My treatment guidelines are that if the baseline cortisol is less than 16 mcg/dl or the cortisol level does not increase by at least 7 mcg/dl at thirty minutes and 11 mcg/dl at one hour, or does not double by one hour and is less than 35 mcg/dl, I treat with a therapeutic trial of 5 to 15 milligrams Cortef in the morning, 2.5 to 10 milligrams at lunchtime, and 0 to 2.5 milligrams at 4 p. m. (maximum of 20 milligrams a day). Most patients find 5 to 7.5 milligrams of Cortef each morning plus 2.5 to 5 milligrams at noon to be optimal (the equivalent of 1.5 to 3 milligrams prednisone daily). Cortef is much more effective than prednisone in CFS/FMS.
After keeping the patient on the initial dose for two to four weeks, adjust the dose up to a maximum of 20 milligrams daily or, if no benefit has been evident, taper it off. Adjust the Cortef to the lowest dose that feels the best. Give most of the Cortef in the morning and at lunchtime. I often tell my patients to take the last dose, 2.5 to 5 milligrams, no later than 4 p. m. Otherwise, the Cortef may keep the patient up at night.
After nine to eighteen months, taper the Cortef off over a period of one to four months. If the other physiologic stresses, such as infections or fibromyalgia, have been eliminated, the patient’s adrenal function may be adequate or normalized. If symptoms recur off the Cortef, continue treatment with the lowest optimal dose.
Improvement is often dramatic, and is usually seen within two to four weeks. The Cortef should be doubled during periods of acute stress and raised even higher during periods of severe stress, such as surgery. Consider also giving the patient 1,000 milligrams of calcium and 400+ international units (IU) of vitamin D daily with the Cortef if the patient is at high risk for osteoporosis.
There are different approaches to treatment and more is not necessarily better. High-dose cortisol taken at night will worsen already disrupted sleep patterns. A study by Mckenzie et al administered patients a high dose (25 to 35 milligrams) of Cortef daily, which disrupted patients’ sleep (p?.02).26 Although they did not treat the disrupted sleep, most patients still felt somewhat better on treatment. A small percentage of the patients had significantly suppressed posttreatment Cortrosyn tests, without complications, and McKenzie et al therefore, I believe incorrectly, recommend against using any dose of Cortef in CFS/FMS.27 Our study did not show adrenal suppression using lower Cortef dosing.3 Dr. Jefferies, with thousands of patient-years’ experience in using low-dose Cortef, recommends an empiric trial of 20 milligrams a day of Cortef in all patients with severe, unexplained fatigue, and has found this to be quite safe for long-term use.24, 25 Our research and clinical experience suggest that using Cortef at 20 milligrams a day or less in CFS and fibromyalgia patients is safe and often very helpful.
DHEA
Dehydroepiandrosterone (DHEA) is a major adrenal hormone that has recently been getting a lot of attention in the press for its role as a “fountain-of-youth” hormone.28 DHEA is stored as DHEA-sulfate (DHEA-S), and levels of free DHEA fluctuate markedly throughout the day. Because of this, I recommend checking DHEA-S levels and not DHEA levels.
Many CFS/FMS patients have suboptimal DHEA-S levels, and the benefit of treatment is sometimes dramatic. Most women need 5 to 25 milligrams a day and most men 25 to 50 milligrams a day. I use the middle of the normal range for a twenty-nine-year-old, keeping the DHEA-S level at 150 to 180 mcg/dl in women and 350 to 480 mcg/dl in men. Too high a dose can cause acne or darkening of facial hair in women.
Low Estrogen and Testosterone
Although we are trained to diagnose menopause by cessation of periods, hot flashes, and elevated FSH and LH, these are late findings. Estrogen deficiency often begins many years earlier, and may coincide with the onset of fibromyalgia.29 To compound the problem, research done by Sarrel shows that the majority of women who have a hysterectomy, even with the ovaries left in, develop estrogen deficiency within six months to two years after their surgery.29 Some physicians suspect that this may also occur in women who have had a tubal ligation, which, like a TAH, may also disrupt the ovarian blood supply.
