradiol, progesterone, among others. When they are properly treated and balanced, tremendous results can be achieved.

Component Four:

Treat the lnfectious Component There are multiple infections that either may be the cause of CFIDS/FM or contribute to the dysfunction. Because of the immune dysfunctions, there is often more than one infection that must be addressed. Potential pathogens include a variety of viruses such as Epstein Barr (EBV), Cytomegalovirus( CMV), Human Herpes Virus 6 (HHV6), Enteroviruses, such as Coxsackie, Echo, and Stealth virus. Bacterial infections include intracellular organisms such as mycoplasma, Chlamydia pneumonia, Borrelia burgdorferi (Lyme disease) and ehrlichia. A number of yeasts such as Candida and parasites must also be evaluated. Infections with many of the above organisms will also further suppress the immunity, often resulting in further infections with other organisms.

Thus, many organisms must be evaluated and treated along with an assessment and treatment of the immune system. If a poor immune system is not addressed, successful eradication of the organisms is not likely, even with the most potent treatments. Treatment may be administered with oral medications or via an intravenous route.

Component Five:

Address Unique Etiologies There are a number of problems that must be addressed in select patients. For instance, some individuals have a coagulation defect that is set off by a chronic infection. This results in the laying down of a fibrin coating on the lumen of the vessel causing impaired oxygen and nutrient transfer. This can result in fatigue, muscle aches and "brain fog". If suspected, diagnosis requires specialized testing. If not treated, not only are the cells starved for oxygen and nutrients, but it is very difficult to eradicate any infection because they will "hide" in the fibrin coating. Also, if the organism is one that produces neurotoxins, this must also be addressed. These substances can remain in the body and continue to cause symptoms long after the organism that produced them are gone. Special testing and protocols must be done to rid the body of these tiny toxins.

Component Six:

Maintenance Here is where the patient is weaned to just a few core medications and supplements to remain symptom free and maintain their health. Significant recovery or complete resolution of symptoms is the rule rather than the exception when a multifaceted treatment plan is instituted.

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are illnesses that often coexists and affect millions of Americans. Symptoms vary amongst individuals and commonly include severe fatigue, sleep disturbances, cognitive problems, commonly called brain fog, muscle pain and multiple infections. Unfortunately, many individuals and physicians continue to deny that these syndromes are legitimate diseases. The medical literature is, however, very clear that these are legitimate diseases and individuals with these syndromes have measurable hypothalamic, pituitary, immune and coagulation dysfunction. These abnormalities then result in a cascade of further abnormalities, in which stress plays a role by suppressing immunity and hypothalamic-pituitary function. The pituitary and hypothalamic dysfunction results in multiple hormonal deficiencies that are often not detected with standard blood tests, as well as autonomic dysfunction, including neutrally mediated hypotension. The immune dysfunction, which includes natural killer cell dysfunction, results in opportunistic infections and yeast overgrowth, making the symptoms worse. Recent studies have shown that the coagulation dysfunction is usually initiated by a viral infection and has genetic predisposition. This abnormal coagulation results in increased blood viscosity (slugging) and a deposition of soluble fibrin monomers along the capillary wall. This results in tissue and cellular hypoxia, resulting in fatigue and decreased cognition (brain fog). Neurotransmitter abnormalities and macro and micro nutrient deficiencies have also been shown to occur with these disorders.

Current research suggests that many triggers can initiate a cascade of events, causing the hypothalamic, pituitary, immune and coagulation dysfunction. The most common initiating cause is a viral or bacterial infection, which is very commonly Epstein Bar Virus (EBV), Cytomegalovirus (CMV), HHV6, mycoplasma, Chlamydia pneumonia or Lyme’s disease. When specialized testing is utilized, these infections are found in 30-80% of CFS and FM patients. Many people with these syndromes can pinpoint the start of their disease to a viral infection that never got better usually during significant life stressors.

Effective treatment, with 70 to 90 percent of individuals achieving significant clinical benefits, can be achieved by simultaneously treating the above problems that an individual is found to have. The mix of treatments needed varies from patient to patients, but there is consistent abnormal pathophysiology. For instance, a high percentage of individuals with these syndromes have low thyroid. This is, however, usually not picked up on the standard blood tests because the TSH is not elevated in these individuals because of the pituitary dysfunction. Many of these individuals will also have high levels of the anti-thyroid reverse T3, which is usually not measured on standard blood tests. In addition, the majority of individuals can also have a thyroid receptor resistance that is not detected on the blood tests. Consequently, thyroid treatment, especially with timed release T3 is effective for many patients. T4 preparations (inactive thyroid) such as Synthroid and Levoxyl do not work well for these conditions. In addition, adrenal insufficiency and growth hormone deficiency are also very common with these disorders, and supplementation with these hormones can often have profound effects. As with thyroid testing, these deficiencies are, unfortunately, usually not detected with the standard screen blood tests and require more specific testing.

When an individual is found to have one of the viruses discussed above, these can be treated with resulting improvement in symptoms. It can require a combination of medications, supplements and sometimes intravenous treatments to eradicate some of the persistent infections.

Although a concept that is sometimes uncomfortable and foreign to traditional medical styles of thinking, the need for multiple interventions is required for effective treatment of an illness that affects a critical control center (such as the hypothalamus), which impacts the multiple systems noted above. Unfortunately, there is not a single treatment that reverses hypothalamic dysfunction directly. Thus, this situation is different from illnesses that affect a single target organ and which can be treated with a single intervention. For example, pituitary dysfunction itself often requires treatment with several hormones. This effect is multiplied in hypothalamic dysfunction, which affects several critical systems in addition to the pituitary gland. An integrated treatment approach based on simultaneously treating the above problems is significantly beneficial in CFS and FMS. Individuals with these devastating syndromes can “get their lives back” despite the fact that they were previously told, “There is nothing that can be done,” or “It is all in your head.”

There is mounting evidence that there is low thyroid activity present in the majority of chronic fatigue syndrome and fibromyalgia patients. Studies demonstrate that in addition to an increased incidence of primary hypothyroidism in chronic fatigue syndrome and fibromyalgia, there is a combination of secondary, tertiary and thyroid resistance in the overwhelming majority of CFS and FM patients, despite having normal thyroid tests because these latter forms of tissue hypothyroidism are not detected by standard thyroid function tests. Thus, many chronic fatigue syndrome and fibromyalgia patients are erroneously told over and over that their thyroid levels are fine.

TSH is secreted by the pituitary in the brain and stimulates the thyroid to secrete T4, which is not the active thyroid hormone. T4 must then be converted in the body to the active thyroid hormone T3. When T4 and T3 levels drop, the TSH should increase indicating hypothyroidism. This is the standard way to diagnose hypothyroidism and is the only way that the majority of physicians (endocrinologists, internists, family practitioners, ect.) know how to test for low thyroid levels. There are, however, multiple abnormalities in CFS and FM that result in tissue hypothyroidism that are not detected using the standard TSH, T4 and T3 testing. In fact, standard thyroid tests fail to detect tissue hypothyroidism 80-90% of the time in patients with chronic fatigue syndrome and fibromyalgia.

There is clearly hypothalamic and pituitary dysfunction in these conditions (can potentially be caused by viruses, bacteria, stress, yeast, inflammation, toxins, pesticides, plastics and mitochondria dysfunction). The hypothalamic dysfunction results in the production of TSH that has diminished biological activity so there are lower T4 and T3 levels for any given level of TSH. In addition, the pituitary dysfunction results in a diminished secretion of TSH, masking low tissue thyroid levels as the TSH is usually in the normal range. Very few doctors understand the significance of this and incorrectly state that the thyroid is fine based on a normal TSH level.

Furthermore, many chronic fatigue syndrome and fibromyalgia patients have relatively diminished T4 to T3 conversion and a relatively increased T4 to reverse T3 conversion, also resulting in low tissue levels of active thyroid hormone levels despite having a normal TSH. (See the handout Fatigued, Depressed, Difficulty Losing Weight). The type II deiodinase that converts T4 to T3 is down regulated in chronic fatigue syndrome and fibromyalgia while the type III deiodinase enzyme that increases T4 to reverse T3 (rT3) is unregulated in these conditions. This maladaptive response decreases the T3/rT3 ratio, further diminishing tissue thyroid levels but are also not detected by standard testing. The T3 and rT3 levels can be measured and the ratio calculated, but merely finding normal T3 and reverse T3 levels is not adequate to detect this abnormality.