In her book on estrogen and testosterone deficiency, Dr. Elizabeth Vliet gives a well-referenced, in-depth foundation for evaluation and treatment of these problems.29 To summarize, the initial symptoms of estrogen deficiency are poor sleep, poor libido, brain fog, achiness, PMS, and decreased neurotransmitter function. Dr. Vliet feels that estradiol levels at midcycle should be at least 100 pg/ml. If a woman’s CFS/FMS symptoms are worse at ovulation and the ten days before her period (times when estrogen levels are dropping), then a trial of estrogen is warranted. While a birth control pill can be used, side effects of bleeding and fluid retention are common for the first three to four months. Bioidentical hormones are better tolerated and likely safer. Therefore natural 17-B-estradiol as Climara patches or Estrace may be preferable. The usual dose of Climara is one 0.05-to 0.1-milligram patch a week, and the usual dose of Estrace is 0.5 to 2 milligrams a day, adjusted to what feels best to the patient. I prefer to use Biest, a compounded natural estrogen that combines estriol with estradiol, which is usually dosed at 1.25 to 2.5 milligrams a day.
Unlike estradiol, early data on estriol suggest that it does not raise breast cancer risk and may actually lower it (see article at end of Chapter 4). In addition, estriol also has immune-modulating effects and other properties that can be beneficial in FMS. In the absence of a hysterectomy, progesterone must be added to prevent uterine cancer. Since progesterone is essential for GABA function, sleep, and the prevention of anxiety, and not only prevention of uterine cancer, I add natural progesterone to the estrogen even if the patient has had a hysterectomy. Natural progesterone is available from most pharmacies as Prometrium 100 milligrams and is better tolerated than Provera. The dose is 100 milligrams at bedtime, instead of Provera 2.5 milligrams, or 200 milligrams a day for ten to fourteen days a month, instead of Provera 10 milligrams. If you are prescribing the BiEst cream, have the compounding pharmacist (e. g., ITC Pharmacy; 303-663-4224) make a combination of BiEst 2.5 milligrams, plus progesterone 30 to 100 milligrams, plus testosterone 2 to 5 milligrams, all in 1 gram of cream (which can be applied to the skin). If estrogen levels drop after two to three years, it suggests dermal absorption is decreasing. Have the compounding pharmacist make a cream that can be applied to the mucosal surface of the labia or intravaginally each evening. If the creams are applied to the skin instead of mucosal surfaces, patients may stop absorbing the cream after a few years of use. Overall, patients respond best to BiEst applied intravaginally.
Testosterone Deficiency
Testosterone deficiency is important in both men and women. It is important to check a free testosterone level rather than total testosterone, since free testosterone is a better measure of testosterone function. If the age-adjusted free testosterone is low or low normal (lowest quartile), a trial of treatment is often very helpful. Among my CFS/FMS patients, seventy percent of men and many women have free testosterone levels in the lowest quartile while their total testosterone levels are usually normal. A recently completed study found that treating low testosterone in women decreases FMS pain. Be sure the free testosterone normal range is age-adjusted using ten-year age groups, since a normal range that includes both twenty-and eighty-year-olds is not clinically meaningful.
Only treat with natural testosterone. In men, the new prescription medication topical Testim 1% actually works fairly well. Applying 25 to 100 milligrams of testosterone once daily keeps testosterone levels around 600 to 750 ng/dl throughout the day. In women, compounded creams should be used. For those without prescription insurance, compounded testosterone creams are much less expensive than standard prescriptions.
In women, acne, intense dreams, or darkening of facial hair suggests that the dose is too high. An elevated testosterone level in women can also increase insulin resistance. Symptoms are generally reversible. These side effects can also be caused by low estrogen relative to the testosterone level, and may be avoided in women by supplementing both together. As noted above, this can be done easil
y by adding 2 to 5 milligrams of testosterone to the estrogen (BiEst) cream.
In men, acne suggests that the dose is too high. Monitor levels because elevated levels of testosterone can cause elevated blood counts, liver inflammation, reversibly decreased sperm counts with transient infertility, and elevated cholesterol with increased risk of heart disease. These are the symptoms seen in athletes given many times the recommended physiologic dose to enhance sports performance. Because of this, in men it may be reasonable to monitor CBC, cholesterol, and liver enzymes intermittently. Testosterone supplementation can also cause elevated thyroid hormone levels in men taking thyroid supplements. If a patient is on thyroid supplements, recheck thyroid hormone levels after six to twelve weeks or sooner if he gets palpitations or anxious or hyper feelings. Despite the concerns about athletes using very high levels of synthetic testosterone, it is important to remember that research shows that raising low testosterone levels in men using natural testosterone actually results in lower cholesterol, decreased angina and depression, and improved diabetes.30
In addition, low testosterone is associated with increased mortality.30A Studies to date also suggest that testosterone therapy does not affect prostate tissue significantly,30B and that there is no increase in prostate cancer in those taking testosterone therapy.