Another significant cause of low tissue thyroid levels in chronic fatigue syndrome and fibromyalgia that is not detected by standard testing is the fact that there has been shown to be a peripheral thyroid hormone resistance found in these patients, meaning that there is a diminished thyroid effect for a given amount of thyroid hormone in the blood. This has been discounted in the past, but more and more evidence is surfacing proving that this is indeed a significant problem with these conditions.

The combination of factors present in chronic fatigue syndrome and fibromyalgia, including hypothalamic and pituitary dysfunction, diminished T3/rT3 production ratios and thyroid resistance, results in most, if not all, chronic fatigue syndrome and fibromyalgia patients having inadequate tissue thyroid effect. T4 preparations such as Synthroid and Levoxyl rarely work and Armour thyroid, a pig glandular product, is somewhat better, but definitely not adequate for most patients. The treating physician must know when to use a T4/T3 combination or straight T3. T3 works the best for many of these patients, but Cytomel, a very short acting T3 available at normal pharmacies, is also a poor choice because the varying blood levels can cause significant side effects. Compounded timed release T3 is usually the best treatment. However, to achieve significant improvement, the treating physician must be very knowledgeable about T3 and must realize that when on T3, standard bloods blood test will lead one to dose incorrectly and not obtain significant benefits. This includes doctors who previously felt that they were thyroid experts and had been using thyroid with in chronic fatigue syndrome and fibromyalgia for a long time. Ultimately, it is the expertise and dosing of the T3 or T4/T3 combinations and the makeup of the medications that determines the optimal treatment regimen and is one major component in the treatment of in chronic fatigue syndrome and fibromyalgia.

New Study in JCFS

New Study on Adrenal Dysfunction in Journal of Chronic Fatigue Syndrome

A review just published in the Journal of Chronic Fatigue Syndrome, a major journal for the specialty treatment of CFS and FM Diagnosis and Treatment of Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction in Patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). Journal of Chronic Fatigue Syndrome. 2008, 14(3):1-14.

Kent Holtorf, MD

KEY POINTS

500 patient study demonstrated that a multi-system treatment protocol that addresses the known physiologic abnormalities in CFS and fibromyalgia resulted in:

94 percent of patients had overall improvement by the 4th visit.

75 percent noted significant overall improvement.

62 percent reported substantial overall improvement.

The average energy level and sense of well-being for patients doubled by the fourth visit.

The effectiveness of this multi-system treatment was further confirmed through the analysis of the cumulative findings of over 40 independent physicians and over 5,000 patients.

Prior to treatment at the Holtorf Medical Group, Inc, the patients had seen an average of 7.2 different physicians for the treatment of CFS and/or FM without significant improvement.

There is controversy regarding the incidence and significance of adrenal dysfunction in chronic fatigue syndrome (CFS) and fibromyalgia (FM) as well as the effectiveness and appropriateness of such treatment.

Analysis of the data in over 50 studies that assessed adrenal function in CFS and FM patients demonstrates that the majority of CFS and FM patients have abnormal adrenal function due to hypothalamic-pituitary dysfunction.

It was also shown that the majority of patients should be treated for this adrenal dysfunction since many of the standard tests do not pick up this particular type of adrenal dysfunction. The data shows that such treatment is safer and more effective than commonly used treatments such as antidepressants.

While these conditions are similar, the abnormality in CFS is in the pituitary while the FM patients have abnormalities of the hypothalamus.

This review provides a new understanding that treating the known causes of illness in CFS and FM can improve the symptoms and quality-of-life of patients who suffer from these conditions.

Adrenal dysfunction in CFS/FM

Treatment of Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) Points addressed:

A review of the literature regarding evidence of significant hypothalamic-pituitary-adrenal axis (HPA) dysfunction in CFS and FM.

Indications and efficacy of treatment with physiological doses of cortisol

Expected risks and benefits of such treatment

Abstract:

There is clear evidence that adrenal axis dysfunction is present in patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM) 1-21,23-28 and that treatment with low physiologic doses of cortisol have been shown to be safe, appropriate and effective.8,9,10,23,30 It should be considered the standard of care to treat patients with CFS and FM who have baseline cortisol levels under 12 ug/ml.8,9,10,31,32,33

Evidence for significant HPA axis dysfunction with resultant adrenocortical dysfunction:

A study published in the Annals New York Academy of Sciences entitled Evidence for and Pathophysiologic Implications of Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Fibromyalgia and Chronic Fatigue Syndrome discussed the evidence for HPA axis insufficiency in CFS and FM. They conclude, “Our group has established the impaired activation of the hypothalamic-pituitary-adrenal axis is an essential neuroendocrine feature of this condition.” 27

Cleare et al published a study in the American Journal of Psychiatry that obtained 24-hour urine collections from 121 consecutive patients with CFS. They found low 24 hour cortisol levels in all of the CFS patients. The authors conclude, “Urinary free cortisol was significantly lower in the subjects with chronic fatigue syndrome regardless of the presence or absence of current or past comorbid psychiatric illness…From whatever cause, low circulating cortisol is associated with fatigue; furthermore, raising cortisol levels can reduce fatigue in chronic fatigue syndrome. Thus, this study provides further evidence that adrenocortical dysfunction in chronic fatigue syndrome, whatever the etiology and whether primary or secondary, may be one piece of the multifactorial jigsaw underlying the production of symptoms in chronic fatigue syndrome.” 7 The authors agree that treating this adrenocortical dysfunction with cortisol replacement is a fundamentally necessary part of the appropriate multi-system treatment of this condition.

Another study published in the Journal of Endocrinological Investigation performed a combination of stimulation tests on FM patients. They found over 95% of these patients had HPA axis dysfunction.3 They state, “The etiology and pathophysiology of this disease is not fully understood but the current data suggests that the PFS [Primary Fibromyalgia Syndrome] is not a primary disease of muscle. In contrast, an increasing amount of evidence suggests that the central stress axis, the HPA axis, seems to play an important role in the development of PFS…This study clearly shows that the HPA axis is underactivated in PFS...” 3

Trophy et al. administered interleukin-6 (IL-6), which is a potent stimulator of the HPA axis, and measured plasma ACTH and cortisol levels. They found a delayed ACTH response in these patients, which is consistent with a defect in the hypothalamic CRH neuronal function as an etiology of symptoms in these patients.2

Cortisol levels normally increase with pain, but it has been shown that patients with CFS and FM either cannot appropriately increase cortisol production with pain or the inability to increase cortisol causes the increased pain. A study published in the November 2005 Journal Arthritis and Rheumatism demonstrated this strong relationship between cortisol levels and pain in individuals with CFS and FM and that low cortisol levels alone explained 38% of the variation in pain upon waking. The authors conclude, “The results of this study indicate that pain symptoms in women with FM are associated with cortisol concentrations during the early part of the day…These data support the hypothesis that HPA axis function is associated with symptoms in FM and accounts for the substantial percentage of pain symptom variance during the early part of the day.” 28

A study published in the Brazilian Journal of Infectious Disease (figure 2) demonstrates that in this type of patient population a baseline cortisol level of less than 12 has a specificity of greater than 90% for adrenocortical dysfunction and a level less than 10 ug/dl has a specificity of 98% for adrenocortical dysfunction.33 The most appropriate cutoff that optimizes specificity and sensitivity as found in this study, as well as by others, is 12 ug/dl.31,33 In addition, a normal ACTH does not rule-out secondary hypoadrenalism, but an abnormally low or low normal ACTH level can be considered confirmatory.