Immune Dysfunction and Infections
Immune dysfunction is part of the CFS/FMS process. In fact, CFIDS, the other name for CFS, stands for chronic fatigue and immune dysfunction syndrome. Opportunistic infections present in CFIDS/FMS include chronic URIs and sinusitis, bowel infections, and chronic, low-grade prostatitis. These need to be treated.
Chronic sinusitis responds poorly to antibiotics but well to antifungals. Conservative measures such as saline nasal rinsing and avoiding refined carbohydrates are more appropriate than chronic antibiotics.31 Our experience has shown, as does research at the Mayo Clinic, that chronic sinusitis is predominantly caused by a sensitivity reaction to yeast, with secondary bacterial infections due to swelling and obstruction. Most of our patients find that their chronic sinusitis goes away on the yeast protocol discussed below. Avoiding antibiotics also decreases the risk of secondary fungal overgrowth in the sinuses and GI tract.
When initially treating the sinusitis and for acute flares, our patients find that a compounded nose spray containing a combination of Sporanox, xylitol, Bactroban, and cortisone can be very helpful. This is available from some compounding pharmacies (e. g., ITC Pharmacy; 303-663-4224). If the spray is irritating, patients can dilute it with a little bit of normal saline. The dose is one to two sprays in each nostril twice a day for two to six weeks. Ordering one bottle is adequate for most patients. Although the chronic sinusitis often resolves after six weeks of Diflucan and the sinus spray, patients can use the spray on an as-needed basis if symptoms recur. If sinusitis or spastic colon symptoms recur, however, patients are likely also having regrowth of candida in the gut, and if other CFS symptoms are recurring, you should consider a six-week retreatment with Diflucan.
In addition to sinusitis, bowel infections with fungal overgrowth, parasitic infections, and alterations of normal bacterial flora are generally present. These are reflected by the patient’s bowel symptoms. Because of the lack of a definitive test for yeast overgrowth, little research is published in this area, and treatment is controversial. Treatment is empiric, and based on the patient’s history. Yeast vaginitis, onchomycosis, sinusitis, a history of frequent antibiotic use such as tetracycline for acne, sinusitis, gas, bloating, diarrhea, or constipation warrants an empiric therapeutic antifungal trial. Many CFIDS/FMS patients who have failed other therapies for spastic colon or sinusitis have responded dramatically to antifungal treatments, though some also require treatment for small intestinal bacterial overgrowth (SIBO) and/or parasites.
Treatment for yeast in CFS/FMS patients consists of:
Acidophilus bacteria, 4 to 8 billion units per day, can also help restore normal bowel flora. I recommend the Probiotic Pearls form from Integrative Therapeutics, two pearls twice a day for five months, as many other products do not have viable acidophilus bacteria. In addition, it is critical that patients avoid sugar, as yeast grows by fermenting sugar. This includes fruit juices, which have as much sugar as sodas. To improve compliance (and show compassion), I do allow patients to have chocolate but recommend an excellent-tasting sugar-free line made by Russell Stover.
Anti-Yeast (an excellent mix of natural antifungals by Ultraceuticals), or nystatin (two 500,000-IU tablets two to three times a day) for five months. The patient’s symptoms, especially fibromyalgia pain, may flare up initially as the yeast dies off. Therefore, begin with a low dose and work up as tolerated.
After four weeks on Anti-Yeast or nystatin, add 200 milligrams of fluconazole (Diflucan) every day for six weeks. Rare and mild liver enzyme elevations are sometimes seen with Diflucan, but taking lipoic acid (already present in Anti-Yeast) 200 milligrams per day seems to decrease this side effect. If symptoms are only partially relieved or recur after the first six weeks on Diflucan, I recommend repeating the 200 milligrams per day for another six weeks. If no benefit is derived from the first course, the candida may be Diflucan resistant. Switch to Nizoral (which may lower cortisol levels) 200 milligrams per day for another six weeks. Patients should continue the Anti-Yeast herbal mix or nystatin for a total of five to eight months. I recommend patients be on these drugs while they are taking Nizoral or Diflucan not only for their antifungal activity but also to avoid development of resistant organisms.
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Because of the immune suppression, most CFS/FMS patients need to be treated empirically for yeast/fungal/candida overgrowth. Nasal congestion/sinusitis and spastic colon are also often caused by the candida, and resolve with the treatments discussed above.