A study published in the Brazilian Journal of Infectious Disease (figure 2) demonstrates that in this type of patient population a baseline cortisol level of less than 12 has a specificity of greater than 90% for adrenocortical dysfunction and a level less than 10 ug/dl has a specificity of 98% for adrenocortical dysfunction.33 The most appropriate cutoff that optimizes specificity and sensitivity as found in this study as well as by others is 12 ug/dl.31,33 In addition, a normal ACTH does not rule-out secondary hypoadrenalism, but an abnormally low or low normal ACTH level can be considered confirmatory.

Dynamic testing:

Dynamic testing is certainly useful in straight forward primary and secondary adrenal insufficiency, but in patients with CFS, there is a complex interaction of hypothalamic and pituitary dysfunction. This results in a complex response that is initially elevated and then blunted, resulting in what is thought to be conflicting results, depending on which stimulation test was used, how an abnormal is defined and whether or not ACTH/cortisol ratios were used. 1,3,8,9,19,34-39 Consequently, the standard criteria does not apply to these patients significantly reducing the usefulness of dynamic testing with CFS and FM.1,9,19,27,34-39

It has been shown that a single ACTH stimulation test misses the majority of FM/CFS patients that have adrenocortical deficiency, but when a combination of stimulation tests are used, such as metyrapone test, or more sophisticated analysis is used, close to 100% of these individuals have documented adrenocortical dysfunction.1,3,8,9,19,27,34-39

Numerous studies demonstrate that this lack of sensitivity likely explains the seemingly contradictory findings between studies using stimulation tests.1,3,8,9,19,27,34-40 For instance, Scott et al in Clinical Endocrinology did 1ug ACTH stimulation tests on subjects with CFS and found a significant decrease in the delta cortisol value of patients with CFS vs. normals, but found that the reliance on this test and the arbitrary cutoffs that apply significantly impacts the sensitivity of stimulation tests in the patient population. They conclude, “In conclusion, the amount of cortisol released following stimulation with 1ug ACTH, is lower in CFS patients than in healthy volunteers…We propose, as has been suggested from previous studies, that the abnormality of HPA regulation is more likely to be central in origin. The demonstration of low basal ACTH in our CFS cohort would have supported this view…There is considerable debate surrounding the optimal dose of ACTH to use, with concern that the 250 mcg dose is “superphysiologic’ and may produce cortisol responses in patients suspected of having pituitary adrenal insufficiency that are falsely reassuring...Disparities between our healthy volunteer data and those of other groups using the 1 microgram ACTH test suggest that the test may not be as reliable as previously indicated…replacement therapy may more appropriately involve not only glucocorticoid, but mineralcorticoid supplements also.” 19

Another study that clearly demonstrates this confusion and that standard stimulation tests are not a reasonable method of evaluation of adrenal-cortical dysfunction is published in the Journal of Clinical Endocrinology and Metabolism entitled Evidence for Impaired Activation of the Hypothalamic Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome. The study found that compared to normal individuals, CFS patients were shown to have significantly reduced basal glucocorticoid levels (average 89 vs 148 nmol/l) and a low 24 hour urinary free cortisol excretion (122.7 nmol/L vs 203 nmol/L). The level of cortisol binding globulin CBG was also significantly higher in CFS patients making the free cortisol index lower in the patients (2.9 vs 8.9). There was a significant attenuated net integrated ACTH response to CRH but there was an initial increased initial sensitivity to ACTH with a reduced maximal response.1

Although this cortisol response to ACTH is clearly abnormal for all of the patients with CFS, the dose response curve varies. There is an initial exaggerated response followed by an abnormally blunted response, which is not the case for patients with primary or secondary adrenocortical insufficiency without a dysfunctional hypothalamus. Consequently, standard dynamic testing is not medically useful in these patients and it is improper to use the defined normal cutoffs of response as is done with other conditions. This has been demonstrated in other studies as well.1,3,8,9,19,27,34-39

Kirnap et al in a study published in Clinical Endocrinology compared standard and low dose ACTH stimulation tests on patients with primary fibromyalgia syndrome (PFS). They found a significantly reduced peak cortisol response in the PFS verses controls. They also found that if the standard cutoff of 550 nmol/l was used with the standard ACTH stimulation, many of the patients would have misdiagnoses as normal.4

There are a number of theories that have been postulated to explain such a response. The author of this study postulates that this is due to a lack of CRH (corticotrophin releasing hormone) with a secondary hyperresponsivness from inadequate levels of ACTH. They alternatively state that this HPA axis defect could be secondary to a chronic viral infection.

Treatment:

Further supporting the use of low dose cortisol in these patients is the fact that such treatment has been shown to improve the HPA axis response in these patients. This is counterintuitive to what physicians are taught and have found with higher pharmacological doses of glucocorticoids. In a study published in the 2001 Journal of Clinical Endocrinology & Metabolism entitled Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy, the authors utilized ACTH and cortisol responses to CRH, insulin stress test, D-fenfluramine and 24 hour urinary free cortisol in 37 patients with CFS and treated these patients with low dose cortisol. They found that the treatment resulted in significant improvement and not only was there no adrenal suppression, but rather there was an improvement in the HPA axis as documented with CRH testing. They concluded, “In this group, there was a significant increase in the cortisol re¬sponse to human CRH, which reversed the previously ob¬served blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone (same as cortisol) treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.” 8

In a randomized, double-blind, placebo controlled, crossover, intent to treat trial published in The Lancet, patients with chronic fatigue syndrome were treated with low dose hydrocortisone (5-10 mg/day) or placebo. The study found significant improvements in those treated with low dose hydrocortisone vs. placebo and 28% improved to normal levels. The authors concluded, “This study shows that low-dose hydrocortisone results in significant reduction in self-rated fatigue and disability in patients with chronic fatigue syndrome…The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone.” 9 This demonstrates the effectiveness and appropriateness of this treatment.

Another randomized control trial published in JAMA also found significant improvement in fatigue scores with hydrocortisone replacement, but they used excessive dosing of 25-35 mg of cortisol. It is recommended that dosing be limited to 5-15 mg/day, as these doses have been shown to not be associated with any untoward effects and carries little to no risk of adrenal suppression.10,23,30,31 This considerable safety and negligible risk is also confirmed in endocrinology texts.54

Bashetti has published a number of studies on cortisol and CFS. He writes in the Journal of Endocrinology and Metabolism, “Hydrocortisone, the glucocorticoid that is routinely prescribed to correct the chronic cortisol deficiency of patients with Addison’s disease, has recently been confirmed to be significantly effective also in the treatment of chronic fatigue syndrome (CFS). This comes as no surprise if we consider that CFS and Addison’s disease share 26 features.” 41

A randomized, double blind placebo-controlled, intent to treat study by Teitelbaum published in the Journal of Chronic Fatigue Syndrome documented the effectiveness of an integrative treatment approach to CFS and FM that includes low dose cortisol (7.5-20 mg/day). The authors conclude,” Significantly greater benefits were seen in the active group than in the placebo group for all primary outcomes. Using an integrated treatment approach, effective treatment is now available for FMS/CFS .” 31

A subsequent editorial in the peer reviewed, Journal of the American Academy of Pain Management reviewed this study and agreed that an integrative approach that includes low dose cortisol is the standard of care for these conditions. The author states, “The study by Dr. Teitelbaum et al. and years of clinical experience makes this approach an excellent and powerfully effective part of the standard of practice for treatment of people who suffer from FMS and MPS [myofacial pain syndrome]— both of which are common and devastating syndrome.” 48 The consensus opinion among those who are experts in the treatment of CSF and FM is that a treatment approach that includes low-dose cortisol is the standard of care.

A subsequent commentary by Teitelbaum published in JAMA states, “Our previously published pilot study and the work of Jefferies suggests that using low-dose hydrocortisone in CFS as dosages of 7.5 mg to 20 mg/day is safe and effective. These low dosages have not caused adrenal suppression…We recently completed a randomized, double-blind study that tested the effectiveness of treating patients with fibromyalgia and CFS for hypothalamic dysfunction in an integrated manner. This included treating suspected hormonal deficiencies (including low hydrocortisone) and the sleep disorder simultaneously. Using this protocol in 72 patients resulted in a significant improvement in active vs. placebo group.” 42 Cortisol replacement appears to be an essential part of a comprehensive treatment approach that can be used successfully in the treatment of CFS and FM.31,42