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Parasitic infections, often with nonpathogenic or normally self-limiting organisms, are also common in CFS/FMS. Stool samples can be sent to your local lab for antigenic and chemical testing for giardia, cryptosporidium, and especially clostridium difficile. One-sixth of our study patients had a positive O&P. Most labs do a poor job of microscope testing for parasites, and I only have my O&P testing done (by mail) at the Genova/Great Smokies Diagnostic Labs (800-522-4762). If patients have parasites, even if usually nonpathogenic, treat them, as these patients should be considered immune suppressed.
In patients with low-grade fevers and/or chronic lung congestion, occult infections such as chlamydia and mycoplasma Incognitus are being found. Empiric therapy with doxycycline, 100 milligrams twice a day, or azithromycin (Zithromax), 250 to 600 milligrams a day for six months to two years, while on Anti-Yeast or nystatin, can be very helpful. Recent research is showing that HHV-6, CMV, and EBV are also sometimes active in CFS/FMS and that in select populations (see Chapter 5) treatment with Valcyte for six months can be very helpful.
An outstanding immune stimulant is Pro Boost (by Klabin Marketing; 800-933-9440). This thymulin mimic is taken sublingually three times a day at the first sign of any infection, and dramatically decreases the duration of the infection. I recommend that most of my patients keep it in their medicine cabinet for themselves and their family. This product is very popular with my patients.
Nutritional Deficiencies
CFS/FMS patients are often nutritionally deficient. This occurs because of (1) malabsorption from bowel infections, (2) increased needs because of the illness, and (3) inadequate diet. B vitamins, ribose, magnesium, iron, coenzyme Q10, malic acid, and carnitine are essential for mitochondrial function.7, 32 These nutrients are also critical for many other processes. Although blood testing is not reliable or necessary for most nutrients, I do recommend that you check B12, Fe, total iron-binding capacity (TIBC), and ferritin levels.
I begin CFS/FMS patients on the following nutritional regimen:
A quality multivitamin suited to their needs. It should contain at least 50 milligrams of B complex, 200 milligrams of magnesium glycinate, 900 milligra
ms of malic acid, 1,000 units of vitamin D, 500 milligrams of vitamin C, 15 milligrams of zinc, 200 micrograms of selenium, 200 micrograms of chromium, and amino acids. A powdered vitamin is generally better tolerated, better absorbed, and less expensive. The one I use in my practice for most of my patients is called the Energy Revitalization System, by Integrative Therapeutics; 800-931-1709. A single good-tasting drink plus one capsule contains more than fifty nutrients and replaces more than thirty-five tablets of nutritional supplements each day. This should be taken long term, and would be an outstanding daily multivitamin for most people. It should be given as a basic nutritional foundation in all fatigue and pain patients.
D-ribose (CORvalen, by Bioenergy Life Science, Inc.; 866-267-8253; www.corvalen.com). As CFS/FMS represents an energy crisis, it is critical that patients have what is needed for optimal mitochondrial function. Although most of these are present in the Energy Revitalization System vitamin powder discussed above, a critical rate-limiting nutrient in the production of energy is called ribose. If you remember your biochemistry training on the Krebs Citric Acid Cycle, your key energy molecules are ATP, FADH, and NADH. These molecules are predominantly made up of ribose plus B vitamins and adenine. Some of our patients improved markedly with improved energy and decreased pain when given one scoop (5 grams) of ribose three times a day for three weeks, followed by one scoop twice a day. This effect was marked enough that we conducted a study on this nutrient in our research center, which showed an astounding average 44.7 percent increase in energy and 30 percent increase in overall quality of life after less than three weeks. In addition, the ribose significantly decreased pain while improving sleep and mental clarity (see the study abstract in Appendix A). One 280-gram container is a fair therapeutic trial. Ribose has also been shown to be dramatically effective in treating cardiac problems, including congestive heart failure (CHF). For example, one of the patients in our ribose study also had atrial fibrillation. After being on ribose for less than three weeks his arrhythmia resolved and he was able to stop taking his arrhythmia medications. For a review of research on ribose in both energy production and heart disease, I invite you to read Chapter 2. Ribose is an outstanding new addition to our therapeutic armamentarium for treating fatigue, pain, and cardiac dysfunction, and I use it in all of these patients. Proper dosing is critical, so it is important to follow the dosing instructions above.
From Fatigued to Fantastic! Page 40