A study published in JAMA found that nearly half of the patients treated with mineralcorticoid reported complete or nearly complete resolution of CFS symptoms.43

The safety of low dose glucocorticoids was addressed in a 48 page review article published in last month’s Annals of Rheumatic Diseases entitled Low-dose glucocorticoid therapy in rheumatoid arthritis - A review on safety: published evidence and prospective trial data. This extensive review assessed the incidence and severity of adverse effects of long-term low-dose glucocorticoid therapy in rheumatoid arthritis. This review considered low dose as any dose below or equivalent to 40 mg hydrocortisone (this patient received a fraction of this dose 10mg/day). They concluded, “Adverse-effects of glucocorticoids are abundantly referred to in literature. However, in the available literature on low-dose glucocorticoid therapy very little of the commonly held beliefs about their incidence, prevalence and impact of GC [glucocorticoid] proved to be supported by clear scientific evidence. Additional data from the randomized controlled clinical trials reviewed showed that the incidence, severity and impact of adverse effects of low dose glucocorticoid therapy in rheumatoid arthritis trials are modest, and often not statistically different to those of placebo.” 10

Low dose cortisol has been shown to improve immunity, as opposed to the well known immunosuppressive effect of pharmacological doses of glucocorticoids, 23,30,45,46 and has been shown to improve recovery from chronic infections such as EBV.47,22,29

In summary, it is becoming clear that the majority of patients with CFS and FM suffer from clinically significant adrenocortical dysfunction and that physiologic replacement of cortisol is an appropriate intervention in these patients. Cortisol doses of 5-15 mg/day have been shown to be safe, with little associated risk including adrenal suppression, and have the potential for significant clinical benefit. The current evidence supports the use of physiologic doses of cortisol in the treatment of CFS and FM, and a therapeutic trial of cortisol should be considered in these patients, especially those with basal cortisol levels less than 12 ug/dl.

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De Becker P, De Meirleir K, Joos E, Campine I, Van Steenberge E, Smitz J, Velkeniers B Dehydroepiandrosterone (DHEA) response to i.v. ACTH in patients with chronic fatigue syndrome. Horm Metab Res 1999 Jan;31(1):18-21

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Adrenal Dysfunction (JCFS)

Key Study Points There is controversy regarding the incidence and significance of adrenal dysfunction in chronic fatigue syndrome (CFS) and fibromyalgia (FM) as well as the effectiveness and appropriateness of such treatment. A review just published in the Journal of Chronic Fatigue Syndrome, a major journal for the specialty treatment of CFS and FM, addresses this controversy.

Kent Holtorf MD, a CFS and FM specialist, analyzed the data in over 50 studies that assessed adrenal function in CFS and FM patients. Through his analysis he discovered that the majority of CFS and FM patients have abnormal adrenal function due to hypothalamic-pituitary dysfunction. It was also shown that the majority of patients should be treated for this adrenal dysfunction since many of the standard tests do not pick up this particular type of adrenal dysfunction. The data shows that such treatment is safer and more effective than commonly used treatments such as antidepressants.

.

Dr. Holtorf demonstrates that while these conditions are similar, the abnormality in CFS is in the pituitary while the FM patients have abnormalities of the hypothalamus.

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Based on a study of 500 patients, Dr. Holtorf found that patients who were given the adrenal hormone cortisol as part of a multi-system treatment protocol that addresses the known physiologic abnormalities experienced significant overall and symptom improvement.

Prior to treatment the patients had seen an average of 7.2 different physicians for the treatment of CFS and/or FM without significant improvement.

94 percent of patients had overall improvement by the 4th visit o 75 percent noted significant overall improvement

62 percent reported substantial overall improvement

The average energy level and sense of well-being for patients doubled by the fourth visit

The effectiveness of this multi-system treatment was further confirmed through the analysis of the cumulative findings of over 40 independent physicians and over 5,000 patients

This review provides a new understanding that treating the known causes of illness in CFS and FM can improve the symptoms and quality-of-life of patients who suffer from these conditions.

Dr. Holtorf’s

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